Fractionated radioimmunotherapy of B-cell malignancies with 131I-Lym-1.

Eighteen patients with Stage 4 B-cell malignancies, which were primarily of intermediate or high grade and progressive despite multiple drug chemotherapy and external irradiation, were treated with fractionated doses of 131I-labeled Lym-1. Lym-1 is an IgG2a monoclonal antibody that was produced by immunizing mice with Raji cell nuclei that originated from a patient with African Burkitt's lymphoma. Despite advanced disease, 10 of the patients had objective evidence for a complete or partial remission. Toxicity was very modest except in one patient who developed hypotension. Dose-dependent hepatic uptake of Lym-1 was observed in the patients and in BALB/c mice suggesting receptor-mediated recognition of this murine antibody.

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma.

PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS: Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS: Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION: (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas.

Hepatosplenic gammadelta T-cell lymphoma is a distinct entity, characterized by occurrence in young adult males with hepatosplenomegaly, B-symptoms, peripheral blood cytopenias, and no lymphadenopathy; lymphomatous infiltrates in the splenic red pulp, hepatic sinusoids, and bone marrow sinuses; T-cell receptor (TCR) gammadelta chains and a cytotoxic T-cell phenotype; isochromosome 7q; and an aggressive clinical course. In comparison, this study describes the clinicopathologic features of 14 hepatosplenic T-cell lymphomas expressing TCR alphabeta chains. They occurred in 11 women and 3 men with a median age of 36 years. Clinical presentation was similar to that described previously for hepatosplenic gammadelta T-cell lymphomas, except for the female preponderance and age distribution (5 patients younger than 13 years of age and 5 patients older than 50 years of age). Disease distribution was primarily in the splenic red pulp and hepatic sinusoids, although liver infiltrates were largely periportal in four cases. Bone marrow involvement, observed in eight patients, was usually interstitial and/or within the sinuses. Lymph nodes were involved in five patients, although lymphadenopathy was demonstrable in only two. Ten cases were composed of intermediate-size tumor cells with round/oval nuclei, slightly dispersed chromatin, inconspicuous nucleoli, and scant to moderate amounts of cytoplasm. Four lymphomas contained primarily large cells with irregular nuclei, dispersed chromatin, discernible nucleoli, and moderate to abundant cytoplasm. Tumor cells in all 14 lymphomas were cytotoxic alphabeta T-cells; 13 co-expressed natural killer cell-associated antigens and showed T-cell clonality. Three lymphomas were associated with Epstein-Barr virus. Two of four cases had an isochromosome 7q. Eleven patients are dead, eight within a year of diagnosis, and two patients have maintained complete remissions after combination chemotherapy. These data show that hepatosplenic T-cell lymphomas include an alphabeta-subtype. This group, along with the previously recognized gammadelta group, should be recognized as phenotypically heterogeneous subtypes of the same disease entity.

Characterization of rhesus macaque B-lymphoblastoid cell lines infected with simian type D retrovirus.

A simian type D retrovirus designated SRV induces a fatal immunosuppressive disease in rhesus macaques. This syndrome shows many clinical similarities to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-infected individuals. To investigate the mechanisms of immune dysfunction in SRV infection, we have focused on the interactions of SRV serotype 1 (SRV-1) with macaque B-lymphoblastoid cell lines (B-LCL). Procedures were optimized for establishing B-LCL by immortalization of macaque B lymphocytes with rhesus Epstein-Barr virus (EBV). These cell lines express B-cell surface markers, secrete immunoglobulins of the IgG or IgM isotypes, and release EBV which transforms monkey B cells. In vitro cultures of B-LCL supported replication of SRV-1. Several B-LCL infected with SRV-1 showed downregulation of major histocompatibility complex (MHC) class II antigen expression whereas levels of MHC class I antigen remained unchanged. Infection of B-LCL with SRV-1 did not alter the level of secreted immunoglobulin. Rhesus EBV was also used to obtain B-LCL from macaques infected with SRV-1; these cell lines were found to release infectious SRV-1. Investigations on the interactions of SRV-1 with B cells will be useful for elucidating mechanisms involved in the immunopathogenesis of primate retroviruses.

Mast cell disease followed by leukemia with clonal evolution.

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.

An immunohistochemical study of hemoglobin A, hemoglobin F, muramidase, and transferrin in erythroid hyperplasia and neoplasia.

