Stanley E. Graber

Diagnostic criteria and histologic grading in multiple myeloma: Histologic and immunohistologic analysis of 176 cases with clinical correlation

Diagnostic criteria in myeloma have not been completely standardized or tested for accuracy; furthermore, marrow findings of prognostic value have not been clearly identified. We studied 176 patients with myeloma to determine the relative value of marrow differential, tissue sections, and immunohistology singly or in concert in the diagnosis of myeloma and to correlate morphologic features with prognosis. Controls were patients with benign marrow plasmacytosis. Homogeneous nodules of plasma cells at least 1/2 high-power field and/or monotypic aggregates of plasma cells filling at least one interfatty marrow space correctly identified myeloma in 83.5% of cases, with no false positives. The current numerical criteria of marrow plasmacytosis > or = 10% occurred in 17.1% of the controls, and 39.7% of patients with myeloma had less than 10% marrow plasmacytosis at presentation. Myeloma was graded histologically into categories of none/minimal, moderate, and marked dysplasia on the basis of dysplastic features and mitoses; these categories correlated well with clinical outcome, with median length of survival of 32.9, 25.2, and 12.9 months, respectively (overall median length of survival of 123 patients with myeloma, 29.2 months). Packing of marrow by tumor and mitoses measuring at least 5/high-power field regardless of grade also was associated with a poor prognosis (median lengths of survival, 15.2 and 11 months, respectively). Myeloma may be diagnosed in the great majority of cases by demonstrating homogeneous nodules and/or monotypic aggregates of plasma cells in the marrow. Prognostic features were shown to include marked dysplasia, mitoses, packing of marrow by tumor, and clinical stage.

Malignant lymphomas of follicular center cell origin in man.III. Prognostic Features

Prognostic features were evaluated in 92 patients with follicular center cell (FCC) lymphomas. Cleaved‐cell lymphomas (N = 73) were associated with significantly better survival than transformed cell lymphomas, 58 months vs. 6 months (p < .001). Among the cleaved‐cell group neither age, sex, heavy or light chain surface immunoglobulin, nor bone marrow involvement was a statistically significant prognostic indicator of survival. With stratification by cell of origin, survival in patients with cleaved‐cell lymphoma having a nodular histologic pattern was statistically equivalent to survival in patients having a diffuse histologic pattern (p = .22). FCC lymphomas of small cleaved cells had a better median survival than lymphomas of large cleaved cells (61 months vs. 33 months) but this only approached statistical significance (p = .08). Patients with symptoms had a median survival of 40 months as compared to 72 months in patients asymptomatic at presentation (p = .07). Involvement of lungs, pleura, or gastrointestinal tract, or extensive hepatic involvement was associated with a median survival of 16 months as compared to 63 months in patients in whom these features were absent (p < .001). Classification of lymphomas with respect to imune origin has clinical significance as it allows the identification of patients with B‐cell neoplasms who may have a clinical course similar to that usually associated with nodular lymphomas despite having a diffuse histologic pattern. Although in cleaved FCC lymphomas marrow involvement apparently has no prognostic value, involvement of other stage IV sites has grave prognostic implications; therefore, use of the term stage IV without specification of involved site may be of limited meaning in patients with these lymphomas.

Use of recombinant human erythropoietin to enhance autologous blood donation in a patient with multiple red cell allo-antibodies and the anemia of chronic disease

We treated a patient with alcohol-induced cirrhosis, intractable pain from a defective hip prosthesis, and multiple red cell allo-antibodies with recombinant human erythropoietin (EPO) in order to facilitate collection of blood for autologous transfusion during an elective total hip revision. This patient had experienced a delayed transfusion reaction 4 months earlier after receiving least incompatible packed red cells for gastrointestinal bleeding. His blood could not be crossmatched because of the development of multiple antibodies to homologous blood given during previous surgery and several episodes of gastrointestinal hemorrhage. Following initiation of EPO therapy, there was a prompt and persistent increase in the reticulocyte count from a baseline of 1.6% to a maximum of 8.6%. This was accompanied by maintenance of the hematocrit between 32% and 38.5% despite withdrawal of seven units of autologous blood over the 45-day treatment period. Poor venous access and availability of blood bank personnel, not hematocrit level, were the limiting factors that determined how frequently blood could be collected. We conclude that EPO stimulated erythropoiesis in this patient with underlying anemia of chronic disease and facilitated harvest of autologous blood for elective surgery.

