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1.	Birgisson, Helgi, et al. (författare) Acute pancreatitis: a prospective study of its incidence, aetiology, severity and mortality in Iceland. 2002 Ingår i: Eur J Surg. ; 168:5, s. 278-82 Tidskriftsartikel (refereegranskat)
2.	Gaber, Alexander, et al. (författare) High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer 2009 Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 100:10, s. 1540-1548 Tidskriftsartikel (refereegranskat)abstract Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan-Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19-2.79) and disease-free survival (HR=1.56; 95% CI=1.05-2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43-5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.
3.	Birgisson, Helgi, et al. (författare) Adverse effects of preoperative radiation therapy for rectal cancer : long-term follow-up of the Swedish Rectal Cancer Trial. 2005 Ingår i: Journal of Clinical Oncology. - : American Scoiety of Clinical Oncology. - 0732-183X .- 1527-7755. ; 23:34, s. 8697-8705 Tidskriftsartikel (refereegranskat)abstract PURPOSE: To analyze the occurrence of subacute and late adverse effects in patients treated with preoperative irradiation for rectal cancer.PATIENTS AND METHODS: The study population included 1,147 patients randomly assigned to preoperative radiation therapy or surgery alone in the Swedish Rectal Cancer Trial conducted 1987 through 1990. Patient data were matched against the Swedish Hospital Discharge Register to identify patients admitted to hospital after the primary treatment of the rectal cancer. Patients with known residual disease were excluded, and patients with a recurrence were censored 3 months before the date of recurrence. Relative risks (RR) with 95% CIs were calculated.RESULTS: Irradiated patients were at increased risk of admissions during the first 6 months from the primary treatment (RR = 1.64; 95% CI, 1.21 to 2.22); these were mainly for gastrointestinal diagnoses. Overall, the two groups showed no difference in the risk of admissions more than 6 months from the primary treatment (RR = 0.95; 95% CI, 0.80 to 1.12). Regarding specific diagnoses, however, RRs were increased for admissions later than 6 months from the primary treatment in irradiated patients for unspecified infections, bowel obstruction, abdominal pain, and nausea.CONCLUSION: Gastrointestinal disorders, resulting in hospital admissions, seem to be the most common adverse effect of short-course preoperative radiation therapy in patients with rectal cancer. Bowel obstruction was the diagnosis of potentially greatest importance, which was more frequent in irradiated than in nonirradiated patients.
4.	Birgisson, Helgi, et al. (författare) Authors' reply: Late gastrointestinal disorders after rectal cancer surgery with and without preoperative radiation therapy (Br J Surg 2008; 95 : 206-213) 2008 Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 95:6, s. 803-803 Tidskriftsartikel (refereegranskat)
5.	Birgisson, Helgi, 1967- (författare) Cancer of the Colon and Rectum : Population Based Survival Analysis and Study on Adverse Effects of Radiation Therapy for Rectal Cancer 2006 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The Swedish Cancer Register was used to determine the relative survival rate in colon and rectal cancer and to estimate the occurrence of second cancers related to radiation therapy for rectal cancer. The Swedish Hospital Discharge Register and hospital records were used to estimate the rate of late adverse effects due to radiation therapy for rectal cancer. The whole Swedish population was the source of the survival studies. Patients participating in the Uppsala Trial and the Swedish Rectal Cancer Trial on radiation therapy for rectal cancer constituted the subjects of the studies on late adverse effects and second cancers.The main results of the survival analysis revealed a significant improvement in the 5-year relative survival rate for both colon and rectal cancer. During the time period 1960-1999, the survival improved from 39.6% to 57.2% in colon cancer and from 36.1% to 57.6% in rectal cancer.Patients irradiated for rectal cancer, in addition to surgery, were at increased risk for a second cancer compared to those treated by surgery alone. This risk increase was mainly found for cancers developing in organs within or adjacent to the irradiated target (relative risk (RR) 2.04; 95% confidence interval (CI) 1.10–3.79). Furthermore, the most important late adverse effects of radiation therapy seem to be those on the gastrointestinal tract, in the form of small bowel obstruction (RR 1.88; 95%CI 1.10–3.20) and abdominal pain (RR 1.92; 95% CI 1.14–3.23). Overall, the benefit of radiation therapy was greater than its drawbacks, as a large reduction in local recurrences and better survival was noted in patients treated preoperatively with irradiation for rectal cancer.In conclusion, significant improvements in the survival of patients with colon and rectal cancers have occurred in the last decades, especially in patients with rectal cancer. These improvements probably are related to advances in surgical and adjuvant treatment. The radiation therapy has several drawbacks, however, including an increased risk of second cancers and of bowel obstruction. This emphasises the need to further improve the radiation technique and to select only those patients for radiation therapy who are most likely to benefit from it.
6.	Birgisson, Helgi, et al. (författare) Effects of Centralization of Colorectal Surgery on the Outcome of Patients with Distal Sigmoid Colonic Cancer 2009 Ingår i: Digestive Surgery. - : S. Karger AG. - 0253-4886 .- 1421-9883. ; 26:2, s. 169-175 Tidskriftsartikel (refereegranskat)abstract Background: In 1996, all colorectal surgery in the county of Västmanland, Sweden, was centralized to the central District Hospital in Västerås. A Colorectal Unit was established and modern surgical procedures were introduced. The aim of this study was to analyze the outcome for patients treated surgically for distal sigmoid colonic cancer before and after the centralization. Methods: Hospital records of all patients with distal sigmoid colonic cancer, treated between 1991-1995, group 1 (n = 64), and 1996-2000, group 2 (n = 82), were studied retrospectively. Results: In group 2, there were fewer reoperations (n = 0) than in group 1 (n = 6; p = 0.005) and the postoperative mortality was lower; one in group 2 compared with five in group 1 (p = 0.047). The amount of lymph nodes examined were higher and the length of distal surgical margin longer in group 2. Curatively treated patients in group 2 had better overall survival compared to group 1 (RR 0.56; 95% CI 0.34-0.93). Conclusion: Centralization of colorectal surgery resulted in an improvement of pathologic specimens and a decrease in postoperative reoperations and mortality in patients treated surgically for distal sigmoid colonic cancer. Moreover, the overall survival of curatively treated patients was improved.
