| 1. |
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| 2. |
- Gustavsson, Bengt, 1947, et al.
(författare)
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Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer.
- 2015
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 1573-0646 .- 0167-6997. ; 33:5, s. 1078-1085
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Tidskriftsartikel (refereegranskat)abstract
- Background Modufolin® ([6R]-5,10-methylene tetrahydrofolate; [6R]-MTHF) is an endogenous biomodulator that is being developed as an alternative to leucovorin, a folate prodrug used in the treatment of colorectal cancer. The objective of this phase 1 dose de-escalation trial was to estimate the minimum tolerated dose of [6R]-MTHF to be used in combination with pemetrexed 500mg/m(2) in the neoadjuvant treatment of patients with rectal cancer. Methods Adult patients (≥18years) with resectable rectal adenocarcinoma were allocated to [6R]-MTHF doses of 500, 100, 50, and 10mg/m(2) in combination with pemetrexed 500mg/m(2). [6R]-MTHF was administered as an intravenous (i.v.) bolus injection 1week prior to the first dose of pemetrexed and then once weekly for 9weeks; pemetrexed was administered by i.v. infusion once every 21days for three cycles. Results Twenty-four patients (mean [SD] age, 63.1 [12.9] years) were enrolled in the study. A total of 72 treatment-related adverse events (AEs) were reported, of which the most common were fatigue (n=17; 23.6%), nausea (n=10; 13.9%), and diarrhea (n=5; 6.9%). The incidence of treatment-related AEs by [6R]-MTHF dose level (500, 100, 50, 10mg/m(2)) was 11.1% (n=8), 13.9% (n=10), 45.8% (n=33), and 29.2% (n=21), respectively. There were no dose-limiting toxicities, and only two (2.8%) treatment-related AEs were grade 3 in severity. Of the 11 serious AEs reported, none were considered to be related to [6R]-MTHF treatment. Conclusions The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100mg/m(2) once weekly in combination with pemetrexed 500mg/m(2). The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer.
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| 3. |
- Naredi, Peter, 1955, et al.
(författare)
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The influence of hepatic artery ligation and of vasopressin on liver tumour blood flow in rats.
- 1992
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Ingår i: Journal of surgical oncology. - : Wiley. - 0022-4790 .- 1096-9098. ; 50:2, s. 70-6
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Tidskriftsartikel (refereegranskat)abstract
- The blood flow in an experimental adenocarcinoma in the rat liver was determined with the 133Xe-washout technique before and after hepatic artery ligation (HAL). There was an initial reduction of the washout of 50%. This was further reduced after 1 day by 50%, which was maintained for 7 days. Seven days after HAL or sham procedures the 133Xe-washout was of similar magnitude in the liver tumours, although after the sham procedure the tumours were larger (3.4 g vs. 1.5 g). The estimated tumour blood flow was then approximately 0.04 ml x min-1 x g-1. The influence on normal liver parenchyma of HAL was a reduction at 30 minutes, which was maintained for 7 days. Postacton--a synthetic vasopressin--did not influence the 133Xe-washout in normal liver parenchyma in non-tumour, as well as in tumour-bearing animals. There was no influence of Postacton on the 133Xe-washout in the liver tumours. Thirty minutes after HAL Postacton gave a reduction of blood flow in normal liver parenchyma of tumour-bearing animals, which is thus only from the portal vein. In tumours Postacton did not significantly reduce the tumour blood flow immediately after HAL.
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| 4. |
- Swartling, Torbjörn, et al.
(författare)
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Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer.
- 2013
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Ingår i: World journal of gastroenterology : WJG. - : Baishideng Publishing Group Inc.. - 1007-9327. ; 19:21, s. 3263-71
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phaseI/II trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stage. and stage. or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero-inferior length by ERUS compared with MRI were within 1.96 standard deviations of the difference between the methods (18 mm) for tumours smaller than 50 mm. The agreement with pathology was within 1.96 standard deviations of the difference between imaging and pathology for all tumours with MRI (15 mm) and for tumours that did not exceed 50 mm with ERUS (22 mm). Tumours exceeding 50 mm in length could not be reliably measured by ERUS due to the limit in the length of each recording. CONCLUSION: MRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS. (C) 2013 Baishideng. All rights reserved.
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| 5. |
- Ahlmanner, Filip, et al.
(författare)
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CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:97, s. 36993-37007
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Tidskriftsartikel (refereegranskat)abstract
- Increasing knowledge of the function and regulation of tumor-infiltrating lymphocytes has led to new insights in cancer immunotherapy. Regulatory T cells (Treg) accumulate in colon tumors, and we recently showed that CD39+ Treg from cancer patients inhibit transendothelial migration of conventional T cells. CD39 mediates the hydrolysis of ATP to immunosuppressive adenosine and adds to the immunosuppressive effects of Treg. Here, we further investigated the regulatory features of intratumoral CD39+ Treg in colon cancer. Using flow cytometry analyses of cells from 46 colon cancer patients, we confirm the accumulation of CD39+ Treg in the tumor tissue compared to unaffected colon tissue, and also show that tumor-infiltrating Treg express more CD39 and Foxp3 on a per cell basis. Furthermore, CD39+ Treg in tumors express markers indicating increased turnover and suppressive ability. In particular, tumor-infiltrating CD39+ Treg have high expression of surface molecules related to immunosuppression, such as ICOS, PD-L1 and CTLA-4. Functional suppression assays also indicate potent suppressive capacity of CD39+ Treg on proliferation and IFN-γ secretion by conventional T cells. In conclusion, our results identify tumor-infiltrating CD39+ Treg as a numerous and potentially important immunosuppressive subset, and suggest that immunotherapy aimed at reducing the activity of CD39+ Treg may be particularly useful in the setting of colon cancer. © 2018 Ahlmanner et al.
