Dennis Goldfinger

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin.

Impairment of platelet function commonly occurs after cardiopulmonary bypass, and may result in substantial bleeding. Because desmopressin acetate (a synthetic analogue of vasopressin) shortens bleeding time in a variety of platelet disorders, a controlled clinical trial of intravenous desmopressin was performed in 39 patients with excessive mediastinal bleeding (greater than 100 ml/h) and a prolonged template bleeding time (greater than 10 minutes) more than 2 hours after termination of cardiopulmonary bypass. Twenty-three desmopressin recipients and 16 control patients (no desmopressin) were similar in surgical procedure, pump time, platelet count, template bleeding time and amount of bleeding before therapy (p = NS). Compared with the control group, the patients receiving desmopressin (20 micrograms; mean 0.3 micrograms/kg) utilized fewer blood products (29 +/- 19 versus 15 +/- 13 units/patient; p less than 0.05), especially platelets (12 +/- 9 versus 4 +/- 7 units/patient; p = 0.004), while achieving a similarly effective reduction in mediastinal bleeding (4.8- and 4.3-fold, p = 0.001 for both). Severe platelet dysfunction was partially corrected within 1 hour after desmopressin infusion, during which interval no blood products were administered: the template bleeding time shortened (from 17 to 12.5 minutes, p less than 0.05), whereas the platelet count remained unchanged (at 96 +/- 35 and 105 +/- 31 X 10(3)/mm3, p = NS). The plasma levels of two factor VIII components increased: procoagulant activity (VIII:C) from 0.97 +/- 0.43 to 1.52 +/- 0.74 units/ml (p less than 0.05) and von Willebrand factor (VIII:vWF) from 1.28 to 1.78 units/ml (p less than 0.05); these increases correlated with the shortening of the bleeding time (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis

To assess the efficacy of pulse/synchronization cyclophosphamide/apheresis in patients with proliferative lupus nephritis.

Rh-Incompatible Platelet Transfusions - Risks and Consequences of Sensitizing Immunosuppressed Patients

Abstract The transfusion records of 102 Rh-negative patients treated with platelet transfusions from Rh-positive donors showed a 7.8 per cent rate of sensitization to the Rh0 (D) antigen. All but o...

Acute hemolytic transfusion reactions--a fresh look at pathogenesis and considerations regarding therapy.

A review of our knowledge of acute hemolytic transfusion reactions indicates that we have learned much in recent years about the pathogenetic mechanisms involved. An approach to effective therapy for patients suffering such reactions should be based on our latest understanding of the pathophysiology of this syndrome. However, changes in our therapeutic approach have not kept abreast of our increased awareness of the etiologic factors, and the patient, therefore, is not getting the benefit of our increased knowledge in this area. The primary pathogenetic mechanisms involved in these reactions appear to be disseminated intravascular coagulation and a series of hemodynamic alterations leading to ischemic necrosis of tissues. Therapy would best be aimed at interfering with these primary pathophysiologic pathways.

Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution's experience and review of the literature

BACKGROUND:  Thrombotic thrombocytopenic purpura (TTP) was once a highly fatal disease with mortality reaching nearly 95 percent; however, application of therapeutic plasma exchange (TPE) has dramatically increased survival. Nevertheless, mortality remains substantial (10%‐30% in many published reports), requiring the search for more efficacious treatments. Vincristine (VCR) has been generally reserved for refractory TTP. Despite its effectiveness in a salvage mode, VCR has not been widely advocated as first‐line therapy in conjunction with TPE. We previously reported improved survival when VCR and TPE were administered at presentation in patients treated from 1979 to 1994. Utilizing this standardized approach, outcomes of an additional group of patients and the results of a literature review of VCR therapy for TTP are reported.

Platelet transfusions in heparin‐induced thrombocytopenia: a report of four cases and review of the literature

BACKGROUND: Heparin‐induced thrombocytopenia (HIT) is a complication of heparin therapy associated with thrombocytopenia and thrombosis. The diagnosis of HIT is based on clinical criteria and laboratory tests, including the serotonin release assay (SRA). Because HIT patients are thrombocytopenic, platelet (PLT) transfusions may be contemplated; however, many published reviews have concluded that PLT transfusions are contraindicated in HIT because they may precipitate thrombotic events. This study reports four patients with clinically suspected HIT who received PLT transfusions without complications, and the literature regarding this subject has been reviewed.

Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment

ACUTE HEMOLYTIC transfusion reactions (HTRs) are among the most feared of transfusion-associated complications, principally because severe toxicity and rapid death may result. Since the majority of such reactions result from clerical error (i.e., transfusion of the wrong unit of blood to a patient), our ability to ensure the avoidance of these reactions remains incomplete. Therefore, it is imperative that we continue to expand our understanding of the pathogenetic mechanisms leading to complications following HTRs and formulate the most effective therapeutic interventions. Recently, there has been a rapid expansion of knowledge concerning the pathophysiology of shock, inflammation, and disseminated intravascular coagulation (DIC), all major factors affecting the outcomes of patients suffering HTRs. It is important, therefore, that we review the current understanding of the mechanisms leading to dangerous or lethal complications in HTRs and devise the most appropriate means for treating patients suffering from this transfusion complication. Although the clinical features of HTRs are well known, our understanding of the specific pathophysiologic conditions underlying these events remains incomplete. Previous hypotheses regarding the pathogenesis of shock, DIC, and acute renal failure, the three major sequelae of HTRs, have been largely conjectural. However, newer insights into the molecular basis for inflammation and thrombosis allow for revised theories of pathogenesis. Recognition of the pathogenetic mechanisms leading to the major complications of HTRs has been limited by an incomplete understanding of inflammation and coagul’ation biochemical pathways. The primary initiating event has been considered to be the release of incompatible red cell (RBC) stroma-antibody complexes into the circulation. The development of shock &d DIC following HTRs

Moderate and severe adverse events associated with apheresis donations: incidences and risk factors

BACKGROUND: The goal of this observational retrospective study was to evaluate various donor and procedural variables as potential risk factors for different types of moderate to severe adverse events (AEs) during apheresis collections.

Use of sentinel sites for daily monitoring of the US blood supply

BACKGROUND : This report describes the first year of a government‐sponsored program that uses daily reports from 29 sentinel sites to monitor the capacity of the US blood supply to meet demand.