7.	Birgisson, Helgi, et al. (författare) Late adverse effects of radiation therapy for rectal cancer : a systematic overview 2007 Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 46:4, s. 504-516 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The use of radiation therapy (RT) together with improvement in the surgical treatment of rectal cancer improves survival and reduces the risk for local recurrences. Despite these benefits, the adverse effects of radiation therapy limit its use. The aim of this review was to present a comprehensive overview of published studies on late adverse effects related to the RT for rectal cancer. METHODS: Meta-analyses, reviews, randomised clinical trials, cohort studies and case-control studies on late adverse effects, due to pre- or postoperative radiation therapy and chemo-radiotherapy for rectal cancer, were systematically searched. Most information was obtained from the randomised trials, especially those comparing preoperative short-course 5 x 5 Gy radiation therapy with surgery alone. RESULTS: The late adverse effects due to RT were bowel obstructions; bowel dysfunction presented as faecal incontinence to gas, loose or solid stools, evacuation problems or urgency; and sexual dysfunction. However, fewer late adverse effects were reported in recent studies, which generally used smaller irradiated volumes and better irradiation techniques; although, one study revealed an increased risk for secondary cancers in irradiated patients. CONCLUSIONS: These results stress the importance of careful patient selection for RT for rectal cancer. Improvements in the radiation technique should further be developed and the long-term follow-up of the randomised trials is the most important source of information on late adverse effects and should therefore be continued.
8.	Birgisson, Helgi, et al. (författare) Late gastrointestinal disorders after surgery for rectal cancer and the relationship to preoperative radiation therapy Annan publikation (övrigt vetenskapligt/konstnärligt)
9.	Birgisson, Helgi, et al. (författare) Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer 2015 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 15 Tidskriftsartikel (refereegranskat)abstract Background: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Methods: Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Results: Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. Conclusions: The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.
10.	Birgisson, Helgi, et al. (författare) Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. 2005 Ingår i: J Clin Oncol. - : ASCO Publications. - 0732-183X .- 1527-7755. ; 23:25, s. 6126-31 Tidskriftsartikel (refereegranskat)
11.	Birgisson, Helgi, et al. (författare) Patients with colorectal peritoneal metastases and high peritoneal cancer index may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy 2020 Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 46:12, s. 2283-2291 Tidskriftsartikel (refereegranskat)abstract Background: Peritoneal cancer index (PCI) >20 is often seen as a contraindication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases (PM) from colorectal cancer. The aim of this study was to compare the overall survival in colorectal PM patients with PCI >20 and PCI <= 20 treated with CRS and HIPEC to those having open-close/debulking procedure only.Methods: All patients with colorectal PM and intention to treat with CRS and HIPEC in Uppsala Sweden 2004-2017 were included. Patients scheduled for CRS and HIPEC were divided into three groups, PCI >20, PCI <= 20, and those not operated with CRS and HIPEC stated as open-close including those treated with palliative debulking.Results: Of 201 operations, 112 (56%) resulted in CRS and HIPEC with PCI <= 20, 45 (22%) in CRS and HIPEC with PCI >20 and 44 (22%) resulted in open-close/debulking. Median survival for CRS and HIPEC and PCI >20 was 20 months (95%CI 14-27 months) with 7% surviving longer than 5 years (n = 3). For CRS and HIPEC and PCI <= 20 the median survival was 33 months (95%CI 30-39 months) with 23% (n = 26) surviving >5years. The median survival for open-close was 9 months (95%CI 4-10 months), no one survived >5years.Conclusion: Patients with PM from colorectal cancer and PCI >20 that were treated with CRS and HIPEC experience a one year longer and doubled overall survival compared with open-close/debulking patients. In addition to PCI, more factors should be taken into account when a decision about proceeding with CRS or not is taken.
12.	Birgisson, Helgi, et al. (författare) Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer : a prospective validation study 2010 Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 46:18, s. 3323-3331 Tidskriftsartikel (refereegranskat)abstract Background: Previous studies have suggested plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) as a stage independent prognostic marker in colorectal cancer (CRC) patients. The aim was to validate plasma TIMP-1 and serum carcino-embryonic antigen (CEA) levels as prognostic indicators in an independent population-based cohort of patients with CRC. Patients and methods: During 2000-2003, plasma and serum were collected preoperatively from 322 patients treated for primary CRC. TIMP-1 and CEA levels were determined by validated ELISA platforms. Results: High TIMP-1 and CEA levels each associated with poor overall survival (OS); TIMP-1 (hazard ratio (HR) 2.1; 95% confidence interval (CI) 1.6-2.7) and CEA (HR 1.2; 95% CI 1.1-1.3), and disease-free survival (DFS); TIMP-1 (HR 2.0; 95% CI: 1.5-2.6) and CEA (HR 1.2; 95% CI: 1.1-1.4) in univariate analyses. In stratified analyses of stages II and III, TIMP-1 levels associated significantly with OS and DFS in stages II and III, associations were not found for CEA. Multivariate analysis for OS, including TIMP-1 and CEA levels and clinico-pathological baseline variables, revealed significant association of TIMP-1 (HR 1.8; 95% CI 1.3-2.4) but not CEA levels. Conclusions: This independent prospective validation study confirms the significant association between preoperative plasma TIMP-1 levels and survival of CRC patients: TIMP-1 provided stronger prognostic information than CEA. Thus, this study brings plasma TIMP-1 to the next level of evidence for its clinical use as a prognostic marker in CRC patients.
