Fatal aplastic anaemia after mesalazine.
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Aged↗
Biomedical subjects
J C Marsh
Publications and source records attributed to J C Marsh.
Bone marrow transplantation in the management of acquired aplastic anemia.
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Adult↗
Aplastic anaemia following exposure to 3,4-methylenedioxymethamphetamine ('Ecstasy').
We report two cases of aplastic anaemia following exposure to 'Ecstasy' (MDMA, 3,4-methylenedioxymethamphetamine). In both cases the aplastic anaemia resolved spontaneously 7-9 weeks after presentation. Long-term bone marrow culture study of one patient demonstrated complete normalization of haemopoiesis at time of haematological recovery, suggesting either that damage to the haemopoietic stem cell had been only transient, or that a more mature, committed progenitor cell was the target. Because MDMA may have been a factor in the aetiology of the bone marrow suppression in these two cases, we recommend close haematological monitoring of young adults presenting with toxicity from MDMA, and a detailed history of exposure to recreational drugs in all new patients presenting with aplastic anaemia.
Adolescent↗
Successful bone marrow transplant for Fanconi anaemia in transformation.
We present a patient who was diagnosed as suffering from Fanconi anaemia at the age of 36 years. At the time of diagnosis his bone marrow showed features of pre-leukaemic transformation. He received an allogeneic bone marrow transplant (BMT) from his HLA-identical sibling. The post-transplant course was unremarkable with evidence of trilineage engraftment at day +32 and no acute or chronic GVHD. He is well with sustained engraftment and no haematological evidence of Fanconi anaemia 18 months post-transplant.
Adult↗
Is there a role for adjuvant therapy in bowel cancer?
Most patients operated on for large bowel cancer who undergo potentially curative resection will benefit from adjuvant therapy. In colon cancer, the current standard therapy is chemotherapy with 5-fluorouracil (5-FU) and levamisole given for 1 year to patients with resectable, node-positive disease. Current clinical trials may define better regimens, as well as the role of adjuvant therapy for some patients with node-negative colon cancer. Patients with resectable rectal cancer, both those who are node positive and those with tumor extending to the serosa (Dukes' B2) are appropriately treated with a combination of postoperative radiation therapy and chemotherapy, the latter given for 6 months. 5-FU alone is currently the preferred chemotherapy regimen from clinical trial data, unless current studies define a more optimal regimen. Preoperative radiotherapy, antitumor vaccines, and intraportal vein therapy have not yet become standard therapy. Resection alone is no longer sufficient for most patients with large bowel cancer. Responsible physicians should see that such patients are considered for adjuvant therapy, or preferably, entered into ongoing controlled clinical trials designed to make current adjuvant therapy better.
Chemotherapy, Adjuvant↗
Aplastic anaemia and remoxipride.
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Adult↗
Avascular necrosis after treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone.
Avascular necrosis of bone (AVN) occurring in patients with aplastic anaemia (AA) treated with antilymphocyte globulin (ALG) followed by high-dose methylprednisolone (HDMP) has been studied retrospectively. Out of 49 patients treated at two centres, seven have developed AVN at a median of 14 months (range 6-30) following treatment. The cumulative incidence of AVN is 21% (95% confidence intervals 7-35%). The hip was involved in six patients, bilaterally in five. Two patients had more than two joints affected. Surgical intervention was necessary in five patients, three of whom required total hip replacement. In contrast, there were no cases of AVN in a historical group of 61 patients with aplastic anaemia treated with an identical regimen of ALG but using a short course of low-dose prednisolone. Lack of convincing evidence for benefit, the considerable morbidity from AVN, and increased risk of early life-threatening infection, suggest that high-dose methyl prednisolone should be omitted from ALG treatment protocols for aplastic anaemia.
Adolescent↗
Response of aplastic anaemia and scleroderma to cyclosporin.
Scleroderma and aplastic anaemia (AA) occurred simultaneously in a patient. Treatment with antilymphocyte globulin (ALG) resulted in some improvement of the scleroderma and a partial, temporary response of the AA. Both the scleroderma and AA then responded dramatically to cyclosporin (CSA) therapy. Subsequently, a positive Ham's test, together with a reduction in the phosphatidyl-inositolglycan (PIG) anchored membrane proteins decay accelerating factor (DAF, CD55) and membrane inhibitor of reactive lysis (MIRL, CD59), confirmed a diagnosis of paroxysmal nocturnal haemoglobinuria (PNH) affecting erythroid, myeloid and lymphoid cell lineages. We hypothesize that the pathogenesis of the bone marrow failure in this patient was a stem cell defect with a secondary immune response involving T-lymphocytes that may have simultaneously triggered the pancytopenia and scleroderma.
Anemia, Aplastic↗
Growth of human umbilical-cord blood in longterm haemopoietic cultures.
