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Biomedical subjects

D L Longo

Publications and source records attributed to D L Longo.

At least 361 records · Page 20Linked to original sources
PubMed1988

Enhancement of natural killer activity in human peripheral blood by flavone acetic acid.

Natural killer cell activity and interferon (IFN) production were measured in 6 patients receiving flavone acetic acid for treatment of cancer. Natural killer cell activity was significantly increased in 3 of 6 patients receiving 6.4 g of flavone acetic acid/m2 by 3-hour iv infusion. Analysis of cell surface markers failed to reveal significant changes in any cell population. There was no evidence of induction of IFN-gamma, but 3 of 4 patients tested had evidence of induction of type I IFN, as measured in a virus neutralization assay.

Adult↗
PubMed1988

Characterization of a murine monoclonal antibody that detects a C-terminal fragment of the raf oncogene product.

A murine mAb, STEGI 1, was generated against a 30-kDa raf protein purified from an Escherichia coli expression vector. Immunoblot analysis confirmed that this antibody recognized the original immunizing protein as well as a 44- to 48-kDa protein from several raf-transformed cell lines. Immunoprecipitation experiments isolated a 48-kDa protein from a cell line transfected with a c-raf construct as well as from normal NIH 3T3 fibroblasts. Parallel experiments with polyvalent antiserum prepared against E. coli-derived v-raf (C terminus)-precipitated proteins with apparent Mr of 48 and 74 kDa, as had been described previously. Immunofluorescence flow cytometry of raf-transformed cell lines revealed intense intracytoplasmic staining. This staining was specifically inhibited by preincubation of STEGI 1 with purified raf 30-kDa protein. It should now be possible to more easily assess the role of the raf oncogene product in malignant transformation.

Amino Acid Sequence↗
PubMed1988

Development of CD4-CD8+ cytotoxic T cells requires interactions with class I MHC determinants.

Differentiation of bone marrow derived precursors into mature T cells takes place in the thymus. During differentiation, T cells develop the receptor repertoire which allows them to recognize antigen in the context of self major histocompatibility complex (MHC) molecules. Mature T helper cells (mostly CD4+ CD8-) recognize antigen in the context of class II MHC molecules, whereas cytotoxic T cells (mostly CD4-CD8+) recognize antigen in the context of class I MHC determinants. Thymic MHC-encoded determinants greatly influence the selection of the T-cell receptor repertoire. In addition to positive selection, a negative selection to eliminate self-reactive T-cell clones is thought to occur in the thymus, but how this 'education' occurs is not well understood. It has been suggested that during differentiation an interaction between the T-cell receptor (TCR) and MHC-encoded determinants occurs, leading to the selection of an MHC-restricted receptor repertoire. In support of this hypothesis, class-II-specific, CD4+ CD8- helper T cells fail to develop in mice neonatally treated with anti-class II monoclonal antibody (mAb). As CD4-CD8+ cells differ from the CD4+ CD8- lineage (in function, MHC-restriction specificity and perhaps site of education) we examined whether interactions with MHC determinants are also necessary for the development of class-I-specific T cells. Here we show that mice chronically treated with anti-class I mAb from birth lack CD4-CD8+ cells and cytotoxic T-cell precursors, indicating that most CD4-CD8+ T cells need interaction with class I MHC molecules during differentiation.

Animals↗
PubMed1988

Influence of bone marrow-derived Ia-bearing cells on the selection of the T-cell repertoire.

We have presented the results of studies using chimeric animals to examine the role of distinct cell subsets in shaping the TCR repertoire. Examination of specificity and TCR expression in antigen-specific long-term T-cell lines derived from these chimeras suggests that bone marrow-derived APC play a role in the selection of T cells for MHC restriction during development, and also profoundly influence the expansion of the TCR repertoire following antigen priming. An understanding of the molecular mechanisms that govern TCR repertoire maturation may await the development of effective in vitro model systems of T-cell differentiation.

Animals↗
PubMed1988

Induction of mitochondrial manganese superoxide dismutase by interleukin 1.

