Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence.

PURPOSE: To determine the frequency of and risk factors for second malignant neoplasms (SMNs) after treatment for Hodgkin's disease diagnosed in children and adolescents. PATIENTS AND METHODS: One hundred eighty-two consecutive, previously untreated patients with Hodgkin's disease who were younger than 20 years of age at diagnosis and who were referred to Roswell Park Cancer Institute (Buffalo, NY) for treatment between January 1, 1960, and December 31, 1989, were studied. Sex-specific standardized incidence ratios (SIRs) were calculated. Kaplan-Meier survival estimates and Cox regression analyses were performed to determine the relationship of several demographic and treatment variables to SMN incidence. RESULTS: Twenty-eight patients developed an SMN at a mean of 14.93 +/- 8.09 years (range, 2.65 to 29.88 years) after diagnosis of Hodgkin's disease. The cumulative percentage of patients who developed an SMN was 26.27 +/- 6.75% at 30 years after diagnosis. The SIR was 9.39 (95% confidence interval [CI], 4.05 to 18.49) for male patients and 10.16 (95% CI, 5.56 to 17.05) for female patients. The most frequent SMNs were thyroid cancer, breast cancer, nonmelanoma skin cancer, non-Hodgkin's lymphoma, and acute leukemia. Multivariate analysis of sex, treatment with any alkylating agent, treatment with doxorubicin, splenectomy, and relapse (as a time-dependent covariate) with time to SMN onset gave nonsignificant results. CONCLUSION: Successfully treated children and adolescents with Hodgkin's disease have a substantial risk for the occurrence of subsequent neoplasms. The most frequent SMNs (skin, thyroid, and breast) are readily detected by physical examination and available screening procedures.

Association of angiogenesis in lymph node metastases with outcome of breast cancer.

BACKGROUND: Microvessel density (MVD) is a measure of the extent of new blood vessel growth or angiogenesis, which is required for tumor progression. Increased MVD in primary breast cancers appears to adversely affect disease-free survival and overall survival in patients with breast cancer. However, the clinical implications of angiogenesis in breast cancer metastases have not been well studied. The purpose of this study was to compare intratumoral MVD in primary breast cancer tissues with MVD in axillary lymph node metastases and to evaluate the relationships among primary- and metastatic-tumor MVD, disease-free survival, and overall survival in patients with lymph node-positive, stage II breast cancer who were treated with adjuvant chemotherapy in Cancer and Leukemia Group B Protocol 8082. METHODS: Immunostaining for factor VIII-related antigen was performed on tissue sections from 47 primary tumors and 91 axillary lymph nodes containing metastases from 110 patients with lymph node-positive breast cancer. Sections were examined for the presence or absence of focal areas of relatively intense neovascularization (vascular hot spots), and a quantitative assessment of intratumoral MVD was performed. RESULTS: The presence of vascular hot spots in axillary lymph node metastases, but not primary breast cancers, was associated with statistically significantly decreased disease-free survival (P =.006) and overall survival (P =.004) by univariate analysis. Similarly, increased MVD in metastases, but not in primary tumors, was statistically significantly associated with diminished overall survival in these patients (P =.02). In multivariate analysis, the number of positive axillary lymph nodes and the presence of vascular hot spots in axillary lymph node metastases predicted decreased disease-free survival (P =.0001 and.02, respectively) and overall survival (P =.0001 and.007, respectively). All P values were two-sided. CONCLUSION: This pilot study suggests that assessing neovascularization in axillary lymph node metastases may provide clinically useful information regarding survival in patients with primary breast cancer.

Thiotepa-associated cardiomyopathy during blood or marrow transplantation: association with the female sex and cardiac risk factors.