13.	Birgisson, Helgi, et al. (författare) Serum concentrations of human chorionic gonadotropin beta and its association with survival in patients with colorectal cancer 2012 Ingår i: CANCER BIOMARK. - 1574-0153 .- 1875-8592. ; 11:4, s. 173-181 Tidskriftsartikel (refereegranskat)abstract Increased serum concentrations of the beta subunit of human chorionic gonadotropin (hCG beta) are associated with adverse prognosis in several cancers. The aim of the present study was to analyse the association between serum hCG beta recurrence, and survival, in patients with colorectal cancer. The concentrations of hCG beta were determined in serum collected preoperatively from 324 patients with colorectal cancer, of whom 270 were curatively treated. The serum concentrations of hCG beta were associated with increasing age and they were higher in women than in men. Using the 75th percentile (1.55 pmol/L) as a cut-off for serum hCG beta, overall survival (OS) was shorter in patients with elevated concentrations (HR 1.95; 95% CI 1.39-2.74; P = 0.004), and this association was stronger in women (P = 0.022) than in men (P = 0.061). In multivariate analyses including age, disease stage, tumour differentiation, vascular invasion and CEA, high serum hCG beta concentrations remained an independent prognostic factor for adverse OS in women (HR 2.26; 95% CI 1.39-3.67), but not in men (HR 0.78; 95% CI 0.41-1.51). The same trend was observed for disease free-and cancer specific survival. High serum concentration of hCG beta is an independent prognostic factor for adverse outcome in women with colorectal cancer.
14.	Birgisson, Helgi, et al. (författare) Skimun fyrir krabbameinum í ristli og endaþarmi : Yfirlitsgrein um nýgengi, dánartíðni, kostnað og árangur 2021 Ingår i: Laeknabladid. - : LAEKNAFELAG ISLANDS-ICELANDIC MEDICAL ASSOC. - 0023-7213 .- 1670-4959. ; 107:9, s. 398-405 Forskningsöversikt (refereegranskat)abstract In this article the incidence and mortality for cancer of the colon and rectum in Iceland is discussed. The two most common screening methods, faecal immunochemical test (FIT) and colonoscopy are compared and an estimate of cost and benefits for the Icelandic society will be made. The incidence of cancer of the colon and rectum has been increasing in Iceland in last decades but mortality has decreased and survival improved. However, more individuals die from cancer of the colon and rectum than from both breast-and cervical cancer added together. It is likely that screening for cancer of the colon and rectum, could prevent at least 6 of the 28 deaths related to those cancers, occurring yearly in Iceland in screening age, given a screening ages of 50-74 years. The extra cost for the Icelandic community due to the implementation of screening for cancer of the colon and rectum will be acceptable due to the lower cost of simpler treatments, lower cancer incidence and reduced mortality.
15.	Birgisson, Helgi, et al. (författare) Survival endpoints in colorectal cancer and the effect of second primary other cancer on disease free survival 2011 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11, s. 438- Tidskriftsartikel (refereegranskat)abstract Background: In cancer research the selection and definitions of survival endpoints are important and yet they are not used consistently. The aim of this study was to compare different survival endpoints in patients with primary colorectal cancer (CRC) and to understand the effect of second primary other cancer on disease-free survival (DFS) calculations. Methods: A population-based cohort of 415 patients with CRC, 332 of whom were treated with curative intention between the years 2000-2003, was analysed. Events such as locoregional recurrence, distant metastases, second primary cancers, death, cause of death and loss to follow-up were recorded. Different survival endpoints, including DFS, overall survival, cancer-specific survival, relapse-free survival, time to treatment failure and time to recurrence were compared and DFS was calculated with and without inclusion of second primary other cancers. Results: The events that occurred most often in patients treated with curative intention were non-cancer-related death (n = 74), distant metastases (n = 66) and death from CRC (n = 59). DFS was the survival endpoint with most events (n = 170) followed by overall survival (n = 144) and relapse-free survival (n = 139). Fewer events were seen for time to treatment failure (n = 80), time to recurrence (n = 68) and cancer-specific survival (n = 59). Second primary other cancer occurred in 26 patients and its inclusion as an event in DFS calculations had a detrimental effect on the survival. The DFS for patients with stage I-III disease was 62% after 5 years if second primary other cancer was not included as an event, compared with 58% if it was. However, the difference was larger for stage II (68 vs 60%) than for stage III (49 vs 47%). Conclusions: The inclusion of second primary other cancer as an endpoint in DFS analyses significantly alters the DFS for patients with CRC. Researchers and journals must clearly define survival endpoints in all trial protocols and published manuscripts.
16.	Birgisson, Helgi, et al. (författare) The correlation between a family history of colorectal cancer and survival of patients with colorectal cancer 2009 Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 8:4, s. 555-561 Tidskriftsartikel (refereegranskat)abstract The purpose was to analyze survival of patients with colorectal cancer and a positive family history for colorectal cancer in first degree relatives compared with those with no such family history and to determine whether differences in survival could be explained by known clinico-pathological factors. During 2000-2003, 318 consecutive patients with colorectal cancer answered a written questionnaire about their family history for colorectal cancer. During a 6-year follow-up, recurrences and survival were registered. Thirty-one (10%) patients had a first-degree relative with colorectal cancer, moreover two patients fulfilled the criteria of hereditary non-polyposis colorectal cancer and were excluded. Patients with a first-degree relative with colorectal cancer had better survival and lower risk for recurrences compared to those with no relatives with colorectal cancer. In a multivariate analysis including age, gender, stage of disease, tumor differentiation, vascular invasion and family history, patients with first-degree relatives with colorectal cancer had lower risks for death (RR 0.37; 95% CI 0.17-0.78) and death from cancer (RR 0.25; 95% CI 0.08-0.80), compared to those with a no relative with colorectal cancer. The differences were seen in patients with colon cancer but not rectal cancer. Family history for colorectal cancer in a first-degree relative is an individual prognostic factor in patients with colon cancer and could not be explained by known clinico-pathological factors. The value of family history taking in patients with colon cancer is therefore not only to identify families with hereditary colorectal cancer, but also to add information to the prognosis of the patients.
