Terence J. Hadley

Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans☆

A reasonably sensitive and specific noninvasive test for doxorubicin cardiotoxicity is needed. In addition, few data exist on the short- and long-term effects of doxorubicin on diastolic filling. To determine if pulsed Doppler indexes of diastolic filling could predict doxorubicin-induced systolic dysfunction, 26 patients (mean age 48 +/- 12 years) were prospectively studied before receiving chemotherapy (control) and 3 weeks after obtaining cumulative doses of doxorubicin. In nine patients developing doxorubicin-induced systolic dysfunction (that is, a decrease in ejection fraction by greater than or equal to 10 ejection fraction units to less than 55%), the isovolumetric relaxation time was prolonged (from 66 +/- 18 to 84 +/- 24 ms, p less than 0.05) after a cumulative doxorubicin dose of 100 to 120 mg/m2. This prolongation preceded a significant decrease in ejection fraction. Other Doppler indexes of filling were impaired after doxorubicin therapy but occurred simultaneously with the decrease in ejection fraction. A greater than 37% increase in isovolumetric relaxation time was 78% (7 of 9) sensitive and 88% (15 of 17) specific for predicting the ultimate development of doxorubicin-induced systolic dysfunction. In 15 patients studied 1 h after the first treatment, doxorubicin enhanced Doppler indexes of filling and shortened isovolumetric relaxation time. In 22 patients, indexes of filling remained impaired and isovolumetric relaxation time was prolonged 3 months after the last doxorubicin dose. In conclusion, doxorubicin-induced systolic dysfunction is reliably predicted by prolongation of Doppler-derived isovolumetric relaxation time. Early after administration, doxorubicin enhances filling and isovolumetric relaxation time. The adverse effects of doxorubicin on both variables persist at least 3 months after cessation of treatment.

Adjuvant Chemotherapy for Breast Cancer: How Presentation of Recurrence Risk Influences Decision-Making

PURPOSE The purpose of this study was to examine the impact of four methods of communicating survival benefits on chemotherapy decisions. We hypothesized that the four methods of communicating mathematically equivalent risk information would lead to different chemotherapy decisions. METHODS Each participant received two hypothetical scenarios regarding their mother (a postmenopausal woman with an invasive, lymph node-negative, hormone receptor-positive breast cancer) and was asked to decide whether they would encourage their mother to take chemotherapy in addition to surgery and tamoxifen. In the part 1, participants received one of four methods of describing the chemotherapy survival benefit: (1) relative risk reduction, (2) absolute risk reduction, (3) absolute survival benefit, or (4) number needed to treat. In part 2, each participant received all four methods. Following each decision, participants were asked to rate their confidence and confusion regarding their decision. RESULTS Participants included 203 preclinical medical students. In part 1, participants who received relative risk reduction information were significantly more likely to endorse chemotherapy. In part 2, there were no treatment decision differences when participants received all four methods of communicating survival benefits of chemotherapy. However, receiving all four methods led to significantly higher ratings of confusion. In deciding on endorsing chemotherapy, participants understood the information best when presented with data in the absolute survival benefit format. CONCLUSION These results support the hypothesis that the method used to present information about chemotherapy influences treatment decisions. Absolute survival benefit is the most easily understood method of conveying the information regarding benefit of treatment.

The Quality of Medical Evidence in Hematology-Oncology

PURPOSE The purpose of this study was to evaluate the quality of the medical evidence available to the clinician in the practice of hematology/oncology. METHODS We selected 14 neoplastic hematologic disorders and identified 154 clinically important patient management decision/interventions, ranging from initial treatment decisions to those made for the treatment of recurrent or refractory disease. We also performed a search of the scientific literature for the years 1966 through 1996 to identify all randomized controlled trials in hematology/oncology. RESULTS We identified 783 randomized controlled trials (level 1 evidence) pertaining to 37 (24%) of the decision/interventions. An additional 32 (21%) of the decision/interventions were supported by evidence from single arm prospective studies (level 2 evidence). However, only retrospective or anecdotal evidence (level 3 evidence) was available to support 55% of the identified decision/interventions. In a retrospective review of the decision/interventions made in the management of 255 consecutive patients, 78% of the initial decision/interventions in the management of newly diagnosed hematologic/oncologic disorders could have been based on level 1 evidence. However, more than half (52%) of all the decision/interventions made in the management of these 255 patients were supported only by level 2 or 3 evidence. CONCLUSIONS We conclude that level 1 evidence to support the development of practice guidelines is available primarily for initial decision/interventions of newly diagnosed diseases. Level 1 evidence to develop guidelines for the management of relapsed or refractory malignant diseases is currently lacking.