Thiotepa (TT) has not been reported to cause cardiomyopathy, whereas cyclophosphamide (Cy)-related cardiomyopathy is well characterized. To search for cases of acute onset cardiomyopathy associated with TT, we retrospectively reviewed 171 patients who received TT-containing conditioning regimens for blood or marrow transplantation (BMT). Nine of 171 patients (5.3%) developed clinical congestive heart failure in the post-BMT period. The median time to onset of heart failure was 15 days after BMT (range 5-30). The median pre-BMT left ventricular ejection fraction (LVEF) was 50% (range 42-65%) as determined by two-dimensional echocardiogram, or gated blood pool scan. At the time of cardiomyopathy onset, LVEF was 30%. Six patients died of causes unrelated to heart failure. All affected patients who developed congestive heart failure following administration of TT had some evidence of cardiac dysfunction prior to transplantation. Significant risk factors for the development of cardiomyopathy included low pre-BMT-LVEF and female sex--particularly in females receiving allogeneic transplantation. The incidence of congestive heart failure with TT-containing regimens was similar to the incidence using other regimens with and without Cy. The mean time to clinical evidence of TT-associated cardiomyopathy was longer than the mean time reported with Cy. We recommend caution in using high-dose TT-containing regimens for patients with histories of cardiac dysfunction.

Aberrant antigen expression detected by multiparameter three color flow cytometry in intermediate and high grade B-cell lymphomas.

The aberrant expression of antigens (Ag) in lymphoproliferative disorders may cause a diagnostic problem when single parameter immunohistochemical assays are performed on frozen or paraffin sections because coexpression by relevant cells is not determined. This aberrant expression also raises the question as to whether mixed lineage (biphenotypic) lymphoid proliferations exist. Marrow (6) and extramedullary (20) tissues from 26 patients with diffuse, intermediate and high grade, B-cell lymphomas (IWF E=1, F=1, G=19, H=1 and J=4) were analyzed with 19 markers using 3-color flow cytometry. The percentages (%) of patients with double Ag coexpression in at least 20% of the CD19+ or CD20+ lymphoma cells were: stem cell (SC) Ag: CD10 = 58 and CD34 = 15; T-cell Ag: CD2 = 38, CD5 = 19 and CD7 = 19; myeloid (My) Ag: CD13 = 19 and CD33 = 8. The corresponding % with unusual triple Ag coexpression in at least 10% of the CD19+ B-cells were SC+T+ Ag: CD10CD2 = 50, CD10CD5 = 27, CD10CD7 = 38, CD34CD2 = 31, CD34CD5 = 19 and CD34CD7 = 27; T+T+ Ag: CD2CD5 = 35, CD2CD7 = 42 and CD5CD7 = 31; T+My+ Ag: CD2CD13 = 35 and CD2CD33 = 12; and My+My+ Ag: CD13CD33 = 12. Ten of 12 lymphomas tested showed clonal immunoglobulin (Ig) heavy chain gene rearrangements in the absence of clonal T-cell receptor (TCR) gene rearrangements. None (0%) of the My Ag positive cases showed immunoreactivity for myeloperoxidase. We conclude that the anomalous T and My Ag expression seen in the above B-cell lymphomas is not indicative of mixed lineage proliferation but represents the aberrant expression of these antigens by the malignant cells.

Engraftment of human tumor-infiltrating lymphocytes and the production of anti-tumor antibodies in SCID mice.

We report here the placement of nondisrupted 1-mm3 pieces of fresh human lung tumor biopsy tissue into the subcutis of severe combined immunodeficient (SCID) mice results in the engraftment of tumor-infiltrating leukocytes (TIL) in all but 5 of 148 mice inoculated with 39 different biopsy tissue specimens. In mice coengrafted with tumor and TIL the normal histologic architecture of the tumor and TIL interface was maintained for up to 22 wk. The TIL in the xenograft were shown to divide and were maintained exclusively at the site of tumor inoculation. It is established here that plasma cells in the TIL population produce Abs that react in western blots with tumor cell lysates. These Abs were shown to react with high and low m.w. proteins derived from both the membrane and cytosolic fractions of tumor cell lysates. The production of human Ig was found to be T cell dependent, and immunohistochemistry and in situ hybridization of DNA, using a human-specific cDNA probe, established the human identity of the tumor and TIL. High levels of human Ig in the sera of mice inoculated with tumor biopsy tissue are associated with the growth arrest of adenocarcinoma xenografts. Our results establish the co-engraftment of human tumors and TIL into SCID mice as new animal model with which to evaluate TIL function and novel therapeutic strategies that are designed to augment TIL anti-tumor activity.

