Phase I study of monoclonal antibody-ricin A chain immunotoxin XomaZyme-791 in patients with metastatic colon cancer.

Monoclonal antibody 791T/36, recognizing a Mr 72,000 antigen on the surface of colon carcinoma cells, has been used to construct an immunotoxin by conjugating to it the ribosomal inhibitor protein, ricin toxin A chain. The antibody 791T/36 has been shown to bind to membranes of freshly disaggregated tumor cells from human colon tumors, and to localize in tumors in vivo. Subacute toxicology testing in rats receiving immunotoxin i.v. showed, at highest doses, weight loss, decreased serum albumin, and hepatocyte vacuolization without elevation in liver function tests. A Phase I dose escalation study was carried out in which 17 patients with metastatic colorectal cancer were treated with doses of immunotoxin ranging from 0.02 to 0.2 mg/kg/day in 1-h i.v. infusions for a 5-day course. Side-effects included a composite of signs and symptoms thought to be generic to ricin A chain immunotoxins, including decreased serum albumin, mild fever, and flu-like symptoms, all being reversible. Two additional findings, reversible proteinuria and mental status changes, were also noted which may be characteristic of this immunotoxin. By 10-20 days after therapy, most patients developed IgM and IgG antibodies against both the ricin toxin A chain and the immunoglobulin portion of the immunotoxin, which were asymptomatic. A strong anticombining site antibody response was seen. Biological activity manifest as mixed tumor regression was seen in five patients.

Colchicine toxicity: a multisystem disease.

A 23-year-old black man survived a life-threatening multisystem disturbance resulting from a large single dose of colchicine administered intraurethrally for condyloma acuminata. Gastroenteritis and probable pancreatitis rapidly evolved into severe respiratory failure, marked neuromuscular problems, alopecia, and complete bone marrow aplasia. Within two months he had completely recovered. This patient demonstrates that colchicine should be used with extreme caution, if at all, for the therapy of condyloma acuminata.

Non-Hodgkin's lymphoma in a population with or at risk for acquired immunodeficiency syndrome: indications for intensive chemotherapy.

PURPOSE: An increased risk of malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma, is found in patients infected with the human immunodeficiency virus type 1 (HIV-1). Treatment of such patients may be complicated by their underlying immunodeficiency, especially when aggressive regimens are used. Clinical presentation and treatment outcomes were assessed in 31 patients with non-Hodgkin's lymphoma who had or were at risk for infection with HIV-1 at a single community institution. PATIENTS AND METHODS: Lymphomas presented in advanced stages and involved extranodal sites. Twenty-six patients received therapy (two radiation, one surgery), and a total of 23 patients received chemotherapy. RESULTS: A 52 percent response rate was seen with the use of chemotherapy. A history of opportunistic infections, or Kaposi's sarcoma, or both impacted negatively on the ability to achieve a complete response. Sixty-four percent of the 11 patients who received an intensive chemotherapeutic regimen, MACOP-B (methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) had complete remissions. Overall median survival for 23 patients who received chemotherapy was seven months. Patients achieving complete responses had a median survival of 20 months. CONCLUSION: Our results support intensive chemotherapy for patients with lymphoma and HIV-1 infection.

Altered factor VIII complexes in patients with acute respiratory insufficiency.

Acute respiratory failure is an often-fatal syndrome of multiple etiologies in which altered factor VIII may be a marker of endothelial disease. 12 women with overwhelming viral pneumonia were studied with serial factor VIII antigen, procoagulant activity, and von Willebrand's factor assays. Antigen levels were elevated (range: 86--1644%) out of proportion to procoagulant activity (range: 35--521% by a one-stage assay), and factor VIII antigen to activity ratios were as high as 16:1. Von Willebrand's factor was normal but correlated best with procoagulant activity. All patients had abnormal antigen patterns on crossed immunoelectrophoresis, with increases in protein of both fast and slow mobility. These changes in factor VIII correlated with the patient's clinical courses.

Effects of matrix contact during gel filtration of human platelets in plasma.

When gel filtration is used to transfer platelets from plasma into an established environment, alterations in platelet characteristics may result from the change in environment or from the effects of platelet contact with the gel matrix. To approach the problem of evaluating the relative contributions from these sources, a Sepharose 2B matrix was employed and platelets transferred from citrate anticoagulated PRP into autologous PPP to yield plasma-GFP. Platelet recoveries averaged 93%. PRP: plasma-GFP pairs were found to be indistinguishable with respect to: morphology; ADP, thrombin or collagen-induced aggregation response; uptake of 5-hydroxytryptamine (5-HT) or adenosine; and thrombin or collagen-induced release of accumulated 5-HT or adenosine. Pairs are distinguishable by prostaglandin E2 synthesis assayed immediately after filtration.

Platelets, hemostasis, and thromboembolism during treatment of acute respiratory insufficiency with extracorporeal membrane oxygenation.

Twenty-eight patients were supported with long-term extracorporeal membrane oxygenation as a treatment for acute respiratory insufficiency. Clinical, laboratory, and autopsy data concerning platelets, hemostasis, and thromboembolic disease are presented for the periods during and after bypass. During bypass, a "foreign-surface coagulopathy" was encountered which consisted of abnormal bleeding plus frequent, generalized, small and large vessel thromboembolic events. The abnormal bleeding is attributed to heparin, thrombocytopenia, and a qualitative platelet defect. Possible causes of the thromboembolic events including disseminated intravascular coagulation are also discussed, and speculations are offered concerning clinical management and directions for future investigation.

Thromboembolic complications after mitral valve replacement with Hancock xenograft.

Case histories of 140 patients who had mitral valve replacement with the Hancock xenograft were reviewed according to the incidence of thromboembolic complications. There were 16 patients with preoperative and/or postoperative low-output syndrome (Group A.) Eight of these patients died, and six had autopsies which showed major thrombi on the heterograft valve. In 126 long-term survivors (followed 1 to 33 months) nine thromboembolic events occurred (thromboembolic incidence 5.3 percent per patient-year). All patients with emboli were in atrial fibrillation. Additional predisposing factors included a history of systemic emboli and the presence of atrial clots at the time of surgery. The majority (7/9) of emboli occurred during the first 3 postoperative months. Two emboli occurred immediately following the operation (before oral anticoagulation therapy could have been begun). Five occurred in patients who were not on anticoagulation (Group B) and two occurred under warfarin treatment (Group C). There was no thromboembolic event in patients taking aspirin (Group D). It is concluded that hemodynamically stable patients have a decreased risk of thromboembolism and do not require anticoagulation. Patients with atrial fibrillation have an increased thromboembolic risk and should be on a regimen of warfarin for 3 months postoperatively and then on aspirin therapy.

Risk-benefit analysis of warfarin therapy in Hancock mitral valve replacement.

The purpose of this investigation was to analyze the thromboembolic and/or major bleeding complications of 124 consecutive but nonrandomized patients who had only mitral valve replacement with the Hancock porcine xenograft between September, 1974 and June, 1979. These patients were treated either with or without anticoagulants. Four basic study groups were created: Group 1, warfarin; Group 2, aspirin; Group 3, no anticoagulants; and Group 4, warfarin and aspirin. Group 5 combined Groups 1 and 4 (warfarin and warfarin plus aspirin) and Group 6 combined Groups 2 and 3 (aspirin and no anticoagulants). The cardiac rhythm, history of embolism, and intraoperative findings of a thrombus in the left atrium were examined as risk factors for later thromboembolism . Follow-up time was 3.03 years (range 2.0 to 4.2 years). The embolic rate was not significantly different in any group (n = NS). In Groups 5 and 6 the embolic rate was 2.97 and 3.25 embolisms per 100 patient-years, respectively. Warfarin therapy resulted in significant major bleeding episodes, including two deaths (p less than 0.05). The number of patients with a history of a previous embolism, the finding of an intraoperative left atrial thrombus, or abnormal cardiac rhythm was insufficient to test embolic risk in the four treatment groups. We conclude that long-term warfarin therapy increases the risk of bleeding complications but may not significantly influence the incidence of thromboembolism arising from the Hancock porcine xenograft mitral valve. Other and larger studies are needed to confirm this last point.

In vivo evaluations of a new thromboresistant polyurethane for artificial heart blood pumps.

To reduce the risk of thromboembolic complications in prosthetic blood pumps, we have developed a new segmented polyurethane elastomer. This material is unique because its mechanical properties for long-term durability and surface properties for biocompatibility have been separated and developed in two distinct materials. Improved thromboresistance is then obtained by a 1% concentration of a new polymeric surface-modifying additive blended with the base polyurethane before fabrication of the blood pump. To evaluate this material in vivo, we performed 10 implants, in calves, of the Pierce-Donachy prosthetic ventricle with blood-pumping sacs and cannulas fabricated from the new surface-modifying additive copolymer blend (Thoratec's BPS-215M). In four control implants the blood sacs and cannulas were fabricated from Ethicon's Biomer segmented polyurethane, which is the present clinical standard for most artificial hearts and circulatory support devices. The blood pumps were connected from the apex of the left ventricle to the descending aorta in male Holstein calves weighing 82 to 108 kg and were driven pneumatically in the full-to-empty mode with flows averaging 5 to 6 L/min. Each calf was medicated with aspirin and dipyridamole throughout the study period and was electively put to death after 4 weeks for evaluation of explanted blood sacs and for examination of the kidneys for infarction. All 10 explanted blood sacs made with the surface-modifying additive copolymer blend were shiny and completely free of thrombus. Three of the four explanted Biomer blood sacs showed visible red thrombus, and all four showed small areas of white thrombus. The average surface area of the Biomer blood sacs covered with thrombus was 45 +/- 32 mm2. Use of a semiquantitative scale to assess renal infarction demonstrated that nine of 10 animals with a surface-modifying additive copolymer blend blood sac had infarction less severe than the mean infarct score of the animals with a Biomer sac. The surface-modifying additive copolymer blend has excellent mechanical and physical properties necessary for use in artificial heart blood pumps. From these experiments, we conclude that the surface-modified polyurethane blend is superior to Biomer polyurethane in blood compatibility and in freedom from thromboembolic risk. This material is now approved by the Food and Drug Administration for investigational device exemption studies in the Pierce-Donachy prosthetic ventricle.

Congenital hypofibrinogenemia and recurrent placental abruption.

A 32-year-old white woman with a history of 2 episodes of abruptio placentae was found to have congenital hypofibrinogenemia. She had no bleeding difficulties except when pregnant. The patient's sisters and her mother also had reduced fibrinogen levels. Results of fibrinogen measurement by clotting assays and immunologic studies were similar. Immunoelectrophoresis, molecular weight of fibrinogen chains, cross-linking by factor XIII, carbohydrate staining, and sialic acid quantitation were all normal, suggesting the diagnosis of hypofibrinogenemia rather than dysfibrinogenemia. Fibrinolysis did not account for the reduced fibrinogen level. This case demonstrates that congenital low fibrinogen levels may be associated with placental abruption and that an abnormal fibrinogen molecule is not necessary.

Heparin bleeding due to qualitative platelet dysfunction.

On two separate occasions, a 26-year-old white woman bled from arterial puncture wounds while receiving heparin for thromboembolic disease. Bleeding time was prolonged after heparin administration at the time that she was ill and bled, and when she was re-challenged 2 years later. Heparin may produce bleeding as a result of a qualitative platelet dysfunction.

Hematologic observations made in patients with acute respiratory distress syndrome in the cooperative ECMO project.

In a recently completed three-year multicenter trial, 90 individuals with adult acute respiratory distress syndrome (ARDS) were randomly allocated to conventional therapy with or without long-term extracorporeal membrane oxygenation (ECMO). This study conclusively demonstrated that ARDS is associated with frequent major bleeding and thrombotic episodes and that the bleeding correlates best with the degree of thrombocytopenia and is enhanced by the machine. Neither heparin's therapeutic efficacy nor its ability to increase bleeding could be proven. ARDS is associated with a complex coagulation disturbance. Besides thrombocytopenia, there were lowered circulating levels of factors VII and XII which may be related to changes in the pulmonary endothelium. ECMO was associated with relative leukopenia and a marked shift to immature circulating leukocytes. Further studies are needed to better define the clinical importance of thrombosis and bleeding in the lung, the role for heparin in treatment, and the meaning of reductions in coagulation factors in defining the course, prognosis and response to therapy of patients with ARDS.

Role of platelets in hemostasis and thrombosis.

Platelets interact with the coagulation factors in a complex way to arrest bleeding or generate thrombi. Recently, the platelet's relationship to endothelial alteration and atheroma production has received renewed attention. At present, tests of platelet function better define "hypocoagulable" rather than "hypercoagulable" states.

The structure of spleen in experimentally induced iron deficiency anemia.

Splenic ultrastructure was studied in experimentally induced severe iron deficiency in rabbits. Fragmentation and phagocytosis of blood cells, particularly red cells and platelets, were observed in the red pulp. Mitochondrial changes similar to those previously described in other sideropenic tissues were noted in the lympholytes and reticular cells of both the red and white pulp. The most striking findings were the changes associated with the membranous structures and endoplasmic reticulum. These changes were similar to those characteristically associated with lipid peroxidation. Glutathione peroxidase was shown to be deficient in the red cells of these sideropenic animals. The morphologic changes observed may be explained on the basis of lipid peroxidation of membranes, and it is suggested that iron deficiency results in "deficiency" of enzymes normally responsible for the protection of tissues against peroxidation injury. Increased susceptibility to peroxides may lead to peroxidation injury of membranous structures and morphologic changes described herein.

Effect of hemin on the synthesis of hemoglobin and other proteins in mammalian cells.

The initiation of globin synthesis in intact reticulocytes and in reticulocyte lysates is maintained by the addition of hemin. The specificity of this effect has been studied to determine whether it is restricted to hemoglobin and erythroid cells. In intact reticulocytes, hemin (500 muM) enhances the synthesis of carbonic anhydrase as well as of hemoglobin. Similar enhancement of protein synthesis is observed on addition of hemin (500 muM) to intact Krebs II ascites tumor cells, in cell-free extracts of these cells, added hemin (50 muM) increases endogenous protein synthesis and the translation of exogenous rabbit globin messenger RNA. These results provide evidence that the effect of hemin is not restricted to globin, and they suggest that hemin may enhance protein synthesis in at least some nonerythroid cells.