John K. Erban

PADGEM protein: A receptor that mediates the interaction of activated platelets with neutrophils and monocytes

PADGEM (platelet activation dependent granule-external membrane protein) is an integral membrane protein of the alpha granules of platelets and Weibel-Palade bodies of endothelial cells that is expressed on the plasma membrane upon cell activation and granule secretion. Activated platelets, but not resting platelets, bind to neutrophils, monocytes, HL60 cells, and U937 cells. This interaction is inhibited by anti-PADGEM antibodies, PADGEM, and EDTA; anti-GPIIb-IIIa, anti-thrombospondin, anti-GPIV, and thrombospondin produce no effect. Neutrophils and U937 cells, in contrast to Jurkatt cells, contain PADGEM recognition sites, as shown by binding of PADGEM contained in phospholipid vesicles. These results indicate that PADGEM mediates adhesion of activated platelets to monocytes and neutrophils. Therefore, PADGEM shares not only structural but also functional homology with ELAM-1 and MEL-14, members of a new family of vascular cell adhesion molecules.

Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer

BACKGROUND We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.

Randomized Phase III Study of Docetaxel Compared With Paclitaxel in Metastatic Breast Cancer

PURPOSE This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Longer Therapy, Iatrogenic Amenorrhea, and Survival in Early Breast Cancer

BACKGROUND Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer. The effectiveness of concurrent versus sequential regimens is not known. METHODS We randomly assigned 5351 patients with operable, node-positive, early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent ACT). The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen. The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women. RESULTS At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-year overall survival, 83%) as compared with the doxorubicin-docetaxel group (overall survival, 79%; hazard ratio for death, 0.83; P=0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P=0.09). Disease-free survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the doxorubicin-docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or death, 0.80; P=0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P=0.01). The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio, 0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status. CONCLUSIONS Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin-docetaxel. Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status. (ClinicalTrials.gov number, NCT00003782.)

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer.

PURPOSE To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.

Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection

Background. A prospective study was initiated to explore an approach of limited therapy in elderly patients with early clinical stage breast cancer.

Screening for the risk for bleeding or thrombosis.

In this article, we review the laboratory tests used to screen patients for bleeding or thrombosis, their sensitivity and specificity, prevalence of bleeding disorders or thrombophilia in several clinical settings, and studies evaluating the clinical utility and economic effects of such testing. We add to past reviews on this topic by updating the literature review and by examining the utility of testing from a Bayesian perspective, using concepts of pretest probabilities, likelihood ratios, and post-test probabilities (for example, positive predictive value and negative predictive value). Screening for the Risk for Bleeding Screening tests include the readily available prothrombin time (PT), partial thromboplastin time (PTT), platelet estimate or count, and template bleeding time. All but the template bleeding time are highly reproducible, automated, and inexpensive on an individual basis but are expensive in the aggregate when routinely used to screen an unselected population (1). Obtaining a detailed history is the most important first step in determining whether testing is warranted (2). Nonsurgical Hospitalized Patients PT and PTT Patients hospitalized for nonsurgical diagnoses do not benefit from routine admission testing of PT or PTT when no evidence of synthetic liver dysfunction or history of oral anticoagulant use exists (3-6). Although randomized trials have not been done to assess the outcomes of hospitalized nonsurgical patients for whom coagulation testing was withheld, observational studies investigating the utility of these tests have failed to show improvement in clinical outcomes (5, 7, 8). Routine admission testing increases both expense and likelihood of false-positive results, leading to unnecessary additional testing. In 1979, Robbins and Rose (6) retrospectively analyzed abnormal results obtained from more than 1000 PTT measurements. Approximately 14% (143 patients) of the values were prolonged; however, 82% of the patients had known risk factors for bleeding (for example, known history of hemophilia, oral anticoagulant use, or history of liver disease). More important, the test did not alter clinical management for any of the patients. In a study of patients admitted to a Veterans Administration medical service for liver disease and bleeding disorders, Eisenberg and Goldfarb (4) found that PT contributed little to information already obtained from the history and physical examination. Only 2 of 107 patients who had a PT screening test had abnormal results, whereas 41 of 121 patients who had a pertinent history or physical examination had prolonged PTs. Erban and colleagues (9) evaluated ordering patterns and clinical indications for PT and PTT in 375 patients admitted to the medical service at the University of Pennsylvania, Philadelphia, Pennsylvania. Eighty-one percent of patients had PT and PTT ordered. When the appropriateness of test ordering compared with guidelines developed by the Medical Necessity Project of the Blue Cross and Blue Shield Associations of America (5) was evaluated, at least 70% of testing was not clinically indicated. They also found that test results had little impact on clinical care. Using 1988 U.S. dollars, they estimated that the direct cost per year attributable to inappropriate ordering of PTs and PTTs was more than

Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancer

60 000 at their institution alone. Although many physicians consider these tests to be inexpensive, small-ticket items, overuse in the aggregate can generate substantial unnecessary medical costs. Platelet Count The performance of routine platelet counts in asymptomatic nonsurgical patients also is not indicated and proves to be expensive. As shown by Robbins and Mushlin in 1979 (3), costs were more than

Menstrual History and Quality-of-Life Outcomes in Women With Node-Positive Breast Cancer Treated With Adjuvant Therapy on the NSABP B-30 Trial

