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Biomedical subjects

J A Sparano

Publications and source records attributed to J A Sparano.

At least 19 recordsLinked to original sources
PubMed2002

Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: preliminary results of a phase I/II study.

Infusional CDE (cyclophosphamide, doxorubicin, etoposide; iCDE) is one of the most effective chemotherapeutic regimen for human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL), with a complete remission rate of 46% and a median overall survival of 8.2 months (Sparano JA, Blood 1993; 81:2810). Since the majority of HIV-associated NHL are CD20-positive we reasoned that the addition of rituximab to iCDE (R-iCDE) could also improve the poor outcome of these patients. As a first step we investigated the safety of R-iCDE in a phase I/II study. Thirty patients with aggressive HIV-associated NHL were enrolled between June 1998 and October 2000. Characteristics of 29 evaluable patients were: median age: 38 years (range 29-65 years); male sex 24/29; histology: DLCL 16 (55%), Burkitt 10 (35%), ALCL 2 (7%), unclassified 1 (3%); stage: I (35%), II (10%), III (10%), IV (45%); International Prognostic Index: 0, 1 (59%), 2 (24%), 3 (17%), 4, 5 (0); CD4 count: median 132/ mm3 (range 3-470/mm3). Patients received rituximab (375 mg/m2) in conjunction with iCDE (five or six cycles). All patients were treated with G-CSF and highly active antiretroviral therapy (HAART). Twenty-six of 29 patients received treatment as planned, while chemotherapy had to be discontinued in three patients (2 persistent thrombocytopenias, 1 cerebral hemorrhage). Grade 3 or 4 toxicity was observed as follows: neutropenia 79%, anemia 45%, thrombocytopenia 34%, bacterial infection 34%, opportunistic infection 7%, mucositis 17%. A dose reduction was necessary in 22%. Complete remission was achieved in 86% of the patients, partial remission in 4%. Ten percent had progressive disease. After a median follow-up of 9 months the median overall survival is not reached. The actuarial survival at 2 years is 80% and the actuarial progression-free survival is 79%. Four of 29 patients (14%) have died, three from NHL and one from cryptosporidiosis. These findings suggest that the combination of rituximab with iCDE in patients with HIV-associated NHL is safe and feasible and that the addition of the anti-CD20 antibody does not increase the risk for infections. The high complete remission rate also indicates a potential therapeutic benefit and warrants further randomized trials.

Adult↗
PubMed2002

A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer.

BACKGROUND: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. PATIENTS AND METHODS: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. RESULTS: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40-200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. CONCLUSIONS: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range.

Adult↗
PubMed2001

Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer.

PURPOSE: To develop a combination of pegylated liposomal doxorubicin (Doxil; Alza Pharmaceuticals, Palo Alto, CA) and docetaxel (Taxotere; Aventis Pharmaceutical, Parsipanny, NJ) that can be safely used for the treatment of advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with locally advanced (n = 10) or metastatic (n = 31) breast cancer received Doxil (30-, 40-, or 45-mg/m(2) intravenous [IV] infusion over 30 to 60 minutes), followed 1 hour later by docetaxel (60 or 75 mg/m(2) by IV infusion over 1 hour) in cohorts of three to six patients. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, prolonged neutropenia, or grade 3 to 4 nonhematologic toxicity that occurred during cycle 1. RESULTS: In conjunction with docetaxel 75 mg/m(2) every 4 weeks, the MTD of Doxil was 30 mg/m(2) and required granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. Without G-CSF, the MTD was docetaxel 60 mg/m(2) and Doxil 30 mg/m(2) every 3 weeks; only 1 (7%) out of 15 patients treated at this dose level had cycle 1 DLT. Infusion reactions were common with Doxil with the recommended infusion schedule during the first cycle (55%) but were reduced with a modified schedule (7%). There was no clinically significant cardiac toxicity. Objective response occurred in eight of nine assessable patients with stage III disease and in 16 (52%) of 31 patients (95% confidence interval, 34% to 70%) with stage IV disease. CONCLUSION: The recommended dose and schedule of this combination for further evaluation is Doxil 30 mg/m(2) and docetaxel 60 mg/m(2) given every 3 weeks without G-CSF. When used with G-CSF, it is Doxil 30 mg/m(2) and docetaxel 75 mg/m(2) every 4 weeks.

Adult↗
PubMed2001

Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials.

Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a humanized version of the murine monoclonal antibody 4D5 that was recently approved for the treatment of advanced breast cancer that overexpresses the HER2/neu oncogene. Cardiac toxicity was an unexpected side effect of trastuzumab treatment in the pivotal trials that led to its approval. The incidence of cardiac dysfunction was highly dependent on prior or concurrent doxorubicin exposure. For patients with minimal prior anthracycline exposure, the risk of cardiac dysfunction was 1%. For patients with more extensive prior doxorubicin exposure, the risk of cardiac dysfunction was 7% for trastuzumab monotherapy and 12% for trastuzumab plus paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ). For patients treated with trastuzumab concurrently with doxorubicin, the risk of cardiac dysfunction was 29%. The etiology of trastuzumab-associated cardiac dysfunction is unknown, although its dependence on concurrent or prior doxorubicin exposure suggests a common pathophysiologic basis with anthracycline-induced myocardial injury. A number of trials are in progress to evaluate the efficacy and safety of trastuzumab in patients with early stage disease and that will investigate novel strategies to circumvent this serious toxicity.

Antibodies, Monoclonal↗
PubMed2001

Clinical aspects and management of AIDS-related lymphoma.

The incidence of non-Hodgkin's lymphoma (NHL) is increased by approximately 100-fold in patients with advanced HIV infection. Clinical presentations may include systemic lymphoma, primary central nervous system (CNS) lymphoma, and primary effusion lymphoma. Systemic lymphoma is the most common presentation, is almost always of intermediate or high-grade histology and B-cell phenotype, and usually involves extranodal sites. The disease is potentially curable with combination chemotherapy used for immunocompetent patients with lymphoma, although cure is achieved in only approximately 10-35% of patients. Primary CNS lymphoma may be difficult to distinguish from cerebral infection. The prognosis is very poor, although approximately 10% of patients selected for therapy may survive beyond 1 year with brain irradiation. Attention to infection prophylaxis and antiretroviral therapy is important. Evidence suggests that highly active antiretroviral therapy (HAART) has resulted in a decreased incidence of lymphoma, and that patients with systemic lymphoma treated in the post-HAART era have a better prognosis.

AIDS-Related Opportunistic Infections↗
PubMed2001

Microvessel density and p53 overexpression in young women with breast cancer: a case-control study.

Several reports have indicated that young women (less than 40 years of age) with breast cancer have a worse prognosis than older women. We performed a case-control study in order to confirm this observation and to determine whether this was attributable to increased microvessel density (MVD) or p53 expression. Twenty-six young women (cases) with stage I-III breast cancer that had adequate paraffin-embedded archival tissue were identified by the Montefiore Medical Center Tumor Registry over a 24-year period. For each case, two or three control subjects at least 40 years of age or older were selected from the registry and matched for nodal status and tumor size. Immunohistochemistry was performed for MVD and p53 overexpression. A Cox proportional hazard model was performed to examine the influence of age, MVD, p53 overexpression, and recognized prognostic factors on disease-free and overall survival. There were 26 cases (median age, 36 years) and 72 controls (median age, 64 years). The groups were well matched for known prognostic variables. There was no significant difference in p53 overexpression or MVD in the cases and controls. In multivariate analysis, the only features associated with an increased risk of recurrence included young age (hazard ratio [HR] = 2.49; 95% confidence interval [CI]: 1.18-5.25; P = 0.02) and positive lymph nodes (HR = 2.44; 95% CI: 1.12-5.30; P = 0.02). We have confirmed previous reports demonstrating a worse prognosis for women younger than 40 years with invasive breast cancer but found no correlation between young age and MVD or p53 overexpression when adjusted for other variables.

Adult↗
PubMed2001

Liposomal anthracyclines for breast cancer.