Abdominal staging of thoracic Hodgkin disease: CT-lymphangiography-Ga-67 scanning correlation.

A retrospective study was performed to assess whether lymphangiography and gallium-67 scanning were complementary to computed tomography (CT) in abdominal staging of disease in 94 patients with early-stage thoracic Hodgkin disease. In 51 patients with surgical or follow-up correlation, the spleen was involved in 16% (n = 8), the spleen and lymph nodes in 22% (n = 11), and only lymph nodes in 2% (n = 1). In these 51 patients, none of the imaging modalities had greater than 50% sensitivity for the detection of nodal involvement. The overall accuracy was similar (71%-82%) for each modality. Analysis of subgroups of patients with lymph nodes measuring less than 10 mm, 10-19 mm, or 20 mm or greater at CT revealed that lymphangiography and gallium scanning added little to the positive or negative predictive values of CT. The sensitivity of CT for detection of splenic disease was 11% (two of 19). On the basis of surgical or follow-up correlation in 51 patients, the authors conclude that lymphangiography and gallium scanning offer minimal or no complementary benefit.

Monoclonal antibody SN10 which shows a highly selective reactivity with human B leukemia-lymphoma and is effectively internalized into cells.

The monoclonal antibody termed SN10 (IgG1-k) which was generated and characterized in the present study shows a highly selective reactivity with fresh (uncultured) human leukemia-lymphoma cells. The antigen defined by SN10 is a cell surface glycoprotein composed of a single polypeptide chain of Mr 36,000 and designated as gp36. The primary reactivity of SN10 is against mature B-lineage leukemia-lymphoma cells. For instance, SN10 reacted with all of the 17 B non-Hodgkin's lymphoma specimens, all of the 15 B chronic lymphocytic leukemia specimens, both of the 2 B prolymphocytic leukemia specimens, all of the 3 B hairy cell leukemia specimens, and 2 of the 3 B acute lymphoblastic leukemia specimens tested. Of normal peripheral blood cells, only a marginal reactivity of SN10 was detected with a minor subpopulation (less than 1-4% among different specimens) of isolated B-cells from healthy donors. No significant reactivity of SN10 was detected against any other isolated normal peripheral blood cells which include T-cells, granulocytes, monocytes, erythrocytes, and platelets. Furthermore, no significant reactivity of SN10 was detected against normal bone marrow specimens. In immunohistological studies using frozen tissue sections, SN10 reacted well with malignant lymphomas and showed varying patterns of reaction with hyperplastic reactive lymph nodes. Various normal human tissues tested were unreactive with SN10. In general, glycoprotein 36 was more abundantly expressed on fresh (uncultured) leukemia-lymphoma cells than on cultured leukemia-lymphoma cell lines. No significant amount of circulating SN10 antigen was detected in the plasma of leukemia-lymphoma patients or normal healthy donors. Scatchard plot analysis of direct binding of radiolabeled SN10 to a fresh (uncultured) B non-Hodgkin's lymphoma cell specimen, a fresh B chronic lymphocytic leukemia cell specimen, and DND-39 (an American Burkitt's lymphoma cell line) showed equilibrium constants of 5.2, 5.8, and 6.8 x 10(8) liters/mol, respectively. Thus, SN10 shows a high binding avidity to each of the 3 B leukemia-lymphoma cell specimens tested. Ricin A chain conjugate of SN10 killed leukemia-lymphoma cells effectively, whereas the same conjugate showed no cytotoxicity against control cells. Thus, SN10 bound to target antigen on the cell surface was effectively internalized into the cell. The present results suggest the potential of SN10 for therapy as well as for diagnosis of various forms of leukemia-lymphoma, particularly mature B-lineage leukemia-lymphoma.

