Biomedical subjects
Publications and source records attributed to M Kadin.
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PURPOSE: To identify clinical factors predictive of treatment outcome after high-dose chemotherapy (HDC) for Hodgkin's disease and to develop a prognostic model for progression-free and overall survival. PATIENTS AND METHODS: 102 patients with relapsed or refractory Hodgkin's disease were treated with high-dose cyclophosphamide, carmustine, and etoposide and autologous marrow and/or peripheral blood progenitor cell support. Median follow-up of survivors is 4.1 years (1.8-7.5 years). Factors potentially important for treatment outcome were examined in univariate analysis, and Cox regression with forward selection was performed. A prognostic model was developed. RESULTS: Poorer progression-free and overall survival were associated with nodular sclerosis histology, abnormal performance status, progressive disease at HDC, more than one extranodal site of disease, and shorter time from initial diagnosis to HDC. These factors and the presence of B symptoms at relapse also predicted for decreased overall survival. Progressive disease immediately prior to HDC, more than one extranodal disease site, and abnormal performance status retained significance for both progression-free and overall survival in multivariate analysis. Progression-free and overall survival are 42% (95% confidence interval, CI, 34 to 53) and 65% (95% CI 54 to 73) at three years. A model based on number of risk factors present divides patients into low, intermediate, and high risk groups with three-year actuarial survival of 82%, 56%, and 19% respectively. Treatment outcome for patients treated with HDC at first chemotherapy relapse was not significantly different from that of the group overall (p > 0.3). CONCLUSIONS: Asymptomatic patients with Hodgkin's disease involving at most one extranodal site whose disease is controlled by conventional dose chemotherapy or radiation therapy at the time of HDC have good outcomes after this therapy. Presence of increasing numbers of risk factors are associated with poorer outcomes. Results of HDC compare favorably to those of standard dose salvage therapy. These data can be used to estimate likely outcomes in patients undergoing HDC for Hodgkin's disease, to identify potential candidates for innovative therapies, and to evaluate strategies for the optimal use of HDC in Hodgkin's disease.
The anti-CD30 immunotoxin (IT) Ber-H2/saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeat IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from < 5 x 10(-13) M to 2.75 x 10(-11) M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxin doses of Ber-H2/MOM (50%LD50), started 24 h after transplantation, prevented tumour development in about 40% of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0.45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting and with the two plant toxins. The results presented in this paper suggest that in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporin, MOM, PAP-S) should be feasible.
PURPOSE: Patients with lymphoblastic non-Hodgkin's lymphoma (LB NHL) were randomized to treatment with either modified LSA2L2 or ADCOMP, which added daunorubicin (DAUN) and asparaginase (L-ASP) to the methotrexate (MTX), cyclophosphamide (CYT), vincristine (VCR), and prednisone (PRED) (COMP) regimen, in a clinical trial to determine the relative effectiveness and toxicity of the two regimens. PATIENTS AND METHODS: Patients with LB NHL were eligible for this randomized study if they were less than 22 years of age at diagnosis and had < or = 25% blasts in the bone marrow. Of 307 patients registered, 281 were fully eligible and assessable. Patients were stratified by extent of disease at diagnosis. RESULTS: The 5-year event-free survival (EFS) rate for patients with localized disease was 84%, and for patients with disseminated disease, 67%. There were four relapses in 28 patients with localized disease. Two hundred six patients had mediastinal primary tumors and despite local radiation, 34 of 63 failures in these patients involved the primary tumor site with or without other involvement. After adjusting for extent of disease at diagnosis, the regimens did not differ significantly with respect to risk for adverse events. The acute toxicity was primarily neutropenia and thrombocytopenia, with greater initial toxicity in patients on the LSA2L2 regimen. Three patients developed acute myelogenous leukemia. CONCLUSION: Long-term EFS in children with LB NHL can be achieved in the majority of patients. Disease progression, which includes recurrence at the primary tumor site, is a major cause of treatment failure in patients with mediastinal presentations. Addition of DAUN and L-ASP to the COMP regimen does not produce a more effective treatment than LSA2L2.