Interleukin 1 (IL 1) inhibits the growth of human melanoma A375 cells. To identify the subcellular events preceding inhibition of growth by IL 1, we have examined the effect of IL 1 on protein synthesis caused by A375 cells. IL 1 selectively and predominantly induced a 25-kDa polypeptide (p25) in A375 cells after 12 h. On subcellular fractionation, p25 was exclusively located in the 10,000 x g-pelleted (mitochondria-enriched) fraction. To identify the p25 moiety, it was purified to homogeneity by sequential chromatography on DEAE-Sephacel and reverse-phase, high-pressure liquid chromatography and its amino-terminal amino acid sequence was determined. The sequence of the 35 amino-terminal amino acids of the p25 moiety was identical to that of human manganese superoxide dismutase (Mn SOD). The enzymatic activities of SOD were induced only in the mitochondria-enriched fraction of IL 1-treated A375 cells. However, IL 1 also induced Mn SOD in normal human skin fibroblasts and peripheral blood mononuclear cells, whose growth was stimulated by IL 1. The results show that induction of Mn SOD by IL 1 is a common biochemical event in IL 1-responsive cells.

Cytosol↗
PubMed1988

Adoptive therapies: quo vadis?

The success of adoptive immunotherapy using interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in treating a percentage of patients with melanoma and renal cell carcinoma has provided impetus to research into both how to optimize this treatment as well as approaches into making immunotherapy in general more successful. As the question on how to optimize IL-2 dose, schedule, cell culture conditions, and other specifics of IL-2 plus LAK therapy are addressed in clinical trials, other approaches suggested by data from in vitro, animal, and the clinical studies using IL-2 are emerging into clinical trials. (table; see text) These include two major areas of focus at the present time: (1) the use of IL-2 +/- LAK in combination with a variety of agents which have been shown to be synergistic with it, including other biological response modifiers (such as interferons), agents which may act both as interferon inducers as well as by other mechanisms (poly-IC:LC and flavone-8-acetic acid), and chemotherapeutic agents (especially cyclophosphamide, doxorubicin and agents which have some activity against the disease being treated such as DTIC for melanoma), and (2) various approaches aimed at inducing and expanding tumor-specific immune cells which appear to have greater antitumor activity than LAK cells and which may be major contributors to the antitumor efficacy of IL-2 therapy. These approaches also have the potential benefit of inducing memory cells with a resultant long-term immune antitumor response. Approaches aimed at activating specific antitumor immune cells include the use of IL-2-expanded infiltrating lymphocytes from tumors, exposure of peripheral blood cells cultured in IL-2 to tumor cells to hopefully expand those with a specific antitumor response, and the use of tumor cell vaccines in conjunction with IL-2. In addition to approaches using activated and expanded LAK effectors or specific T cells, the potential role of activated (e.g. by gamma interferon) and expanded (e.g. by macrophage colony stimulating factor) macrophages in the adoptive immunotherapy of cancer remains an area of ongoing exploration both in preclinical studies and clinical trials. As a greater understanding of the antitumor mechanisms of IL-2 and LAK therapy and other forms of adoptive immunotherapy is achieved, therapeutic approaches can be defined which will maximize the ability to mediate the immune destruction of tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Residual abdominal masses in aggressive non-Hodgkin's lymphoma after combination chemotherapy: significance and management.

When patients with aggressive lymphoma present with intraabdominal disease, a stable residual mass is frequently detected radiographically at the time of the clinical complete remission. To discern the optimal management for this clinical problem, we reviewed 241 patients with aggressive lymphoma treated at the National Cancer Institute (NCI) from 1977 to 1986. Seventy-two/241 patients (30%) had an abdominal mass at diagnosis and 29/72 (40%) were left with a radiographically detectable residual mass at clinical complete remission. The likelihood of a residual mass was much higher for patients with bulky disease (P2 less than .0003) (two-tailed test [P2]). Twenty-nine patients had radiologically stable residual masses after therapy, and of 22 (76%) with pathologic evaluations, 21 had negative specimens (95%) and one was positive (5%). None of the patients with negative pathologic evaluation has relapsed in the abdominal site (median follow-up, 31 months). Seven patients were observed clinically without laparotomy: five are alive, without evidence of disease, at 2 to 9 years; two relapsed with disseminated disease within 2 months of chemotherapy. Initial tumor size and size of the residual mass did not correlate with residual disease, since residual masses identified by radiographic examination did not usually harbor viable lymphoma cells. Aspiration cytology was negative for residual tumor in 15/16 cases. One negative result was not confirmed at laparotomy, presumably due to sampling error. The one positive aspiration was followed by a negative laparotomy, possibly due to subsequent tumor necrosis. Restaging laparotomy has a low yield. In most patients with aggressive lymphoma who have otherwise completely responded to carefully administered full-dose combination chemotherapy, stable residual abdominal masses can be closely followed clinically without surgical exploration.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The determination of an immunologically active dose of interferon-gamma in patients with melanoma.

