Transition in health care--critical planning for the 1990s: Part One.
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Biomedical subjects
Publications and source records attributed to E Jaffe.
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Dual parameter flow cytometry studies (cell DNA content and electronic cell volume) were performed in 220 cases of non-Hodgkin's lymphoma. All cases were characterized as B or T cell malignancies, based on immunologic surface marker characteristics. Aneuploidy by flow cytometry was more common among the B cell lymphomas than among the T cell lymphomas, and was most common among the large B cell lymphomas and B cell lymphomas of intermediate size. Ploidy index distributions showed a prominent hyperdiploid peak, as well as tumor cell populations with near-tetraploid DNA contents. In serial studies, a decrease in ploidy index was observed in association with clinical and histologic transformation in one case. The highest S fractions were observed among the large and intermediate B cell lymphomas and among the aggressive T cell lymphomas. In clinical samples consisting of mixtures of diploid and aneuploid populations, the data on the aneuploid components could often be separated from other components of the mixture in multiparameter studies on the basis of the larger electronic cell volumes of the aneuploid cells. In each case, the aneuploid large cell component almost invariably had a higher S fraction than the residual component(s) of the mixture. Overall, the data are consistent with a model of clonal selection and clonal evolution in the lymphomas in which early cytogenetic abnormalities that involve little or no change in total cell DNA content are followed by cell tetraploidization that is associated with cytogenetic instability and chromosome loss over the course of time.
Seventy-nine patients with nodular mixed lymphoma were treated at the National Cancer Institute between 1966 and 1978. Fifteen patients had stage I or II disease, and 64, stage III or IV disease. The overall complete response rate for the patients that received various primary treatment regimens was 76%, with 52% of complete responders remaining in their first remission at a median follow-up of 7 years. Median survival of complete responders is projected to be more than 13 years. Median survival of patients who do not achieve complete remission is less than 2 years. Patients with B symptoms, bone marrow involvement, or a lactate dehydrogenase level greater than 250 U/mL had significantly shorter survivals than did patients without these features. Patients with advanced-stage (III and IV) nodular mixed lymphoma had a 72% complete response rate, with the average remission lasting more than 6 years. Although relapses have been seen up to 8 years after diagnosis in patients with nodular mixed lymphoma given C-MOPP chemotherapy (cyclophosphamide, vincristine, procarbazine, prednisone), prolonged initial remissions can be achieved with this therapy.
We studied the clinical features of 11 patients with adult T-cell lymphoma associated with the human T-cell lymphoma virus. The patients were predominantly young, black, and born in the southeastern United States. They had an aggressive course, with the rapid onset of disseminated skin lesions or symptoms related to hypercalcemia and other metabolic disturbances, or both. Common findings included rapid enlargement of peripheral, hilar, and retroperitoneal lymph nodes, with sparing of the mediastinum; invasion of the central nervous system, lungs, or gastrointestinal tract; and opportunistic infections. A paraneoplastic syndrome characterized by increased bone turnover, abnormal bone scintigraphy, and hypercalcemia was present in all patients. Intensive combination chemotherapy produced prompt complete clinical remissions, which were generally of short duration. Similar features have been described in patients in Japan and the West Indies who had adult T-cell lymphoma, which is also associated with the human T-cell lymphoma virus. This syndrome should be suspected in patients presenting with the acute onset of widespread T-cell lymphoma in association with metabolic bone disease and hypercalcemia. The presence of the syndrome can be confirmed by appropriate serologic and virologic studies.
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To determine whether the human T-cell lymphoma-leukemia virus (HTLV) is associated with particular cancers, patient sera were surveyed for HTLV-specific antibodies. An association was seen with aggressive cancers of mature T-cells, specifically Japanese adult T-cell leukemia (ATL) and T-cell lymphosarcoma cell leukemia (TLCL), a similar cancer of Caribbean blacks. Ninety to 100% of these patients possessed HTLV-specific antibody. Forty-seven and 20% of relatives of ATL and TLCL patients, respectively, and 12 and 4% of healthy donors from ATL and TLCL endemic areas were also antibody positive. Visceral organ involvement, hypercalcemia, and skin manifestation, features of ATL and TLCL, were often seen in other antibody-positive patients. Childhood cancers, most cutaneous T-cell and all non-T-cell leukemias and lymphomas, myeloid leukemias, Hodgkin's disease, and solid tumors were not associated with HTLV. Healthy United States donors and European patients with non-malignant diseases were antibody negative. HTLV is thus associated with a subtype of adult T-cell leukemia-lymphoma, clustered in viral endemic areas, with apparent racial and geographic predilection.
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A man with long-standing common variable hypogammaglobulinemia was treated with chemotherapy and local radiation for diffuse mixed lymphoma. He continues in complete remission 42 months after the completion of therapy. Vigorous therapy for lymphoma can be used in the face of preexistent immunodeficiency. Complete staging and appropriate combination chemotherapy or radiation therapy should be carried out for lymphomas that occur in certain immunodeficient patients.
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Two adults who had T-cell lymphoma-leukemia and recurrent hypercalcemia in the absence of radiographic evidence of bone disease are described. Bone histopathology showed marked osteoclastic activation. Bone resorbing factors, including both prostaglandin E and a material produced in the presence of a prostaglandin synthetase inhibitor, were detected in the in-vitro culture fluids of malignant cells of one of the patients. Serum levels of parathyroid hormone were not elevated. These findings suggest that hypercalcemia resulted from in-vitro osteoclast activation by tumor cell product(s), one of which may be similar, if not identical, to the lymphocyte product osteoclast-activating factor. Two other patients having T-cell lymphoma-leukemia and hypercalcemia have been identified in the literature: the malignant cells of one of these patients also released a calcium-mobilizing factor in vitro.
