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Sökning: WFRF:(Yachnin Jeffrey)

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  • Nilsson, S., et al. (författare)
  • Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study
  • 2007
  • Ingår i: Lancet Oncol. - : Elsevier. - 1470-2045 .- 1474-5488. ; 8:7, s. 587-94
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra. METHODS: Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. FINDINGS: Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression). INTERPRETATION: (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
  • Eriksson, Fredrik, et al. (författare)
  • DNA vaccine coding for the rhesus prostate specific antigen delivered by intradermal electroporation in patients with relapsed prostate cancer
  • 2013
  • Ingår i: Vaccine. - 0264-410X .- 1873-2518. ; 31:37, s. 3843-3848
  • Tidskriftsartikel (refereegranskat)abstract
    • We tested safety, clinical efficacy and immunogenicity of a DNA vaccine coding for rhesus prostate specific antigen (PSA) delivered by intradermal injection and skin electroporation. Fifteen patients with biochemical relapse of prostate cancer without macroscopic disease participated in this phase I study. Patients were started on a 1 month course of androgen deprivation therapy (ADT) prior to treatment. Vaccine doses ranged from 50 to 1600 mu g. Study subjects received five vaccinations at four week intervals. All patients have had at least one year of follow-up. No systemic toxicity was observed. Discomfort from electroporation did not require analgesia or topical anesthetic. No clinically significant changes in PSA kinetics were observed as all patients required antiandrogen therapy shortly after completion of the 5 months of vaccination due to rising PSA. Immunogenicity, as measured by T-cell reactivity to the modified PSA peptide and to a mix of overlapping PSA peptides representing the full length protein, was observed in some patients. All but one patient had pre-study PSA specific T-cell reactivity. ADT alone resulted in increases in T-cell reactivity in most patients. Intradermal vaccination with skin electroporation is easily performed with only minor discomfort for the patient. Patients with biochemical relapse of prostate cancer are a good model for testing immune therapies.
  • Irenaeus, Sandra, et al. (författare)
  • First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies
  • 2019
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 145:5, s. 1189-1199
  • Tidskriftsartikel (refereegranskat)abstract
    • Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 mu g/kg up to 400 mu g/kg) or intravenously (dosing at 75 mu g/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNF alpha and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.
  • Joensuu, Heikki, et al. (författare)
  • Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer The SOLD Randomized Clinical Trial
  • 2018
  • Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 4:9, s. 1199-1206
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear.Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab.Design, Setting, and Participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries.Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year.Main Outcomes and Measures: The primary objective was DFS; secondary objectives included distant disease–free survival, overall survival, cardiac DFS, and safety.Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease–free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group.Conclusions and Relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.Trial Registration: ClinicalTrials.gov Identifier: NCT00593697
  • Lehmann, S, et al. (författare)
  • Targeting p53 in vivo : a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer
  • 2012
  • Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.PATIENTS AND METHODS: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.RESULTS: MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.CONCLUSION: We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
  • Ronquist, Karl Göran, et al. (författare)
  • Energy-requiring uptake of prostasomes and PC3 cell-derived exosomes into non-malignant and malignant cells
  • 2016
  • Ingår i: Journal of Extracellular Vesicles. - 2001-3078 .- 2001-3078. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Epithelial cells lining the prostate acini release, in a regulated manner (exocytosis), nanosized vesicles called prostasomes that belong to the exosome family. Prostate cancer cells have preserved this ability to generate and export exosomes to the extracellular space. We previously demonstrated that human prostasomes have an ATP-forming capacity. In this study, we compared the capacity of extracellular vesicles (EVs) to generate ATP between normal seminal prostasomes and exosomes secreted by PC3 cells (PC3 exosomes), a prostate cancer cell line. Proteomic analyses identified enzymes of the glycolytic chain in both prostasomes and PC3 exosomes, and we found that both of them were capable of generating ATP when supplied with substrates. Notably, the net production of extracellular ATP was low for prostasomes due to a high ATPase activity contrary to an elevated net ATP level for PC3 exosomes because of their low ATPase activity. The uptake of the 2 types of EVs by normal prostate epithelial cells (CRL2221) and prostate cancer cells (PC3) was visualized and measured, demonstrating differential kinetics. Interestingly, this uptake was dependent upon an ongoing glycolytic flux involving extracellular ATP formation by EVs and/or intracellular ATP produced from the recipient cells. We conclude that the internalization of EVs into recipient cells is an energy-requiring process also demanding an active V-ATPase and the capacity of EVs to generate extracellular ATP may play a role in this process.