BACKGROUND: The etiology of Hodgkin disease remains uncertain. Patterns of presentation of Hodgkin disease are analyzed by histologic subtype with implications for etiology and pathogenesis. METHODS: The authors performed a detailed analysis of anatomic sites of involvement, histopathologic findings, and clinical features in 719 patients with Hodgkin disease who underwent staging laparotomy with splenectomy between April 1969 and December 1986. The presence of disease in each of 17 sites of potential nodal involvement was determined for each patient from a combination of clinical and surgical staging. Association among nodal sites was assessed in 2 x 2 tables by estimating the odds ratio and testing the significance with the chi-square test. A strict significance level (P = 0.01) was used. Log-linear models were used for assessing association in 2 x 2 tables while adjusting for other factors. RESULTS: The mediastinum, left side of neck, and right side of neck were the most common sites involved for patients with nodular sclerosing (NS) or mixed cellularity (MC) histologic subtypes. Each of these sites was involved 60% of the time. These sites were four or more times as common as other nodal sites above or below the diaphragm. In contrast, the mediastinum was involved in only 8% of patients with lymphocyte predominance (LP) histologic subtype. Significant associations were found between mediastinal disease and low cervical/supraclavicular lymph node disease, mediastinal disease and NS histologic subtypes, peripheral nodal disease and LP histologic subtypes, and between splenic disease and mixed cellularity/lymphocyte depletion (MC/LD) Hodgkin disease. The age at onset and sex of patients with Hodgkin disease and the patterns of nodal distribution were somewhat different for NS and MC/LD histologic subtypes. Even greater differences were seen between LP and other histologic subtypes. CONCLUSIONS: This study supports the conclusion that NS and MC Hodgkin disease spread by continguity, most often originating in the neck or mediastinum, and is consistent with evidence suggesting an infectious agent in the pathogenesis of these subtypes of Hodgkin disease. In contrast, LP Hodgkin disease is characterized by different sites of presentation and patterns of spread. This suggests that two or perhaps three clinicopathologic subtypes of Hodgkin disease exist. Implications for etiology and pathogenesis are discussed.
Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine which promotes fibroblast growth and collagen synthesis, but suppresses growth and differentiation of immune lymphocytes and killer cells. Immunohistochemical detection of TGF-beta 1 in Hodgkin's disease (HD) has been shown to correlate with the histologic feature of nodular sclerosis, which is associated with a favorable prognosis (American Journal of Pathology 1990, 136:1209). In that study, TGF-beta 1 was localized mainly at the margins of broad collagen bands (presumably sites of new collagen synthesis) and in areas containing numerous Hodgkin/Reed-Sternberg cells (H/RS). In these areas, TGF-beta 1 protein was found on the membrane and occasionally within the cytoplasm of H/RS cells. To determine whether TGF-beta 1 is synthesized by H/RS cells or secondarily bound to their membrane and sometimes internalized, we performed in situ hybridization (ISH) using 1.5 Kb 35S-labeled anti-sense and sense RNA probes to TGF-beta 1. Paraffin-embedded tissues of 10 cases from all histologic types of HD were examined. Somewhat unexpectedly, the major site of TGF-beta 1 mRNA was in eosinophils; TGF-beta 1 mRNA was not detected in H/RS cells. TGF-beta 1 mRNA was found in eosinophils in all cases of nodular sclerosis but not in other types of HD, despite the presence of numerous eosinophils in mixed cellularity cases. The presence of TGF-beta 1 mRNA coincided with immunohistochemical detection of TGF-beta 1 protein using antibody CC (1-30). These results confirm the role of TGF-beta 1 in the histogenesis of nodular sclerosing HD and indicate that eosinophils are the major source of TGF-beta 1 in this type of HD.