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Human vascular endothelial cells (EC) separated from the umbilical vein are capable of presenting antigen to in-vivo-sensitized T cells, leading to an immunoproliferative response to various antigens in vitro. Optimal T-cell response was only observed when the EC donor shared both HLA-D/DR determinants with the T-cell donor. The T-cell response normally observed when using antigen-pulsed EC was significantly and specifically inhibited by xeno- and allo-antisera reacting with the HLA-DR molecules. Moreover, antibodies reacting with the native antigen determinats (rubella virus) also appeared capable of inhibiting the response elicited by primed T cells to antigen-pulsed EC.
Progressive multiple organ failure in association with septic complications in the surgical, trauma and burn patient is of major clinical importance. Reticuloendothelial system host defense mechanisms are abnormal following severe trauma and burn. Failure in systemic host defense is, in part, mediated by a deficiency in a circulating opsonic alpha 2 surface binding (SB) glycoprotein. This opsonic deficiency and reticuloendothelial host defense failure appears etiologic in the genesis of organ failure with sepsis. Opsonic alpha 2SB glycoprotein is identical to cold-insoluble globulin or plasma fibronectin. Plasma fibronectin is antigenically related to cell surface fibronectin which appears to be synthesized by both fibroblasts and vascular endothelial cells. Although these two proteins are antigenically related, they may or may not be identical with respect to biochemical properties and function. Cell surface fibronectin appears to be an adhesive glycoprotein mediating cell-cell interaction and cell adhesion to a substratum. Plasma fibronectin is a more soluble form which mediates reticuloendothelial or macrophage clearance of particulates such as fibrin microaggregates, collagenous debris, perhaps other bacterial or nonbacterial particulates. Since opsonic glycoprotein is identical to cold-insoluble globulin which can be readily concentrated in plasma cryoprecipitate, it has been shown that cryoprecipitate infusion can reverse opsonic deficiency in the injured patient with sepsis. Reversal of opsonic deficiency by cryoprecipitate infusion results in a marked improvement in cardiopulmonary function which includes a decline in the pulmonary shunt, a decrease in the physiologic dead space, an increase in limb blood flow, an increase in reactive hyperemia of the peripheral circulation and an increase in limb oxygen consumption. This cardiopulmonary response is paralleled by a decline in the septic state and normalization of other hematologic parameters. These studies suggest an important homeostatic role for fibronectins in organ and microvascular integrity, especially in the septic injured patient. Cell surface fibronectin which participates in cell adhesion may, in part, modulate microvascular integrity, vascular permeability and would repair. In contrast, the more soluble plasma fibronectin or opsonic alpha 2SB glycoprotein may mediate reticuloendothelial clearance of blood-borne particulates to prevent pulmonary and peripheral vascular microembolization and organ injury. Thus, reversal of opsonic deficiency may be an effective modality of therapy in the septic injured patient with organ failure.
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Fifteen of 16 lymphoma-derived cell lines and the Faji and P3HR1 cell lines were characterized with regard to certain surface markers, particularly immunoglobulins, complement receptors, Epstein-Barr virus (EBV) receptors, and Fc receptors. Ten lines positive for EBV nuclear antigen (EB-pos) were stained weakly or not at all by antihuman immunoglobulin fluorescein isothiocyanate conjugates, whereas EBV nuclear antigen negative (EB-neg) cell lines stained brightly. EB-pos lines frequently manifested Fc receptors, particularly for 7S antibody, whereas EB-neg lines did not. Receptors for the C3b component of complement and for EBV, which correlated significantly with each other, were expressed to a much lesser extent by EB-neg lines than by EB-pos lines. These findings are pertinent to an understanding of the infrequent association of this virus with American undifferentiated lymphomas of the Burkitt's and non-Burkitt's types.
In 38 patients with non-Hodgkin's lymphoma, involvement of the central nervous system (CNS) by malignant lymphoma developed during an eight year period. All patients had lymphomatous meningitis; clinical involvement of the spinal nerves or cranial nerves suggested the diagnosis. Spinal fluid was abnormal in 97 per cent of the patients although a positive cytology could be documented in only 67 per cent by lumbar puncture. The histology in 82 per cent of the patients was diffuse. Involvement of the CNS in nodular lymphoma was uncommon (3 per cent), and the histology in virtually all of these patients had converted to diffuse. At the time of diagnosis of CNS disease, 95 per cent of the patients had other evidence of advanced disease; 66 per cent had bone marrow involvement. In only 18 per cent of the patients did CNS disease develop while they were in clinical remission. Eighty-five per cent of the patients treated with whole brain irradiation and intrathecal chemotherapy had a good clinical response. Knowledge of these risk factors permits definition of a group of patients who may benefit from CNS prophylaxis.
Guinea pig megakaryocytes were isolated from femoral marrow and cultured in the presence of radioactive amino acids. Radioactivity was incorporated into several proteins including a 42 000 dalton polypeptide identified as actin by DNAase agarose affinity chromatography. Quantitative immunoelectrophoresis of megakaryocyte extract revealed that 3.0% of the total solubilized cellular protein was fibrinogen. Immunoabsorption studies using anti guinea pig fibrinogen beads failed to reveal the presence of newly synthesized radioactive fibrinogen in the cellular extract, however, radioactive actin was detected in the eluates obtained from the immune beads. When guinea pig fibrinogen was clotted with thrombin in the presence of radioactive megakaryocyte extract, a complex formed between a high molecular weight species of fibrin and actin. No actin fibrinogen complex was detected. The results suggest that actin synthesized by megakaryocytes complexes with fibrin formed from a relatively large pool of non-radioactive intracellular fibrinogen.