Identification of the Fy6 epitope recognized by two monoclonal antibodies in the N-terminal extracellular portion of the Duffy antigen receptor for chemokines

The epitope Fy6 recognized by two monoclonal antibodies (i3A and BG6), which inhibit binding of chemokines to the Duffy antigen, was characterized by means of peptides synthesized on pins (Epitope Scanning Kit) and deletion mutagenesis. Both antibodies showed very similar specificities. They recognized a linear epitope, the essential portion of which was the heptapeptide Gln-Leu-Asp-Phe-Glu-Asp-Val comprising amino acid residues 21-27, located between two glycosylation sites of the Duffy protein. All the amino acid residues of the epitope, except Glu, were essential for antibody binding, since they could not be replaced by any other amino acid residues or by only one or two. The Glu residue could be replaced by most other amino acid residues, and its replacement by 10 amino acid residues gave a distinct increase in the antibody binding. The results were in full agreement with the finding that the mutant of the Duffy antigen, lacking amino acid residues 23-25 (-Asp-Phe-Glu-), did not bind the i3A antibody, but bound the anti-Fy3 monoclonal antibody similarly to the wild type of the Duffy antigen. The apparent affinity constants of both anti-Fy6 antibodies were determined by surface plasmon resonance, using immunopurified Duffy protein as a ligand.

Comparison of the quality of life between HIV-positive haemophilia patients and HIV-negative haemophilia patients.

Summary. In a prospective study, we tested the hypothesis that an already reduced quality of life in haemophilia patients is further diminished in those haemophilia patients who contracted the human immunodeficiency virus (HIV) as a result of transfusion of coagulation factor preparations. From an available pool of 92 males with haemophilia A or B, 18 patients seropositive for HIV infection and 11 seronegative patients were randomly selected for the study.

Safety and efficacy of purified factor IX concentrate and antifibrinolytic agents for dental extractions in hemophilia B

This study evaluated the safety and efficacy of combined treatment with ϵ‐aminocaproic acid or tranexamic acid and monoclonal antibody purified factor IX (MAb factor IX) for prophylaxis against bleeding in eight hemophilia B patients undergoing nine dental extraction procedures. All patients achieved excellent hemostasis without clinical evidence of thrombosis. There were no significant changes in hemoglobin or hematocrit or in markers of hemostatic system activation (prothrombin fragment F1–2, fibrinopeptide A, and fragment B β15–42) after surgery. Thus, a highly purified factor IX concentrate and antifibrinolytic therapy can be effectively and safely combined in hemophilia B patients undergoing dental extractions.

High-dose chlorambucil and dexamethasone for relapsed non-Hodgkin's lymphomas

Twenty patients with relapsed or refractory non-Hodgkins lymphoma were treated with high-dose chlorambucil (14 mg/m2 every 6 hours for 6 doses) and dexamethasone (40 mg/day for 5 days). There was a 45% response rate with 17% complete responses. The median duration of complete response was 7 months. The regimen was well tolerated and had minimal toxicity.

Disseminated intravascular coagulation after factor IX complex resolved using purified factor IX concentrate.

Excerpt Patients with hemophilia B can be effectively treated with prothrombin complex concentrates (factor IX complex) that contain factors II, VII, IX, and X (1). A complication of therapy with f...

First-Line Carboplatin, Pemetrexed, and Panitumumab in Patients with Advanced Non-Squamous KRAS Wild Type (WT) Non-Small-Cell Lung Cancer (NSCLC)

ABSTRACT Background: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC. Methods: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m2 IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity. Results: 29 of 66 patients (44%) had objective responses. The median TTP was 6 months; median overall survival (OS) was 17 months. Panitumumab increased treatment-related toxicity, notably skin rash. Conclusions: The addition of panitumumab increased toxicity, and had no discernible impact on efficacy.

Phase II trial of 5-fluorouracil, folinic acid, and N,N1,N11-triethylenethiophosphoramide (thiotepa) in patients with advanced breast cancer.

A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34–67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment; 18 had hormonal therapy; and 15 had radiation treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant: nadir WBC count: < 1,000/mm3 (10 patients); 1,000–1,999/mm3 (13 patients); nadir platelet count: < 20,000/mm3 (8 patients); 20,000–49,000/mm3 (8 patients); 50,000–99,000/mm3 (10 patients). We conclude that the combination of thiotepa, 5FU, and leucovorin has significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer.