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  • Henningsson, Anja, et al. (författare)
  • Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
  • 2003
  • Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 39:8, s. 1105-1114
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.
  • Hultman, Bo, et al. (författare)
  • Costs and clinical outcome of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from gastric cancer
  • 2012
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 51:1, s. 112-121
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThe costs for loco-regional treatment of peritoneal carcinomatosis from gastric cancer are not well investigated. The aims of this study were to evaluate the costs and clinical outcome of systemic chemotherapy followed by cytoreductive surgery and intraperitoneal chemotherapy compared to systemic chemotherapy only in patients with peritoneal carcinomatosis from gastric cancer.Material and methodsTen patients were scheduled for systemic chemotherapy followed by loco-regional treatment. A reference group of 10 matched control patients treated with systemic chemotherapy only were used and both groups were evaluated with respect to clinical outcome and cost.ResultsThe mean overall cost in the loco-regional group was $145 700 (range $49 900-$487 800) and $59 300 (range $23 000-$94 800) for the control group. The mean overall survival for the loco-regional group was 17.4 months (range 6.0-34.3), and 11.1 months (range 0.1-24.2) for the systemic chemotherapy only group. The gain in life-years was 0.52 and in quality-adjusted life-years 0.49, leading to incremental cost per life-year and quality-adjusted life-years gained of $166 716 and $175 164, for loco-regional group compared to systemic chemotherapy.DiscussionTreatment of peritoneal carcinomatosis from gastric cancer is costly irrespective of treatment modality. If the survival benefit from adding loco-regional treatment to systemic chemotherapy indicated from this comparison is true, the incremental cost is considered high.
  • Hultman, Bo, et al. (författare)
  • Phase II study of patients with peritoneal carcinomatosis from gastric cancer treated with preoperative systemic chemotherapy followed by peritonectomy and intraperitoneal chemotherapy
  • 2013
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 52:4, s. 824-830
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThe aim was to evaluate the feasibility and the effectiveness of neoadjuvant systemic chemotherapy followed by cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) in patients with peritoneal carcinomatosis (PC) from gastric cancer.Material and methodsEighteen patients (median age 57 years, range 38-74) were scheduled for three months' neoadjuvant systemic chemotherapy followed by CRS + HIPEC + EPIC.ResultsAt the time of surgery, the peritoneal tumor burden was extensive with tumor growth on the entire peritoneal cavity. Only eight patients received the entire treatment and OS was 14.3 months (range 6.1-34.3, 95% CI 6.6-20.3). Six patients had macroscopically radical (CC0) surgery and for this subgroup OS was 19.1 months (range 6.1-34.3, 95% CI 6.9-27.1). Postoperative 90-day mortality was 10% (one patient) and the perioperative grades II-IV adverse events (AE) rate was 62.5%.DiscussionNeoadjuvant chemotherapy followed by CRS + HIPEC + EPIC does not seem to be associated with prolonged OS in patients with extensive PC growth from gastric cancer unless macroscopically radical surgery is achieved. However, morbidity from this treatment is considerable and it cannot be recommended for routine care until a prospective randomized trial has been performed.
  • Händel, Peter, et al. (författare)
  • Smartphone-Based Measurement Systems for Road Vehicle Traffic Monitoring and Usage-Based Insurance
  • 2014
  • Ingår i: IEEE Systems Journal. - : IEEE Press. - 1932-8184 .- 1937-9234. ; 8:4, s. 1238-1248
  • Tidskriftsartikel (refereegranskat)abstract
    • A framework is presented to deploy a smartphone-based measurement system for road vehicle traffic monitoring and usage-based insurance (UBI). Through the aid of a hierarchical model to modularize the description, the functionality is described as spanning from sensor-level functionality and technical specification to the topmost business model. The designer of a complex measurement system has to consider the full picture from low-level sensing, actuating, and wireless data transfer to the topmost level, including enticements for the individual smartphone owners, i.e., the end users who are the actual measurement probes. The measurement system provides two data streams: a primary stream to support road vehicle traffic monitoring and a secondary stream to support the UBI program. The former activity has a clear value for a society and its inhabitants, as it may reduce congestion and environmental impacts. The latter data stream drives the business model and parts of the revenue streams, which ensure the funding of the total measurement system and create value for the end users, the service provider, and the insurance company. In addition to the presented framework, outcome from a measurement campaign is presented, including road vehicle traffic monitoring (primary data stream) and a commercial pilot of UBI based on the driver profiles (secondary data stream). The measurement system is believed to be sustainable due to the incitements offered to the individual end users, in terms of favorable pricing for the insurance premium. The measurement campaign itself is believed to have an interest in its own right, as it includes smartphone probing of road traffic with a number of probes in the vicinity of the current state of the art, given by the Berkeley Mobile Millennium Project. During the ten-month run of the project, some 4500 driving h/250 000 km of road vehicle traffic data were collected.