17.	Bratulic, Sinisa, 1981, et al. (författare) Noninvasive detection of any-stage cancer using free glycosaminoglycans. 2022 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:50 Tidskriftsartikel (refereegranskat)abstract Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
18.	Darmanis, Spyros, et al. (författare) Multiplexed solid-phase proximity ligation assays: Highly specific and parallel protein measurements with DNA sequencing readout Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Identification and validation of protein biomarkers is a very important step towards the understanding of the underlying mechanisms of disease, early diagnosis and efficient patient treatment. To carry out this task, methods are needed that would allow us to mine the proteome with sufficient sensitivity and specificity in large sets of samples. We present herein the development of a Multiplexed Proximity Ligation Assay (MultiPLAy), to facilitate efficient protein profiling in a parallel, sensitive and specific manner. We showed that for the simultaneous analysis of 35 proteins MultiPLAy exhibited an improved sensitivity over conventional sandwich assays as well as a smaller susceptibility to background signal increase in the transition from singleplex to multiplex. We used MultiPLAy to identify putative biomarkers in two separate sample cohorts of colorectal cancer (CRC) and cardiovascular disease (CVD) and with the use a novel multivariate analysis approach were able to identify new, as well as already known diagnostic biomarkers. Furthermore we were able to combine MultiPLAy with the use of next-generation sequencing allowing for the first time digital recording of protein profiles in blood. We demonstrated good reproducibility of MultiPLAy coupled to next-generation sequencing, as well as a satisfactory correlation to standard real-time PCR readout. We conclude that MultiPLAy has great potential as a basis for highly multiplexed protein detection assays that can be utilized for the identification of large numbers of proteins or protein variants. This will allow extensive validation of protein expression patterns in biobanked samples and in prospective studies, and can provide a much-needed platform for efficient validation of diagnostic markers for clinical use.
19.	Enblad, Malin (författare) Colorectal and appendiceal peritoneal metastases : From population studies to genetics 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Peritoneal dissemination of colorectal and appendiceal origin was previously considered the end-stage of malignant disease. Today, treatment with cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) has prolonged survival and cured some patients with peritoneal metastases (PM). Unfortunately, a majority of patients still have fatal outcomes. In this thesis, colorectal and appendiceal PM were studied from a wide population-based perspective down to the detailed perspectives of histopathology and genetics, with the aim of further contributing to prolonged survival.In Paper I, the heterogeneous histopathology of PM was investigated and a substantial proportion of patients undergoing CRS and HIPEC were found to have surgical specimens lacking neoplastic epithelium. These patients had a favourable prognosis and the results illustrate the importance of thorough analysing and reporting of histopathology for understanding differences in survival outcomes and for improving patient selection. In Paper II, the role of inflammation in colorectal and appendiceal carcinogenesis was investigated at a population-based level. Patients with non-surgical treatment of appendicitis had an increased incidence of cancer (especially of appendiceal and right-sided colon cancer) compared to the general population. This should be taken into consideration in the discussion of optimal management of patients with appendicitis. In Paper III, risk factors for PM were studied with the aim of aiding in the detection of PM at earlier stages. Appendiceal and right-sided colon cancer, advanced tumour and node stages, mucinous histopathology and vascular invasion were identified as high risk features for developing PM, and should increase awareness of potential PM. In Paper IV, genome-wide chromosomal copy number alterations of PM were explored and associated with prognosis after CRS and HIPEC. Colorectal PM exhibited a wide range of alterations of which copy number gain on parts of chromosome 1p and 15q were significantly associated with poor prognosis and have the potential to be used as prognostic molecular markers in the future.In conclusion, this thesis provides new insights into the field of colorectal and appendiceal cancer and PM to be used for improved patient selection, early detection and prevention, ultimately contributing to improved survival.
20.	Enblad, Malin, et al. (författare) Gains of Chromosome 1p and 15q are Associated with Poor Survival After Cytoreductive Surgery and HIPEC for Treating Colorectal Peritoneal Metastases 2019 Ingår i: Annals of Surgical Oncology. - : Springer Nature. - 1068-9265 .- 1534-4681. ; 26, s. 4835-4842 Tidskriftsartikel (refereegranskat)abstract Purpose: Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)Methods: All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays.Results: There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19-16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis.Conclusions: This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers.
21.	Enblad, Malin, et al. (författare) Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy 2016 Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 23:4, s. 1149-1156 Tidskriftsartikel (refereegranskat)abstract The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
22.	Enblad, Malin, et al. (författare) No Indication for Routine Resection of Surgical Scars during Cytoreductive Surgery and HIPEC 2024 Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:11 Tidskriftsartikel (refereegranskat)abstract Background: Careful macroscopic assessment of surgical scars is needed to avoid routine scar resection during cytoreductive surgery (CRS) for peritoneal metastases (PM). This study aimed to analyze the correlation between macroscopically suspected and microscopically confirmed scar metastases (SMs), and to analyze the prognostic impact of not undergoing routine scar resection.Method: All patients with previous surgery, treated with CRS and hyperthermic intraperitoneal chemotherapy, for colorectal PM or pseudomyxoma peritonei (PMP), at Uppsala University Hospital in 2013–2021, were included. Macroscopic SMs in surgical reports were compared with histopathological analyses.Results: In total, 227 patients were included. Among colorectal PM patients (n = 156), SM was macroscopically suspected in 41 (26%) patients, and 63 (40%) underwent scar resection. SM was confirmed in 19 (30%). Among patients with macroscopic suspicion, 45% had confirmed SM (positive predictive value, PPV). A total of 1 of 23 (4%) patients with no macroscopic suspicion had SM (negative predictive value, NPV = 96%). Among the PMP patients (n = 71), SM was macroscopically suspected in 13 (18%), and 28 (39%) underwent scar resection, of whom 12 (43%) had SM. The PPV was 77%. Occult SM was found in 1 of 14 (NPV = 93%). Not undergoing routine scar resection did not affect recurrence-free survival (RFS, p = 0.2) or overall survival (OS, p = 0.1) in colorectal PM patients or PMP patients (RFS p = 0.7, OS p = 0.7).Conclusion: Occult SM is uncommon and scar resection does not affect RFS or OS. Therefore, macroscopically benign-appearing scars can be left without resection, though resection should be performed upon suspicion or uncertainty.