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| 6. |
- Akeus, Paulina, et al.
(författare)
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Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
- 2018
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Ingår i: Cancer Immunology Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 67:7, s. 1067-1077
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC(min/+) mouse model. By breeding APC(min/+) mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors.
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| 7. |
- Andersson, J., et al.
(författare)
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Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF
- 2005
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Ingår i: Ann Oncol. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 16:5, s. 743-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: TP53 has been described as a prognostic factor in many malignancies, including breast cancer. Whether it also might be a predictive factor with reference to chemo- and endocrine therapy is more controversial. PATIENTS AND METHODS: We investigated relapse-free (RFS), breast cancer-corrected (BCCS) and overall survival (OS) related to TP53 status in node-positive breast cancer patients that had received polychemotherapy [cyclophosphamide, methotrexate, 5-fluorouracil (CMF)] and/or endocrine therapy (tamoxifen). Sequence analyses of the whole TP53 coding region was performed in 376 patients operated on for primary breast cancer with axillary lymph node metastases between 1984 and 1989 (median follow-up time 84 months). RESULTS: TP53 mutations were found in 105 patients (28%). We found 90 (82%) of the 110 mutations in the more frequently analysed exons 5-8, while the other 20 (18%) were located in exons 3-4 and 9-10, respectively. Univariate analyses showed TP53 to be a significant prognostic factor with regard to RFS, BCCS and OS in patients who received adjuvant CMF. CONCLUSIONS: TP53 mutations might induce resistance to certain modalities of breast cancer therapy. Sequence-determined TP53 mutation was of negative prognostic value in the total patient population and in the CMF treated patients.
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| 8. |
- Bexe-Lindskog, Elinor, et al.
(författare)
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Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer.
- 2014
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Ingår i: BMC clinical pathology. - : Springer Science and Business Media LLC. - 1472-6890. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- 5-Fluorouracil (5-FU) is the cornerstone of chemotherapeutic treatment for patients with colorectal cancer. The enzyme thymidine phosphorylase (TP) catalyzes the conversion of 5-FU to its active metabolite, 5-fluoro-2'-deoxyuridine. TP is expressed in tumour epithelial cells and stromal cells, particularly in tumour-associated macrophages. These macrophages may affect sensitivity to chemotherapy. Previously, we identified TP as a predictive factor in microdissected tumour samples of patients with advanced colorectal cancer. In the present study, we analysed TP expression in tissues and associated stromal cells from patients with advanced colorectal cancer and associated TP levels to tumour response and time-to-event variables during first-line chemotherapy treatment. We also investigated the association between serum TP levels at the time of surgery and gene expression in primary tumour tissues.
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| 9. |
- Bexe-Lindskog, Elinor, et al.
(författare)
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Thymidine Phosphorylase Gene Expression in Stage III Colorectal Cancer.
- 2012
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Ingår i: Clinical Medicine Insights. Oncology. - 1179-5549. ; 6, s. 347-53
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Tidskriftsartikel (refereegranskat)abstract
- The thymidine phosphorylase (TP) enzyme has several tumor-promoting functions. The aim of this study was to explore TP gene expression in relation to clinical and histopathological data obtained from patients with stage III colorectal cancer.
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| 10. |
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| 11. |
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| 12. |
- Carlsson, Göran, 1951, et al.
(författare)
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Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy.
- 2014
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Ingår i: Cancer chemotherapy and pharmacology. - : Springer Science and Business Media LLC. - 1432-0843 .- 0344-5704. ; 74:4, s. 757-63
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Tidskriftsartikel (refereegranskat)abstract
- 5-fluorouracil (5-FU) competes with uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD). Low DPD activity impairs breakdown of Ura to dihydrouracil (UH2) and is associated with toxicity during 5-FU-based chemotherapy. Calculation of the 5-FU dose is based on body surface area, and new tools are needed to individualize treatment. The aim of study was to measure Ura and UH2 in saliva of patients with colorectal cancer and relate levels to treatment-induced toxicity.
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| 13. |
- Corin, Irina, 1969, et al.
(författare)
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A study of the expression of Cyclin E and its isoforms in tumor and adjacent mucosa, correlated to patient outcome in early colon cancer.
- 2010
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 49:1, s. 63-69
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cyclin E, a key regulator in the cell cycle, is often over-expressed in malignant disease. It can present as full length (FL) and low-molecular-weight (LMW) isoforms. The purpose of this study was to characterize the expression pattern of cyclin E in colon cancer, both in tumor and in macroscopically normal adjacent mucosa. A secondary aim was to study the possible correlation to clinical factors and patient outcome. MATERIAL AND METHOD: Tumor and mucosa tissue from 114 patients with radically operated, non-metastatic colon tumors were analyzed. The cyclin E expression was measured by Western Blot in the tumor and adjacent mucosa using the antibody targeting C-terminal. The cyclin E expression was correlated to both pathology factors as differentiation grade and to the patient outcome. RESULTS: Cyclin E was detected in both tumor and adjacent mucosa and in both FL and LMW-forms. FL was present in 29 (25.4%) tumors and only in three (2.6%) mucosa samples, the corresponding figures for the LMW-isoforms were 80 (70.2%) and 67 (58.8%). There was no correlation between the cyclin E expression and gender, age, tumor location or tumor pathology. Patients with a high expression of LMW isoforms (p < 0.03) or a high total expression (FL+LMW) (p < 0.006) had higher risks of recurrence and thus a worse survival. CONCLUSION: Cyclin E is expressed in FL- and LMW-forms in both colon tumors and the macroscopically normal adjacent mucosa. A high expression of cyclin E in tumor was associated with an increased risk of tumor recurrence and a worse outcome. It could be a possible prognostic marker in non-metastatic colon cancer.
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| 14. |
- Danenberg, P. V., et al.
(författare)
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Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action
- 2016
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Ingår i: Critical Reviews in Oncology Hematology. - : Elsevier BV. - 1040-8428. ; 106, s. 118-131
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Tidskriftsartikel (refereegranskat)abstract
- Folates have been used with cytotoxic agents for decades and today they are used in hundreds of thousands of patients annually. Folate metabolism is complex. In the treatment of cancer with 5-fluorouracil, the administration of folates mechanistically leads to the formation of [6R]-5,10-methylene-tetrahydrofolate, and the increased concentration of this molecule leads to stabilization of the ternary complex comprising thymidylate synthase, 2'-deoxy-uridine-5'-monophosphate, and [6R]-5,10-methylene-tetrahydrofolate.The latter is the only natural folate that can bind directly in the ternary complex, with other folates requiring metabolic activation. Modulation of thymidylate synthase activity became central in the study of folate/cytotoxic combinations and, despite wide use, research into the folate component was neglected, leaving important questions unanswered. This article revisits the mechanisms of action of folates and evaluates commercially available folate derivatives in the light of current research. Better genomic insight and availability of new analytical techniques and stable folate compounds may open new avenues of research and therapy, ultimately bringing increased clinical benefit to patients. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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| 15. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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A phase I/II study of neoadjuvant chemotherapy with Pemetrexed (Alimta) in rectal cancer.
- 2011
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Ingår i: European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. - : Elsevier BV. - 1532-2157. ; 37:7, s. 583-8
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to assess the feasibility of preoperative chemotherapy and possible tumour response using Pemetrexed (Alimta) in rectal cancer.
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| 16. |
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| 17. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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A study of lymph node ratio as a prognostic marker in colon cancer.
- 2008
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Ingår i: European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. - : Elsevier BV. - 1532-2157. ; 34:7, s. 771-5
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this study was to evaluate and describe the lymph node ratio (LNR) as a prognostic parameter for patients with colon cancer. As lymphatic involvement is the key, focus was set at stage III disease. Interest was directed at the possibility of identifying high-risk groups and the clinical implementation and consequence. METHOD: The study was retrospective using a database of clinical data of all cancer patients treated at our unit. It has been continuous in registration, inclusion and update since 1999 including survival and clinical features. All patients (n=265) diagnosed with stage III colon cancer during 1999-2003 were included for the study. LNR was calculated and quartile groups were created. LNR and associated parameters were analysed towards 3-year disease-free survival (DFS). Basic patient data as well as surgery, pathology and postoperative treatment were taken into consideration. RESULTS: Significant differences in disease-free survival were found for TNM N-status, tumour differentiation grade and LNR quartile group. There was a difference in 3-year DFS from 80% in LNR group 1 compared with less than 30% in group 4. These results were of prognostic interest both independently and in interaction with each other. High-risk groups could be identified and in the worst prognosis LNR group we also found a tendency towards more side effects with adjuvant chemotherapy. CONCLUSION: The lymph node ratio, the quota between the number of lymph node metastasis and assessed lymph nodes, is a highly significant (p<0.001) prognostic factor in stage III colon cancer. It can be an aid in identifying risk groups that could benefit from a more intense postoperative surveillance and possibly bring changes in adjuvant treatment strategy. More studies of clinical data, genetic and biochemical markers are needed in this patient group to understand the possible difference in tumour behaviour and tailor the treatment.
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| 18. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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A study of lymph node ratio in stage IV colorectal cancer.
- 2008
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Ingår i: World journal of surgical oncology. - : Springer Science and Business Media LLC. - 1477-7819. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The finding of metastasis in colorectal cancer, stage IV disease, has a major impact on prognosis and treatment strategy. Known important factors include the extent of the metastasis and the patients' performance status. The lymph node factors are of known importance in earlier cancer stages but less described in metastatic disease. The aim of the study was to evaluate lymph node status and ratio as prognostic markers in stage IV colorectal cancer. METHOD: The study was retrospective and assessing all patients operated, with bowel resection, for an initial stage IV colorectal cancer during 1999-2003 (n=136). Basic demographic data as well as given treatment was assessed. The Lymph node ratio (LNR), the quota between the number of lymph node metastasis and assessed lymph nodes, was calculated. LNR groups were created by ratio thirds, 3 equally sized groups. The analysis was made by LNR group and by eligibility for chemotherapy with cancer specific survival as outcome parameter. RESULTS: The median survival (CSS) for the entire group was 431 days with great variability. For the patients eligible for chemotherapy it ranged from 791 days in LNR-group 1 to 433 days for the patients in group 3. For patients ineligible for chemotherapy the corresponding figures were 209 and 91 days. The eligibility for chemotherapy was a major prognostic factor which also takes co-morbidity, age and performance status into consideration. The LNR (p<0.01) and the tumour differentiation grade were also significant (p<0.05) factors regarding survival. The LNR group 3 was also associated with a higher frequency of multiple metastasis locations (p<0.05) and of more side effects with chemotherapy and thus of reductions in dosage or pre-emptive treatment ending (p<0.05). CONCLUSION: Stage IV colorectal cancer is a heterogeneous group regarding the survival prognosis. The lymph node ratio was found to be a significant marker for the survival prognosis (p<0.0049). High and low risk groups could be identified with a survival difference of up to one year. It could be of importance when planning a treatment strategy or evaluating clinical data materials. A pathology report should include a node assessment even at presence of synchronous metastasis.
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| 19. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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A study of the MTHFR gene polymorphism C677T in colorectal cancer.
- 2009
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Ingår i: Clinical colorectal cancer. - 1533-0028. ; 8:1, s. 43-8
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to examine the clinical significance of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T in colorectal cancer (CRC). The hypothesis was that the genotype could affect the risk of cancer development and the results of cancer treatment. PATIENTS AND METHODS: Genotyping was made for a random 30% (n = 544) of all patients treated for CRC at our unit from 1999 to 2006 (n = 1812). Basic clinical and pathologic factors were analyzed by genotype group and also compared with those of the entire cohort. Tolerability of chemotherapy and possible side effects were analyzed by genotype. Survival was analyzed by genotype for all stages for patients treated between 1999 and 2003. The genotype prevalence was also compared with a control material of healthy blood donors. RESULTS: No genotype was associated with an increased risk of CRC or higher cancer stage. The patients with CT/TT genotype had significantly greater risk of suffering side effects from fluoropyrimidine (5-fluorouracil) treatment (P < .05). In stage III colon cancer, the patients with CT/TT genotype had a poorer prognosis than those with the CC genotype. The difference was significant in univariate (P < .003) and multivariate (P < .040) analysis. Though the genotype-associated side effect risks remained in stage IV, the effect on survival was not significant (P < .1). CONCLUSION: The MTHFR polymorphism C677T does, in our material, not affect the risk of CRC; however, it can affect the sensitivity to chemotherapy and the risk of side-effects and therefore survival in stage III and possibly stage IV colon cancer. It could be a future predictive factor in the choice of a treatment regimen.
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| 20. |
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| 21. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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Stage migration in colorectal cancer related to improved lymph node assessment
- 2007
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Ingår i: Eur J Surg Oncol. - 0748-7983. ; 33:7, s. 849-53
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of the study was to evaluate the clinical impact of improved cooperation between the treating surgeons and pathologists in a high volume surgical unit. As a measure we used the staging process with special focus on lymph node assessment. FINDINGS: Comparing two periods 5years apart, we found a significant increase in the number of nodes examined and also an increase in the number of metastasis-positive nodes. Concurrently, we observed a trend in stage migration from stage I/II towards stage III, whilst stage IV remained unchanged. This was one factor that contributed to an increase in the number of patients treated with adjuvant chemotherapy. We also found that the number of assessed nodes had an impact on survival in stage II. The major change in practise was the implementation of a multidisciplinary team conference and the associated possibility of reciprocal feedback. CONCLUSION: Lymph node status has a key role in cancer staging and in the selection of further therapy. The quality and the standard of the assessment can be improved through multidisciplinary cooperation and it has an impact on the clinical decisions and can affect long-term survival. A correct node status should be mandatory in the evaluation of prognostic factors.
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| 22. |
- Derwinger, Kristoffer, 1969, et al.
(författare)
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Variations in demography and prognosis by colon cancer location.
- 2011
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Ingår i: Anticancer research. - 0250-7005. ; 31:6, s. 2347-50
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Tumours of the right and left colon are suggested to be different entities with different prognosis. The aim was to explore differences related to the location of a colonic tumour. PATIENTS AND METHODS: A single-centre retrospective analysis of all patients treated for colon cancer during 1999-2008 (n=1558) was carried out. Assessed data included demography, pathology and survival by cancer location, with left colon also sub-divided into left and sigmoid colon. RESULTS: Right colon carcinoma was associated with female gender, higher age and poor grade of differentiation; left colon carcinoma had characteristics of worse stages and requiring emergency surgery. Sigmoid tumours were of better grade and stage. Survival was related the staging, which varied with location. Right colon carcinoma conferred a worse overall survival (OS) (p<0.037) but not cancer-specific survival (CSS) or disease-free survival compared to the entire left colon, whilst sigmoid tumours conferred a better OS and CSS (p<0.001) when the left colon was sub-divided. CONCLUSION: There are differences in demography and pathology related to the location of colon cancer. Sigmoid location carries the best prognosis.