50 000 per patient found to have asymptomatic thrombocytopenia. However, platelet counts may be useful to follow treatment involving certain medications. In a prospective study of more than 1100 consecutive patients with venous thromboembolism, Monreal and coworkers (10) demonstrated that patients who had heparin-induced bleeding had lower platelet counts before treatment (mean [ SD], 227 112 109/L vs. 262 110 109/L; P = 0.01). Monitoring platelet counts during heparin therapy is also appropriate because of the possibility of heparin-induced thrombocytopenia, which has an incidence of approximately 1% to 3% (11). In type I, thrombocytopenia occurs during the first few days of heparin therapy. The platelet count seldom decreases below 100 109/L and often returns to normal despite continued heparin therapy. In contrast, type II causes severe thrombocytopenia starting approximately 5 to 15 days after initiation of heparin therapy (12-14). Early detection of thrombocytopenia and immediate discontinuation of heparin therapy are critical in preventing or reducing the risk for potentially life-threatening complications (15-18). Surgical Patients PT and PTT The PT and PTT were originally designed and optimized to detect deficiencies of coagulation factors, not to assess clinical risk for hemorrhage (1). Normal ranges are based on the general population and do not reflect values of postsurgical patients without significant bleeding. Equally important, the likelihood of a significant hereditary deficiency of a coagulation factor in an unselected patient population is smallapproximately 17 per 100 000 men (factor VIII and factor IX deficiencies and von Willebrand disease) and 5 per 100 000 women (von Willebrand disease) (5, 8, 19). The prevalence of an isolated congenital deficiency of factor VII is even lower: 2 to 3 per 1 million persons (20, 21). Acquired deficiencies of factor VII are generally suspected in the presence of advanced hepatic disease, malabsorption, or malnutrition. One population that bears special mention, however, are Ashkenazic Jews. These persons originate from eastern Europe and make up about 80% of North American Jews. The prevalence of heterozygous factor XI deficiency (an autosomal dominant trait with incomplete penetrance) is between 5.5% and 11%, whereas the prevalence of the homozygous deficiency is between 0.1% and 0.3% in this population (22-24). Three percent of Ashkenazic Jews have sufficiently low factor levels to have abnormal hemostasis, and about 1% actually do have excessive postoperative bleeding (25). Unlike other inherited coagulation disorders, factor XI deficiency often remains occult until surgery, at which time bleeding can be severe (24, 25). Furthermore, hemorrhage can be prevented by administering fresh frozen plasma before surgery. Nearly all factor XIdeficient patients have prolonged PTTs (22). If a cutoff point at the 80th percentile of the normal range of PTT is used to identify patients at risk for bleeding (factor XI level < 0.3 U/mL), only 4.4% of these cases will be missed (confidence limits, 0.1% to 21%that is, sensitivity of 95.6%) (22). Therefore, it may be reasonable to screen Ashkenazic Jewish patients by using PTT. If results are abnormal, the test should be repeated; if the results are still abnormal, factor XI level should be measured. When which patients to screen is being considered, it is useful to stratify patient risk on the basis of known clinical factors associated with perioperative bleeding. In 1983, Rapaport (26) published a simple questionnaire to estimate the risk for perioperative hemorrhage. In another study that used data from all surgical patients admitted in 1981 to Strong Memorial Hospital in Rochester, New York, Suchman and Mushlin (27) found the probability of postoperative hemorrhage to be 0.22% in low-risk patients and 1.7% in high-risk patients. Patients were assigned to the high-risk group if they had any of the following criteria: known coagulopathy, potential factor deficiency (for example, history of liver disease, malabsorption, or malnutrition), trauma, or hemorrhage. In a prospective multicenter study, Houry and colleagues (28) followed 3242 patients scheduled for general surgical procedures in 17 centers in France between 1988 and 1992. A questionnaire was used to determine whether patients had any historical risk factors or physical examination findings for bleeding (Table 1). In 2291 patients without clinical findings suggestive of an increased risk for bleeding (Table 2), 3 deaths were related to hemorrhage (0.13%), while 109 patients had bruises (4.8%) and 68 had hematomas (3.0%); 11 patients required another operation to control hemorrhage (0.48%). In 951 patients with at least 1 clinical risk factor, 2 deaths were related to hemorrhage (0.21%), 83 patients had bruises (8.7%), and 38 had hematomas (4.0%); 11 patients required another procedure for hemorrhage control (1.2%). Table 1. Preoperative Assessment of Bleeding Risk Table 2. Risk for Bleeding Complications on the Basis of Clinical History and Physical Examination After pretest probabilities of bleeding complications have been established on the basis of clinical risk factors, the next step is to note the post-test or posterior probability of hemorrhage in patients with both normal and abnormal test results. In their study of more than 2000 patients who had preoperative coagulation testing, Suchman and Mushlin (27) found that PTT had a sensitivity of 33% and a specificity of 84% in predicting postoperative hemorrhage. As shown in Table 3, they next calculated sensitivity and specificity in patients with and without prolonged PTT. The likelihood ratio of a positive test result (true-positive rate/false-positive rate) can be used to determine the probability of disease given a positive test result (29). A test result with a likelihood ratio of 1.0 provides no additional information to the pretest probability. Therefore, a patient with a positive result is no more likely to have disease than before the test was performed. In Suchman and Mushlins study (30), the likelihood ratio among low-risk patients was actually less than 1.0 (0.6 [95% CI, 0.16 to 2.3]). However, the 95% CI crosses 1.0, meaning t

The effects of postradiation treatment with tamoxifen on local control and cosmetic outcome in the conservatively treated breast

PURPOSE To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)--overexpressing breast cancer. PATIENTS AND METHODS Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast. RESULTS Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). CONCLUSION With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.