Malignant plasmacytic ascites a report of two cases and a review of the literature

Two patients with ascites due to peritoneal involvement by multiple myeloma are reported and seven previously described cases of plasmacytic ascites are reviewed. In all nine cases, ascitic fluid contained large numbers of bizzare, immature plasma cells. Although the cells were often difficult to characterize by light microscopy, they could be rapidly identified as malignant plasma cells by immunofluorescent demonstration of monoclonal, intracellular immunoglobulin as performed in one of the patients. This rare extramedullary complication of plasma cell neoplasia has been unresponsive to therapy and rapidly fatal, with a median survival of 2 months. Cancer 56: 2001‐2004, 1985.

Attenuation of Endotoxin-Induced Cytotoxicity and Prostacyclin Production in Cultured Bovine Pulmonary Artery Endothelial Cells by Phosphodiesterase Inhibition

Exposure of cultured bovine pulmonary endothelial cells to endotoxin (lipopolysaccharide, LPS) causes cytotoxicity and increased prostacyclin production. Since cyclic nucleotides have been proposed as modulators of inflammation, we wondered whether they were involved in LPS-induced endothelial damage. Bovine pulmonary endothelial cells were exposed for 24 h to LPS and the effects of 1-methyl-3-isobutylxanthine (MIX), a phosphodiesterase inhibitor, dibutyryl cyclic AMP (db-cAMP), forskolin (an adenylate cyclase activator), and sodium nitroprusside (an agent known to stimulate intracellular cyclic GMP generation) on LPS-induced injury were determined. Injury was assessed by measurement of lactate dehydrogenase (LDH) (activity) and prostacyclin (6-keto-PGF1 alpha) in the bathing medium. Incubation with MIX attenuated LPS-induced endothelial cytotoxicity and prostacyclin production in a dose-dependent manner (ANOVA, p less than 0.001). Dibutyryl cyclic AMP also inhibited LPS-stimulated LDH release from the endothelial cells but did not suppress increased prostacyclin production. The combinations of MIX and dibutyryl cyclic AMP produced protection similar to that of MIX alone. Neither nitroprusside nor forskolin affected LPS-induced endothelial injury. Measurements of intracellular cyclic nucleotide concentrations showed that MIX caused marked increases in both cyclic AMP and cyclic GMP within 30 min of incubation, while forskolin and nitroprusside failed to cause such early elevations. Thus, phosphodiesterase inhibition protects endothelial cells from the effects of LPS. Increased intracellular concentrations of cyclic AMP also protect endothelial cells from LPS-induced cytotoxicity but do not alter the prostanoid response. We conclude that increased intracellular concentrations of cyclic AMP protect against LPS-induced endothelial cytotoxicity if present early in the exposure. We further conclude that LPS-mediated endothelial cytotoxicity can be separated from increased prostacyclin production.