23.	Enblad, Malin, et al. (författare) Prognostic importance of genetic alterations in colorectal peritoneal metastases Annan publikation (övrigt vetenskapligt/konstnärligt)
24.	Enblad, Malin, et al. (författare) Risk factors for appendiceal and colorectal peritoneal metastases 2018 Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 44:7, s. 997-1005 Tidskriftsartikel (refereegranskat)abstract BackgroundEarly diagnosis to target minimal volume disease has received increased attention in the management of appendiceal and colorectal peritoneal metastases (PM). This study aimed to identify risk factors for appendiceal, colon and rectal PM.MethodsData were retrieved from the Swedish Colorectal Cancer Registry for all patients undergoing bowel resection of appendiceal and colorectal tumours, in Sweden, 2007–2015. Risk factors for synchronous and metachronous PM were analysed with multivariate logistic and Cox proportional hazard regression models.ResultsSynchronous PM was most common in appendiceal cancer (23.5%), followed by colon (3.1%) and rectal (0.6%) cancer. The 5-year cumulative incidence was 9.0% for appendiceal, 2.5% for right colon, 1.8% for left colon and 1.2% for rectal cancer. In appendiceal cancer (n = 327), T4, N2, mucinous tumour, and non-radical surgery were associated with PM. In colon cancer (n = 24,399), synchronous PM were primarily associated with T4 (OR 18.37, 95% CI 8.12–41.53), T3 and N2 but also with N1, right-sided tumour, mucinous tumour, vascular and perineural invasion, female gender, age <60 and emergency surgery. These factors were also associated with metachronous PM. In rectal cancer (n = 10,394), T4 (OR 19.12, 95% CI 5.52–66.24), proximal tumour and mucinous tumour were associated with synchronous PM and T4 and mucinous tumour with metachronous PM.ConclusionsThis study shows that appendiceal cancer, right-sided colon cancer, advanced tumour and node stages and mucinous histopathology are the main high-risk features for PM and should increase the awareness of current or future PM.
25.	Enblad, Malin, et al. (författare) Signet Ring Cell Colorectal and Appendiceal Cancer : A Small Signet Ring Cell Component Is Also Associated with Poor Outcome 2023 Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:9 Tidskriftsartikel (refereegranskat)abstract Background: Colorectal signet ring cell (SRC) carcinoma with ≥50% SRCs (SRC ≥ 50) has a poor prognosis, but the prognostic role of SRCs < 50% (SRC < 50) is unclear. The aim of this study was to provide a clinicopathological characterization of SRC colorectal and appendiceal tumours and analyse the importance of the SRC component size.Methods: All patients in the Swedish Colorectal Cancer Registry diagnosed with colorectal or appendiceal cancer in 2009–2020 at Uppsala University Hospital, Sweden, were included. The SRCs were verified, and the components estimated by a gastrointestinal pathologist.Results: Of the 2229 colorectal cancers, 51 (2.3%) had SRCs, with a median component size of 30% (interquartile range of 12.5–40) and 10 (0.45%) had SRC ≥ 50. The SRC tumours were primarily localized in the right colon (59%) and appendix (16%). No patients with SRCs had stage I disease, and 26 (51%) had stage IV, of whom, 18 (69%) had peritoneal metastases. The SRC tumours were often high grade with perineural and vascular invasion. The 5-year overall survival (OS) rate for patients with SRC ≥ 50 were 20% (95% confidence interval (CI) 6–70), for SRC < 50, 39% (95% CI 24–61); and for non-SRCs, 55% (95% CI 55–60). Among the patients with SRC < 50 and <50% extracellular mucin, the 5-year OS was 34% (95% CI 19–61), while those with ≥50% extracellular mucin had an OS of 50% (95% CI 25–99). The 5-year recurrence-free survival rates were 51% (95% CI 13–83) for patients with SRC tumours, as compared to 83% (95% CI 77–89) and 81% (95% CI 79–84) for mucinous and non-mucinous adenocarcinoma, respectively.Conclusions: The presence of SRCs was strongly associated with aggressive clinicopathological features, peritoneal metastases, and poor prognosis, also when they make up <50% of a tumour.Simple SummarySignet ring cell (SRC) carcinoma of colorectal and appendiceal cancer is rare but is recognized as the histopathological subtype with the poorest prognosis. However, the prognostic relevance of a SRC component <50% is unclear. The aim of this study was to provide a clinicopathological characterization of all SRC-containing colorectal and appendiceal cancers, including those with <50% SRCs. The results showed that SRCs, both ≥50% and <50%, were associated with aggressive histopathological features, advanced stages, and, particularly, peritoneal metastases. Information about the presence of SRCs in tumour tissue, not only in the case of ≥50% SRCs, should be routinely registered in pathology reports and clinical registers to enable larger studies that can aid our understanding of SRCs in colorectal and appendiceal cancers.
