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Biomedical subjects

Robert G Maki

Publications and source records attributed to Robert G Maki.

8 recordsLinked to original sources
PubMed2003

Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma.

BACKGROUND: Recurrent osteosarcoma is a drug-resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET-743) as a salvage therapy in these patients. METHODS: Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET-743 was administered at a dose of 1500 microg/m(2) as a 24-hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle. RESULTS: Twenty-five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12-67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty-one cycles were administered (median number of cycles per patient was 2; range, 1-9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 +/- 29.3 ng x hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 +/- 17.2 ng x hr/mL [n = 12]) or Grade 1-2 (52.6 +/- 15.6 ng x hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response. CONCLUSIONS: ET-743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET-743 with cisplatin or doxorubicin should be considered.

Adolescent↗
PubMed2003

Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses.

NY-ESO-1 is one of the most immunogenic proteins described in human cancers, based on its capacity to elicit simultaneous antibody and CD8+ T cell responses in vivo. Although HLA class II restricted epitopes from NY-ESO-1 have been identified, no broad survey has yet established the status of natural CD4+ T cell responses in cancer patients in relation to CD8+ and antibody responses. We used a recently developed general strategy for monitoring CD4+ responses that overcomes the need for prior knowledge of epitope or HLA restriction to analyze a series of 31 cancer patients and healthy donors for the presence of CD4+ T cells to NY-ESO-1, and related this response to NY-ESO-1 expression in tumor cells and serum antibodies to NY-ESO-1. None of the 18 patients that tested seronegative for NY-ESO-1 had detectable CD4+ T cell responses. On the contrary, 11 of 13 cancer patients with serum antibodies to NY-ESO-1 had polyclonal CD4+ T cell responses directed against various known and previously undescribed NY-ESO-1 epitopes. NY-ESO-1 peptide 80-109 was the most immunogenic, with 10 of 11 patients responding to this peptide. We show here that 12-mer determinants from NY-ESO-1 eliciting a CD4+ T cell response were peptide 87-98 with promiscuous HLA class II presentation, peptide 108-119 restricted by HLA-DP4, and peptides 121-132 and 145-156, both shorter epitopes from previously described HLA-DR4 peptides, also presented by HLA-DR7. This study represents the next step in compiling a comprehensive picture of the adaptive immune response to NY-ESO-1, and provides a general strategy for analyzing the CD4+ T cell response to other tumor antigens eliciting a humoral immune response.

Amino Acid Sequence↗
PubMed2003

Immunity against soft-tissue sarcomas.

Recent advances in basic medical sciences have led to a deeper understanding of the molecular characteristics of soft-tissue sarcomas. Likewise, novel technologies have led to a better appreciation of the relationship between an antigenic stimulus and the subsequent immune response against the antigen. In the past few years, the intersection of the understanding of the immune system and the knowledge of sarcoma biology has become apparent. As seen with other forms of cancer, there is a detectable autologous immune response against sarcomas. It is the hope of many investigators that the hints of a tumor-specific immune response will be enough to generate a signal that can be amplified and directed against the host sarcoma. The data regarding the initial evidence of immune responses against sarcomas are reviewed in the context of current or potential clinical studies.

Antigens, Neoplasm↗
PubMed2003

Classification and subtype prediction of adult soft tissue sarcoma by functional genomics.

Adult soft tissue sarcomas are a heterogeneous group of tumors, including well-described subtypes by histological and genotypic criteria, and pleomorphic tumors typically characterized by non-recurrent genetic aberrations and karyotypic heterogeneity. The latter pose a diagnostic challenge, even to experienced pathologists. We proposed that gene expression profiling in soft tissue sarcoma would identify a genomic-based classification scheme that is useful in diagnosis. RNA samples from 51 pathologically confirmed cases, representing nine different histological subtypes of adult soft tissue sarcoma, were examined using the Affymetrix U95A GeneChip. Statistical tests were performed on experimental groups identified by cluster analysis, to find discriminating genes that could subsequently be applied in a support vector machine algorithm. Synovial sarcomas, round-cell/myxoid liposarcomas, clear-cell sarcomas and gastrointestinal stromal tumors displayed remarkably distinct and homogenous gene expression profiles. Pleomorphic tumors were heterogeneous. Notably, a subset of malignant fibrous histiocytomas, a controversialhistological subtype, was identified as a distinct genomic group. The support vector machine algorithm supported a genomic basis for diagnosis, with both high sensitivity and specificity. In conclusion, we showed gene expression profiling to be useful in classification and diagnosis, providing insights into pathogenesis and pointing to potential new therapeutic targets of soft tissue sarcoma.

