Chemotherapy for Hodgkin's disease: the remaining challenges.
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Antineoplastic Agents↗
Biomedical subjects
D L Longo
Publications and source records attributed to D L Longo.
Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules.
A system has been described that produces a murine syngeneic mixed lymphocyte response (MLR) comparable in magnitude to an allogeneic MLR. The responder cells in these cultures exhibit the classic immunologic characteristics of both memory and specificity. Studies using radiation-induced bone marrow chimeras of F(1) {arrow} parent type indicated that, similar to many other T cell-mediated immune responses, the response of the T lymphocytes in the syngeneic MLR was major histocompatibility complex-restricted and was determined by the environment in which the T cells matured. Using responder T cells from F(1) {arrow} parent chimeras and stimulator cells from H-2 recombinant strains, it was possible to map the genes involved in the stimulation to the K and/or I regions. In addition, blocking studies with monoclonal anti-Ia antibodies suggested that in the B10.A strain the critical molecules were products of both the I-A(k) and I-E(k) subregions. The issue of whether the syngeneic MLR is directed solely at self I-region antigens or whether the response represents proliferation to an unknown antigen in association with self I-region determinants was also addressed. Secondary syngeneic MLR were successfully performed in normal mouse serum and with stimulator cells prepared in the absence of bovine serum albumin to rule out the possibility that xenogeneic serum antigens were involved in the stimulation. The possibility that the syngeneic MLR might represent a secondary response to environmental antigens was eliminated by using germ- free mice as a source of stimulator cells and by demonstrating that spleen cells from unimmunized, fully allogeneic chimeras (B10.A {arrow} B10) could generate a normal syngeneic MLR even though such chimeras could not be primed to respond to any foreign antigens unless supplemented in vivo with a source of antigen-presenting cells syngeneic to the B10 host. The possibility that the syngeneic MLR was a primary response to a foreign antigen was considered unlikely because by using our culture conditions we could not obtain a primary antigen response or a secondary antigen response after in vitro priming to a variety of potent foreign antigens. Finally, the possibility that the syngeneic MLR represents a response to a variety of minor histocompatibility self antigens in association with self Ia molecules was eliminated by showing that the secondary responses to H-2 compatible, non-H-2 different strain (A/J vs. B10.A and C3H, or BALB/c vs. B10.D2 and DBA/2) were comparable to the secondary responses to syngeneic stimulators. Thus, we conclude that the target antigens in the syngeneic MLR are solely determinants on self Ia molecules, although the functionally equivalent possibility of a single, nonpolymorphic, minor self antigen seen in association with self Ia molecules cannot be excluded.
Animals↗
Peripheral destruction of platelets in chronic lymphocytic leukemia: recognition, prognosis and therapeutic implications.
In patients with chronic lymphocytic leukemia and depressed platelet counts, it is important to discriminate between the thrombocytopenia due to bone marrow replacement with abnormal lymphocytes and that caused by increased peripheral destruction of platelets. The former is due to progressive chronic lymphocytic leukemia and, as a Rai Stage IV, carries a poor prognosis. The latter, as illustrated in four patients seen at the National Cancer Institute, may be remediable by either splenectomy alone or splenectomy followed by immunosuppressive and antitumor therapy. In all four patients, survival was substantially longer than for patients whose condition was classified as Rai Stage IV. The importance of identifying the subgroup of patients with chronic lymphocytic leukemia with reversible thrombocytopenia is emphasized by these examples.
Aged↗
Inhibition of antigen-induced proliferation of T cells from radiation-induced bone marrow chimeras by a monoclonal antibody directed against an Ia determinant on the antigen-presenting cell.