26.	Folkesson, Joakim, et al. (författare) Swedish Rectal Cancer Trial : long lasting benefits from radiotherapy on survival and local recurrence rate. 2005 Ingår i: J Clin Oncol. - : ASCO Publications. - 0732-183X .- 1527-7755. ; 23:24, s. 5644-50 Tidskriftsartikel (refereegranskat)
27.	Frühling, Petter, et al. (författare) Oxaliplatin-based hyperthermic intraperitoneal chemotherapy with single drug versus multiple drug treatment for colorectal cancer with peritoneal metastases : an observational cohort study 2021 Ingår i: Journal of Gastrointestinal Oncology. - : AME PUBL CO. - 2078-6891 .- 2219-679X. ; 12:2, s. 516-526 Tidskriftsartikel (refereegranskat)abstract Background: Long-term survival for selected patients with peritoneal metastases (PM) from colorectal cancer (CRC) is possible when treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The objective of this study was to compare three different oxaliplatin-based (OX)-HIPEC regimens. Primary end-point was disease-free survival (DFS), and secondary endpoints, morbidity and overall survival (OS).Methods: This is a retrospective study of all patients with colorectal PM treated with CRS and HIPEC between 2004 and 2015 from the prospectively maintained Uppsala HIPEC database. One hundred and thirty-three patients were identified. Three HIPEC regimens were included: OX-HIPEC, OX-HIPEC + post-operative intraperitoneal chemotherapy (EPIC) with 5-fluorouracil (5-FU), and oxaliplatin-irinotecan-based (OXIRI)-HIPEC. Multivariable Cox regression for DFS was performed.Results: Sixty-one patients received OX-HIPEC, 24 patients received OX-HIPEC + 5-FU EPIC, and 48 patients received OXIRI-HIPEC. The DFS for the OX-HIPEC group was 10.5 months, OX-HIPEC + EPIC 11.9 months, and OXIRI-HIPEC 13.4 months (OX-HIPEC vs. OXIRI HIPEC, P=0.049). The morbidity and OS did not differ between the groups. In the multivariable analysis, low peritoneal cancer index (PCI), absence of liver metastases, low completeness of cytoreduction (CC) score, and multiple drug (EPIC or OXIRI) HIPEC regimen were independent prognostic factors for DFS.Conclusions: This study showed improved DFS with an intensification of HIPEC by adding irinotecan or EPIC compared to oxaliplatin alone without an increase in morbidity or mortality.
28.	Gaber, Alexander, et al. (författare) Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients 2010 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10, s. 498- Tidskriftsartikel (refereegranskat)abstract Background: There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI). Methods: Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni-and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA. Results: Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.032.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI. Conclusions: High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.
29.	Ghanipour, Arezo, et al. (författare) The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer 2009 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:11, s. 2949-2956 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Tryptophanyl-tRNA synthetase (TrpRS) is an aminoacyl-tRNA synthetase involved in protein synthesis and regulation of RNA transcription and translation and is an inhibitor of angiogenesis. TrpRS has been shown to be differentially expressed in colorectal cancer (CRC) and has thus been identified as a potential prognostic marker. The aim of this study was to analyze the correlation of TrpRS to the prognosis of patients diagnosed and treated for CRC within a defined population. METHODS: With a polyclonal, monospecific IgG antibody, TrpRS expression was assessed by immunohistochemistry on tissue microarrays with tumors from a population-based CRC cohort (n = 320). Staining intensity and fraction of positive tumor cells were recorded. A Cox multivariate model including TrpRS expression, carcinoembryonic antigen, age, stage, tumor differentiation, and lymphatic and vascular vessel invasion was used to calculate the hazard ratio and 95% confidence interval (95% CI) for time to recurrence, disease-free survival, and overall survival. RESULTS: Low expression of TrpRS correlated to increased risk for lymph node metastasis (P = 0.025) and a more advanced tumor stage (P = 0.001). Patients with tumors and increased levels of TrpRS expression had better survival than patients with low expression levels. Multivariate analyses revealed significantly better disease-free survival (relative risk, 0.59; 95% CI, 0.38-0.95) for patients with high expression than for patients with low expression of TrpRS. For colon cancer patients, a reduced risk for recurrence was seen in patients with increased TrpRS expression (relative risk, 0.23; 95% CI, 0.07-0.80). CONCLUSION: Low expression of TrpRS in tumor tissue correlates with increased risk for recurrence and worse survival in patients with CRC. This can be related to its antiangiogenic properties and could aid in the future selection of new drugs in the treatment of CRC.
30.	Ghanipour, Lana (författare) Colorectal Cancer : Aspects of Heredity, Prognosis and Tumour Markers 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Colorectal cancer (CRC) is one of the most common cancer types and leading causes of cancer death worldwide. Since CRC is a heterogenic disease, there is a demand for increased knowledge of the underlying genetic and epigenetic mechanisms. The aim of this thesis was to investigate heredity and potential tumour markers in relation to prognosis. In paper I, survival of patients with CRC and a positive family history of CRC in first-degree relatives was analysed. Patients with colon cancer and positive family history of CRC had improved survival compared to patients with negative family history. This improvement in survival could not be explained by known clinico-pathological factors. In paper II, we investigated the prognostic value of Tryptophanyl t-RNA synthetase (TrpRS) in tissues from patients operated for CRC. Low protein expression of TrpRS in primary tumour tissues correlated with increased risk of recurrence and poorer survival. In paper III, the prognostic value of microsatellite instability (MSI) and the correlation to heredity for CRC in first-degree relatives was investigated. Patients with proximal colon cancer and MSI had improved cancer specific survival. There were no correlation between MSI and heredity. In paper IV, we evaluated the potential use of proximity ligation assay (SP-PLA) in patients with CRC, by simultaneous analysis of 35 proteins in only 5 μl plasma. SP-PLA is a suitable method for protein detection and might give valuable guidance in pursuing new prognostic and predictive tumour markers. However, none of the markers selected for present SP-PLA analyses gave better prognostic information than CEA. In conclusion, heredity is related to better survival independent of MSI in patients with CRC and MSI is associated with better prognosis in proximal colon cancer. Detection and increased knowledge of molecular mechanism in CRC is important, however it needs to be further investigated and validated in clinical use.
