PubMed Health⌕ Search

Biomedical subjects

S Dent

Publications and source records attributed to S Dent.

6 recordsLinked to original sources
PubMed2001

Application of a new multinomial phase II stopping rule using response and early progression.

PURPOSE: A multinomial stopping rule had previously been developed that incorporated both objective response and early progression into decisions to stop or continue phase II trials of anticancer agents. The purpose of this study was to apply the multinomial rule to two independent sets of phase II data to assess its utility in appropriately recommending early trial closure as compared with other stopping rules. MATERIALS AND METHODS: Data from completed phase II trials of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and European Organization for Research and Treatment of Cancer Early Clinical Studies Group (ECSG) formed the basis of the study. Based on observed results for each trial, the recommendation of the multinomial stopping rule was applied, as was the recommendation of the actual stopping rule used (Fleming or Gehan). The appropriateness of the recommendations was evaluated based on interpretation of final study results. RESULTS: The standard and multinomial rules disagreed on early stopping in one of 16 NCIC CTG trials and in seven of 23 ECSG trials. In all cases, the standard rule advised continuing to the second stage whereas the multinomial rule advised stopping early because of excessive numbers of patients experiencing early disease progression. Final trial results indicated that the multinomial recommendation was appropriate, because in no study did final results lead to conclusions of activity. CONCLUSION: In this series of trials, the multinomial stopping rule performed more efficiently than the Fleming or Gehan rules in advising early stopping of trials. These results encourage continued exploration of this approach for phase II trials of cytotoxic and noncytotoxic anticancer agents.

Clinical Trials, Phase II as Topic↗
PubMed1999

Phase II trial of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada clinical trials group study.

PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naïve metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin. PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naïve metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m(2)) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles. RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16). CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m(2) in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting.

Adult↗
PubMed1997

Insulin-like growth factor binding proteins as mediators of IGF-I effects on colon cancer cell proliferation.

Human colon cancer cell lines COLO205, HT29 and SW620 are known to secrete insulin-like growth factor II (IGF-II) and its modulatory binding proteins (IGFBPs). We have characterised the sensitivity of these cell lines to exogenous IGF-I and have examined the effects of their autocrine IGFBPs on these responses. Cells cultured in serum-free medium were treated with 1-100 ng/ml IGF-I, or des(1,3)IGF-I, a truncated IGF-I with low affinity for IGFBPs. DNA synthesis was determined by 24 h incorporation of 3H-thymidine. Experiments were repeated in the presence of 24 h cell-conditioned media containing endogenous IGFBPs. In all 3 cell lines, cell-conditioned media reduced sensitivity to IGF-I but not to des(1,3)IGF-I suggesting that IGFBPs in the cell-conditioned media of colon cells inhibit IGF-I action. IGFBPs in the cell layer and 24 h cell-conditioned media were identified by Western ligand and antibody analyses. IGFBP-4 was secreted by all cell lines and IGFBP-2 from the COLO205 and SW620 cells lines but not the HT29 cells. No IGFBP-3 was secreted by any of the cell lines but IGFBP-3 was found in the cell layer in all of the cell lines. When endogenous secreted IGFBPs were removed, cell lines were consistently more sensitive to IGF-I than des(1,3)IGF-I suggesting that IGFBP-3 associated with the cell layer enhances responses to IGF-I. This is in contrast to the effects of the secreted IGFBPs. Differential modulating actions of IGFBPs may be important in regulating colon cell turnover.

Cell Division↗
PubMed1996

PROMACE-MOPP and intrathecal chemotherapy for CNS lymphomas.