Lymphocyte-depleted hodgkin's disease. Clinicopathologic review of 25 patients

Clinicopathologic material from 25 patients with lymphocyte-depleted Hodgkins disease was reviewed. The median age of the patients was 57 years. The patients had no prior diagnosis of Hodgkins disease and were divided according to pathologic subtype of lymphocyte-depleted Hodgkins disease: 11 diffuse fibrosis, 10 reticular, and four not otherwise specified. The clinical presentation included B symptoms of fever, weight loss, or night sweats (92 percent), subdiaphragmatic disease (88 percent), frequent marrow involvement (56 percent), and advanced-stage disease (100 percent). Four of 11 patients with diffuse fibrosis had peripheral adenopathy as compared with seven of 10 patients with the reticular subtype (p = 0.3); 10 of 11 patients with diffuse fibrosis had marrow involvement compared with two of nine patients with the reticular subtype (p = 0.006). Among patients who received chemotherapy, median survival was longer in the diffuse fibrosis subtype (nine patients, 39 months) than in the reticular subtype (10 patients, 10 months), p = 0.005. Of the 17 patients who received more than one cycle of combination chemotherapy with mechlorethiamine, vincristine, procarbazine, and prednisone, the median survival was 36 months with 11 (65 percent) complete remissions. In eight patients, disease remains in remission (12 to 127 months) with five patients surviving beyond five years. These results indicate that lymphocyte-depleted Hodgkins disease has at least two clinicopathologic subtypes and is curable if adequate therapy can be given.

The Effect of Cyclic AMP on Heme Synthesis by Rat Bone Marrow Cells in Vitro

Summary Cyclic AMP, db-cAMP, epinephrine, and MIX failed to stimulate heme synthesis in rat marrow cultures at all concentrations tested and in relatively large amounts (10-3 M) greatly inhibited both base line and Ep-stimulated 59Fe incorporation into heme. The inhibition may be nonspecific since identical concentrations of ATP and AMP produce a similar effect. Insulin, which is known to lower cyclic AMP levels, was the only material tested other than Ep that stimulated heme synthesis. The possibility that cAMP mediates the action of Ep is discussed.

Marked Plasmacytosis and Immunoglobulin Abnormalities Following Infusion of Streptokinase

Marked plasmacytosis is an uncommon clinical finding associated with plasma cell dyscrasias and certain reactive states, particularly serum sickness. Moreover, serum sickness-like reactions are a well-recognized complication of therapy with streptokinase. In this report, the authors describe a patient who developed a transient, but striking, plasmacytosis and an unexplained fever following streptokinase treatment for a pulmonary embolus. An evaluation for multiple myeloma was completely negative except for the occurrence of serum monoclonal-like proteins which largely disappeared over an eight month period.

Further Characterization of the Effect of Bacterial Lipopolysaccharide Preparations on Cyclic GMP Levels: The Importance of Macromolecular Synthesis

Abstract Bacterial lipopolysaccharides (LPS) greatly increase cGMP levels in short term cultures of rat fetal liver cells without affecting the concentration of cAMP. This effect is produced by very small (1 ng) amounts of LPS and is both dose and time dependent. The time dependence is characterized by an initial lag period of 60-120 min followed by a rapid, persistent increase in cGMP levels. Since this time course suggests that synthesis of an intermediate might play an important role in the cGMP elevation, a series of experiments was done to evaluate the effect of LPS on DNA, RNA, and protein (macromolecular) synthesis. LPS did not measurably effect total macromolecular synthesis. However, inhibitors of RNA and protein synthesis markedly reduced cGMP levels in LPS-treated cells, whereas inhibition of DNA synthesis did not. Addition of sodium nitroprusside to control and inhibitor-treated cultures produced large equivalent increases of cGMP levels in both cases, indicating that the cells present were fully capable of responding to a stimulus of guanylate cyclase. Taken together, this data suggests that expression of the LPS-cGMP response in fetal liver cells is dependent on synthesis of an intermediary protein(s) during the lag phase.

Lithium and Granulocytopenia During Induction Therapy of Acute Myelogenous Leukemia: Update of an Ongoing Trial

Administration of lithium carbonate to normal subjects and psychiatric patients causes increased production of granulocytes (Rothstein et al., 1978; Stein et al., 1978b). The administration of lithium carbonate to patients receiving cancer chemotherapy can attenuate neutropenia when regimens of moderate myelotoxicity are employed (Stein et al., 1977; Greco and Brereton, 1977). We have previously reported in preliminary form (Stein et al., 1978a) that lithium can limit the duration of the severe neutropenia associated with chemotherapy of acute myelogenous leukemia (AML), a situation in which effective therapy is associated with severe neutropenia. This report presents an update of that clinical trial.