A randomized trial of high dose cyclophosphamide, vincristine, and prednisone plus or minus doxorubicin (CVP versus CAVP) with long-term follow-up in advanced non-Hodgkin's lymphoma.

Ninety-three stage III and IV patients with non-Hodgkin's lymphoma were randomized to either high dose CVP (cyclophosphamide 1500 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 day 1, and prednisone 40 mg/m2 orally days 1-10) or high dose CAVP (cyclophosphamide 1000 mg/m2 i.v. day 1, doxorubicin 45 mg/m2 i.v. day 1, vincristine and prednisone as above). Overall, the complete response (CR) rates were similar (CVP 51%, CAVP 51%). Patients with the International Working Formulation diffuse large cell lymphoma had significantly higher CR with CAVP. No difference in CR duration was detected between the two regimens. CRs were durable with 68% of diffuse and 86% of diffuse large cell complete responders alive and disease free at 7 years. Survival was similar with both regimens except for patients with diffuse large cell lymphoma who survived longer with CAVP. Both regimens were equitoxic with neutropenia less than 1.0 x 10(9)/liter in 36% of courses, infections in 15% of courses, and fatal infections in three patients. These intermittent high dose cyclophosphamide equitoxic regimens produced durable responses. However, the doxorubicin-containing regimen is superior in diffuse large cell lymphoma.

Unique epitopes of common acute lymphoblastic leukemia antigen detected by new monoclonal antibodies.

In the present study we have generated four new monoclonal antibodies (mAbs), termed SN5, SN5a, SN5b, and SN5c, which are directed toward the human common acute lymphoblastic leukemia antigen (CALLA). SN5 and SN5c were generated separately by immunizing two mice with a leukemia antigen preparation isolated from uncultured non-T-/non-B-acute lymphoblastic leukemia cells whereas SN5a and SN5b were generated by immunizing a third mouse with intact KM-3 (a cultured non-T-/non-B-acute lymphoblastic leukemia cell line) cells. It was found that the binding activities of mAbs SN5 and SN5c generated by using an isolated leukemia antigen preparation were approximately twice as large as those of mAbs SN5a and SN5b generated by using intact leukemia cells. All four of the present mAbs induced antigenic modulation of CALLA on the leukemia cells in vitro; subclasses of mAbs appear to be an important factor which influences the kinetics of antigenic modulation. SN5, SN5a, and SN5c immunoprecipitated a distinct Mr 100,000 component from detergent-solubilized cell membrane antigens but SN5b failed to do so. These four mAbs together with J5, another anti-CALLA mAb, were individually tested in a solid phase radioimmunoassay for reactivity with the detergent extracts of various human tissues, i.e., kidney, lymph node, spleen, brain, liver, pancreas, lung, and heart. SN5, SN5a, SN5c, and J5 showed reaction only with kidney whereas SN5b did not show significant reaction with any tissues including kidney. However, SN5b as well as SN5 showed a significant reaction with kidney in an immunoperoxidase-staining test. These results indicate that the interaction of SN5b with a unique epitope on the CALLA moleucle is strongly disturbed by relatively mild detergents (deoxycholate, taurocholate, and Nonidet P-450). These detergents did not significantly disturb the reaction between other mAbs (SN5, SN5a, and SN5c) and the corresponding epitopes on the CALLA molecule. Competitive binding experiments show that the three epitopes recognized by SN5, SN5b, and SN5c are sufficiently close to each other to allow complete or nearly complete reciprocal inhibition of binding to CALLA present on leukemia cells. Peculiar inhibition patterns, however, were observed between SN5a and the other three mAbs. SN5, SN5b, and SN5c inhibited only partially the subsequent binding of SN5a to the leukemia cells. Conversely, SN5a inhibited nearly fully the subsequent bindings of SN5, SN5b, and SN5c. These results suggest another unique epitope defined by SN5a.(ABSTRACT TRUNCATED AT 400 WORDS)

Monoclonal antibody SN2 defining a human T cell leukemia-associated cell surface glycoprotein.

