| 41. |
- Berglund, Åke, et al.
(författare)
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First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies
- 2015
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 33:6, s. 1232-1241
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.
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| 42. |
- Bidleman, Terry, et al.
(författare)
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Atmospheric pathways of chlorinated pesticides and natural bromoanisoles in the northern Baltic Sea and its catchment
- 2015
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 44, s. 472-483
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Tidskriftsartikel (refereegranskat)abstract
- Long-range atmospheric transport is a major pathway for delivering persistent organic pollutants to the oceans. Atmospheric deposition and volatilization of chlorinated pesticides and algae-produced bromoanisoles (BAs) were estimated for Bothnian Bay, northern Baltic Sea, based on air and water concentrations measured in 2011-2012. Pesticide fluxes were estimated using monthly air and water temperatures and assuming 4 months ice cover when no exchange occurs. Fluxes were predicted to increase by about 50 % under a 2069-2099 prediction scenario of higher temperatures and no ice. Total atmospheric loadings to Bothnian Bay and its catchment were derived from air-sea gas exchange and bulk'' (precipitation ? dry particle) deposition, resulting in net gains of 53 and 46 kg year(-1) for endosulfans and hexachlorocyclohexanes, respectively, and net loss of 10 kg year(-1) for chlordanes. Volatilization of BAs releases bromine to the atmosphere and may limit their residence time in Bothnian Bay. This initial study provides baseline information for future investigations of climate change on biogeochemical cycles in the northern Baltic Sea and its catchment.
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| 43. |
- Bidleman, Terry F., et al.
(författare)
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Air-water exchange of brominated anisoles in the northern baltic sea
- 2014
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 48:11, s. 6124-6132
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Tidskriftsartikel (refereegranskat)abstract
- Bromophenols produced by marine algae undergo O-methylation to form bromoanisoles (BAs), which are exchanged between water and air. BAs were determined in surface water of the northern Baltic Sea (Gulf of Bothnia, consisting of Bothnian Bay and Bothnian Sea) during 2011-2013 and on a transect of the entire Baltic in September 2013. The abundance decreased in the following order: 2,4,6-tribromoanisole (2,4,6-TBA) > 2,4-dibromoanisole (2,4-DBA) ≫ 2,6-dibromoanisole (2,6-DBA). Concentrations of 2,4-DBA and 2,4,6-TBA in September were higher in the southern than in the northern Baltic and correlated well with the higher salinity in the south. This suggests south-to-north advection and dilution with fresh riverine water enroute, and/or lower production in the north. The abundance in air over the northern Baltic also decreased in the following order: 2,4,6-TBA > 2,4-DBA. However, 2,6-DBA was estimated as a lower limit due to breakthrough from polyurethane foam traps used for sampling. Water/air fugacity ratios ranged from 3.4 to 7.6 for 2,4-DBA and from 18 to 94 for 2,4,6-TBA, indicating net volatilization. Flux estimates using the two-film model suggested that volatilization removes 980-1360 kg of total BAs from Bothnian Bay (38000 km(2)) between May and September. The release of bromine from outgassing of BAs could be up to 4-6% of bromine fluxes from previously reported volatilization of bromomethanes and bromochloromethanes.
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| 44. |
- Bidleman, Terry F., et al.
(författare)
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Sea-air exchange of bromoanisoles and methoxylated bromodiphenylethers in the Northern Baltic
- 2016
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Ingår i: Marine Pollution Bulletin. - : Elsevier. - 0025-326X .- 1879-3363. ; 112:1-2, s. 58-64
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Tidskriftsartikel (refereegranskat)abstract
- Halogenated natural products in biota of the Baltic Sea include bromoanisoles (BAs) and methoxylated bromodiphenyl ethers (MeO-BDEs). We identified biogenic 6-MeO-BDE47 and 2'-MeO-BDE68 in Baltic water and air for the first time using gas chromatography - high resolution mass spectrometry. Partial pressures in air were related to temperature by: log p/Pa=m/T(K)+b. We determined Henry's law constants (HLCs) of 2,4-dibromoanisole (2,4-DiBA) and 2,4,6-tribromoanisole (2,4,6-TriBA) from 5 to 30°C and revised our assessment of gas exchange in the northern Baltic. The new water/air fugacity ratios (FRs) were lower, but still indicated net volatilization in May-June for 2,4-DiBA and May - September for 2,4,6-TriBA. The net flux (negative) of BAs from Bothnian Bay (38,000km2) between May - September was revised from -1319 to -532kg. FRs of MeO-BDEs were >1, suggesting volatilization, although this is tentative due to uncertainties in their HLCs and binding to dissolved organic carbon.
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| 45. |
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| 46. |
- Bjersand, Kathrine, et al.