To test the possibility that interleukin-9 (IL-9), the human homologue of the mouse T-cell growth factor P40, may be involved in the pathogenesis of human lymphomas, we examined IL-9 expression in a variety of tumors both by Northern blot analysis and by in situ hybridization. Of 18 B-cell non-Hodgkin's lymphomas and 11 peripheral T-cell lymphomas, none expressed IL-9 message. By contrast, IL-9 message was found in two of six cases of large cell anaplastic lymphoma (LCAL) and in 6 of 13 cases of Hodgkin's disease (HD). In HD the strongest signals were observed in Hodgkin (H) and Sternberg-Reed (SR) cells, but IL-9 mRNA was also detected in small lymphocytic cells. A search for IL-9 message in a panel of 20 cell lines derived both from hematopoietic and nonhematopoietic tumors confirmed the unique association of IL-9 expression with HD and LCAL in as much as the only two cell lines with IL-9 message were derived from cases of HD and LCAL. These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas, but that it may play a role in HD and LCAL.
Four patients with chronic refractory plaque-type psoriasis without arthropathy were treated with extracorporeal photopheresis every other week for 6 to 13 months. In patients 1 and 2, methotrexate was administered concomitantly during the initial part of the trial; the dose was gradually tapered and the drug was discontinued by 6 months. Both patients improved to 23% and 62% of baseline values for percentage of body surface involvement, but their disease then flared when maintenance extracorporeal photopheresis was used alone. Substantial improvement again occurred when lower doses of methotrexate were administered with extracorporeal photopheresis. Patients 3 and 4 were treated initially with extracorporeal photopheresis alone and both improved to 50% and 52% of baseline body surface involvement, respectively, after 4 months of treatment. However, their disease flared because of factors unrelated to treatment. Extracorporeal photopheresis was well tolerated by all patients without evidence of overt toxicity. However, prolonged treatment with extracorporeal photopheresis/methotrexate was accompanied by a decrease in skin reactivity to recall antigens and by decreased capacity of lymphocytes to produce interleukin 2 in response to polyclonal stimuli in vitro. These findings indicate that alternate-week extracorporeal photopheresis has a definite but incomplete suppressive effect on psoriasis vulgaris that may be mediated through an effect on lymphokine production by photomodified cells and that the therapeutic effect of extracorporeal photopheresis may be enhanced by concomitant administration of low doses of methotrexate.
The diagnosis of pulmonary lymphangitic carcinoma usually requires fiberoptic bronchoscopy with transbronchial biopsy, percutaneous needle aspiration of the lung, and/or open lung biopsy. We performed right heart catheterization in three patients with adenocarcinoma, in whom the diagnosis of pulmonary lymphangitic carcinoma was made on the basis of cytologic examination of pulmonary capillary blood.
Adult T-cell leukemia (ATL) is a disease found endemic in Southern Japan and the Caribbean basin. The human T-cell leukemia virus I (HTLV-I) has been implicated epidemiologically as the causative agent in this disease. This paper describes the identification of this disease in Hawaii in a second generation immigrant from Southern Japan. The disease was initially indolent, then clinically explosive, characterized by cutaneous lesions, leukemic lymphocytes with convoluted nuclei of T-cell phenotype, hypercalcemia, and a terminal infection.
A distinctive immunologic phenotype was demonstrated for the characteristic large atypical cells in skin lesions of 9 patients with lymphomatoid papulosis (LP). Coexpression of Hodgkin's disease (HD)-associated antigen(s) Ki-1, and often Leu-M1, with helper T-cell antigens T11, T4, and T3 and cellular activation antigens Tac, Ia, and T9 was the most common phenotype, observed in 6 of 9 cases. In 2 cases T-cell-specific antigens were not detected, and the phenotype was indistinguishable from Reed-Sternberg (RS) cells of HD. Numerous Ki-1 positive cells and infrequent expression of Leu-1 antigen by large atypical cells in LP cases facilitated the differential diagnosis between LP and mycosis fungoides. A possible transition between small, medium, and large cells expressing only T-cell antigens and large transformed RS-like cells expressing both T-cell and HD-associated antigens was shown by immunoelectron microscopy. These immunologic findings should prove useful for the diagnosis of LP and may help to explain the unexpectedly frequent clinical associations of LP, mycosis fungoides, and HD.
