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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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