UNLABELLED: We conducted a Phase II study of PROMACE-MOPP and intrathecal (IT) therapy followed by cranial radiation in 7 patients (4 male, 3 females) with diffuse large cell lymphomas (including one T cell) involving the central nervous system (CNS). Median age was 47 years (range, 25-78). Median performance status was 2 (range, 2 to 3). Two patients had positive CSF cytology. No patients had prior chemotherapy or radiotherapy. Treatment consisted of PROMACE (cyclophosphamide 650 mg/m2, etoposide 120 mg/m2 days 1 and 8, methotrexate (MTX) 1.5 g/m2 and folinic acid 50 mg/m2 (x 5) day 15, and prednisone 60 mg/m2 days 1-14) x 3-4 courses. MOPP consisted of mustargen 6 mg/m2 and vincristine 1.4 mg/m2 days 1 and 8, procarbazine 100 mg/m2 and prednisone 40 mg/m2 po days 1-14 x 3-4 courses. IT drugs were MTX 20 mg and hydrocortisone 20 mg day 1 and cytosine arabinoside 100 mg day 8, courses 2 to 6, or more frequently if CSF cytology was positive. Following MOPP, 4000 cGy whole brain radiation (XRT) and 2000 cGy boost was given. Response was evaluated before XRT. Two patients declined XRT, 3 declined MOPP and 2 declined IT drugs. Two patients had extracerebral disease and 5 were primary CNS lymphomas. Response after PROMACE was CR: 3 patients; PR 2: stable 1. One patient, with extracerebral disease, experienced PR in the abdomen and CR by CT scan in the brain, but had persistent positive CSF cytology. This patient died from pneumocystis pneumonia 10 weeks after her last CSF cytology and 17 weeks after her diagnosis. After PROMACE +/- MOPP 6 patients experienced CR's. Median (range) survival was 100 (17-334) weeks, with 1 patient lost to follow up at 32 weeks. Toxicity included febrile neutropenia; 6 patients; pneumocystis pneumonia: 1 (fatal); thrombocytopenia; 5; stomatitis: 3; diarrhea; 2; nausea; 3. CONCLUSION: This regimen is active in the treatment of CNS lymphomas, although toxicity is substantial.

Adult↗
PubMed1995

Quantification of the volume of articular cartilage in the metacarpophalangeal joints of the hand: accuracy and precision of three-dimensional MR imaging.

OBJECTIVE: Cartilage loss is central to the development of joint failure in arthritis. However, radiographic assessment of cartilage loss is highly unreliable. This study examined the accuracy and reproducibility of a noninvasive technique for quantifying the volume of articular cartilage in the metacarpophalangeal joints of the hand by use of three-dimensional (3D) MR imaging. SUBJECTS AND METHODS: Eight metacarpophalangeal joints (four normal, one rheumatoid arthritic, and three normal cadaveric) each were imaged three times with a 1.5-T clinical MR imaging scanner with a small partial volume coil and a fat-saturated 3D spoiled gradient-echo sequence optimized for delineating articular cartilage. The volumes of cartilage over the metacarpal and phalangeal surfaces were quantified by summing the voxels within segmented 3D reconstructions of the images. Cartilage volumes in the three cadaver joints also were estimated by scraping cartilage off the articular surfaces and measuring water displacement in graduated cylinders. These values were used as the gold standard for assessing the accuracy of cartilage volume quantification by MR imaging. RESULTS: The fat-saturated sequence discriminated the articular cartilage from adjacent joint structures with high contrast and high spatial resolution. Cartilage volumes determined by MR imaging for the different subjects ranged from 115 microliters to 222 microliters for metacarpal cartilage and from 34 microliters to 86 microliters for proximal phalangeal cartilage. Accuracy errors for quantifying cartilage volume by MR imaging were -1.8% (95% confidence interval, -3.5% to -0.7%) for metacarpal cartilage and 9.1% (4.3% to 14.7%) for proximal phalangeal cartilage. Reproducibility errors were 5.2% (95% confidence interval, 2.9% to 7.6%) and 9.9% (5.4% to 15.1%), respectively. CONCLUSION: Fat-suppressed T1-weighted 3D MR imaging provides sufficient contrast and spatial resolution to allow accurate and reproducible quantification of articular cartilage volume in the metacarpophalangeal joints of the hand. This technique may be useful for monitoring cartilage loss in patients with arthritis.

Adult↗