We generated a monoclonal antibody, termed SN2, which defines a human T cell leukemia-associated cell surface glycoprotein, GP37, with an approximate m.w. of 37,000. This antibody was generated by using a human leukemia antigen preparation. The reactivity and specificity of SN2 were characterized by a sensitive radioimmunoassay against a variety of cultured and uncultured human cells. In selected cases, the cell specimens were tested further by indirect immunofluorescence staining. Among the various cultured malignant and nonmalignant human cell lines tested, SN2 reacted only with leukemic T cell lines, with one exception. It reacted with 10 of 11 leukemic T cell lines tested; the 10 reactive cell lines are PEER, JM, MOLT-4, CCRF-CEM, CCRF-H-SB2, RPMI 8402, DND-41, HPB-ALL, SKW-3, and HPB-MLT; the unreactive line was HUT 78. The reactive cell lines were derived from patients either with T cell-type acute lymphoblastic leukemia (the first eight cell lines), with T cell chronic lymphocytic leukemia (SKW-3), or with Japanese adult T cell leukemia-lymphoma (HPB-MLT). The unreactive cell line, HUT 78, was from a patient with Sezary syndrome. Results consistent with the above were obtained from studies in which uncultured malignant cell specimens from different cancer patients were tested against SN2; SN2 reacted only with T leukemia cells. Among various uncultured normal cell specimens tested, SN2 did not react with thymocytes, bone marrow cells, peripheral blood lymphocytes containing B and T cells, purified T cells, monocytes, granulocytes, or erythrocytes. It did, however, react with platelets.

Monoclonal antibody that defines a unique human T-cell leukemia antigen.

We have generated and characterized a hybridoma monoclonal antibody, termed SN1, that defines a unique human T-cell leukemia antigen. This antibody was generated by using a human leukemia antigen preparation isolated from cell membranes of MOLT-4, a leukemia T-cell line derived from a patient with T-cell-type acute lymphoblastic leukemia (T-ALL). SN1 was characterized by a sensitive microscale radioimmunoassay using a variety of cultured and uncultured human cells. In selected cases, the cell specimens were further tested by immunoperoxidase staining and an immunofluorescence staining test. The results of the radioimmunoassay were in agreement with those of the two other tests. Among the various cultured malignant and nonmalignant cell lines, SN1 reacted only with leukemia T-cell lines derived from patients with T-ALL; it reacted with all six T-ALL cell lines tested-i.e., JM, CCRF-CEM, CCRF-H-SB2, RPMI 8402, PEER, and MOLT-4. In the case of uncultured cell specimens derived from cancer patients, SN1 reacted with four of four cases of T-ALL but did not react with specimens derived from 41 patients with other types of cancer. SN1 did not react with any normal human cell specimens tested, both cultured and uncultured. These specimens include normal lymphoblastoid cell lines, thymocytes, bone marrow cells, spleen cells, lymph node cells, peripheral blood mononuclear cells, lymphocytes containing B and T cells, purified T cells, monocytes, granulocytes, erythrocytes, and platelets. Furthermore, SN1 did not react with phytohemagglutinin-activated T cells nor with concanavalin A-activated T cells. The results show that monoclonal antibody SN1 defines a type of human leukemia antigen that is expressed on the cell surface of T-cell-type ALL cells. The results further show the usefulness of SN1 in the diagnosis of cancer patients and suggest its therapeutic potential. We designate this antigen TALLA, a T-cell ALL antigen.

