Citations

Abstract Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.

AbstractWe have reported that i.d. injection of plasmids encoding hsp70 and a suicide gene transcriptionally targeted to melanocytes generates specific proinflammatory killing of melanocytes. The resulting CD8+ T cell response eradicates systemically established B16 tumors. Here, we studied the consequences of that CD8+ T cell response on the phenotype of preexisting tumor. In suboptimal protocols, the T cell response selected B16 variants, which grow extremely aggressively, are amelanotic and have lost expression of the tyrosinase and tyrosinase-related protein 2 (TRP-2) antigens. However, expression of other melanoma-associated antigens, such as gp100, was not affected. Antigen loss could be reversed by long-term growth in culture away from immune-selective pressures or within 96 hours by treatment with the demethylating agent 5-azacytidine (5-Aza). When transplanted back into syngeneic animals, variants were very poorly controlled by further vaccination. However, a combination of vaccination with 5-Aza to reactivate antigen expression in tumors in situ generated highly significant improvements in therapy over treatment with vaccine or 5-Aza alone. These data show that inflammatory killing of normal cells activates a potent T cell response targeted against a specific subset of self-antigens but can also lead to the immunoselection of tumor variants. Moreover, our data indicate that emergence of antigen loss variants may often be due to reversible epigenetic mechanisms within the tumor cells. Therefore, combination therapy using vaccination and systemic treatment with 5-Aza or other demethylating agents may have significant therapeutic benefits for antitumor immunotherapy.

Abstract Learning Objectives After completing this course, the reader will be able to: Describe the single-agent activity of carboplatin for metastatic breast cancer. Discuss the results of phase II trials of taxanes with platinum agents for breast cancer. Explain the hypothesis for the preclinical interaction between trastuzumab and platinum agents. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Background. Anthracycline-based regimens have a limited role in patients with metastatic breast cancer due to cumulative cardiotoxicity and their common use in adjuvant chemotherapy. New nonanthracycline regimens are, therefore, needed for metastatic disease. Single-agent carboplatin is active in patients with previously untreated metastatic breast cancer, producing response rates of 20%–35%. Preclinical studies have demonstrated synergistic antitumor efficacy of carboplatin and trastuzumab in HER2+ models. Methods. Phase II and III clinical trial data of combination therapy with carboplatin (Paraplatin®; Bristol-Myers Squibb; Princeton, NJ), a taxane, and/or trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) in metastatic breast cancer were identified from multiple sources, including: A) clinical trial data published in peer-reviewed journals within the last 5 years; B) preliminary clinical trial data from abstracts recently presented at national meetings; and C) phase III protocols currently evaluating carboplatin-based combination regimens. Results. In several phase II studies, combination carboplatin and paclitaxel (Taxol®; Bristol-Myers Squibb) therapy was active and reasonably well tolerated in the first-line treatment of metastatic breast cancer, producing objective response rates of 53%–62%—substantially higher rates than those seen in other phase II trials of either drug alone. Similar phase II data for carboplatin with docetaxel (Taxotere®; Aventis; Bridgewater, NJ) have been reported, and recent phase III data suggest that adding carboplatin to a paclitaxel/trastuzumab regimen produces superior efficacy than paclitaxel/trastuzumab alone for patients with HER2+ metastatic disease. Drug scheduling plays an important role in the therapeutic ratio of this combination treatment. Conclusions. Incorporation of carboplatin as a standard agent in first-line treatment of metastatic breast cancer has support from several recent studies. Preliminary results of combination carboplatin/taxane therapy with trastuzumab in metastatic disease are encouraging, and other carboplatin combinations are also being investigated in other phase II and III trials in patients selected based on the HER2 status of their cancer. Results are eagerly awaited.

Purpose To evaluate changes in left ventricular ejection fraction (LVEF) after four cycles of adjuvant doxorubicin plus cyclophosphamide (AC) in women with human epidermal growth factor receptor 2–positive (node-positive or node-negative) breast cancer enrolled onto the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. Patients and Methods Patients were randomly assigned to receive standard doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 3 weeks for four cycles followed by (1) weekly paclitaxel for 12 weeks; (2) weekly paclitaxel for 12 weeks, then weekly trastuzumab for 52 weeks; or (3) weekly paclitaxel plus trastuzumab for 12 weeks, then weekly trastuzumab for 40 weeks. LVEF was monitored before and after AC. Results Of the 1,576 eligible patients who completed AC, 1,458 had pre- and post-AC LVEF measurements taken using the same methodology (multiple-gated acquisition in 1,153 patients and echocardiogram in 305 patients). Among these 1,458 patients, 745 (51.1%) had ≤ 15% decrease in LVEF and LVEF that remained at or above the radiologic lower limit of normal (LLN); 42 patients (2.9%) had ≤ 15% decrease in LVEF and LVEF that decreased to or below the LLN; and 37 patients (2.5%) had an LVEF decrease of more than 15%. There was grade 2 LVEF toxicity in 96 (6.6%) of the 1,458 patients. Conclusion Standard AC chemotherapy is associated with frequent decreases in LVEF, which are noted when measured 3 weeks after completion of the fourth cycle. Patients are being observed to determine the long-term significance of this and the potential impact on subsequent treatment options.