Chimeric B10.A T cells that had matured in a (B10.A X B10.Q)F1 environment acquired the ability to respond to poly(Glu56Lys35Phe9) (GL pi), an antigen to which the B10.A mouse is a nonresponder. The response of the chimeric B10.A T cells was initiated by GL phi on responder B10.Q antigen-presenting cells (APC) but not by GL phi on nonresponder B10.A APC. Similarly, chimeric B10.Q T cells that had matured in a (B10.A X B10.Q)F1 environment acquired the ability to respond to poly(Glu60Ala30Tyr10) (GAT) when the antigen was presented on responder B10.A APC, but not when GAT was presented on nonresponder B10.Q APC. No syngeneic haplotype preference was observed for either antigen. These interactions between H-2 nonidentical T cells and APC were inhibited by anti-H-2 antisera and a monoclonal anti-Ia antibody directed against the APC but not by such antibodies when they were directed against the T cell. These data suggest that, when they develop in a responder chimeric environment, genotypic nonresponder T cells become responders by acquiring receptors that allow them to recognize responder I region products on the surface of APC. Furthermore, the data demonstrate that the site of action of the blocking effects of the anti-Ia antibodies is the APC, thus providing strong evidence in support of the idea that Ia antigens on APC are the Ir gene products.
Animals↗
The natural history and treatment of ovarian cancer.
Several advances in the understanding of the biology and treatment of ovarian cancer over the past five years have changed the pessimistic view of this disease that was formerly commonplace. A cornerstone of the management of patients with ovarian cancer is careful pathological staging both prior to and at the cessation of therapy. Patients with all grades of Stage I lesions except the well-differentiated ones should have some form of adjuvant therapy, although the best choice is still unclear. Similarly, Stage II patients, though few in number, have only a 50% change of surviving five years without some adjuvant treatment. Since the best choice is unclear, it would be ideal if such all patients could be treated in a study setting. Every early stage patient treated off study slows the identification of definitive therapy. For the majority of patients with advanced disease, the treatment of choice is aggressive debulking surgery followed by combination chemotherapy. After six cycles of therapy, patients should be restaged sequentially moving all the way to repeat laparotomy, if necessary, to find residual disease before therapy is discontinued. If no disease is found, we randomize patients to either careful follow-up or six cycles of intraperitoneal adjuvant therapy in an effort to prevent relapse. If residual disease is found at restaging (but less disease than at the beginning of treatment), the patient is given six more cycles of combination chemotherapy, though often at reduced doses because of cumulative bone marrow toxicity. After the twelfth cycle of chemotherapy, restaging is repeated. If disease is still present, it is unlikely that the primary therapy will be curative; however, therapy is continued until progressive disease demands a change. The ongoing joint study sponsored by the Ovarian Cancer Study Group and the Gynecologic Oncology Group in early stage disease should assist the clinician in determining the role of adjuvant single-agent chemotherapy or radioisotopes. Given the poor prognosis associated with bulky residual Stage II disease, such patients might benefit from adjuvant combination chemotherapy. In advanced disease, a number of ongoing trials are attempting to evaluate the role of radiation therapy in minimal residual Stage III disease and to improve the efficacy of combination chemotherapy. The work along with research aimed at understanding etiology and prevention and speeding diagnosis may further improve the outlook of victims of this disease.
Female↗
The control of chemotherapy-induced emesis.
Nausea and vomiting are frequent and serious toxicities of cancer chemotherapy that have been largely ignored in the past. Recently there has been renewed interest in this significant problem, with important advances in understanding the physiology of vomiting and a burgeoning number of clinical trials that use newer classes of antiemetics. At present phenothiazines are the only class of antiemetics that have shown both efficacy and safety in large numbers of cancer patients, but they are inadequate against strongly emetic agents such as cisplatin. New agents and new approaches have shown promise but need additional testing before they can be recommended for routine use.
Antiemetics↗
T-cell specificity for H-2 and Ir gene phenotype correlates with the phenotype of thymic antigen-presenting cells.
Experiments with chimaeric animals have demonstrated that the H-2 restriction specificity and immune response (Ir) gene phenotype of the T cell is acquired during development in the thymus. The mechanism by which this process occurs is unclear. One level of obligate expression of H-2 and Ir gene products is on the surface of antigen-presenting cells (APCs) which come from bone marrow precursors. We have now examined the turnover of APCs in the thymuses of F1 leads to parent (P) radiation-induced bone marrow chimaeras and found that APCs of donor phenotype appear at about 2 months after reconstitution. If the peripheral T-cell population is depleted after this time, new T cells emerging from the parental thymus (containing F1 APCs) behaving like F1 T cells, suggesting that cells from the bone marrow can influence thymic-directed T-cell differentiation. The thymic APC is an attractive condidate to play such a part in the development of the T-cell repertoire.