This study was undertaken to determine an immunologically active regimen for the administration of recombinant gamma-interferon (rIFN-gamma). The patient population included patients with completely resected melanoma, stage I (Clark's level IV or V) or stage II. All patients exhibited no evidence of disease (NED) at the time of the study. Patients received rIFN-gamma by intramuscular (IM) injection daily for 15 days at 0.0001 mg/m2, 0.001 mg/m2, 0.01 mg/m2, 0.1 mg/m2 (ten patients/group), or 0.25 mg/m2 (five patients). Interferon (IFN) was well tolerated, with non-dose-limiting constitutional symptoms occurring in the majority of patients at 0.1 mg/m2 and 0.25 mg/m2. All five patients receiving 0.25 mg/m2 developed elevated transaminase levels, which led to a discontinuation of therapy in one patient. Immunological activity was assessed by serial measurements of natural killer (NK) cell activity, hydrogen peroxide production by monocytes, and changes in expression of Fc receptors and human leukocyte class II antigen (HLA-DR) on monocytes. These changes were determined at baseline (X2), six to seven time points during rIFN-gamma therapy, and two times after the last dose of rIFN-gamma. No changes were observed at the two lowest doses. At the 0.01 mg/m2 dose, all parameters were elevated but not as consistently nor to the same levels as seen following administration of 0.1 mg/m2. At 0.25 mg/m2, H2O2 production was enhanced, but unlike at 0.1 mg/m2, it declined during the last few days of IFN therapy. Subcutaneous (SC) administration was compared with IM administration using the 0.1 mg/m2 dose. SC administration resulted in enhanced H2O2 production and Fc receptor expression by monocytes. More consistent elevations in peroxide generation and higher levels of Fc receptor expression were seen following SC administration. No significant difference was found between the two routes of administration. A comparison of two schedules, daily and three times weekly, suggested that monocyte activation may return to normal 72 hours after IFN administration. Of the doses tested, 0.1 mg/m2 administered daily appeared to be the most effective biological response modifier (BRM) regimen, and because of ease of administration, we favor the SC route.

Dose-Response Relationship, Drug↗
PubMed1988

Preliminary results of treatment of Ewing's sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance.

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.

Adolescent↗
PubMed1988

Clinical, biologic, and therapeutic aspects of malignancies associated with the acquired immunodeficiency syndrome: Part I and Part II.

The incidence of malignant disease in AIDS patients is around 40%. Ninety percent of the tumors are Kaposi's sarcoma and 10% are malignant lymphomas, predominantly of B cell origin. The natural history of the AIDS-associated Kaposi's sarcoma is variable. It may remain entirely asymptomatic without treatment for many months or it may be rapidly progressive and produce life-threatening pulmonary, cardiac, or gastrointestinal symptoms requiring acute therapeutic intervention. The malignant lymphomas occurring in AIDS patients are usually very aggressive in their natural history. The treatment of choice for symptomatic Kaposi's sarcoma and malignant lymphoma is chemotherapy. In general, such treatment can alleviate symptoms and improve the quality of life in AIDS patients; however, the underlying immune defect is not improved by such treatment and the patients remain susceptible to life-threatening opportunistic infections. The ultimate control of the malignancies associated with AIDS depends upon the development of therapies capable of reversing the underlying immune defect.

Acquired Immunodeficiency Syndrome↗
PubMed1988

The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment.