(författare)
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Drug Sensitivity Testing in Cytoreductive Surgery and Intraperitoneal Chemotherapy of Pseudomyxoma Peritonei
- 2015
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Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 22, s. S810-S816
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an established therapy for pseudomyxoma peritonei (PMP). However, the role of IPC is unclear. By ex vivo assessment of PMP tumor cell sensitivity to cytotoxic drugs, we investigated the basis for IPC drug selection and the role of IPC in the management of PMP.METHODS: Tumor cells were prepared by collagenase digestion of tumor tissue from 133 PMP patients planned for CRS and IPC. Tumor cell sensitivity to oxaliplatin, 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin was assessed in a 72-h cell-viability assay. Drug sensitivity was correlated to progression-free survival (PFS) and overall survival (OS).RESULTS: Samples from 92 patients were analyzed successfully. Drug sensitivity varied considerably between samples. Peritoneal mucinous carcinomatosis (PMCA), compared with PMCA intermediate or disseminated peritoneal adenomucinosis, was slightly more resistant to platinum and 5FU and tumor cells from patients previously treated with chemotherapy were generally less sensitive than those from untreated patients. Multivariate analysis showed patient performance status and completeness of CRS to be prognostic for OS. Among patients with complete CRS (n = 61), PFS tended to be associated with sensitivity to mitomycin C and cisplatin (p ≈ 0.06). At the highest drug concentration tested, the hazard ratio for disease relapse increased stepwise with drug resistance for all drugs.CONCLUSIONS: Ex vivo assessment of drug sensitivity in PMP provides prognostic information. The results suggest a role for IPC as therapeutic adjunct to CRS and for individualization of IPC by pretreatment assessment of drug sensitivity.
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| 47. |
- Bjersand, Kathrine, et al.
(författare)
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Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome
- 2022
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 61:4
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short-term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross-resistance and association with progression-free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment-naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross-resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.
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| 48. |
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| 49. |
- Bjorke, Ann Christin Helgesen, et al.
(författare)
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Which exercise prescriptions optimize V̇O2max during cancer treatment? : a systematic review and meta-analysis
- 2019
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 29:9, s. 1274-1287
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Forskningsöversikt (refereegranskat)abstract
- The aims of the present systematic review and meta-analysis were to investigate the effect of exercise on maximal oxygen uptake ((V) over dot O(2)max) and to investigate whether exercise frequency, intensity, duration, and volume are associated with changes in (V) over dotO(2)max among adult patients with cancer undergoing treatment. Medline and Embase through OvidSP were searched to identify randomized controlled trials. Two reviewers extracted data and assessed the risk of bias. The overall effect size and differences in effects for different intensities and frequencies were calculated on change scores and post-intervention (V) over dot O(2)max data, and the meta-regression of exercise duration and volumes was analyzed using the Comprehensive Meta-Analysis software. Fourteen randomized controlled trials were included in the systematic review, comprising 1332 patients with various cancer types receiving (neo-) adjuvant chemo-, radio-, and/or hormone therapy. Exercise induced beneficial changes in (V) over dotO(2)max compared to usual care (effect size = 0.46, 95% Confidence Interval = 0.23-0.69). Longer session duration (P = 0.020), and weekly duration (P = 0.010), larger weekly volume (P < 0.001), and shorter intervention duration (P = 0.005) were significantly associated with more beneficial changes in (V) over dot O(2)max. No differences in effects between subgroups with respect to frequency and intensity were found. In conclusion, exercise has beneficial effects on (V) over dotO(2)max in patients with cancer undergoing (neo-) adjuvant treatment. As interventions with larger exercise volumes and longer session durations resulted in larger beneficial changes in (V) over dot O(2)max, exercise frequency, intensity, and duration should be considered carefully for sufficient exercise volume to induce changes in (V) over dot O(2)max for this patient group.
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| 50. |
- Björn, Erik, et al.
(författare)
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Determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry
- 2007
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697. ; 363, s. 135-42
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Tidskriftsartikel (refereegranskat)abstract
- A fast and robust method for the determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry was developed, characterized, and validated. Samples of isolated DNA and exosome fractions from human ovarian (2008) and melanoma (T289) cancer cell lines were used. To keep the sample consumption to approximately 10 μl and obtain a high robustness of the system, a flow injection sample introduction system with a 4.6-μl sample loop was used in combination with a conventional pneumatic nebulizer and a spray chamber. The system was optimized with respect to signal/noise ratio using a multivariate experimental design. The system proved to be well suited for routine analysis of large sample series, and several hundreds of samples could be analyzed without maintenance or downtime. The detection limit of the method was 0.12 pg (26 pg/g) platinum. To avoid systematic errors from nonspectral interferences, it was necessary to use reagent matched calibration standards or isotope dilution analysis. An uncertainty budget was constructed to estimate the total expanded uncertainty of the method, giving a quantification limit of 2.3 pg (0.5 ng/g) platinum in DNA samples. The uncertainty was sufficiently low to study quantitative differences in the formation of Pt–DNA adducts after treatment with cisplatin using different exposure times and concentrations.
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