Purpose: The primary objective of this study was to determine the maximum tolerated dose (MTD) of CT-2103 (poly L-glutamic acid-paclitaxel) in combination with carboplatin in patients with ...histologically proven solid tumors that were either refractory to conventional treatment or for which no conventional therapy was available. Patients and Methods: Twenty-two adult patients with advanced solid tumors were treated in this dose escalation study. Patients were treated every 21 days with CT-2103 at 175, 210, 225, or 250 mg/m2 (doses expressed as units of conjugated-paclitaxel) via 10-20 minute intravenous (IV) infusion, followed one hour later with carboplatin administered at AUC 5 or 6 via 30 minute IV infusion. No prophylaxis for hypersensitivity was administered with initial treatment. Doses were administered every 21 days until progressive disease or dose-limiting toxicity (DLT) was observed. Toxicity was evaluated using NCI Common Toxicity Criteria for Adverse Events v2.0 (CTCAE v2.0); response to treatment was evaluated using Response Criteria in Solid Tumors (RECIST). Results: The MTD was determined to be 225 mg/m2. DLTs observed at 250 mg/m2 were neutropenia and thrombocytopenia. No hypersensitivity reactions were observed. Three patients achieved partial responses (PR). Fifteen patients received at least 3 cycles of treatment without observation of progressive disease. Median survival time was 5.9 months. Patients that demonstrated partial responses were all ovarian cancer patients that had previously failed paclitaxel therapy. The only Grade 4, nonhematologic treatment-related toxicity was febrile neutropenia. Grade 4 neutropenia (9 patients) was observed across all dose groups. Twelve patients developed thrombocytopenia (Grade 3/4) while receiving combination therapy. All had resolution of thrombocytopenia with discontinuation of carboplatin, suggesting that carboplatin, and not CT-2103, contributed mainly to platelet toxicity. Conclusion: CT-2103 administered at 225 mg/m2 every 21 days in combination with carboplatin administered at AUC 6 has a manageable safety profile in patients with solid tumors; further clinical investigation is recommended, especially in patients with ovarian or non-small cell lung cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Described is the structure-based design and synthesis of a series of tris-triazole G-quadruplex binding ligands utilising the copper catalysed azide-alkyne 'click' reaction. The results of ...G-quadruplex stabilisation by the ligands are reported and discussed.
A structure-based design and syntheses of a series of tris-triazole G-quadruplex binding ligands was achieved. These novel compounds display excellent selectivity for quadruplex DNA over duplex DNA.
Objectives: The aim of this study was to assess the cost-effectiveness of a class-based exercise program supplementing a home-based program when compared with a home-based program alone. In addition, ...we estimated the probability that the supplementary class program is cost-effective over a range of values of a decision maker's willingness to pay for an additional quality-adjusted life-year (QALY). Methods: The resource use and effectiveness data were collected as part of the clinical trial detailed elsewhere. Unit costs were estimated from published sources. The net benefit approach to cost-effectiveness analysis is used to estimate the probability of the intervention being cost-effective. Results: The addition of a supplementary class-based group results in an increase in QALYs and lower costs. For all plausible values of a decision maker's willingness to pay for a QALY, the supplementary class group is likely to be cost-effective. Conclusions: The addition of a class-based exercise program is likely to be cost-effective and, on current evidence, should be implemented.
A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described ...antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethoxyquinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.
This collection of papers from the Twentieth British Legal History Conference explores the relationship between substantive law and the way in which it actually worked. Instead of looking at what the ...courts said they were doing, it is concerned more with the reality of what was happening. To that end, the authors use a wide range of sources, from court records to merchants' diaries and lawyers' letters. The way in which the sources are used reflects the possibilities of legal historical research which are opening up in the twenty-first century, as large databases and digitised images – and even online auction sites – make it a practical possibility to do work at a level which was almost unthinkable only a short time ago.
We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and ...a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.
Melanoma metastases were harvested from 82 patients for the purpose of growing and expanding tumor‐infiltrating lymphocytes (TIL). Tumor tissue cell suspensions were incubated with interleukin‐2 ...(IL‐2), followed by repeated exposure to tumor antigen with or without OKT3 monoclonal antibody (MoAb). Initial growth success was achieved in 56 of 82 cultures (72%). Efforts were made to expand 26 of these 56 cultures for therapeutic TIL; 23 of 26 early cultures (88%) were successfully expanded for in vivo therapy. It took a mean of 78.5 ± 25.4 days to grow sufficient TIL for treatment. Therapy included cyclophosphamide (1 g/m2) on day 1, followed by a 96‐hour continuous infusion of IL‐2 (18 × 106 IU/m2/d) on days 2 to 5, and approximately 1011 (mean 1.49 ± 0.93 × 1011) TIL on day 2. Patients who responded received monthly IL‐2 as a 96‐hour infusion. Median patient age was 45 years of age. Sixty‐seven percent of the patients were men. Performance status was 0 to 1 in 77% of patients. Thirty‐four percent of the patients had liver metastases. The usual IL‐2 toxicities were seen. Response rate for 21 patients was 24% (95% confidence interval, 10% to 49%). One complete response was achieved with cells 98% CD4+; four partial responses were achieved with cells 80%, 94%, 98%, and 98% CD8+, respectively. Four of eight patients who received TIL, which had never been stimulated with OKT3, had tumor response. The authors conclude that a treatment plan for IL‐2/TIL is technically difficult, costly, and effective for only a minority of patients. Overall, clinical results are not clearly superior to those obtained with other IL‐2 regimens.
We evaluated adoptive cellular therapy with recombinant interleukin-2 (rIL-2) plus lymphokine-activated killer (LAK) cells alternating with sequential dacarbazine chemotherapy in 27 patients with ...metastatic melanoma. rIL-2 was given to the patients as a 5-day continuous-infusion priming cycle followed by 1 day of rest, 4 days of leukapheresis for in vitro LAK cell expansion, and then 4 1/2 days of continuous rIL-2 infusion in conjunction with reinfusion of LAK cells during the first 3 days of the continuous infusion. Two weeks later, patients received dacarbazine (1,200 mg/m2) chemotherapy. Two patients achieved complete remission, and five achieved a partial remission for a response rate of 26% (95% confidence interval = 12%-47%). Three patients had mixed responses. The partial and mixed responses were brief, ranging from 1 month to 6 months, whereas the two complete responses have been sustained for 13+ and 24+ months. There were no additive toxic effects except for thrombocytopenia, which delayed treatment in two patients. Alternating adoptive immunotherapy and dacarbazine chemotherapy appear to be reasonably tolerated by patients, but the response rate is not clearly better than that achieved with other rIL-2 regimens or with chemotherapy alone.