31.	Ghanipour, Lana, et al. (författare) Detection of prognostic biomarkers with solid-phase proximity ligation assay in patients with colorectal cancer 2016 Ingår i: Translational Oncology. - : Elsevier BV. - 1944-7124 .- 1936-5233. ; 9:3, s. 251-255 Tidskriftsartikel (refereegranskat)abstract Background: In the search for prognostic biomarkers a significant amount of precious biobanked blood samples is needed if conventional analyses are used. Solid-phase proximity ligation assay (SP-PLA) is an analytic method with the ability to analyse many proteins at the same time in small amounts of plasma. The aim of this study was to explore the potential use of SP-PLA in patients with colorectal cancer (CRC).Material and methods: Plasma from patients with stage I-IV CRC, with (n=31) and without (n=29) disease dissemination at diagnosis or later, was analysed with SP-PLA using 35 antibodies targeting an equal number of proteins in 5 ml plasma. Carcinoembryonic antigen (CEA), analysed earlier on this cohort, was used as a reference.Results: A total of 21 of the 35 proteins were detectable with SP-PLA. Patients in stage II-III with disseminated disease had lower plasma concentrations of HCC-4 (p=0.025). Low plasma levels of TIMP-1 were seen in patients with disseminated disease stage II (p=0.003). The level of CEA was higher in patients with disease dissemination compared to those without (p=0.007).Conclusion: SP-PLA has the ability to analyse many tumour markers simultaneously in a small amount of blood. However, none of the markers selected for the present SP-PLA analyses gave better prognostic information compared with CEA.
32.	Ghanipour, Lana, et al. (författare) Efficacy of hyperthermic intraperitoneal chemotherapy in colorectal cancer : A phase I and III open label randomized controlled registry-based clinical trial protocol 2024 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:3 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.
33.	Glimelius, Bengt, et al. (författare) U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. 2018 Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194 Tidskriftsartikel (refereegranskat)abstract Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
34.	Graf, Wilhelm, et al. (författare) ASO Author Reflections : Can Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy be Improved? 2020 Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 27:1, s. 301-302 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
35.	Graf, Wilhelm, et al. (författare) Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases from Colorectal Cancer-An Overview of Current Status and Future Perspectives 2024 Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:2 Forskningsöversikt (refereegranskat)abstract Simple Summary The concept of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy perfusion for the treatment of colorectal cancer peritoneal metastases has been debated based on the results of recent controlled trials. In this review, we describe the development of this "package" treatment and discuss various aspects of the selection and indications, as well as future fields of research.Abstract Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.
36.	Graf, Wilhelm, et al. (författare) Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC 2020 Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 27:1, s. 293-300 Tidskriftsartikel (refereegranskat)abstract BackgroundKRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC.Patients and MethodsIn a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation.ResultsMutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis.ConclusionsBRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.
37.	Johansson, Anna L., V, et al. (författare) Were cancer patients worse off than the general population during the COVID-19 pandemic? : A population-based study from Norway, Denmark and Iceland during the pre-vaccination era 2023 Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 31 Tidskriftsartikel (refereegranskat)abstract Background In a population-based setting, we investigated the risks of testing positive for SARS-CoV-2 and developing severe COVID-19 outcomes among cancer patients compared with the general population.Methods In nationwide cohorts, we identified all individuals in Norway, Denmark and Iceland who tested positive for SARS-CoV-2 or had a severe COVID-19 outcome (hospitalisation, intensive care, and death) from March until December 2020, using data from national health registries. We estimated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) comparing cancer patients with the general population.Findings During the first wave of the pandemic, cancer patients in Norway and Denmark had higher risks of testing SARS-CoV-2 positive compared to the general population. Throughout 2020, recently treated cancer patients were more likely to test SARS-CoV-2 positive. In Iceland, cancer patients experienced no increased risk of testing positive. The risk of COVID-19-related hospitalisation was higher among cancer patients diagnosed within one year of hospitalisation (Norway: SIR = 2.43, 95% CI 1.89-3.09; Denmark: 2.23, 1.96-2.54) and within five years (Norway: 1.58, 1.35-1.83; Denmark: 1.54, 1.42-1.66). Risks were higher in recently treated cancer patients and in those diagnosed with haematologic malignancies, colorectal or lung cancer. Risks of COVID-19-related intensive care and death were higher among cancer patients. Interpretation Cancer patients were at increased risk of testing positive for SARS-CoV-2 during the first pandemic wave when testing availability was limited, while relative risks of severe COVID-19 outcomes remained increased in cancer patients throughout 2020. Recent cancer treatment and haematologic malignancy were the strongest risk factors.