The bone marrow biopsy specimens of 35 patients with benign and malignant erythroid hyperplasias were examined for the presence of hemoglobin A, hemoglobin F, muramidase (lysozyme), and transferrin, using an indirect immunoperoxidase method (PAP) on Zenker's-fixed paraffin-embedded bone marrow biopsy specimens and particles. Five cases of each of the following entities were studied: erythroleukemia and erythremic myelosis, acute granulocytic leukemia with maturation (FAB M2), polycythemia rubra vera, myeloproliferative syndrome in childhood, megaloblastic anemia (B12 and folate deficiency), erythroid hyperplasia (regenerating bone marrow and hemolytic anemia), and Ph' chromosome positive chronic granulocytic leukemia. Hemoglobin A was present in both the early and late erythroid precursors in all conditions. Hemoglobin F was the predominant hemoglobin in early erythroblasts of pernicious anemia and in both early and late erythroid elements in erythroleukemia and erythremic myelosis. Small quantities of hemoglobin F were present in a few isolated clusters in other conditions. Staining for hemoglobin F may be useful in identifying immature erythroid precursors and in distinguishing some cases of dysplastic erythroid hyperplasia from neoplasia. Additionally, these findings suggest that the maturational switch in hemoglobin synthesis operates with distinct pathways under different conditions.

Diffuse large cell, B-cell type lymphoma with a novel translocation (2;22)(p23;q11.2).

We observed a translocation (2;22)(p23;q11.2) in the bone marrow cells of a patient with multiple subcutaneous nodules. Tumor histology and immunohistochemical staining demonstrated a malignant lymphoma, diffuse large cell type, displaying a CD30 negative B cell immunophenotype. To our knowledge, this is the first report of this specific translocation in lymphoma, which may join the site of the anaplastic lymphoma kinase (ALK) gene at 2p23 to the region of the immunoglobulin lambda light chain gene at 22q11.2. The ALK gene was initially identified through its involvement in the t(2;5)(p23;q35) found most commonly in anaplastic large cell lymphoma. This observation in a CD30 negative large cell lymphoma of B cell lineage further extends the relationship of anaplastic large cell morphology, ALK activation, lymphoid lineage, and expression of the CD30 antigen.

Effects of medical advances and political climate upon psychonephrology.

Two relatively recent medical advances have enlarged the options open to patients with renal failure. Continuous ambulatory peritoneal dialysis (CAPD), a form of home care that does not utilize the circulatory system, offers an alternative to those with vessel access compromise. Cyclosporine, a new, but expensive immunosuppressant, has substantially improved chances of success of renal transplantation. However, on the negative side, the federal government has attempted to diminish its expenditure in support of treatment of renal failure by favoring less costly modalities and diminishing its reimbursement of physicians and facilities. Patients are pressured into less expensive forms of treatment, such as CAPD and home hemodialysis, at times with little regard for individual needs. Diminished reimbursement places a greater financial burden upon not-for-profit centers over those that are proprietary.

A "hateful epileptic" patient in the burn unit.

An interdisciplinary team discussed the case of a 31-year-old woman who sustained second- and third-degree burns while having a seizure. She was a difficult patient who elicited a good deal of negative feelings from the staff. The interview raised the possibility of this burn having been a suicidal attempt, and the subsequent discussion centered on effective ways of relating to her pathologic defense mechanisms. The need for a comprehensive approach that took into consideration the biologic, psychologic, and social aspects of her needs became evident to all the participants.

Current attitudes of medical students and house staff toward terminal illness.

A survey questionnaire about attitudes toward terminal illness was administered to all medical students, interns, and all medical, surgical, and psychiatric residents at the Downstate Medical Center. The majority of students and new physicians surveyed reported that patients with terminal illness should be told their diagnosis--a reversal of attitudes as compared with those revealed by studies done before 1970. Most of the respondents also expressed the view that they would want to be told of their own fatal illness. The attitudes at different levels in medical school, internship, and residency did not differ significantly despite the differences in formal education and clinical experience of the respondents. Implications of these findings are discussed with particular emphasis on the need to teach an individualized approach to the dying patient.

Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function.

Nine depressed patients with normal kidney function and seven depressed patients with renal failure undergoing hemodialysis were treated with open-label fluoxetine 20 mg/day in an 8-week study. The study was designed to evaluate the pharmacokinetics of fluoxetine during repeated administration and to acquire preliminary data regarding the effectiveness of this antidepressant in a population undergoing hemodialysis. Six patients in each group completed the study. Of these, five patients undergoing hemodialysis and five patients with normal renal function experienced moderate to marked improvement in their depression. Side effects were equal and minor in both groups, indicating that fluoxetine is safe in patients with renal impairment. The mean +/- standard deviation steady-state plasma concentrations of the sum of fluoxetine plus its metabolite norfluoxetine for patients completing 8 weeks (N = 6, both groups) were comparable for the patients undergoing hemodialysis (253 +/- 61 ng/ml) and those with normal kidney function (218 +/- 122 ng/ml; t = 1.5, df = 70, p > 0.13). These data suggest that the efficacy of fluoxetine in patients with renal failure undergoing hemodialysis is comparable to that in patients with normal kidney function. These data further suggest that renal failure and the process of hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine.