Animals↗
Gene complementation. Neither Ir-GLphi gene need be present in the proliferative T cell to generate an immune response to Poly(Glu55Lys36Phe9)n.
The cellular requirements for immune response (Ir) gene expression in a T cell proliferative response under dual Ir gene control were examined with radiation-induced bone marrow chimeras. The response to poly(Glu55Lys36Phe9)n (GLphi) requires two responder alleles that in the [B10.A X B10.A(18R)]F1 map in I-Ab and I-Ek/Cd. Chimeras in which a mixture of the nonresponder B10.A parental cells (which possess only I-Ek/Cd) and the nonresponder B10.A(18R) parental cells (which possess only I-Ab) were allowed to mature in a responder F1 environment did not respond to GLphi, which suggests that at least one cell participating in the response needed to possess both responder alleles to function. When T cells from such A + 18R leads to F1 chimeras were primed in the presence of responder antigen-presenting cells (APC), the chimeric T cells responded to GLphi, which suggests that both responder alleles must be expressed in the APC but not necessarily in the T cell. Interestingly, acutely irradiated F1 animals were found not to be an adequate source of responder APC for priming the proliferating T cell because of the rapid turnover of peripheral APC after irradiation. In adoptive transfer experiments, T cell-depleted bone marrow had to be used as a source of responder APC. When bone marrow cells from (B10.A X B10)F1 responder animals were allowed to mature in a low-responder B10 of B10.A parental environment, neither chimera, F1 leads to A or F1 leads to B, could respond to GLphi. This demonstrated that the presence of high-responder APC, which derive from the donor bone marrow, was not sufficient to generate a GLphi response. It appears that in addition it is essential for the T lymphocytes to mature in a high-responder environment. Finally, B10.A(4R) T cells, which possess neither Ir-GLphi responder allele, could be educated to mount a GLphi-proliferative response provided that they matured in a responder environment and were primed with APC expressing both responder alleles. Therefore, the gene products of the complementing Ir-GLphi responder alleles appear to function as a single restriction element at the level of the APC. T cells that do not possess responder alleles are not intrinsically defective, because they could be made phenotypic responders if they developed in an environment in which responder major histocompatibility complex (MHC) products were learned as self and if antigen was presented to them by APC expressing responder MHC products.
Animals↗
Gallium-67 scanning: limited usefulness in staging patients with non-Hodgkin's lymphoma.
The records of 122 patients with non-Hodgkin's lymphoma were reviewed, and the findings of the gallium scan analyzed. The scans of 93 patients were reread without knowledge of the previous readings. Two nuclear medicine physicians agreed with the original readings in 70 per cent of the cases and with each other in 89 per cent of the cases. When the data are analyzed case by case, 52 per cent true positive, 13 per cent false positive and 34 per cent false negative scans were found with only 17 per cent of the scans locating disease not found by routine physical examination and roentgenograms. Looking at individual sites of disease, the gallium scan yields an over-all detection of diseased sites of 18.5 per cent, with 72 per cent of all sites being correctly classified as positive or negative. The diffuse histiocytic, mixed and undifferentiated histologies were detected more accurately than all others, with mediastinal and extranodal sites being identified more frequently than any nodal site. The gallium scan revealed a site of disease which advanced the clinical stage in only one of 122 patients (upstaged). Only one of 122 patients was upstaged as a result of gallium scanning. These data suggest that gallium scanning may not be cost effective in the routine staging of patients with non-Hodgkin's lymphoma.
Cost-Benefit Analysis↗
Focal neurologic symptoms in hypercalcemia.