Patients with advanced indolent lymphoma often have long survival (median, 4 to 8 years) in spite of frequent relapses. The inability of combination chemotherapy or radiation therapy (RT) to render patients disease free has led to radically divergent treatment approaches. Initial treatment may vary from aggressive combined modality therapy to no initial treatment. We sought to evaluate these two divergent approaches in a randomized trial of advanced indolent lymphomas (nodular, poorly differentiated lymphocytic; nodular mixed; diffuse, well-differentiated lymphocytic; diffuse, intermediately differentiated lymphocytic; and diffuse, poorly differentiated lymphocytic). A total of 104 patients were entered: 44 were randomly assigned to "watch and wait" in which only carefully defined, limited RT was administered if necessary; 45 were randomly assigned to aggressive combined modality treatment with prednisone, methotrexate, doxorubicin, cyclophosphamide, plus etoposide plus mechlorethamine, vincristine, procarbazine, prednisone (ProMACE-MOPP), followed by total nodal irradiation (TNI); and 15, with symptoms requiring initial therapy, received the identical combined treatment but were not randomly assigned. Of 41 evaluable patients on watch and wait, 23 (56%) have still not required systemic therapy, although 16 (39%) have received limited RT. Median time to crossover was 34 months. Of 18 patients crossed over, seven of the 16 who completed therapy (43%) achieved CR; two (11%) have relapsed. Histologic progression was seen in six (15%) of 41 patients on watch and wait without intervening chemotherapy. Of 45 patients randomly assigned to chemotherapy, 37 (82%) have completed induction therapy, and 29 of the 37 (78%) achieved CR. Twenty-five of those 29 patients (86%) are still in their first remission. Median duration of initial remission has not been reached but will exceed 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2.

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.

Adult↗
PubMed1988

The role of chemotherapy in diffuse aggressive lymphomas.

Diffuse aggressive lymphomas are curable by combination chemotherapy in advanced stages, with 30% to 60% of all treated patients alive and disease free 2 to 5 years from the end of treatment, depending on the program used. The fact that combination chemotherapy can cure this disease has led, since 1975, to several new directions in therapy such as (1) the development of a variety of new combination chemotherapy programs, using older drugs more aggressively, adding additional drugs to each program, or manipulating the scheduling of drugs; (2) the close scrutiny of study results to identify risk factors that influence the ability to attain a durable complete remission; and (3) the use of combination chemotherapy in early stage disease instead of, or with, radiotherapy (RT). The recently developed aggressive programs have been reported to produce results superior to the original studies, but because important prognostic factors have only recently been identified, there remains some uncertainty about the significance of the reported differences between studies. Also, dose intensity, a poorly controlled treatment variable in all studies, has recently been identified as a significant factor affecting outcome. Schedule variation, while reported to exert some independent effect on outcome, appears to influence results by its effect on dose intensity. Regardless of the uncertainty over the ideal program for patients with advanced diffuse aggressive lymphoma, the results in early-stage disease have uniformly favored the use of combination chemotherapy as the primary treatment, with or without subsequent RT, depending on the quality of the response to drugs, reaffirming the invariable inverse relationship between cell number and curability by chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Lymphomas.

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Hodgkin Disease↗
PubMed1988

Serum soluble IL-2 receptor as a tumor marker in patients with hairy cell leukemia.

Activated T cells synthesize and express a cell membrane-bound receptor for interleukin-2 (IL-2) and have recently been shown to secrete a soluble form of the same receptor. Hairy cell leukemia is a chronic disorder caused by expansion of a clonal population of an unusual mononuclear cell of B cell origin. These cells have previously been shown to express an IL-2 receptor on the cell membrane. The sera of 26 patients with hairy cell leukemia were examined for the presence of a soluble IL-2 receptor before and during therapy with either recombinant interferon alpha-2a or 2'-deoxycoformycin. Before therapy, all patients had markedly elevated levels of this soluble IL-2 receptor ranging from five to 60 times the highest level observed in normal control sera. In individual patients changes in the level during therapy correlated well with clinical assessments of tumor response; levels fell to near the normal range in patients responding to therapy. Patients not responding to interferon alpha had no significant change in the soluble IL-2 receptor level. These results suggest that hairy cells secrete a soluble IL-2 receptor and that serial measurements of the level of this receptor in the serum can be used as a noninvasive means to assess disease response to therapy.

Biomarkers, Tumor↗