Immunohistochemical staining of metastatic ductal carcinomas of the breast by monoclonal antibodies used in imaging and therapy: A comparative study.

Five monoclonal antibodies (MoAbs)(L6, 170H.82, 155, BrE-3 and BR96), most of which have been previously shown to target breast cancer and not normal tissues by immunoscintigraphic imaging, were evaluated for their frequency and pattern and immunohistochemical staining in 67 to 116 metastatic lesions from patients with ductal carcinoma of the breast. Immunoperoxidase staining in 75% or more of the cells occurred in 56/116 (48%) for L6, 44/89 (49%) for Br, -96, 58/102 (57%) for 155, 62/99 (84%) for 170H.82, and 65.67 (97%) for BrE-3. With the first three MoAbs, an additional 6-10% of the tumors showed staining in 50-75% of tumor cells. These results illustrate that most patients with metastatic ductal carcinoma have cancer tissue in which a high percent of cells will react to several of these selected MoAbs that target different epitopes. The high expression of the MoAb targets throughout the tumor tissue makes these antibodies potential candidates to carry immunologically directed radioimmunotherapy and is an aid in selecting patients for treatment.

The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine.

Renal and hepatic diseases have a significant impact on the plasma concentration profiles and the dose requirements for almost all drugs. This paper reviews the effect of these diseases and their associated physiological derangements on the pharmacokinetics of fluoxetine and norfluoxetine. Metabolic studies of fluoxetine in man show that more than 70% of the radiolabelled compound is excreted in the urine. Most of the urinary radiolabelled products are metabolites and not the parent compound nor its active metabolite, norfluoxetine. Cirrhosis of the liver significantly reduces the clearance of fluoxetine and norfluoxetine, but mild, moderate, or severe renal dysfunction does not affect fluoxetine or norfluoxetine pharmacokinetics. Daily administration of fluoxetine, 20 mg, for more than 2 months to renally impaired, depressed patients (who require haemodialysis) produces steady-state fluoxetine and norfluoxetine plasma concentrations that are comparable to the concentrations in depressed patients with normal renal function. Renal function is not an important determinant of the steady-state concentrations of fluoxetine or norfluoxetine, though the concentrations may be higher in patients with significantly impaired liver function.

Low-dose, fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody.

PURPOSE: This trial was conducted to assess the toxicity and efficacy of 131I-Lym-1 in patients with either malignant B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) using low-dose, fractionated radioimmunotherapy (RIT). MATERIALS AND METHODS: Thirty adult patients who had advanced B-cell malignancies (25 NHL and 5 CLL) had progressed despite standard therapy; 12 patients entered the trial with Karnofsky performance status (KPS) of equal to or greater than 60. Patients were treated with a series of intravenous doses of 131I-Lym-1 with a goal of reaching a cumulative dose in each patient of at least 300 mCi. All patients were Lym-1 reactive. Clinical responses and immediate toxicity were evaluable in all 30 patients and delayed toxicity in 26. RESULTS: Toxicity to Lym-1 antibody occurred with 28% of the 176 doses and was transient. Human antimouse antibodies (HAMA) were generated in 30% after a mean of 4 doses, but interrupted therapy in only 10% of the patients. Thrombocytopenia was dose-limiting; there were no deaths due to toxicity. Tumor regression occurred in 25 (83%) of the patients and was great enough, and durable enough, in 17 (57%) to qualify them as responders; 13 NHL patients and 4 CLL patients. Advanced disease often interrupted therapy prematurely. However, 18 patients received at least 180 mCi of 131I-Lym-1; 17 (94%) of these responded to the therapy. CONCLUSION: Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.

Moment in History. In the beginning.

The purpose of this editorial is to give the reader a picture of the earliest days in the delivery of chronic dialysis. It is viewed by a psychiatrist who was asked to help evaluate patients in one of the first hemodialysis centers, not only in the United States, but in the world.

The teaching of liaison psychiatry in the hemodialysis center.

The hemodialysis unit is usually a uniquely desirable place for liaison teaching because of the importance and variety of behavioral problems seen there. The trainee may be educated at these units about the syndrome of delirium because of the potential for his seeing in a given patient the presentation and resolution of the syndrome before and after each run. Because of the abject dependency of these patients, issues surrounding patient dependency "needs" and frustration of their independence are common with patient "uncooperativeness", an important area in which the professional staff need education and patients need intervention. Depression, common among these patients because of their many losses, is among the host of psychological problems to be potentially diagnosed and treated by the liaison trainee and/or teacher. The theme of life setting conductive to medical illness and the setting of realistic rehabiliation goals are also important areas of liaison training, particularly suitable for demonstration there. Therefore, hemodialysis centers offer usual wide variety and often untapped resources for liaison education.