Cryopreserved human umbilical-cord (HUC) blood is an alternative to bone marrow as a source of haemopoietic "stem" cells for HLA-identical transplantation of children with leukaemia or Fanconi's anaemia. We have studied the in-vitro growth potential of HUC blood in clonogenic assays and in longterm haemopoietic cultures. Clonogenic assays showed that HUC blood produced as many haemopoietic-cell colonies as normal adult bone marrow and a higher proportion of primitive-cell colonies. In longterm culture on preformed irradiated marrow stroma, both progenitor-cell production and lifespan of cultures were significantly greater in HUC blood than in normal bone marrow (p = 0.0007). Our findings indicate that the quality and quantity of HUC-blood-derived haemopoietic "stem" cells are better than those of normal bone marrow. Therefore, single HUC-blood donations are probably sufficient for adults requiring transplantation for leukaemia and other haemopoietic disorders. Banking of HLA-typed HUC blood to facilitate transplantation of patients who lack a family donor should be considered.
Blood Transfusion↗
"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita.
We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.
Adolescent↗
In vitro revelations of aplastic anemia.
Aplastic anemia (AA) is a most difficult disease to study in vitro. By the time the disease presents, the marrow is already hypocellular and the peripheral blood shows pancytopenia, leaving little material remaining for study. However, an understanding of its pathogenesis could provide insight into the control of normal hemopoiesis since AA is an in vivo manifestation of failure of normal hemopoiesis and may provide a way of examining stromal cell-stem cell relationships. Recent interest in the pathogenesis of AA has resulted from a) new laboratory techniques, such as stem cell purification used with modifications of the long-term bone marrow culture system and analysis of stem cells at the molecular level with X-linked DNA probes, and b) the availability of recombinant human hemopoietic growth factors (HGF) in large quantities. Consequently, analyses of the function of some of the individual components of stromal cell mediated hemopoiesis in AA patients have been performed. This has been paralleled, and in some instances preceded, by clinical trials of HGF in patients with AA.
Anemia, Aplastic↗
Percutaneous isolated liver perfusion for treatment of hepatic malignancy: preliminary report.
Chemotherapy for primary or metastatic hepatic malignancy is limited by poor tumor response and dose-related systemic toxicity. As an alternative to chemotherapy infusion by vein or by the hepatic artery, the authors have developed a percutaneous technique of isolated liver perfusion that allows the regional delivery of high-dose chemotherapy to the liver with little systemic toxicity. After placement of a hepatic artery infusion catheter, an 18-F double-balloon catheter is placed into the inferior vena cava through the opposite femoral vein. Balloons are inflated above and below the hepatic veins, thus isolating hepatic venous outflow. The effluent passes through fenestrations in the catheter and is pumped through charcoal hemoperfusion filters where the drug is removed. The filtered blood is returned to the patient through the internal jugular vein. Fifteen treatments have been conducted in eight patients in a phase I dose-escalation study with use of 5-fluorouracil (5-FU). While it is premature to assess tumor response to isolated liver perfusion, the data demonstrate that the procedure is safe and is tolerated by patients. Pharmacokinetic studies show a 5-FU extraction of up to 85%, with minimal drug leakage into the systemic circulation. This technique shows potential for improving liver tumor response while decreasing systemic toxicity.
Administration, Cutaneous↗
Autoimmune hemolytic anemia associated with anti-Sc1.
A case of autoimmune hemolytic anemia (AIHA) in a young child is described. The hemolysis was resistant to steroid therapy but responded to splenectomy and intravenous immunoglobulin. The autoantibody was shown to be anti-Sc1 by both serologic and immunoblotting techniques. This seems to be the first report of an autoanti-Sc1 detected by immunoblotting and the first example of AIHA in a child caused by autoanti-Sc1.
Anemia, Hemolytic, Autoimmune↗
Phase II study of pulse 5-fluoro-2'-deoxyuridine and leucovorin in advanced colorectal cancer patients previously treated with chemotherapy.
Because of possibly better activity against colorectal cancer of 5-fluoro-2'-deoxyuridine [floxuridine (FUdR)] compared to 5-fluorouracil (5-FU), and because of improved therapeutic results of leucovorin (LV) modulation of 5-FU, we carried out a phase II study of systemic FUdR and LV in 5-FU-treated patients with metastatic colorectal cancer. Weekly regimens consisted of a 4-hour infusion of LV, 200 mg/m2, and at 2 hours, a 2-hour infusion of FUdR, 30 mg/kg, with weekly dose escalation, as tolerated, to a maximum of 60 mg/kg. Twenty-nine patients were treated; they had a median age of 66, most had good performance status, and all had measurable disease. All had received 5-FU, although three had received it as adjuvant therapy only. Two patients had partial responses (6.9% response rate, 95% confidence interval, 1.9-21.9%) lasting 29 and 19 weeks, and five had stable disease. Median time to progression was 8 weeks and median survival was 36.5 weeks. The median number of courses was 6.5; escalation of FUdR was carried out in 27 patients. Hematologic toxicity was minimal and gastrointestinal toxicity was most frequent, although mild. This regimen, although well tolerated, is minimally effective in previously 5-FU-treated patients with metastatic colorectal cancer.
Adenocarcinoma↗
Human cord blood: a source of transplantable stem cells?
