DNA polymorphism, allogenic bone marrow transplantation and peripheral cell chimerism

BACKGROUND: Bone marrow transplantation or transplantation of peripheral stem cells is an effective treatment of a number of diseases. Its increasing success and expanding use in associated with the development of molecular diagnostic methods which enable to follow up the graft from its engraftment in a recipient and then during the whole posttransplantation period at the level extremely small numbers of cells. METHODS AND RESULTS: In peripheral blood of patients, genotypes of the following loci were examined by polymerase chain reaction (PCR): APOB, COL2A1, D17S20, D1S80, HVR/1G, SRY and AMXY. Technique of restriction analysis was used for loci DXYS20 and DXYS75. 1. The first signs of donor bone marrow activity were observed in 50% of patients already at the beginning of the second week after transplantation, while in the second half of patients increasing number of donor cells in peripheral blood was noticed in the second and third week. 2. Engraftment with full and permanent substitution of own bone marrow without presence of recipients cells in peripheral blood--complete chimerism--was achieved only in a part of patients (cca 50%). 3. Peripheral blood of other patients did not contain only donor cells but also recipients cells--mixed chimerism. With regard to its onset, the authors have divided mixed chimerism into early and late, taking into account that some patients can develop both types. In patients under study, early chimerism was found more frequently, which apparently resulted from a shorter period of observation of lately transplanted patients. 4. In cases of oncohaematologic patients, which allowed to study specifically the presence of a pathologic clone, the follow-up of chimerism enabled to distinguish between relapse of the original disease and "biologic" recovery--resurrection of original disease-free haematopoiesis. 5. Regression of mixed chimerism was supposed to be the result of treatment focused at the original disease (CML), in some patients, however, it was a spontaneous process. CONCLUSIONS: Follow-up of cellular chimerism in transplanted patients by means of molecular genetic methods provides substantial information about patient's shape which can be utilized it is necessary to decide on treatment procedures. For this reason it is desirable that examination of chimerism by molecular methods should form integral part of care of these patients.     

Use of studies on genome polymorphism in follow up after allogenic bone marrow transplantation

The study of structures polymorphic in size found in the human genom (the VNTR loci) enables us to differentiate two individuals or--after bone marrow transplantation--to detect the simultaneous presence of two genoms in patients' blood or marrow. The existence of mixed chimerism may influence the therapy. The authors have screened 54 patients, transplanted in their Institute, and their donors by determination of four polymorphic loci. Informative marker was found in 43 cases. The bone marrow transplantation immunotherapy of 29 patients could be followed over 2-36 months. To increase the sensitivity of the polymerase chain reaction method used, the authors introduced the blotting/hybridization steps using isotop labeled repetitive sequences. The results are presented in comparison with literature data.     

Fulminant angiopathy caused by allogenic transplantation of bone marrow with cerebral involvement: clinico-pathologic correlation

We present a 41 woman who underwent an allogeneic bone marrow transplantation as a treatment for a multiple myeloma. After presenting graft-versus-host disease, hyperbilirubinemia, cyclosporine toxic levels, renal failure and peripheral schistocytosis, she developed complex partial seizures and bilateral hypodensity lesions in occipital lobes. Fulminant microangiopathy was diagnosed; though promptly treated with immunoglobulins and fenitoin, she died in few days. Necropsy showed diffuse thrombotic disease and a haematoma in left occipital lobe. We review the types of thrombotic microangiopathy described up to now, and the different pathogenic theories related to them. According to our reviewing of the literature, this is the first case of fulminant thrombotic microangiopathy ever described in Spanish language.     

Bone marrow allogenic transplantation in malignant osteopetrosis]

In recent studies, the economic criteria has begun to be integrated to the appraisal in cancerology. The question asked by the economist can be framed as follows: what incremental cost should the collectivity or the health insurance system consent, in order to improve the care of cancer patients? This involves first that the cost of the strategies, foreseen or already implemented, can be appraised, then, that indicators can be defined to capture health improvement, and finally, that this health improvement can be quantified. In this article, we present the process of integrated appraisal (cost/result approach). We specifically analyze costs in cancerology, their source and their evolution. We demonstrate the meaning of the integration of economic costs and medical results. We emphasize on the fact that part of the costs, especially those supported by the patient and his close relations, are most of the time excluded from the analysis. Two main points should be carefully analyzed, when proceeding to an appraisal in cancerology: the measurement of the patient's QoL, which represents an expression of the results of the strategy of care; the financing modalities, for the same type of care, if we consider the specificity of the structures involved and the organization of the care. We conclude by mentioning how difficult this task is and under which conditions it should be developed.     

Allogeneic bone marrow transplantation in Korea: 1983-92

Between March 1983 and December 1992, we performed 178 allogeneic BMTs for patients with hematopoietic stem cell disorders: 48 acute myelogenous leukemia (AML), 27 acute lymphoblastic leukemia (ALL), 40 chronic myelogenous leukemia (CML), 55 severe aplastic anemia (SAA), 6 myelodysplastic syndrome (MDS), 1 non-Hodgkin's lymphoma and 1 hybrid leukemia. Twenty-five of 48 AML are in disease-free survival (DFS). Fifteen of 27 ALL are in unmaintained remission. Twenty-four of 40 CML are in DFS. Forty-four out of 55 SAA patients are alive and well. Comparing the survival between standard (< or = CR1: 21 of 31 (68%)) and high risk (> or = CR2: 4 of 17 (24%)) AML, our data suggest that the preparative regimen for high risk AML was not potent enough to eradicate the residual disease in advanced AML. Although our cases are limited and the follow-up period is short, the result of ALL (overall: 56%, standard risk (adult < or = CR1, children < or = CR2: 10 of 14 (71%) and high risk (adult > or = CR2, children > CR2): 5 of 13 (38%)) and CML (overall: 60%; CP: 19 of 27 (70%), AP or BC: 5 of 13 (38%)) are promising. The probability of 5 year survival of SAA was 80 +/- 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