  • Högberg, T, et al. (författare)
  • A systematic overview of chemotherapy effects in ovarian cancer
  • 2001
  • Ingår i: Acta oncologica (Stockholm, Sweden). - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 40:2-3, s. 60-340
  • Forskningsöversikt (refereegranskat)abstract
    • A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview on chemotherapy for epithelial ovarian cancer is based on a total of 176 scientific reports. Five meta-analyses including 17,291 patients, 33 prospective randomised studies including 12,340 patients, 36 prospective studies including 3,593 patients and one retrospective study including 421 patients. The studies include approximately 33,642 patients. The conclusions reached can be summarized into the following points: Radically operated patients with low-risk early ovarian cancer (stage IA or IB non-clear-cell well-differentiated carcinomas or borderline tumours) have a very good prognosis and there is no indication for adjuvant therapy. Radically operated patients with high-risk early ovarian cancer (clear cell carcinomas or FIGO stage IA or IB moderately or poorly differentiated carcinomas or stage IC) have a substantial risk for micrometastatic disease. However, the role of adjuvant chemotherapy is unclear and such therapy should, thus, only be used within clinical trials. The median overall survival for patients with advanced (FIGO stages II-IV) ovarian cancer randomised to paclitaxel/platinum-containing chemotherapy in three large studies ranged between 36-39 months. Compared with historical data, this represents a six to seven times longer median survival time than after surgery only. The probability for long-term survival for patients treated with a paclitaxel/platinum combination is too early to define. In two prospective randomised trials in advanced ovarian cancer, paclitaxel in combination with cisplatin has provided a survival benefit over cyclophosphamide/cisplatin. Based on these trials, paclitaxel/cisplatin is considered to be the standard treatment. This choice of standard therapy might, however, be questioned based on the results of the hitherto largest randomised study in advanced ovarian cancer, ICON3, which is, as yet only available in abstract form. It compared paclitaxel/carboplatin with carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). There were no statistically significant differences in progression-free or overall survival. The drug regimen in the control arms of the previous studies showing superiority of the paclitaxel-cisplatin combination may not have been the optimal non-paclitaxel platinum-containing regimen. Three randomised studies have compared carboplatin/paclitaxel with cisplatin/paclitaxel. All three are hitherto only published as abstracts with short follow-up precluding survival analyses. None of them shows any difference in response rates. All three show less toxicity and one also better quality of life with carboplatin. Thus, there are preliminary data supporting the substitution of cisplatin with carboplatin. Intraperitoneal therapy with cisplatin caused improved survival compared with intravenous therapy in one ramdomised study. Further studies have shown trends to better survival and longer progression-free interval with intraperitoneal therapy. The accrual to studies on intraperitoneal chemotherapy has been poor reflecting that it is a cumbersome and not easily accepted treatment. In advanced ovarian cancer, no convincing advantage has been shown from more dose-intensive chemotherapy, without cytokines or bone marrow stem cell support, compared with standard doses. High response rates are achieved with high-dose chemotherapy with stem cell support in the salvage situation but response duration is short. Phase III studies evaluating high-dose chemotherapy in the first-line situation are ongoing. Until supportive controlled clinical trials are presented, high-dose chemotherapy should be confined to clinical trials. Tumour response is frequently observed on re-treatment with the same drugs as given first-line in patients sensitive to first-line platinum-based chemotherapy with a long progression-free interval. Thus, in these patients treatment with a platinum/paclitaxel combination might be recommended. albeit based on limited data. In patients resistant to first-line therapy, a number of single agents induce tumour responses in the range of 10-30%. The literature does not permit general treatment recommendations in these patients, which are recommended to be included in controlled clinical trials.