Doxorubicin and other anthracyclines are an important class of agents for the treatment of early and advanced stage breast cancer, but produce substantial acute and chronic toxicities. One strategy for reducing anthracycline-associated toxicity is packaging them in liposomes. Liposomes are closed vesicular structures that envelop water-soluble molecules. They may serve as vehicles for delivering cytotoxic agents more specifically to tumor, and limit exposure of normal tissues to the drug. Liposomal anthracyclines are more effective and less toxic in a number of preclinical models compared with conventional anthracyclines. Several liposomal anthracyclines have been extensively studied in humans with a variety of cancer types, including TLC D-99 (Myocet; The Liposome Company, Elan Corporation, Princeton, NJ), liposomal daunorubicin (Daunoxome; NeXstar Pharmaceuticals, Inc, San Dimas, CA), and pegylated liposomal doxorubicin (Doxil; Alza Pharmaceuticals, Palo Alto, CA, Caelyx; Schering Corporation, Kenilworth, NJ). Although none of these agents are currently approved for the treatment of breast cancer in the United States, the liposomal doxorubicin preparations seem to have comparable activity and less cardiac toxicity than conventional doxorubicin. Furthermore, they have been safely combined with other cytotoxic agents, including cyclophosphamide, 5-fluorouracil, vinorelbine, paclitaxel, and docetaxel. Further studies will be required do determine their role in the treatment of breast cancer.

Animals↗
PubMed2000

Cell-cycle dysregulation in breast cancer: breast cancer therapies targeting the cell cycle.

Breast cancer is the most commonly diagnosed cancer in American women. The underlying mechanisms that cause aberrant cell proliferation and tumor growth involve conserved pathways, which include components of the cell cycle machinery. Proto-oncogenes, growth factors, and steroids have been implicated in the pathogenesis of breast cancer. Surgery, local irradiation, and chemotherapy have been the mainstay of treatment for early and advanced stage disease. Potential targets for selective breast cancer therapy are herein reviewed. Improved understanding of the biology of breast cancer has led to more specific "targeted therapies" directed at biological processes that are selectively deregulated in the cancerous cells. Examples include tamoxifen for estrogen receptor positive tumors and imunoneutralizing antibodies such as trastuzumab for Her2/neu overexpressing tumors. Other novel anticancer agents such as paclitaxel, a microtubule binding molecule, and flavopiridol, a cyclin dependent kinase inhibitor, exert their anticancer effects by inhibiting cell cycle progression.

Adenocarcinoma↗
PubMed2000

Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E1196.

PURPOSE: The purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%. PATIENTS AND METHODS: Fifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m(2) by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m(2) by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF. RESULTS: Objective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7. 6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27. 5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m(2) (range, 60 to 480 mg/m(2)). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure. CONCLUSION: Using criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.

Adult↗
PubMed2000

Taxanes for breast cancer: an evidence-based review of randomized phase II and phase III trials.

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early-or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin-cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-hodgkin lymphoma.

BACKGROUND: Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL. METHODS: Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31). RESULTS: Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived >1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence. CONCLUSIONS: The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow.

Adult↗
PubMed1999

Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center.

The widespread use of highly active antiretroviral therapy (HAART) since 1996 has led to a substantial decline in morbidity and mortality in patients infected with HIV, although its effect on the incidence of HIV-associated malignancies is unknown. We retrospectively reviewed the annual number of outpatient visits to our HIV clinic, inpatient admissions for HIV disease, and first admissions for patients with cancer and HIV disease at our center between 1990 and 1997. Between 1990 and 1995, there was a progressive increase in the annual number of admissions for HIV disease and HIV-associated cancers that paralleled the increasing HIV clinic volume. In 1997, however, the annual number of first admissions for Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma compared with 1995 decreased by 36% and 63%, respectively, despite a continued increase in the annual number of HIV clinic visits. Similar declines were also noted in the number of new cases of biopsy-confirmed KS and primary central nervous system (CNS) lymphoma. In contrast, there was no decrease in the number of first admissions for patients with HIV infection and other cancers not typically associated with HIV infection. These findings suggest a declining incidence of HIV-associated malignancies since the introduction of HAART.

AIDS-Related Opportunistic Infections↗
PubMed1999

Molecular cloning of LMO41, a new human LIM domain gene.

We have identified a new human LIM domain gene by isolating an autoantigenic cDNA clone from a human breast tumor cDNA library. The predicted amino acid sequence of the cDNA clone's 495 bp open reading frame contains two tandem LIM domain motifs, and within the LIM domain region there is 62% identity with the analogous region of the LIM-only gene LMO1. The homology to LMO1 is restricted to the 360 bp region encoding the tandemly repeated LIM domains, the rest of the open reading frame as well as the extensive, GC-rich 5' untranslated region, and 3' region of the 2 kb cDNA sequence are unrelated to any known genes. This gene has been designated LMO4.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study.

PURPOSE: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.

Adenocarcinoma↗