Strategies for immunological monitoring.
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Biomedical subjects
Publications and source records attributed to D L Longo.
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A small (2.8-kilobase, kb) major breakpoint region localized to segment 18q21 rearranges in greater than 70% of t(14;18)(q32;q21) lymphomas. This rearrangement interrupts the Bcl-2 gene and introduces it into the Ig locus at 14q32. The rearrangement between the joining region (JH) of Ig on chromosome 14 and the 18q21 region creates a translocation-specific DNA rearrangement. We generated probes that distinguish the 14;18 juncture on the derivative (der) 14 and der (18) chromosomes, providing a molecular approach to t(14;18) identification. Approximately 60% of unselected follicular lymphomas, 20% of diffuse large cell lymphomas, and 50% of adult undifferentiated non-Burkitt lymphomas demonstrated 14;18 rearrangements within the major breakpoint region. Examination of DNA for 14;18 rearrangements resolved the identity of 14q+ chromosomes in two patient's cells that lacked an obvious reciprocal partner. Identification of the exact restriction fragments that mediate translocations complements routine cytogenetics. The detection of DNA rearrangements does not require dividing cells or the presence of an identifiable reciprocal partner and can detect clonal translocation rearrangements when the neoplastic cells are only a minority of all cells present.
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Heteroaggregates containing anti-T3 cross-linked to anti-target cell antibodies have been shown to cause human T cells to lyse target cells that express antigens recognized by the anti-target cell antibody. In this study, we test targeted human T cells for the ability to lyse human tumor cells as a first step toward the application of this phenomenon to tumor immunotherapy. Several monoclonal anti-human tumor antibodies were assayed for binding to a number of human tumor lines and for the ability to promote specific tumor cell lysis when cross-linked with anti-T3. We found that anti-T3 cross-linked to anti-tumor monoclonal antibodies caused cloned human T cells and fresh peripheral blood T cells to lyse the tumor cells with the same specificity as predicted by the binding studies. Peripheral blood T cells were then tested in the presence of various heteroaggregates for the ability to lyse single cell suspensions prepared from fresh tumor or fresh normal tissue. These studies showed that heteroaggregates containing anti-T3 cross-linked to anti-tumor antibody cause fresh human T cells to specifically lyse fresh tumor cells, but not (with one exception) fresh normal cells.
While the appearance of a mediastinal mass in a patient in remission from Hodgkin's disease frequently indicates recurrence, a number of benign processes may present in a similar manner. Tissue confirmation of relapse should be obtained prior to initiating further chemotherapy to avoid the morbidity of unnecessary treatment. We present a case of thymic hyperplasia that developed in a patient previously treated for Hodgkin's disease. Thymic hyperplasia is a poorly understood, apparently benign process that may be confused with recurrent lymphoma. Total excision of such a mass is recommended to rule out coexistent malignancy.
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Pulmonary infiltrates in the patient with acquired immunodeficiency syndrome (AIDS) may be associated with a spectrum of unusual neoplastic and infectious process. Transbronchial biopsy frequently reveals the cause of these infiltrates; however, when transbronchial biopsy is nondiagnostic or contraindicated, or if the patient fails to improve after a diagnostic transbronchial biopsy, further investigation is warranted to direct appropriate therapy. Efficacy of 23 open-lung biopsies in 19 AIDS patients with pulmonary infiltrates was evaluated to define the indications for and the diagnostic yield of open-lung biopsy. Pulmonary infiltrates were recognized for a mean duration (+/- standard error) of 16 +/- 2 days before open-lung biopsy and were associated with fever and cough. These patients did not have prior transbronchial biopsy, and open-lung biopsy was diagnostic in all of these. Prior transbronchial biopsy performed in the remaining 16 patients was nondiagnostic in 10. Open-lung biopsy was diagnostic in 70% of these patients (Pneumocystis carinii pneumonia, 2 patients; Kaposi's sarcoma, 3 patients; Kaposi's sarcoma and Legionella pneumophila, 1 patient; cytomegalovirus, 1 patient). The other 6 patients having a previous diagnostic transbronchial biopsy failed to improve with therapy, and open-lung biopsy resulted in a therapeutic change in 67% of these patients. Two deaths were attributable to open-lung biopsy in patients with postoperative thrombocytopenic hemorrhage. Open-lung biopsy should be performed in AIDS patients when transbronchial biopsy is nondiagnostic or contraindicated, or in patients who fail to improve with appropriate therapy after diagnostic transbronchial biopsy, especially in patients with Kaposi's sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
The past several years have witnessed innovative approaches to clinical management as well as significant insights into the basic biology of the nodular lymphomas. Clinical studies have explored two apparently widely disparate approaches to the treatment of patients with nodular lymphoma. On the one hand, withholding initial therapy (watch and wait) has proved to be a viable option in the management of some patients. This approach has provided information regarding the natural history of disease, such as the relative incidence of spontaneous tumor regression vs. histologic transformation to more aggressive forms of lymphoma. Alternatively, recent data also suggest that the administration of intensive chemotherapy, shown to induce long-term remissions in a high percentage of patients with diffuse aggressive lymphomas, may also produce a significant number of durable remissions in at least certain histologic subtypes of nodular lymphomas. Clinical studies which attempt to achieve a synthesis of the above two approaches are currently in progress. Advances in immunology and molecular biology have also found application in the study of nodular lymphoma. Monoclonal antibodies have been employed diagnostically, as, for example, in detecting small numbers of persistent abnormal lymphoid clones in patients in apparent remission, and therapeutically, as exemplified by the clinical use in vivo of monoclonal antibodies directed against unique idiotypic determinants expressed by surface immunoglobulin on the malignant B lymphocytes. The demonstration of the immunoglobulin gene rearrangements in nodular lymphoma cells has established a more definitive criterion for their phenotypic characterization. Finally, molecular cloning of the breakpoint of the t(14; 18) chromosome translocation frequently found in nodular lymphoma cells has led to the identification of a potential new transforming gene which could be activated as a direct consequence of its rearrangement in proximity to the immunoglobulin in heavy chain gene locus.