Adult↗
PubMed2002

Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial sarcoma usually affecting the trunk, with significant risk of local recurrence. It is characterized by the presence of ring chromosomes or chromosomal translocations fusing the promoter of the collagen gene COL1A1 to the platelet-derived growth factor beta-chain gene PDGFB, increasing the production of PDGF locally and promoting autocrine or paracrine tumor growth. Fewer than 5% of patients with DFSP develop metastatic sarcoma, with a poor subsequent prognosis. Imatinib (STI-571) was developed as an inhibitor of the PDGF receptor tyrosine kinase and has proven clinical activity against chronic myelogenous leukemia (expressing bcr-abl) and gastrointestinal stromal tumors (expressing c-kit). We describe 2 patients with metastatic and unresectable metastases from DFSP treated with imatinib. After confirmation of negative CD117 status of 2 sarcomas arising from DFSP, patients were given imatinib 400 mg po qd and assessed at regular intervals for their tolerance and response to therapy. One patient had a transient response, then progressed rapidly and died of disease. Another patient showed a partial response to therapy after 2 months, with resolution of superior vena cava syndrome and shrinking of metastatic lung lesions. His response is ongoing after 6 months of therapy. These clinical data confirm findings from models of DFSP and support the use of imatinib in the rare setting of metastatic DFSP. Imatinib may be useful for patients with locally advanced DFSP, when other options for local therapy are limited.

Adult↗
PubMed2002

Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous intravenous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity.

PURPOSE: Ecteinascidin 743 (ET-743) is a potent cytotoxic alkaloid of marine origin that has shown promising evidence of antitumor activity during phase I clinical trials. In the study reported here, the influence of clinical characteristics and pretreatment pathophysiological variables on the pharmacokinetics of ET-743 and their associations with drug-related toxicity was examined in sarcoma patients treated in three phase II clinical trials. METHODS: Adult patients with various histological subtypes of soft tissue sarcoma received 1.5 mg/m(2) of ET-743 by 24-h continuous i.v. infusion once every 3 weeks. Eligibility criteria were similar for each study, except for the histological subtype of the tumor or the extent of prior treatment with other anticancer agents, and all patients had normal or near-normal liver and renal function. The maximum plasma concentration (C(max)) and area under the plasma profile from time zero to infinity (AUC) of the drug were determined during the first cycle of therapy. Patients were evaluated for toxicity every week. RESULTS: Geometric mean +/- SD values of the pharmacokinetic parameters in 69 patients were: C(max) 1.14 +/- 0.52 ng/ml, AUC 39.9 +/- 16.6 ng.h/ml, and total body clearance (CL) 36.7 +/- 16.4 l/h per m(2). The only significant correlation involving physical characteristics of the patients or pretreatment pathophysiological variables was a very weak relationship between alkaline phosphatase and AUC (r=0.39, P<0.01). The 15 patients with any baseline liver function test exceeding the upper limit of the normal ranges had a significantly greater (P=0.02) incidence of severe toxicity (80% vs 44%). Although the mean AUC of ET-743 in patients with elevated serum levels of hepatic enzymes was 17% greater than that in patients with normal pretreatment liver function tests, the difference was not significant ( P=0.22). In addition, there was no distinct relationship between the grade of the most severe drug-related toxicity that occurred during the first cycle of therapy and the AUC for the entire cohort. The CL of ET-743 was found to be 27% greater in patients concurrently receiving dexamethasone as a preventative antiemetic than in those who were not, but the difference did not achieve statistical significance (P=0.08). There were no significant associations between CL (liters per hour) and body surface area or any other variable related to body size. CONCLUSIONS: The risk of developing severe toxicity was substantially enhanced in patients with relatively moderate indications of hepatic dysfunction without a coincident effect on the CL of ET-743. Dexamethasone cotreatment appeared to decrease the incidence of severe toxicity as well as the AUC of the drug. Delivering a fixed amount of drug without adjustment for the height or weight of the patient may be more appropriate than dose normalization due to the absence of an association between CL and body surface area. Optimizing dosing strategies to further enhance the therapeutic index of ET-743 may depend upon obtaining a better understanding of the metabolic fate of the drug in humans.

Adult↗