| 1. |
- 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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| 2. |
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| 3. |
- Falk, Peter, 1962, et al.
(författare)
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Colorectal Cancer Cells Adhere to Traumatized Peritoneal Tissue in Clusters, An Experimental Study.
- 2018
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Ingår i: Journal of investigative surgery. - : Informa UK Limited. - 0894-1939 .- 1521-0553. ; 31:4, s. 349-356
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Tidskriftsartikel (refereegranskat)abstract
- Purpose/Aim: Colorectal malignity is one of the most common forms of cancer. The finding of free intraperitoneal colorectal cancer cells during surgery has been shown to be associated with poor outcome. The aim of this study was to develop an experimental model designed to investigate adhesion of colorectal cancer cells to the peritoneal surface.Two human experimental models were developed, the first using cultured mesothelial cells and the second consisting of an ex vivo model of peritoneal tissue. Both models were subjected to standardized trauma, following which labeled colorectal cancer cells (Colo205) were introduced. Adhesion of tumor cells was monitored using microscopy and detection of fluorochromes.The mesothelial cell layers and peritoneal membranes remained viable in culture medium for several weeks. In our experimental model, the tumor cells added were seen to adhere to the edges of the traumatized area in cluster formations.The use of human peritoneal tissue in an ex vivo model would appear to be a potentially useful tool for the study of interaction between human peritoneal membrane and free tumor cells. Experimental surgical trauma increases the ability of tumor cells to adhere to the peritoneal membrane. This ex vivo model should be useful in future studies on biological interactions between peritoneum and tumor cells in the search for novel forms of peritoneal cancer therapy.
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| 4. |
- Falk, Peter, 1962, et al.
(författare)
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Role of matrix metalloproteinases in tumour invasion: immunohistochemistry of peritoneum from peritoneal carcinomatosis
- 2018
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 35:5
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is one of the most common forms of cancer. Spread of tumour to the peritoneal cavity may lead to seeding of cancer cells that adhere to and invade the peritoneal membrane causing peritoneal carcinomatosis. Matrix metalloproteinases (MMPs) play an essential role in cancer cell invasion and dissemination. The aim of this study was to evaluate the morphology and presence of matrix metalloproteinases in peritoneal carcinomatosis. Biopsy samples of the parietal peritoneum were taken from patients undergoing cytoreductive surgery for peritoneal carcinomatosis. The samples were fixed in formalin, dehydrated and embedded in paraffin prior to cutting into 4-mu m slices. Staining with haematoxylin/eosin was used for morphology studies, and MMP-1, MMP-2 and TIMP-1 levels were evaluated using immunohistochemistry and light microscopy. The microscopically tumour-free areas of the peritoneal membrane were thin compared to the peripheral invasion zone and the areas invaded by tumour. Peritoneum invaded by tumour was richly vascularised and contained inflammatory cells. MMP-1 was expressed in tumour-free peritoneum and in the invasion zone between tumour and peritoneal tissue, but not in tumour-invaded areas. MMP-2 and TIMP-1 were mostly expressed in the proximity of blood vessels and inflammatory cells in tumour-invaded areas, but was not seen in tumour-free areas. MMPs play an important role in the process of cancer cell invasion of the peritoneum in peritoneal carcinomatosis. The peripheral zone of the tumour appears to be of importance for tumour invasion.
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| 5. |
- Ghanipour, Lana, et al.
(författare)
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Efficacy of hyperthermic intraperitoneal chemotherapy in colorectal cancer : A phase I and III open label randomized controlled registry-based clinical trial protocol
- 2024
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:3
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Tidskriftsartikel (refereegranskat)abstract
- Standard treatment for patient with peritoneal metastases from colorectal cancer is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In recent years, the efficacy of oxaliplatin-based HIPEC has been challenged. An intensified HIPEC (oxaliplatin+irinotecan) in combination with early postoperative intraperitoneal chemotherapy (EPIC) has shown increased recurrence-free survival in retrospective studies. The aim of this trial is to develop a new HIPEC/EPIC regimen and evaluate its effect on morbidity, oncological outcome, and quality-of-life (QoL). This study is designed as a combined phase I/III multicenter randomized trial (RCT) of patients with peritoneal metastases from colorectal cancer eligible for CRS-HIPEC. An initial phase I dose escalation study, designed as a 3+3 stepwise escalation, will determine the maximum tolerable dose of 5-Fluorouracil (5-FU) as 1-day EPIC, enrolling a total of 15–30 patients in 5 dose levels. In the phase III efficacy study, patients are randomly assigned intraoperatively to either the standard treatment with oxaliplatin HIPEC (control arm) or oxaliplatin/irinotecan-HIPEC in combination with single dose of 1-day 5-FU EPIC (experimental arm). 5-FU is administered intraoperatively after CRS-HIPEC and closure of the abdomen. The primary endpoint is 12-month recurrence-free survival. Secondary endpoints include 5-year overall survival, 5-year recurrence-free survival (registry based), postoperative complications, and QoL up to 3 years after study treatment. This phase I/III trial aims to identify a more effective treatment of colorectal peritoneal metastases by combination of HIPEC and EPIC.
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| 7. |
- 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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| 8. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Motivation: Cancer is known to stem from multiple, independent mutations, the effects of which aggregate to drive the cell into a cancerous state. To understand the complex interplay between affected genes, their gene regulatory network (GRN) needs to be uncovered, to revealing detailed insights of regulatory mechanisms. We therefore decided to infer a reliable GRN from perturbation responses of 40 genes known or suspected to have a role in human cancers yet whose regulatory interactions are poorly known.Results: siRNA knockdown experiments of each gene were done in a human squamous carcinoma cell line, after which the transcriptomic response was measured. From these data GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. The best GRN was shown to be significantly more predictive than the null model, both in crossvalidated benchmarks and for an independent dataset of the same genes but subjected to double perturbations. It agrees with many known links in addition to predicting a large number of novel interactions, a subset of which were experimentally validated. The inferred GRN captures regulatory interactions central to cancer-relevant processes and thus provides mechanistic insights that are useful for future cancer research.
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| 9. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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| 10. |
- Swartling, Torbjörn
(författare)
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Aspects on Minimally Invasive Surgery for Rectal Tumours
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Transanal endoscopic microsurgery (TEM) and laparoscopic rectal resection are minimally invasive methods of surgery for rectal tumours. One aim of this thesis was to analyse the inflammatory response after minimally invasive surgery compared with open resection. Other aims were to investigate patient selection using magnetic resonance imaging (MRI) and endorectal ultrasound (ERUS) and to investigate the outcome of TEM for rectal cancer. Methods: Inflammatory mediators were measured using enzyme-linked immunosorbent assays (ELISA) in patients undergoing TEM, laparoscopic or open resection. Assessments of tumours using MRI and ERUS were compared with histopathology. Registry data from TEM procedures and salvage resection for rectal cancer were analysed. Low-risk tumours were defined as tumour stage T1, submucosal invasion Sm1-2, <3 cm, without adverse features, and these were separately analysed for outcome. Results: The increases of interleukin-6 and C-reactive protein were less pronounced after TEM and laparoscopic resection than after open resection. The staging accuracy using MRI was increased from 0.65 to 0.83 by combining lymph node assessment using MRI with bowel wall assessment using ERUS. There were no local recurrences after TEM for low-risk tumours. Conclusions: The inflammatory response after TEM and laparoscopic resection was limited compared with open resection. The staging accuracy was increased by a combined use of MRI and ERUS. The population-based oncological outcome of TEM for low-risk tumours was excellent.
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