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| 23. |
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| 24. |
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| 25. |
- Gustavsson, Bengt, 1947, et al.
(författare)
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A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer.
- 2015
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Ingår i: Clinical colorectal cancer. - : Elsevier BV. - 1938-0674 .- 1533-0028. ; 14:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.
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| 26. |
- Gustavsson, Bengt, 1947, et al.
(författare)
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Molecular determinants of efficacy for 5-FU-based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy-related genes.
- 2009
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 124:5, s. 1220-6
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Tidskriftsartikel (refereegranskat)abstract
- 5-Fluorouracil (5-FU)-based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5-FU-based treatment outcomes. One hundred and forty-four CRC patient samples (collected from 1983 to 2004) were analyzed via real-time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time-to-event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross-complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time-to-progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5-FU- or other novel antifolate-based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted.
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| 27. |
- Gustavsson, Bengt, 1947
(författare)
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Simultaneous surgery for primary colorectal cancer and metastatic lesions?
- 2012
-
Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 47:3, s. 269-76
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended.
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| 28. |
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| 29. |
- Haller, Daniel G, et al.
(författare)
-
Potential regional differences for the tolerability profiles of fluoropyrimidines.
- 2008
-
Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 26:13, s. 2118-23
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. METHODS: Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study). RESULTS: In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. CONCLUSION: Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
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| 30. |
- Hardling, Mats, et al.
(författare)
-
Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate
- 2004
-
Ingår i: Med Oncol. - 1357-0560. ; 21:4, s. 349-58
-
Tidskriftsartikel (refereegranskat)abstract
- Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.
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| 31. |
- Kjersem, J B, et al.
(författare)
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AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.
- 2016
-
Ingår i: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1473-1150 .- 1470-269X. ; 16:3, s. 272-279
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.54.
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| 32. |
- Kodeda, Karl, et al.
(författare)
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Genomic CGH-assessed structural DNA alterations in rectal carcinoma as related to local recurrence following primary operation for cure.
- 2012
-
Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 41:4, s. 1397-1404
-
Tidskriftsartikel (refereegranskat)abstract
- Several factors determine overall outcome and possible local recurrence after curative surgery for rectal carcinoma. Surgical performance is usually believed to be the most pertinent factor, followed by adjuvant oncological treatment and tumor histopathology. However, chromosomal instability is common in colorectal cancer and tumor clones are assumed to differ in aggressiveness and potential of causing local recurrence. The aim of this study was, therefore, to evaluate if genetic alterations in primary rectal carcinoma are predictive of local recurrences. A large clinical database with linked bio-bank allowed for careful matching of two patient groups (R0) resected for rectal carcinoma. One group had developed early, isolated local recurrences and the other group seemed cured after 93months follow-up. DNA from the primary tumors was analysed with array-CGH (comparative genomic hybridization) including 55,000 genomic probes. DNA from all primary tumors in both groups displayed previously reported and well-recognised DNA aberrations in colorectal carcinoma. Significant copy number gains were confirmed in the 4q31.1-31.22 region in DNA from tumors with subsequent local recurrence. Twenty-two affected genes in this region code for products with high relevance in tumor biology (p53 regulation, cell cycle activity, transcription). DNA from rectal carcinoma displayed well-known aberrations as described for colon carcinoma with no obvious prediction of local rectal recurrence. Gains in the 4q31.1-31.22 DNA region are highly potential for local recurrence despite R0 resection to be confirmed in larger patient materials.
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| 33. |
- Kodeda, Karl, et al.
(författare)
-
Local recurrence of rectal cancer: a population based cohort study of diagnosis, treatment and outcome.
- 2012
-
Ingår i: Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. - : Wiley. - 1463-1318. ; 14:5, s. 230-7
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Local recurrence is an important endpoint of rectal cancer treatment, but details of this form of treatment failure are less well described. The aim of this study was to acquire deeper knowledge of local recurrence regarding symptoms, diagnostic work-up, clinical management, health-care utilization and outcome. Method: Of 671 patients with rectal cancer, 57 were diagnosed with local recurrence within 5 years after surgery. Their records were analysed. Results: At diagnosis of local recurrence 49(86%) of 57 patients were symptomatic and 40 (70%) were diagnosed between scheduled follow-up visits. The predominant symptom was pain. Forty five of the 57 (79%) had a palpable tumour. Most were deemed incurable at presentation and less than 10 (18%) were operated on with curative intent. Five years after the initial rectal cancer surgery, two patients were alive, with one free of disease. Despite the need for multiple interventions, including surgery, only 4 out of 40 patients were classified as being well palliated in the terminal stage. Conclusion: Follow-up after rectal cancer surgery by annual clinical examination is not sufficient to detect local recurrence when it is asymptomatic. Local recurrence of rectal cancer is often associated with intractable symptoms. These patients require frequent interventions and can rarely be cured if diagnosed at an advanced stage. Strategies for early detection of local recurrence and the management thereof require improvement.
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| 34. |
- Langenes, Veronica, et al.
(författare)
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Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas.
- 2013
-
Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62:11, s. 1687-1695
-
Tidskriftsartikel (refereegranskat)abstract
- Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.
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| 35. |
- Lebrero-Fernandez, Cristina, et al.