  • Jacob, M, et al. (författare)
  • Synthesis of structurally controlled nanocarbons – in particular the nanobarrel carbon
  • 2003
  • Ingår i: Solid State Sciences. - : Editions scientifiques Elsevier. - 1293-2558 .- 1873-3085. ; 5, s. 133-137
  • Tidskriftsartikel (refereegranskat)abstract
    • Nanoporous carbons have been prepared through a selective etching reaction, performed by halogenisation of aluminum carbide. The structures obtained can be controlled by varying the chlorination temperature. The unique set of nanocarbons obtained include nanoporous amorphous structures, the nanobarrel structure and a nanographitic structure as chlorination temperatures were increased from 400 °C to 1000 °C. The synthesis process gives a pure product with high yield, and may be scaled up to produce bulk amounts
  • Jarvius, Malin, et al. (författare)
  • Piperlongumine induces inhibition of the ubiquitin-proteasome system in cancer cells
  • 2013
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 431:2, s. 117-123
  • Tidskriftsartikel (refereegranskat)abstract
    • Piperlongumine, a natural product from the plant Piper longum, has demonstrated selective cytotoxicity to tumor cells and to show anti-tumor activity in animal models [1]. Cytotoxicity of piperlongumine has been attributed to increase in reactive oxygen species (ROS) in cancer cells. We here report that piperlongumine is an inhibitor of the ubiquitin-proteasome system (UPS). Exposure of tumor cells to piperlongumine resulted in accumulation of a reporter substrate known to be rapidly degraded by the proteasome, and of accumulation of ubiquitin conjugated proteins. However, no inhibition of 20S proteolytic activity or 19S deubiquitinating activity was observed at concentrations inducing cytotoxicity. Consistent with previous reports, piperlongumine induced strong ROS activation which correlated closely with UPS inhibition and cytotoxicity. Proteasomal blocking could not be mimicked by agents that induce oxidative stress. Our results suggest that the anti-cancer activity of piperlongumine involves inhibition of the UPS at a pre-proteasomal step, prior to deubiquitination of malfolded protein substrates at the proteasome, and that the previously reported induction of ROS is a consequence of this inhibition. 
  • Lindman, Henrik, et al. (författare)
  • Individually tailored toxicity-based 5-fluorouracil, epirubicin and cyclophosphamide (FEC) therapy of metastatic breast cancer
  • 2007
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 46:2, s. 165-171
  • Tidskriftsartikel (refereegranskat)abstract
    • Chemotherapy dosing only based on body surface area (BSA) results in marked pharmacokinetic and toxicity variations, which may result in an inferior outcome for some patients. A toxicity-based dosing schedule for individually tailored treatment with granulocyte colony-stimulating factor (G-CSF) supported 5-fluorouracil (F), epirubicin (E) and cyclophosphamide (C) (dFEC) was developed and studied in patients with metastatic breast cancer with the purpose to determine its efficiency and toxicity. Twenty-six women, median age 48 years, were included and the individual E and C doses were tailored stepwise based on the recorded hematological toxicity. Twenty-one patients (81%; 95% confidence interval (CI), 66% to 96%) had an objective response, including six complete responses (23%; CI, 7%-39%). At median follow-up of 113 months, the median time to progression and median overall survival were 14 and 36 months, respectively. The delivered dose intensity was high but varied substantially between patients (ranges F 126-202, E 14.4-36.0, C 160-510 mg/m2/w). The dominating grade III/IV toxicity was nausea (12% of patients) and febrile neutropenia (31% of patients). The tailored and dose-escalated FEC was highly active and feasible in metastatic breast cancer and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.
  • Mahteme, Haile, et al. (författare)
  • Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
  • 2008
  • Ingår i: European Journal of Surgical Oncology. - 0748-7983 .- 1532-2157. ; 34:5, s. 547-552
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: To investigate if the pattern of cytotoxic drug sensitivity in vitro in patient samples of peritoneal carcinomatosis (PC) is supportive to the current standardized approach for drug selection for perioperative intraperitoneal chemotherapy (IPC). METHODS: The cytotoxic effect of cisplatin, oxaliplatin, irinotecan, 5-fluorouracil, mitomycin-C, doxorubicin and melphalan was investigated in vitro on tumour cells from 223 patient tumour samples of different PC origins. RESULTS: Considerable differences in cytotoxic drug sensitivity between tumour types of the PC entity and within each tumour type were observed. Cisplatin showed high cross-resistance with oxaliplatin but low cross-resistance with doxorubicin and irinotecan. No cross-resistance was found between irinotecan and doxorubicin. The dose-response relationships for melphalan and irinotecan in individual samples showed great variability. CONCLUSIONS: The activity in vitro of cytotoxic drugs commonly used in IPC for PC is very heterogeneous. Efforts for individualizing drug selection for PC patients undergoing IPC seem justified.
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