In this study the authors attempted to establish immunopathologic criteria for the distinction of various T-cell lymphomas affecting the skin. We studied skin specimens from 27 patients with mycosis fungoides (MF) (n = 12), the Sézary syndrome (SS) (n = 6), adult T-cell leukemia (ATL) (n = 4), and nonepidermotropic T-cell lymphoma of large cell (n = 4) and lymphoblastic (n = 1) types. Identification of tumor cells in mixed cell populations and detection of weak expression of surface antigens by tumor cells was facilitated by immunoelectron microscopy. The mature helper T-cell phenotype (T11+ T3+ T4+) was found in 14 of 18 cases of MF/SS. One case of MF had a cytotoxic/suppressor (T4- T8+ 3A1+) phenotype; one with frequent blastic cells showed only weak expression of T4 antigen; 2 cases of SS were T11-. Tumor cells infiltrating the skin expressed 3Al antigen in 44% and cellular activation antigens Ia and/or Tac in 78% of patients with MF/SS. No consistent phenotypic differences were found between ATL cells from ATLV (HTLV) antibody-positive patients and tumor cells of patients with MF/SS who lacked this antibody. In contrast, a group of nonepidermotropic T-cell lymphomas showed phenotypic differences from MF/SS and ATL in all but 1 case. These cases were distinguished by the frequent absence of T3, T4, and Leu 1 antigens in 3 large-cell lymphomas; frequent expression of Ki-1 antigen, a Hodgkin's disease-associated antigen, in 2 cases with RS-like cells; and an immature thymocyte phenotype in lymphoblastic lymphoma. These findings demonstrate that tumor-cell phenotypes can be useful in distinguishing different histologic types of cutaneous T-cell lymphoma.
Experimental evidence suggests that the fibroblastic proliferation often associated with the myeloproliferative disorders is not part of the neoplastic process, but is secondary to an unknown stimulus. This stimulus may be a factor derived from platelets which promotes the proliferation of fibroblasts in vitro (PDGF). Platelet-derived growth factor is localized to platelet alpha-granules together with PF4 and beta-TG. As an indicator of alpha-granule release, we have measured PF4 levels in plasma, platelets and urine in 46 normal subjects and 49 patients with myeloproliferative disorders, secondary thrombocytosis and miscellaneous malignancies. All 11 patients with elevated urinary PF4 excretion exhibited myelofibrosis, whereas 11 of 22 patients with documented myelofibrosis had urinary PF4 excretion in the normal range. No correlation was seen between marrow fibrosis and plasma levels or the platelet content of PF4. The data are consistent with the possibility that release of mitogen(s) from platelet or megakaryocyte alpha-granules in some patients with myeloproliferative disorders is pathogenetically related to the development of marrow fibrosis.
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LW-negative (LW4) red blood cells and anti-LW antibody were discovered in the blood of a 50-year-old white male with Hodgkin's disease and blood type O. Compatible red blood cells for transfusion could not be obtained because available LW-negative cells were either type A, LW4, or type O, LW3. Following cytotoxic therapy for his basic disease, the anti-LW disappeared and his red blood cells developed normal reactions with anti-LW sera.
Acute lymphoblastic leukemia (ALL) patients could be subclassified into two groups depending on whether or not their leukemia cells expressed a B-lymphocyte antigen. The antigen was detected by an indirect immunofluorescence test using rabbit antisera. In the positive group, consisting of 26 of 32 patients, the leukemia cells were of the "null"-cell type, i.e., they did not appear to express currently recognized T- and -b-cell markers. Absroption studies indicated that the positive null-cell group expressed a common antigen which was not expressed on the negative group. Of the 6 negative cases,, 5 expressed complement receptors and 3 expressed T-cell markers. The negative group was also characterized by high white cell counts and the pressence of a mediastinal mass.
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