(författare)
-
Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer
- 2016
-
Ingår i: Immunity Inflammation and Disease. - : Wiley. - 2050-4527. ; 4:2, s. 191-200
-
Tidskriftsartikel (refereegranskat)abstract
- Several Butyrophilin (BTN) and Btn-like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real-time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2(-/-)) and intestinal tumorigenesis (Apc(Min/+)). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2(-/-) mice significantly down-regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from Apc(Min/+) mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family.
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| 36. |
- Lindnér, Per, 1956, et al.
(författare)
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Biochemical modulation of intraperitoneal fluorouracil by allopurinol-the effect on an experimental adenocarcinoma in the liver.
- 1994
-
Ingår i: Anticancer research. - 0250-7005. ; 14:3A, s. 847-52
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Tidskriftsartikel (refereegranskat)abstract
- In a rat liver tumour system with a nitrosoguanidine-induced carcinoma and in an in vitro system with the same tumour, the effect of allopurinol on the toxicity and antitumour effect of 5-fluorouracil (5-FU) was explored. Two doses of 5-FU, 30 and 60 mg/kg b.w. intraperitoneally (i.p.), were tested with a large dose of allopurinol subcutaneously (s.c.( (300 mg) in rats. The drugs were given for three consecutive days. The lethal toxicity of 60 mg 5-FU i.p. could not be counteracted by allopurinol. Allopurinol and 30 mg 5-FU reduced the tumour growth rate more than 5-FU alone. The spleen was smaller, as a sign of increased toxicity, without allopurinol. The concentration of allopurinol and its metabolites in the general circulation was high. In vitro, there was no additive or specific effect of allopurinol. These results indicate some in vivo metabolic modulation of 5-FU efficacy by allopurinol if 5-FU is administered intraperitoneally and allopurinol systemically.
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| 37. |
- Lindnér, Per, 1956, et al.
(författare)
-
Hepatic artery occlusion and energy charge in rat liver tumour.
- 1994
-
Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. - 0923-7534. ; 5:10, s. 961-3
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatic artery ligation (HAL) is a model for inducing a vascular attack on liver tumours which causes a reduction in tumour growth. To determine in an experimental rat liver adenocarcinoma the duration and magnitude of changes in adenonucleotide concentration and energy charge (EC) after HAL, analyses of energy-rich nucleotides were performed at 1, 2, 24 and 168 hours after HAL or a SHAM procedure. There was a significant decrease of the ATP content and energy charge in the tumour one hour after HAL. Two hours after HAL this difference had decreased and with longer observation it was not detectable. Twenty-four hours of starvation did not significantly alter the effects of HAL on the tumour. HAL gives rise to a transient energy depletion of the tumour which is not completely compensated for by glycolysis after 1 hour, but is restored after 2 hours.
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| 38. |
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| 39. |
- Muthuswamy, Rangarajan V., et al.
(författare)
-
Impaired migration of IgA-secreting cells to colon adenocarcinomas.
- 2013
-
Ingår i: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 62, s. 989-97
-
Tidskriftsartikel (refereegranskat)abstract
- Local inflammation is a strong risk factor for the development of gastrointestinal adenocarcinomas. Mucosal regulatory T cells and IgA-secreting cells both contribute to reduce inflammatory responses, and their recruitment to tissues is dependent on local production of chemokines. More specifically, IgA-secreting cells are recruited to mucosal tissues by CCL28 signalling through CCR10. Here, we examined the recruitment of IgA-secreting plasma cells to tumor-associated mucosa in patients suffering from colon adenocarcinoma. Flow cytometric analyses of single cell suspensions from tumor-associated and unaffected colon mucosa showed a marked decrease in CD19(+)CD38(high)IgA(+) plasmablasts in the tumor-associated mucosa, while the total frequencies of B and T cells were similar. This finding was confirmed in ELISPOT assays, demonstrating a 64% reduction in the frequencies of IgA-secreting cells among cells from the tumor-associated mucosa. The few IgA(+) plasmablasts present in the tumor did not express CCR10, and functional migration assays demonstrated that IgA-secreting cells from tumor-associated mucosa did not migrate in response to CCL28. Taken together, our results show an impaired migration of IgA-secreting cells to colon tumors, presumably caused by a decreased production of CCL28 in the tumor. The lack of local IgA antibodies may lead to impaired barrier function and increased bacterial colonization, driving further inflammatory responses and promoting tumor growth.
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| 40. |
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| 41. |
- Nygren, Olle, et al.
(författare)
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A test method for assessment of spill and leakage from drug preparation systems
- 2005
-
Ingår i: Ann Occup Hyg. - : Oxford University Press. - 0003-4878 .- 1475-3162. ; 49:8, s. 711-8
-
Tidskriftsartikel (refereegranskat)abstract
- Anti-cancer drugs are reactive compounds with known adverse health effects. To prevent occupational exposure to these drugs, there are, in most countries, regulations for handling anti-cancer drugs. Many preparation systems are available, e.g. isolators, biological safety cabinets (BSCs), filter spikes (venting spikes with micro-pore filter) and closed systems (e.g. PhaSeal). Although these systems are used, there are reports of exposure. This causes concern over how efficient these systems are to prevent spill and leakage that may cause undesired exposure when handling cytotoxic drugs. Today, this knowledge is lacking. This paper presents a method (Tc-method) for testing drug preparation systems for spill and leakage. The Tc-method is based on 99Tc(m) as a tracer, with which drug vials used for test preparations are spiked. Wipe samples are then collected around the working area to measure spill and leakage. The Tc-method has been validated using an independent method, showing good agreement between the methods. Spills down to 1 nl cm(-2) can be determined. In an appendix, the Tc-method is described in a detailed step-by-step procedure.
