Antonio Raichs lecture. Autologous bone marrow transplantation.
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Biomedical subjects
Publications and source records attributed to G W Santos.
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Observations of 20 consecutive bone marrow transplantation recipients disclosed two distinctive categories of pulmonary interstitial changes. Interstitial infiltrates occurring less than 14 days after transplantation were observed in 13 of 20 patients and are believed to represent pulmonary edema. A late pulmonary interstitial process, which appears more than 30 days following transplantation (median 57 days), was encountered in 10 of 14 patients with successful grafts; the late changes represent interstitial pneumonia, a common cause of morbidity and mortality following bone marrow transplantation. It is probably attributable to a combination of factors including the preparatory chemotherapy and radiotherapy, and delayed immunologic reconstitution following transplantation.
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In the short space of the last 10 years, marrow transplantation has become a reasonable treatment option for persons with severe aplastic anemia. It has not as yet convincingly established itself in the treatment of leukemia and other malignancies but shows promise with new approaches. Many of the immunologic problems generic to bone marrow transplantation have been identified, and solutions are actively being pursued in the clinic and at the laboratory bench. As solutions to some of the present-day obstacles to the full therapeutic potential of bone marrow transplantation are met, we should see, in the next 10 years, a wider application of this therapy to various hematologic and malignant disorders.
We have shown that it is possible to collect and viably store sufficient numbers of stem cells to hematologically reconstitute patients following marrow-lethal doses of chemoradiotherapy. While no current procedure can be guaranteed to eliminate clonogenic tumor from the bone marrow, the fact that hematopoietic stem cells capable of reconstituting the host can be obtained after intensive chemotherapy makes it possible to clear microscopic foci of tumor from the marrow prior to storage. Such patients are now included in our protocol. The initial treatment results indicate that, in selected circumstances, tumor in otherwise refractory patients can be eliminated or partially controlled by a single intensive pulse of chemoradiotherapy with severe but acceptable extramedullary toxicity. The fact that patients can be rescued from otherwise lethal myelotoxicity by the reinfusion of cryopreserved autologous bone marrow permits wider exploration of new, more intensive cytoreductive regimens in a variety of cancers.
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Preliminary clinical trials using cryopreserved autologous bone marrow reinfusion have now been carried out at our institution in 5 children and 2 adults with advanced stages of neuroblastoma, rhabdomyosarcoma, non-Hodgkin's lymphoma and small cell carcinoma of the lung. Normal numbers of in vitro colony forming cells (CFU-C) were obtained from these patients despite prior courses of combination chemotherapy. The dose of marrow cells cryopreserved ranged from 1-6 X 10(8) cells/kg and recovery of CFU-C after thawing averaged 50%. Partial or complete hematologic reconstitution was achieved in all patients. The time for recovery ranged from 10-43 days for leukocytes (greater than 1000 cells/mm3) and 23-45 days for platelets (greater than 50,000/mm3). Two patients have died of interstitial pneumonitis due to cytomegalovirus. Three patients have died of recurrent tumor at 40, 48 and 156 days post-transplant. Two patients have had significant therapeutic benefit. One of these had a stable partial response permitting the use of further post-transplant therapy and is alive and well 16+ months post-transplant. The other patient had a complete response and remains tumor-free 25+ months following therapy. We conclude: 1) Autologous bone marrow reinfusion permits hematologic reconstitution following marrow-ablative therapy. 2) A quantity of marrow sufficient for this purpose remains viable following cryopreservation even when obtained from patients previously exposed to chemotherapy. 3) Autologous bone marrow reinfusion now allows the exploration of more intensive cytoreductive therapy in selected malignancies.
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Graft-versus-host disease, a complication of allogeneic bone-marrow transplantation, involves primarily the skin, liver and intestines, but may also be associated with pneumonia. To determine the relation of graft-versus-host disease with pneumonia, we evaluated the autopsies of 59 allogeneic and two autologous recipients and 74 control patients with various pulmonary diseases, who had not received a bone-marrow transplant. Lymphocytic bronchitis, characterized by lymphocyte-associated necrosis of the bronchial mucosa and often the submucosal glands, was present in 12 of 20 patients with Grade 2 or greater graft-versus-host disease but in only three of 39 with Grade 0 to 1 disease (P less than 0.0005). Onset of respiratory disease correlated with the time of onset of graft-versus-host disease. Patients with lymphocytic bronchitis had a higher incidence of bronchopneumonia and acute bronchitis of the lower respiratory tract. Lymphocytic bronchitis did not occur in the controls and appears to be a component of graft-versus-host disease that leads to bronchopneumonia, probably through destruction of the mucociliary apparatus.
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