A simple model of the optimal time for allogenic bone marrow transplantation in chronic granulocytic leukemia

Allogenic bone marrow transplantation is the treatment of choice in chronic granulocyte leukemia patients, while the best results are achieved when it is performed in the chronic phase of the illness. That is why time optimization for bone marrow transplantation in chronic granulocyte leukemia means making priority lists for transplantation according to medical indications. This study comprises a very simple model of optimal time for bone marrow transplantation in chronic granulocyte leukemia. It is based on data of the International Bone Marrow Transplant Registry (IBMTR) on bone marrow transplantation results in different phases of chronic granulocyte leukemia and prognostic model for survival of younger leukemic patients according to which there are three groups of patients. The mathematical method estimated cumulative risks of the final therapeutic results. This model has shown that the time limit for transplantation is the fourth year of the disease in the low risk group; the third year of the disease in the medium risk group and the second year in the high risk group of patients.     

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.     

Allogeneic bone marrow transplantation in Japan

Allogeneic bone marrow transplantation (BMT) is being used increasingly to treat diverse diseases in Japan. The distinctive aspects of allogeneic BMT in Japan include the lower incidence of acute graft-versus-host disease, which may be attributable to less disparity in histocompatibility antigens in Japanese. Research in the field of allogeneic BMT in Japan has covered the use of recombinant hemopoietic growth factors, especially granulocyte colony-stimulating factor, and novel immunosuppressive agents.     

Endothelium and bone marrow transplantation

Thrombotic complications may occur early after marrow transplantation and many data suggest that endothelial injury plays a pivotal role in their pathogenesis. Since plasma thrombomodulin and P-selectin are thought to be of value as markers of vascular endothelial cell membrane injury, we investigated their plasma concentration in bone marrow transplant patients aiming better to clarify the degree of endothelial involvement. Plasma thrombomodulin and P-selectin were monitored in 25 patients without thrombotic complications before transplant, on day 0 and weekly for 1 month thereafter, while in three patients who developed VOD monitoring continued until day +52. These proteins were in the normal range in all the uncomplicated patients and in two with reversible VOD, while they were always very high in the only patient who developed very severe and lethal VOD. In conclusion, we suggest that endothelial activation/damage occurs rarely in the course of BMT for hematological malignancies; we were able to document endothelial injury in only one patient with very severe thrombotic complication.     

Pregnancy after renal transplantation: 25 years experience in Spain

OBJECTIVES: To evaluate the kinetics of calcitriol (1,25(OH)2D3) administered subcutaneously. STUDY DESIGN: Calcitriol kinetics and efficacy after subcutaneous administration were studied in 13 CAPD patients with varying degrees of increased plasma levels of parathyroid hormone (i-PTH). A single dose of 2 micrograms of calcitriol was administered subcutaneously, and its serum levels at baseline and after 1, 2, 6, 12, and 24 hours were determined. Plasma ionized calcium and i-PTH were also determined at these periods. RESULTS: Serum calcitriol levels reached peak levels of 60 and 70 pg/mL at 1 and 2 hours after administration, respectively. These levels decreased thereafter, but remained above baseline values during 24 hours. The mean value of the area under the curve (AUC) was 809 +/- 226 pg/mL/hour. Plasma i-PTH levels showed a slight decrease after 1 and 2 hours, returning to baseline levels after this period. Plasma ionized calcium did not show significant changes during the study. A slight pain at the site of injection was mentioned by some patients. CONCLUSIONS: The subcutaneous route for calcitriol administration achieves theoretically adequate plasma levels in continuous ambulatory peritoneal dialysis (CAPD) patients. This is important when parenteral administration of calcitriol is considered in the treatment of secondary hyperparathyroidism.     

Hypophosphataemia in patients undergoing bone marrow transplantation

We studied the prevalence of hypophosphataemia (< 0.80 mmol/l) in seventeen patients who had undergone bone marrow transplantation (BMT). Thirteen (77%) of the seventeen patients had hypophosphataemia at some stage during the conditioning phase or after their BMT. Seven (41%) of the seventeen patients had hypophosphataemia in the peri-BMT period that is during the conditioning phase or within one week thereafter. Two of the patients showed severe hypophosphataemia (< 0.30 mmol/l). We suggest that plasma phosphate should be monitored in patients with a bone marrow transplant.     

Allogenic bone marrow transplantation in Wiskott-Aldrich syndrome

Two males of 3 and 3 1/2 years of age with the Wiskott-Aldrich syndrome who underwent bone marrow transplantation from an HLA compatible brother following conditioning treatment with busulphan and cyclophosphamide are described. In both patients the taking of the graft was proven by study of blood subgroups and correction of the immunodeficiency, normalization of platelet number and function and disappearance of cutaneous eczema were seen. At 3 and 1 year respectively of the transplantation the patients showed no evidence of graft versus host disease and no severe infections or hemorrhagic episodes have seen.     

Bone marrow necrosis in bone marrow transplantation: the role of MR imaging

We describe an ALL patient who developed extensive bone marrow necrosis at the time of relapse 2 months after allogeneic bone marrow transplantation from an HLA-identical sibling. The excruciating and diffuse bone pain, fever and precipitous drop in peripheral blood counts were characteristic. This case illustrates the importance of repeat bone marrow biopsies for the diagnosis of disease relapse and the potential application of MR imaging in the assessment of patients with bone marrow necrosis.