Malignant lymphoma of pre-T-cell type terminating in acute myelocytic leukemia. A case report with enzymic and immunologic marker studies.

We report a case of a T-zone malignant lymphoma of a cervical lymph node developing in a 25-year-old man. Only 14% of the marrow was originally involved, but within two months massive, leukemic dissemination ensued. The blast cells were unable to bind sheep erythrocytes (E) but expressed human thymus leukemia antigen (HTLA) and common ALL-stem-cell (cALL) antigen and had high terminal deoxynucleotidyl transferase (TdT) and acid phosphatase activity. These findings suggest a malignant lymphoproliferative disorder of pre-T-cell type. Complete remission was achieved with intensive chemotherapy. Two months later, acute myelomonocytic leukemia was diagnosed; at this time, over 90% of the blast cells were peroxidase, sudan black, and chloracetate-esterase positive. Consistent with loss of high TdT activity and HTLA and cALL antigens, 86% of the blasts now expressed Ia-like antigens. Cytogenetic studies demonstrated hyperdiploidy. Reports of granulocytic leukemia in lymphoma are reviewed in the context of the above findings and the hypothesis that a leukemogenic factor affects a multipotential stem cell.

Gastrointestinal involvement in non-Hodgkin's lymphoma.

A total of 813 patients admitted to Roswell Park Memorial Institute from 1963--1972 with non Hodgkin's lymphoma (NHL) were reviewed for gastrointestinal (GI) involvement. Primary involvement was found in 71 and secondary involvement in 31 patients. Occult GI involvement was detected in 46% of the autopsy cases. The median survival time after the diagnosis of secondary GI involvement was nine months. The occurrence of primary GI-NHL was: 33 in the stomach, 18 in the small intestine, 14 in the ileocecal area including appendix, and 6 in the large intestine. Retrospective staging according to the Ann Arbor staging classification showed 24 to have presented as Stage I, 30 as Stage II, 4 as Stage III, and 13 as Stage IV. The primary diagnostic and therapeutic approach was operative, except in 2 patients with rectal lymphoma. Resection of the principally involved site was carried out in 42 patients. The remainder had palliative procedures or biopsy examinations only. Postoperative radiation therapy was given to 38 patients. Prognostically important features for primary GI-NHL were: stage; histologic type; site of the primary disease; and whether or not radiotherapy was administered. The age of the patient, size or degree of local extension, and type of operative procedure were prognostically of no importance. The results of this study would indicate that in Stage I and II primary GI-NHL, elective resection is not necessary prior to radiation therapy and that resection alone cannot be considered adequate treatment. A modified staging classification is proposed.

Blindness in a patient with malignant histiocytosis.

Malignant histiocytosis (MH) is a rapidly fatal systemic disease for which there is no adequate therapy. A case of MH with involvement of both eyes resulting in bilateral blindness is presented. Infiltration with malignant cells was seen in the ciliary bodies at autopsy. Attempts at treatment for this complication are discussed.

Radioimmunoassay for human T-cell associated antigens on MOLT 4 cultured cells.

We have detected antigens associated with two malignant T-cell lines by use of a sensitive radioimmunoassay. Baboon antisera to a cultured malignant T cell line (MOLT 4F) were prepared and the gammaG-anti-MOLT 4F was enriched by specific adsorption onto, and elution from, MOLT 4F cells followed by repeated absorption with pools of 21 established, long-term cultured B cell lines. Purified 125I-gammaG-anti-MOLT 4F preparation was tested for relative binding to autologous (MOLT 4F) and allogenetic (Sommer-RPMI 8402) T cells as well as B cells, including Sommer B cells (RPMI 8392). The degree of enrichment of antibody to malignant T cell associated antigens, expressed in terms of the ratios of the amount of globulin bound by T cells relative to the amount bound by B cells, were 6.3 and 5.0 for MOLT 4F and Sommer T cells, respectively.