Patients with Hodgkin's disease of the lymphocyte-depleted subtype (LDHD) have been said to have a poor prognosis. However, reports of this subtype are complicated by the fact that the histologic diagnosis of LDHD is often not straightforward, and its distinction from aggressive non-Hodgkin's lymphomas (NHL) can be difficult. We have reviewed our patients with LDHD at the National Cancer Institute (NCI) in light of an additional decade of experience with neoplastic and non-neoplastic conditions mimicking Hodgkin's disease. Of 198 patients who received MOPP (mechlorethamine, vincristine, procarbazine, prednisone) treatment at the NCI for Hodgkin's disease between 1964 and 1976, 43 (22%) were originally classified as LDHD. The initial diagnostic biopsies from 39 of these patients were reviewed and revealed ten with NHL, nine with LDHD, and 13 with nodular sclerosing Hodgkin's disease of the lymphocyte-depleted subtype (NSLD). The other seven patients had Hodgkin's disease without a lymphocyte-depleted component. The NHL patients were further subclassified as diffuse, large-cell (two cases) and large-cell, immunoblastic (eight cases). The pathologic review was done without knowledge of clinical features which were examined after review in the three major subgroups. Of ten patients with NHL, only three had a complete remission (CR), and median survival was 7 months. Nine of the NHL patients presented with features that are unusual for patients with Hodgkin's disease, such as bulky abdominal disease, epitrochlear lymphade-nopathy, or hypercalcemia. CRs were attained by 67% and 85% of patients in the LDHD and NSLD groups, respectively: median survival had not been reached in either group with a median of 14 years of follow-up. Lymphocyte-depleted Hodgkin's disease, adequately treated, is in our limited group of patients no worse than other histopathologic subtypes of Hodgkin's disease. The erroneous inclusion of patients with high-grade NHLs into this subtype of Hodgkin's disease may be one reason for earlier literature reports of its more aggressive nature. The diagnosis of LDHD should be made cautiously, particularly in patients with clinical features that are unusual for Hodgkin's disease at presentation.
Diagnosing recurrent Hodgkin's disease is an important oncologic problem. When relapse does not occur in peripheral nodal sites, then a major surgical exploration is often considered. Lymph node aspiration is proposed as a less invasive approach capable of establishing a diagnosis in some instances. In this retrospective study, 19 patients with Hodgkin's disease underwent 64 lymph node aspirations. Of these patients, 17 had suspected Hodgkin's disease with involvement at an inaccessible site. Two patients with a primary diagnosis of Hodgkin's disease underwent aspiration of a peripheral site. Of these 19 patients, five (26.3%) had a positive aspirate and only two (10.5%) had an unsatisfactory aspirate. No patient had a false-positive aspirate. Of 15 patients with a negative aspirate, five (33%) had a false-negative aspirate. In no case did a false-negative aspirate delay appropriate therapy. In those patients with a positive aspirate, surgical exploration was avoided. We conclude that lymph node aspiration cytology is useful as an initial step to document clinical relapse of Hodgkin's disease at a site that might require a major surgical procedure for diagnosis.
The results of treatment of 198 patients with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) for Hodgkin's disease were analyzed after a median of 14 years of follow-up. Throughout the period of follow-up, 103 patients have remained continuously free of disease. Review of biopsy specimens of 43 patients originally classified as Hodgkin's disease, lymphocyte-depleted type, revealed that ten of these patients actually had diffuse immunoblastic or large cell non-Hodgkin's lymphomas. Of the 188 patients with Hodgkin's disease, 157 achieved a complete response (CR) (84%), and 66% of them (101 patients) have remained disease-free more than 10 years from the end of treatment. Absence of B symptoms and receiving higher doses of vincristine were factors associated with a higher CR rate and longer survival. Patients entering complete remission in five cycles or less had significantly longer remissions than those requiring six or more cycles. Forty-eight percent of the Hodgkin's disease patients have survived between 9 and 21 years (median, 14 years) from the end of treatment. Nineteen percent of the CRs have died of intercurrent illnesses, free of Hodgkin's disease.
A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.
Hodgkin's disease and mycosis fungoides have been rarely reported in the same patient. This coexistence has been debated in the medical literature. We studied such a patient and report, to our knowledge, the first immunophenotypic evidence for such a coexistence. Reed-Sternberg cells and their variants stained with anti-Leu-M1, Hefi-1, anti-Tac, anti-HLA-DR, and OKT9, but were negative for T cell markers 3A1, Leu-1, Leu-2a, and Leu-3a, a phenotype typical of Hodgkin's disease; infiltrating small lymphocytes were predominantly T cells and were phenotypically normal. In the skin lesions, cells with the phenotype of Hodgkin's disease were not present; the infiltrate was composed of helper T lymphocytes that were 3A1-negative, a phenotype characteristic of the malignant cells of mycosis fungoides. Unexpectedly, a dermatopathic lymph node from the same patient showed the presence of the Leu-M1 antigen on the majority of normal-appearing interdigitating reticulum cells; this was not the case with control dermatopathic lymph nodes from patients without a malignancy. The significance, implications, and possible interrelationships of the findings are discussed.