| 1. |
- Hansson, Johan, 1964-
(författare)
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Loco-regional Treatment of Peritoneal Carcinomatosis: Survival, Morbidity and Quality of Life
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.
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| 2. |
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| 3. |
- 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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| 4. |
- Byström, Per, et al.
(författare)
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Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer
- 2009
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 20:6, s. 1057-1061
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.
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| 5. |
- Dreilich, Martin, et al.
(författare)
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Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines
- 2006
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 17:5, s. 503-509
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.
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| 7. |
- Fryknäs, Mårten, et al.
(författare)
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Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
- 2006
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 11:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
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| 8. |
- Fryknäs, Mårten, et al.
(författare)
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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
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| 9. |
- Hagell, Peter, et al.
(författare)
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The 39-item Parkinson's disease questionnaire (PDQ-39) revisited: implications for evidence-based medicine.
- 2007
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 78:Apr 18, s. 1191-1198
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Tidskriftsartikel (refereegranskat)abstract
- Background: The 39 item Parkinson's disease questionnaire (PDQ-39) is the most widely used patient reported rating scale in Parkinson's disease. However, several fundamental measurement assumptions necessary for confident use and interpretation of the eight PDQ-39 scales have not been fully addressed. Methods: Postal survey PDQ-39 data from 202 people with Parkinson's disease (54% men; mean age 70 years) were analysed regarding psychometric properties using traditional and Rasch measurement methods. Results: Data quality was good ( mean missing item responses, 2%) and there was general support for the legitimacy of summing items within scales without weighting or standardisation. Score reliabilities were adequate (Cronbach's alpha 0.72-0.95; test-retest 0.76-0.93). The validity of the current grouping of items into scales was not supported by scaling success rates ( mean 56.2%), or factor and Rasch analyses. All scales represented more health problems than that experienced by the sample ( mean floor effect 15%) and showed compromised score precision towards the less severe end. Conclusions: Our results provide general support for the acceptability and reliability of the PDQ-39. However, they also demonstrate limitations that have implications for the use of the PDQ-39 in clinical research. The grouping of items into scales appears overly complex and the meaning of scale scores is unclear, which hampers their interpretation. Suboptimal targeting limits measurement precision and, therefore, probably also responsiveness. These observations have implications for the role of the PDQ-39 in clinical trials and evidence based medicine. PDQ-39 derived endpoints should be interpreted and selected cautiously, particularly regarding small but clinically important effects among people with less severe problems.
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| 10. |
- Hansson, Johan, et al.
(författare)
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Postoperative adverse events and long-term survival after cytoreductive surgery and intraperitoneal chemotherapy
- 2009
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 35:2, s. 202-208
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Peritoneal carcinomatosis (PC) is fatal without special combined cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). This study was designed to identify factors that may increase the risk of postoperative morbidity and mortality from combined CRS and IPC interventions for PC. Survival based on primary tumour type and extent of surgery is reported. METHODS: Between May 1991 and November 2004, 123 patients were treated with CRS and IPC for PC. Based on the National Cancer Institute Common Toxicity Criteria for grade 3 and 4, data on 30 days postoperative morbidity and 90 days mortality were analysed. RESULTS: Grade 3-4 adverse events were observed in 51 patients (41%) and were associated with stoma formation, duration of surgery, peroperative blood loss and peritoneal cancer index (PCI). Excision, or electrocautery evaporation, of tumour from small bowel surface was correlated to bowel morbidity. Five patients had treatment-related mortality (4%) within 90 days. Survival was associated with macroscopic radical surgery, prior surgical score, PCI and primary tumour type. CONCLUSIONS: CRS and IPC for PC are associated with high morbidity and mortality. However, in light of the potential benefit indicated by long-term survival, the adverse event from this treatment is considered acceptable.
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