An unusual clinical presentation of moderate hypercalcemia as a result of primary hyperparathyroidism is described. The patient complained of fatigue, depression, thirst, polyuria, and focal neurologic symptoms including amaurosis fugax, anomia, right upper-extremity dysesthesias, and a left cerebral transient ischemic attack. No structural central nervous system abnormality could be documented. Signs and symptoms disappeared when serum calcium levels were reduced from 13.2 to 9.8 mg/100 ml. They have not recurred in 30 months of follow-up. The association of focal neurologic disease and hypercalcemia is uncommon. Although the precise pathophysiologic mechanism is unclear, this patient's symptoms suggest a vascular etiology.
Female↗
Cellular requirements for antigen presentation in the induction of a thymus-independent antibody response in vitro.
The ability of various cell populations to bind and present the thymus-independent antigen TNP-Ficoll to a responding cell population was assessed. The in vitro antibody response to TNP-Ficoll depends upon the presence of B lymphocytes and plastic-adherent accessory cells, but does not require T lymphocytes. Purified B cells were the most effective population in binding and presenting TNP-Ficoll, and adherent cells did not perform this function. Antigen binding and presentation was antigen specific and could be blocked with anti-mu antibody, but not by antibodies directed against other immunoglobulin classes. Spleen cells from mice genetically unresponsive to TNP-Ficoll (CBA/N X BALB/c F1 males) were equally effective as normal spleen cells in antigen binding and presentation. We conclude that the initial events in the induction of the antibody response involves antigen binding by B cells, and that subsequent activation of the subset of B cells that can respond to TNP-Ficoll proceeds either via B cell-B cell interaction or B cell-dependent transfer of antigen to macrophage-like cells.
Animals↗
Cosmetic talc and ovarian cancer.
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Cosmetics↗
Cosmetic talc and ovarian cancer.
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Adult↗
A comparison between combination chemotherapy and total body irradiation plus combination chemotherapy in non-Hodgkin's lymphoma.
Thirty-nine untreated patients with either lymphocytic or nodular mixed/nodular histiocytic non-Hodgkin's lymphoma, stage II--IV, were randomized to treatment with total body irradiation (TBI), 100 rads in 10 fractions over 12 days, plus combination chemotherapy with either cyclophosphamide, vincristine and prednisone (CVP) or cyclophosphamide, vincristine, procarbazine and prednisone (C-MOPP) or to treatment with combination chemotherapy (CVP or C-MOPP) alone. Remission rate and duration was comparable for both treatment groups; thus the use of both treatment modalities ab initio provides no therapeutic advantage.
Adult↗
Unmasking covert folate deficiency in iron--deficient subjects with neutrophil hypersegmentation: dU suppression tests on lymphocytes and bone marrow.
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Adult↗
Myeloproliferative syndromes: a unique presentation of chronic myelogenous leukemia (CML) as a primary tumor of bone.
A 45-yr-old female presented with a rapidly enlarging bony tumor that was eventually identified as a Philadelphia chromosome (Ph1)-positive myeloproliferative disorder with extramedullary blastic transformation. This transformation occurred in the absence of demonstrable chronic or acute leukemic phase. She had no history of a chronic or prodromal illness in spite of a bone marrow biopsy showing myelofibrosis and liver biopsy documenting extramedullary hematopoiesis. This case represents a unique constellation of features of the myeloproliferative syndrome in which the diagnosis was obscure until special stains of the bony tumor and cytogenetic studies were performed.
Bone Neoplasms↗
Pathology of the adrenal gland in refractory low-renin hypertension.
The adrenal glands of 13 patients with low-renin hypertension that was refractory to medical treatment were examined. Eight patients underwent total adrenalectomies and five underwent subtotal adrenalectomies. All of these patients had grossly visible adrenocortical changes. Ten patients had gross cortical nodules, and ten showed nonnodular cortical hyperplasia; seven had both. All ten patients with gross nodules had microscopic nodules as well. Of the 13 patients with low-renin hypertension, 12 (92%) had substantially lower blood pressure postoperatively without medication. During a follow-up period ranging from 14 to 38 months, three patients were normotensive without medication, nine patients had lowered blood pressures without medication and were easily maintained normotensive on antihypertensive medication, and one patient had no significant reduction in blood pressure postoperatively and no improvement in blood pressure control with antihypertensive drugs.
Adrenal Cortex↗