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| 42. |
- Odin, Elisabeth, 1955, et al.
(författare)
-
Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients.
- 2003
-
Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 9:16 Pt 1, s. 6012-9
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of this study was to analyze whether gene expression levels of folate enzymes in adjacent mucosa were associated with outcome of colorectal cancer patients. EXPERIMENTAL DESIGN: Real-time PCR was used to quantify expression levels of folate-associated genes including the reduced folate carrier (RFC-1), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH),and thymidylate synthase (TS) in tumor tissue and adjacent mucosa of patients with primary colorectal cancer (n=102). Furthermore, reduced folates in the tissues were measured with a binding-assay method. RESULTS: Mean gene expression levels of RFC-1, FPGS, GGH, and TS were significantly higher in tumor biopsies compared with mucosa. Univariate and multivariate analyses showed that the FPGS gene expression level in mucosa, but not in tumor, was a prognostic parameter independent of the clinicopathological factors with regard to survival. Patients with high FPGS levels (>0.92) in mucosa also showed significantly higher total folate concentrations (P=0.03) and gene expression levels of RFC-1 (P<0.01), GGH (P<0.01), and TS (P=0.04) compared with patients with low FPGS levels. The total reduced folate concentration correlated with the gene expression levels of RFC-1 and FPGS but not with TS or GGH. CONCLUSION: Our results suggest that normal-appearing colonic mucosa adjacent to primary colon cancer can show altered gene expression levels of FPGS that may have bearing on the development of aggressive metastatic behavior of the tumor and on tumor-specific survival.
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| 43. |
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| 44. |
- Odin, Elisabeth, 1955, et al.
(författare)
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Determination of reduced folates in tumor and adjacent mucosa of colorectal cancer patients using LC-MS/MS.
- 2013
-
Ingår i: Biomedical chromatography : BMC. - : Wiley. - 1099-0801 .- 0269-3879. ; 27:4, s. 487-495
-
Tidskriftsartikel (refereegranskat)abstract
- A liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS) method has been developed for the determination of 5,10-methylenetetrahydrofolate (methyleneTHF), tetrahydrofolate (THF) and 5-methyltetrahydrofolate (methylTHF) in colorectal mucosa and tumor tissues. The folate extraction method includes homogenization, heat and folate conjugase treatment to hydrolyze polyglutamyl folate to monoglutamyl folate. Before analysis on LC-MS/MS, simple and fast sample purification with ultrafiltration (molecular weight cut-off membrane, 10kDa) was performed. Folates were detected and quantified using positive electrospray. The method described in the present paper was successfully applied to determine the level of three folate monoglutamates in mucosa and tumor samples from 77 colorectal cancer patients, starting from a limited amount of tissue. The results showed that the LC-MS/MS method has a great advantage over other previously used methods because of its high sensitivity and selectivity. Significantly higher levels of methyleneTHF and THF were found in tumor compared with matched mucosa tissues. Folate levels in adjacent mucosa were associated with tumor location, age and gender. The correlation between folate levels and tumor site further strengthens the fact that development of right- and left-sided tumors follows different pathways. Copyright © 2012 John Wiley & Sons, Ltd.
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| 45. |
- Odin, Elisabeth, 1955, et al.
(författare)
-
Expression and clinical significance of methylenetetrahydrofolate reductase in patients with colorectal cancer
- 2006
-
Ingår i: Clin Colorectal Cancer. - 1533-0028. ; 5:5, s. 344-9
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the study was to investigate the influence of methylenetetrahydrofolate reductase (MTHFR) gene expression levels and MTHFR polymorphism C677T on the outcome of patients with colorectal cancer (CRC). Furthermore, we wanted to evaluate the interaction between MTHFR and thymidylate synthase (TS) and folylpolyglutamate synthase (FPGS) and to investigate the impact of folate concentration on patients with CRC with different MTHFR genotypes. PATIENTS AND METHODS: The frequency of MTHFR polymorphism C677T was determined (n = 147), and gene expression levels of MTHFR, TS, and FPGS were quantified with real-time polymerase chain reaction (n = 157). Reduced folates in tissue were measured with a binding assay (n = 40). RESULTS: We observed a significantly lower concentration of tetrahydrofolate (THF) in patients with CT or TT genotypes compared with patients having the CC genotype. Twenty-six patients with Dukes A to C tumors who had not been subjected to chemotherapy relapsed. Out of these, 18 had CT or TT genotypes, and only 8 had the CC genotype (P = 0.045). Furthermore, 75 patients did not relapse, and out of these, 35 had CT or TT genotypes, and 40 had the CC genotype. The relative gene expression level of MTHFR in patients subgrouped by CC and CT or TT genotypes was significantly lower in carcinomas compared with adjacent mucosa (P < 0.0001 and P < 0.0001, respectively). A significant difference in MTHFR expression level was also observed according to MTHFR genotype in the tumor but not in adjacent mucosa. The MTHFR gene expression level in mucosa was a prognostic parameter independent of the clinicopathologic factors with regard to survival for patients with MTHFR C677T mutation. CONCLUSION: Our results showed that it is possible to identify patients with CRC with a higher risk for relapse. Furthermore, patients with a mutant genotype in combination with low MTHFR expression have a poor clinical outcome.