Abstract Learning Objectives After completing this course, the reader will be able to: Understand how evaluation of risk of relapse, results of clincial trials, risk/benefit ratio, and patient preference each contribute to the selection of appropriate adjuvant therapy of breast cancer. Understand the important prognostic and predictive factors in the adjuvant therapy of breast cancer. Understand the roles of local therapy, hormonal treatment, and chemotherapy in the adjuvant therapy of breast cancer. Understand the recommendations of the 2000 NIH Consensus Development Conference: Advances in Breast Cancer. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Determining the optimal individual adjuvant systemic therapy for breast cancer patients is a challenging undertaking because it requires translating data from clinical trials that have involved thousands of patients into a highly individualized, risk-adjusted approach for the patient at hand. Choosing adjuvant therapy for women with breast cancer includes consideration of four issues: A) evaluation of risk of relapse; B) extrapolation of results from clinical trials; C) therapeutic ratio, and D) the patient's preferences following a thorough discussion with her physician. Data from recently completed phase III adjuvant trials and worldwide consensus conferences document the benefits of adjuvant therapy in improving disease-free survival and overall survival for patients diagnosed with invasive breast cancer >1.0 cm in size. The benefits of hormonal therapy are clear, but limited to patients with estrogen receptor-positive breast cancer. Anthracyclines lead to improved outcomes compared with nonanthracycline regimens. Taxanes appear to improve disease-free survival in patients with node-positive disease, although longer follow-up is required to assess their impact on overall survival. Some countries have reported a reduction in the mortality rate from breast cancer over the past several years. The improved survival rate is due, at least in part, to the use of adjuvant systemic therapy. Ongoing studies are evaluating targeted therapies, with the potential of remarkably improving patient outcome.

Purpose A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules. Patients and Methods MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m2 every 3 weeks. Results The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with ≥ 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm. Conclusion Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

Rupture of an intracranial aneurysm (subarachnoid hemorrhage) is a potentially devastating condition frequently complicated by delayed cerebral ischemia from sustained contraction of intracranial arteries (cerebral vasospasm). There is mounting evidence linking the formation of intracranial aneurysms and the pathogenesis of post-subarachnoid hemorrhage vasospasm to aberrant bioavailability and action of the vasodilator molecule nitric oxide generated by isoforms of nitric oxide synthase. In humans, the gene encoding the endothelial isoform of nitric oxide synthase (eNOS) is known to be polymorphic, with certain polymorphisms associated with increased cardiovascular disease susceptibility. In this prospective clinical study involving 141 participants, we used gene microarray technology to demonstrate that the eNOS gene intron-4 27-base pair variable number tandem repeat polymorphism (eNOS 27 VNTR) predicts susceptibility to intracranial aneurysm rupture, while the eNOS gene promoter T-786C single nucleotide polymorphism (eNOS T-786C SNP) predicts susceptibility to post-subarachnoid hemorrhage vasospasm. We believe that genetic information such as this, which can be obtained expeditiously at the time of diagnosis, may be used as a helpful adjunct to other clinical information aimed at predicting and favorably modifying the clinical course of persons with intracranial aneurysms.

Purpose This review provides an update on the current understanding of the clinical cardiac tolerability of trastuzumab, a humanized monoclonal antibody effective in the treatment of patients with advanced breast cancer overexpressing or amplifying HER2. Methods and Results We produced a summary of currently available information regarding the incidence and natural history of trastuzumab-associated cardiac dysfunction. Data from new, prospective clinical studies that incorporate close cardiac monitoring and standardized follow-up in patients with either advanced or earlier stages of breast cancer are also presented, and hypotheses regarding potential mechanisms of trastuzumab-related cardiotoxicity are discussed. Patients treated with trastuzumab in the pivotal trials were found to have increased risk for cardiac dysfunction, mostly when used concurrent with anthracyclines. Recent trials have required more stringent and consistent cardiac monitoring criteria and excluded patients with abnormal cardiac function, pre-existing heart disease, and/or high cumulative doses of anthracyclines. Decreases of ejection fraction and a few cases of congestive heart failure (CHF) requiring medical therapy have been detected. Improvements in ejection fraction and the symptoms of CHF have been subsequently noted in a significant number of these patients. Conclusion Trastuzumab is associated with an increased risk of asymptomatic decreases in ejection fraction, and, in a small number of patients, CHF that is almost always responsive to medical management. This risk is greatest in patients receiving concurrent anthracyclines. More data are needed to help elucidate the pathophysiology of this syndrome.

Gene therapy is being investigated as a putative treatment option for cardiovascular diseases, including cerebral vasospasm. Because there is presently no information regarding gene transfer to human cerebral arteries, the principal objective of this study was to characterize adenovirus-mediated expression and function of recombinant endothelial nitric oxide synthase (eNOS) gene in human pial arteries. Pial arteries (outer diameter 500 to 1000 μm) were isolated from 30 patients undergoing temporal lobectomy for intractable seizures and were studied using histologic staining, histochemistry, electron microscopy, and isometric force recording. Gene transfer experiments were performed ex vivo using adenoviral vectors encoding genes for bovine eNOS (AdCMVeNOS) and Escherichia coli β-galactosidase (AdCMVLacZ). In transduced arteries, studied 24 hours after exposure to vectors, expression of recombinant β-galactosidase and eNOS was detected by histochemistry, localizing mainly to the adventitia (n = 4). Immunoelectron microscopy localized recombinant eNOS in adventitial fibroblasts. During contractions to U46619, bradykinin-induced relaxations were significantly augmented in AdCMVeNOS-transduced rings compared with control and AdCMVLacZ-transduced rings ( P < 0.01; n = 6). The NOS inhibitor L-nitroarginine methylester (L-NAME) caused significantly greater contraction in AdCMVeNOS-transduced rings ( P < 0.001; n = 4) and inhibited bradykinin-induced relaxations in control and transduced rings ( P < 0.001; n = 6). The current findings suggest that in AdCMVeNOS-transduced human pial arteries, expression of recombinant eNOS occurs mainly in adventitial fibroblasts where it augments relaxations to NO-dependent agonists such as bradykinin. Findings from the current study might be beneficial in future clinical applications of gene therapy for the treatment or prevention of cerebral vasospasm.