William R. Friedenberg

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Platelet Dysfunction Associated with Cardiopulmonary Bypass

The clinical significance and pathogenesis of the platelet dysfunction following cardiopulmonary bypass were studied in conjunction with the degree of functional impairment associated with the use of membrane and bubble oxygenators. Forty consecutive patients had the following tests preoperatively and postoperatively: complete blood count (CBC), platelet count, prothrombin consumption time, bleeding time, prothrombin time, partial thromboplastin time, fibrinogen, euglobulin clot lysis, fibrin degradation products, and platelet aggregation tests. Six patients were given 14C-serotonin tests before and after operation, and preoperative and postoperative electron micrographs were made of the platelets of 3 patients. The amount of blood lost, the blood transfused, and plasma hemoglobin levels were also measured. Abnormal aggregation of platelets was found, with no difference between the membrane and bubble oxygenators. In vitro aggregation tests with protamine sulfate and hemoglobin solutions, as well as the 14C-serotonin studies and electron micrographs, suggest that platelets acquire storage pool deficiency and an abnormal membrane during cardiopulmonary bypass.

High-dose cytosine arabinoside-associated pancreatitis

Thirty patients with leukemia and lymphoma have been treated at our institution with high doses of cytosine arabinoside (Ara‐C). Gastrointestinal symptoms were frequent after therapy, and 6 of the 30 patients had severe abdominal pain. Of the six, two had pancreatitis; two had normal amylase and lipase determinations; and in two, neither amylase nor lipase levels were determined. The two patients with pancreatitis are presented because this complication of high‐dose Ara‐C therapy has not been described. The authors conclude that pancreatitis can follow high‐dose Ara‐C chemotherapy and that patients with abdominal pain following this treatment be evaluated for pancreatitis. Cancer 56: 1940‐1942, 1985.

Multi-drug resistance in chronic lymphocytic leukemia

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were repeated as patients became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC-833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but not with either the MTT assay or any of the monoclonal antibodies. None of the tests correlated with prior chlorambucil treatment. Correlation of dox retention with the monoclonal antibodies was mild to moderate and became stronger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 increases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especially MRK-16). Patients who become resistant to VAD more frequently express p-gp 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-A (CsA) ex vivo, and correlates better with stage of disease.

Hyperimmunoglobulin E syndrome: response to transfer factor and ascorbic acid therapy.

Abstract This report presents the case history of a 29-year-old man with hyperimmunoglobulin E syndrome and the successful treatment with transfer factor and ascorbic acid. The patient presented with a marked defect in the ability of his lymphocytes to respond to mitogens, in skin test response to DNCB challenge and other recall antigens, and a variety of in vitro granulocyte function defects. The presence of a serum inhibitor to lymphocyte and granulocyte function was found. This individual had multiple episodes of mucocutaneous candidiasis and staphylococcal infections. Clinical improvement was evident after transfer factor and ascorbic acid treatment. Many of the in vitro functions also returned to normal.

Transforming growth factor-β and multidrug resistance in chronic lymphocytic leukemia

Patients with chronic lymphocytic leukemia (CLL) frequently respond to initial treatment, but then become resistant to chemotherapy. Studies have shown one important cause of chemotherapeutic resistance to be multidrug resistance (MDR). To investigate the potential role of MDR and transforming growth factor-β (TFG-β), a potent growth inhibitor of B lymphocytes, in the development of chemotherapeutic resistance in CLL, we evaluated 22 CLL patients for loss or mutation of TGF-β receptors (TβR), plasma TGF-β1 levels, and expression of MDR1 mRNA. Receptor crosslinking and immunoprecipitation experiments did not demonstrate loss of TβRs in any patients studied. No relationship between plasma TGF-β1 levels and expression of MDR1 mRNA was seen. Correlation of plasma TGF-β1 levels to disease stage revealed a consistent decline in plasma TGF-β1 levels with advancing disease stage (P=0.031).

Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM‐CSF with intermediate‐dose cytarabine and mitoxantrone was conducted in patients with high‐risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an “S” phase increase of 2.55× at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients. Am. J. Hematol. 66:23–27, 2001.

The Bactericidal Defect of Neutrophil Function with Lithium Therapy

Lithium has been promoted for the treatment of granulocytopenia and as an adjuvant for cancer chemotherapy (Jacob and Herbert, 1974; Gupta et al., 1975; Greco, 1976; Greco and Brereton, 1977; Charron et al., 1977; Tisman and Wu, 1977; Catane et al., 1977; Stein et al., 1977). In preliminary studies of 8 normal volunteers we found a significant bactericidal defect of the granulocytes when studied after 1 week of lithium therapy. We also assessed lymphocyte subpopulations, function, and cell mediated immunity both in vivo and in vitro and could find no defect of lymphocyte function except for a reduction in the response of the lymphocytes to PPD antigen. The rational for the use of lithium is to decrease the incidence of infection in patients who have granulocytopenia. With such defects demonstrated in normals after short term doses, granulocyte and lymphocyte functions were studied in patients on long term lithium therapy.

The Treatment of Multiple Myeloma Using Vincristine, Carmustine, Melphalan, Cyclophosphamide, and Prednisone (VBMCP) Alternating With High-dose Cyclophosphamide and α2β Interferon Versus VBMCP Results of a Phase III Eastern Cooperative Oncology Group Study E5A93

A randomized controlled trial tested the hypothesis that aggressive initial therapy using high‐dose cyclophosphamide (HiCy) and α2β interferon (IFN) may be superior to standard combination alkylating agent regimens in the treatment of newly diagnosed myeloma.BACKGROUND A randomized controlled trial tested the hypothesis that aggressive initial therapy using high-dose cyclophosphamide (HiCy) and alpha(2)beta interferon (IFN) may be superior to standard combination alkylating agent regimens in the treatment of newly diagnosed myeloma. METHODS This Eastern Cooperative Oncology Group trial evaluated 268 previously untreated patients with active multiple myeloma randomized to vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) or VBMCP plus HiCy and recombinant IFN. RESULTS The overall objective response was 62% in the VBMCP regimen and 68% in the VBMCP + HiCy + IFN group. The near complete response and complete response rates were 8.1% and 8.9%, respectively. Progression-free survival was 22.1 and 25.3 months, respectively. The median overall survival was 37.1 months for patients treated with VBMCP and 41.3 months for those treated with VBMCP + HiCy + IFN (P = .38). The 5-year overall survival rates were not significantly different between the 2 arms: 26.4% and 33%, respectively. Lethal toxicities occurred in 15 patients, including 10 from infection, but there was no significant difference in lethal toxicities between the 2 regimens. CONCLUSIONS The study showed no significant benefit with the addition of HiCy and IFN to VBMCP.

Skeletal muscle lymphoma.

Lymphoma usually presents with painless lymphadenopathy. However, it can also present at an extranodal site. Presentation with skeletal muscle infiltration is relatively uncommon and can be confused with a wide variety of both inflammatory as well as neoplastic conditions. We report a patient who presented with progressive swelling of the lower extremity resembling inflammatory necrosis on computed tomography scan, but was later diagnosed as skeletal muscle lymphoma on biopsy.