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| 46. |
- Odin, Elisabeth, 1955, et al.
(författare)
-
Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status following Adjuvant Bolus 5-FU-Based Chemotherapy.
- 2015
-
Ingår i: Molecular medicine (Cambridge, Mass.). - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 21, s. 597-60
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation, and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3-5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p<0.001 and p<0.01, respectively) with decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in transport of folates into the cells, and function optimally at different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin.
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| 47. |
- Odin, Elisabeth, 1955, et al.
(författare)
-
Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer
- 2019
-
Ingår i: Tumor Biology. - : IOS Press. - 1010-4283 .- 1423-0380. ; 41:6
-
Tidskriftsartikel (refereegranskat)abstract
- 5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes SLC46A1/PCFT, SLC19A1/RFC-1, ABCC3/MRP3, GGH, and MTHFD1L, which are involved in folate transport, polyglutamation, or metabolism, was associated with longer disease-free survival of the patients. Each of these genes either encodes mitochondrial enzymes or is being regulated by mitochondrial transcription factors. Expression of the SLC46A1/PCFT gene was most strongly associated with disease-free survival, regardless of treatment regimen. In conclusion, the results show that expression of folate pathway genes are associated with outcome of colorectal cancer patients treated with adjuvant 5-fluorouracil in combination with leucovorin. A prospective study needs to be conducted to determine if expression of these genes can be used to predict response to leucovorin and other folates that are now being tested in clinical studies. Moreover, there seems to be a link between folate metabolism and mitochondrial biogenesis and respiration that deserves further exploration. © The Author(s) 2019.
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| 48. |
- Odin, Elisabeth, 1955, et al.
(författare)
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Rapid method for relative gene expression determination in human tissues using automated capillary gel electrophoresis and multicolor detection
- 1999
-
Ingår i: J Chromatogr B Biomed Sci Appl. - 1387-2273. ; 734:1, s. 47-53
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate a direct and automated post-polymerase chain reaction (PCR) detection system to simultaneously determine the relative gene expression levels of nine cancer-related human genes. Total RNA was prepared from flash-frozen biopsies derived from human colorectal tumors or normal mucosa and reverse-transcribed to cDNA which was PCR-amplified using primer pairs corresponding to the studied genes. In each reaction, the forward primer was labeled with a fluorescent dye. The PCR products were pooled and an internal size standard with a uniquely colored fluorescent dye was added. The samples were then subjected to automated capillary gel electrophoresis. Fragment analysis software was used to calculate the relative gene expression using beta-actin as the reference gene. We found that automated capillary gel electrophoresis with multicolor detection is a rapid, accurate and highly reproducible method for separation and quantification of PCR-amplified cDNA.
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| 49. |
- Oman, M, et al.
(författare)
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Treatment of non-resectable pancreatic cancer with intraperitoneal 5-FU and leucovorin IV.
- 2001
-
Ingår i: European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. - : Elsevier BV. - 0748-7983. ; 27:5, s. 477-81
-
Tidskriftsartikel (refereegranskat)abstract
- To explore the feasibility of intraperitoneal (IP) 5-fluorouracil (5-FU) and (IV) leucovorin for patients with advanced pancreatic carcinoma.
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| 50. |
- Persson, Eva, 1953, et al.
(författare)
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Information to the relatives of people with ostomies: is it satisfactory and adequate?
- 2005
-
Ingår i: Journal of wound, ostomy, and continence nursing : official publication of The Wound, Ostomy and Continence Nurses Society / WOCN. - 1071-5754. ; 32:4, s. 238-45
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to evaluate how relatives of patients with an ostomy rated the various aspects of care, how they perceived the quality of the care provided, and how they ranked their involvement in the care. Patients' satisfaction was also sought, particularly their perception of relatives' involvement. DESIGN: Descriptive cross-sectional. SETTINGS AND SUBJECTS: The study comprised a colostomy group (32 pairs) and an ileostomy group (28 pairs). All patients attended a stoma outpatient clinic. METHODS: Quality of care was assessed using the identity-oriented dimension of the validated questionnaire Qualityof Care from the Patient's Perspective. Questionnaires were mailed to patients and their relatives. RESULTS: Relatives and patients in both study groups considered most topics covered by the questionnaire to be important. Half of the patients with an ileostomy and their relatives and approximately 30% of those in the colostomy group were dissatisfied with the information they received, however. Moreover, a greater proportion (41-89%) of the patients were unhappy with the opportunities they were offered to participate in the decision-making process. Patients with an ileostomy and their relatives tended to be more dissatisfied with the quality of care than the colostomy group, but the difference was not statistically significant. CONCLUSION: The topics covered by the questionnaire were considered important to both patients and their relatives. Information and counseling offered by the ET nurses and the colorectal surgeons were judged to be unsatisfactory, indicating the need for frequently assessing and improving general standards of quality of care.
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