  • Maison-Blanche, Pierre, et al. (författare)
  • An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors
  • 2014
  • Ingår i: Cancer Chemotherapy and Pharmacology. - 0344-5704 .- 1432-0843. ; 73:6, s. 1241-1252
  • Tidskriftsartikel (refereegranskat)abstract
    • This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade a parts per thousand yen3 cardiovascular adverse events. Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety. The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade a parts per thousand yen3 cardiac adverse events were observed; Grade a parts per thousand yen3 hypotension and lymphocele occurred in two patients and one patient, respectively. These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.
  • Yachnin, Jeffrey R (författare)
  • Chemical, pharmacokinetic and biological aspects of platinum-based drugs
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The use of cisplatin for the treatment of metastatic testicular cancer is a medical historical landmark given that, for the first time, patients could be cured with drug therapy. A third generation platinum-based drug, oxaliplatin, has been registered for use in the treatment of colorectal cancer. Cisplatin and oxaliplatin have limited cross-resistance and display markedly different toxicity profiles. Platinum-based drugs (PBD) are chemically transformed to produce a variety of compounds that are of importance with respect to both wanted and unwanted toxicities. DNA-dependent protein kinase (DNA-PK), best known for its role in repair of DNA double-strand breaks, is involved in signaling pathways leading to cell death. It is unclear whether or not DNA-PK is a determinant of the cytotoxicity of PBD. The monohydrated complex of cisplatin (MHC) is thought to be the main intracellular form of the drug. Based upon a HPLC technique developed at the Karolinska Hospital Pharmacy, MHC was isolated and quantified. MHC was found to be more cytotoxic than cisplatin. Low extracellular chloride concentration by itself had relatively little affect upon drug stability. In media with low chloride concentration and pH MHC was rapidly transformed. This could have practical implications given that solid tumours often have microenvironments that are extremely acidic. We describe a method for synthesizing the dihydrated oxaliplatin complex (DOC). DOC was formed by hydrolyzing oxaliplatin at 70oC in sodium hydroxide. The cytotoxicity of DOC was compared to oxaliplatin in a lung cancer cell line. DOC was found to be significantly more cytotoxic than oxaliplatin. The pharmacokinetic profile of intact oxaliplatin was determined in patients receiving treatment for metastatic colon cancer. The in vivo clearance was compared with the rate of oxaliplatin degradation in vitro in whole blood samples taken from the patients immediately prior to the start of drug infusion. A good correlation between clearance of oxaliplatin in vivo and degradation in vitro was noted. We observed a short elimination half-life which is in sharp contrast to previous reports based upon analysis of platinum content. Trifluoperazine (TFP) has been shown to enhance the cytotoxicity of cisplatin. We tested a panel of phenothiazines for their inhibitory properties on DNA-PK. TFP was found to be an inhibitor of purified DNA-PK and DNA-PK in cell lysate. In a lung cancer cell line treated with TFP, DNA-PK activity was decreased with associated cleavage of DNA-PKcs and Ku86 after 30 minutes of incubation. Using a cell line defective in Ku86, we observed that the cytotoxicity of PBDs is enhanced especially with respect to cisplatin. While both drugs were able to induce apoptosis, no caspase-3 activation was noted after treatment with oxaliplatin. Cells lacking Ku86 had constitutional expression of activated p38. Oxaliplatin activated p38 more rapidly than cisplatin. We noted perinuclear translocation of p38 irregardless of Ku86 status in cells exposed to oxaliplatin. In cells exposed to cisplatin, p38 activation was localized to the nucleus in Ku86 deficient cells only. Our data supports a role for Ku86 in influencing the cytotoxicity of PBDs. This influence differs depending upon the platinum carrier ligand in question.
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