In a preliminary study we have shown that optimally collected human umbilical cord (HUC) blood cells grow significantly better in long term cultures (LTC) than normal adult marrow cells (NBM) p = 0.0007. The LTC findings are supported by the observation in clonogenic assay that a similar number of GM-CFC colonies can be grown from HUC blood and NBM mononuclear cells (MNC). Also there is a trend towards a higher proportion of primitive erythroid (BFU-E) and primitive megakaryocyte colonies (MK-CFC containing greater than 20 cells) in HUC blood compared with NBM. We suggest that further work on the feasibility of a HLA typed, cryopreserved HUC blood bank as a source of unrelated haemopoietic 'stem' cells for clinical transplantation is indicated.
Blood Cell Count↗
Differential sensitivity of CD34 epitopes to cleavage by Pasteurella haemolytica glycoprotease: implications for purification of CD34-positive progenitor cells.
Our previous studies have shown that a unique glycoprotease from Pasteurella haemolytica specifically cleaves only proteins containing sialylated O-linked glycans. The hematopoietic progenitor cell antigen, CD34, which is heavily glycosylated with both N- and O-linked glycans, is readily cleaved by this protease. In this study, we demonstrate that the epitopes detected by five of the seven CD34 monoclonal antibodies are removed by the glycoprotease. The differential sensitivity of the CD34 epitopes to cleavage with either neuraminidase and/or glycoprotease establishes three classes of epitopes: 1) (class I) those identified by MY10, B1.3C5, 12.8, and ICH3 that are differentially affected by neuraminidase and removed by the glycoprotease; 2) (class II) the epitope detected by QBEND 10 that is removed only by the glycoprotease; and 3) (class III) those identified by TUK3 and 115.2 that are not removed by either enzyme. Cleavage of the 110-kd CD34 structure by the glycoprotease generates a major cell-bound fragment of about 75 kd, identified by the class III antibodies. We have also used the enzyme to improve the rapid recovery of CD34+ cells selected by immunomagnetic affinity techniques. In a preclinical model, we separated CD34+ KG1 cells with high yield (90%-95%) and high purity (94%-98%) from sham mixtures containing 50% CD34- cells. We also separated CD34+ blast cells from a patient in megakaryoblastic crisis of chronic myelogenous leukemia. In this case, the purity and yield were 93% and 94%, respectively. Enzyme treatment had no detrimental effect on cell viability, and the treated cells showed a normal quantitative expression and distribution of CD34 antigen as assessed with class III antibodies. We conclude that the P. haemolytica glycoprotease has potential to improve the isolation, from human bone marrow, of primitive hematopoietic cells that carry the CD34 antigen.
Antigens, CD↗
Retention of progenitor cell function in CD34+ cells purified using a novel O-sialoglycoprotease.
We previously showed that the sialoglycoprotein, CD34, which is expressed on primitive human hematopoietic progenitor cells, is cleaved by a unique glycoprotease from Pasteurella haemolytica (P.h. glycoprotease). This proteolytic enzyme specifically cleaves glycoproteins rich in O-sialoglycans. Glycoproteins containing only N-linked glycans are not cleaved. Cleavage of the CD34 antigen results in the loss of epitopes detected by five of seven CD34-designated antibodies. In this study, we investigated the role of the P.h. glycoprotease in isolating CD34+ cells from unfractionated normal human bone marrow mononuclear cells (MNCs), and determined the effect of the glycoprotease on the proliferative capacity of the progenitor-enriched fraction. CD34+ cells were isolated from MNCs using immunomagnetic beads attached via a CD34 antibody whose epitope is susceptible to removal by the cleavage with the glycoprotease. Subsequent cleavage with P.h. glycoprotease for 30 min at 37 degrees C released the CD34+ cells from the beads with a recovery of up to 78%. Using a CD34 antibody whose epitope was not removed by the glycoprotease, up to 95% of the recovered cells expressed CD34. Compared to unseparated MNCs, the CD34+ cells showed the following enrichment of committed hematopoietic progenitors, as assayed in semi-solid media: CFU-GM, 45-fold; CFU-M, 13-fold; BFU-E, 26-fold and CFU-GEMM, 81-fold. Hematopoiesis was also studied in two-stage long-term bone marrow cultures in which the CD34+ cells were co-cultured over irradiated, allogeneic adherent layers. Output of CFU-GM over a seven week period from these cultures was similar to that from control cultures with autologous adherent-cell-depleted marrow MNCs. These data suggest that the loss of O-sialo-glycosylated peptide moieties from P.h. glycoprotease-released CD34+ cells neither affects the functional capacity of committed progenitors, nor impairs the proliferation of long-term culture-generating cells. The P.h. glycoprotease can be used to facilitate the isolation and recovery of functionally competent CD34+ cells at high yield and purity, without prior removal of other adherent cells. The ability to rapidly purify CD34+ cells using this non-cytotoxic enzyme has important implications for bone marrow transplantation as well as for gene transfer studies in vitro.
Antigens, CD↗