38.	Kodeda, Karl, et al. (författare) Time trends, improvements and national auditing of rectal cancer management over an 18-year period 2015 Ingår i: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 17:9, s. O168-O179 Tidskriftsartikel (refereegranskat)abstract Aim: The main aims were to explore time trends in the management and outcome of patients with rectal cancer in a national cohort and to evaluate the possible impact of national auditing on overall outcomes. A secondary aim was to provide population-based data for appraisal of external validity in selected patient series.Method: Data from the Swedish ColoRectal Cancer Registry with virtually complete national coverage were utilized in this cohort study on 29925 patients with rectal cancer diagnosed between 1995 and 2012. Of eligible patients, nine were excluded.Results: During the study period, overall, relative and disease-free survival increased. Postoperative mortality after 30 and 90days decreased to 1.7% and 2.9%. The 5-year local recurrence rate dropped to 5.0%. Resection margins improved, as did peri-operative blood loss despite more multivisceral resections being performed. Fewer patients underwent palliative resection and the proportion of non-operated patients increased. The proportions of temporary and permanent stoma formation increased. Preoperative radiotherapy and chemoradiotherapy became more common as did multidisciplinary team conferences. Variability in rectal cancer management between healthcare regions diminished over time when new aspects of patient care were audited.Conclusion: There have been substantial changes over time in the management of patients with rectal cancer, reflected in improved outcome. Much indirect evidence indicates that auditing matters, but without a control group it is not possible to draw firm conclusions regarding the possible impact of a quality control registry on faster shifts in time trends, decreased variability and improvements. Registry data were made available for reference.
39.	Larsson, Anna H., et al. (författare) Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer 2016 Ingår i: Journal of Translational Medicine. - : BioMed Central. - 1479-5876. ; 14 Tidskriftsartikel (refereegranskat)abstract Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. Results: High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.
40.	Larsson, Anna H, et al. (författare) Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer 2012 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12, s. 282- Tidskriftsartikel (refereegranskat)abstract Background: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. Method: PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman's Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). Results: High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels and clinicopathological parameters or survival. Conclusions: Here, we have validated the previously demonstrated association between immunohistochemical expression of PODXL and poor prognosis in CRC in two additional independent patient cohorts. The results further underline the potential utility of PODXL as a biomarker for more precise prognostication and treatment stratification of CRC patients.
41.	Lomnytska, M., et al. (författare) Complications Related To Surgery For Ovarian Cancer With Intestinal Involvement 2015 Ingår i: International Journal of Gynecological Cancer. - 1048-891X .- 1525-1438. ; 25:9, s. 492-492 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
42.	Magnusson, Kristina, et al. (författare) SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas 2011 Ingår i: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 35:7, s. 937-948 Tidskriftsartikel (refereegranskat)abstract The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n = 1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.
43.	Martling, A., et al. (författare) Risk of second primary cancer in patients treated with radiotherapy for rectal cancer 2017 Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 104:3, s. 278-287 Tidskriftsartikel (refereegranskat)abstract Background: Many patients with rectal cancer receive radiotherapy (RT) to reduce the risk of local recurrence. Radiation may give rise to adverse effects, including second primary cancers. In view of the divergent results of previous studies, the present study evaluated the risk of second primary cancer following RT in all randomized RT rectal cancer trials conducted in Sweden and in the Swedish ColoRectal Cancer Registry (SCRCR).Methods: Patients included in five randomized trials and the SCRCR were linked to the Swedish Cancer Registry. Cox regression models estimated the hazard ratio (HR) of second primary cancer among patients who received RT compared with those who did not.Results: A total of 13 457 patients were included in this study; 7024 (52.2 per cent) received RT and 6433 (47.8 per cent) had surgery alone. Overall, no increased risk of second primary cancer was observed with RT (HR 1.03; 95 per cent c. i. 0.92 to 1.15), independently of follow-up time and location within or outside of the irradiated volume. In the randomized trials, with longer follow-up (maximum 31 years), a slight increase was observed outside of (HR 1.33, 1.01 to 1.74) but not within (HR 1.11, 0.73 to 1.67) the irradiated volume. Irradiated men had a lower risk of prostate cancer than those treated with surgery alone (HR 068, 0.51 to 091).Conclusion: Overall, there was no increased risk of second primary cancer following RT for rectal cancer within or outside of the irradiated volume up to 20 years of follow-up. Men with rectal cancer who received RT had a reduced risk of prostate cancer.
44.	Mathot, Lucy, et al. (författare) Somatic Eph receptor mutations in primary colorectal cancers are associated with metastasis Annan publikation (övrigt vetenskapligt/konstnärligt)
45.	Mathot, Lucy, et al. (författare) Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer 2017 Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:7, s. 1730-1740 Tidskriftsartikel (refereegranskat)abstract The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.
46.	Mayrhofer, Markus, et al. (författare) 1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer 2014 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14, s. 872- Tidskriftsartikel (refereegranskat)abstract Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.
47.	Mezheyeuski, Artur, et al. (författare) Digitalized multiparametric analyses of tumor stroma for identification of low perivascular PDGFBR expression and low vessel density as independent prognosis markers for stage IV CRC 2014 Ingår i: Journal of Clinical Oncology. - Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus. Akad Univ Hosp, Uppsala, Sweden. Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark. Oslo Univ Hosp, Dept Genet, Inst Canc Res, Oslo, Norway. Oslo Univ Hosp, Dept Oncol, Oslo, Norway. Univ Oslo, Oslo, Norway. Haukeland Hosp, N-5021 Bergen, Norway. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden. Dept Surg, Uppsala, Sweden. Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden. : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:15 Tidskriftsartikel (refereegranskat)
48.	Moberger, Peter, et al. (författare) Evaluation of the Swedish Colorectal Cancer Registry : an overview of completeness, timeliness, comparability and validity 2018 Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 57:12, s. 1611-1621 Tidskriftsartikel (refereegranskat)abstract Background: The Swedish Colorectal Cancer Registry (SCRCR) is a national registry established in 1995 for rectal cancer, and also including colon cancer since 2007. Knowledge of the quality of the registry is vital in order to draw correct conclusions from studies based on the registry. The aim of this study was to assess the completeness, timeliness, comparability and validity of the SCRCR. Material and methods: Completeness, timeliness and comparability of the registry were estimated. From the SCRCR year 2008, 500 cases were randomly selected to examine the validity of the registry and 486 cases were retrieved. Using hospital patient records as source documents, 130 variables in the SCRCR were reabstracted using the SCRCR registration forms and then compared with the original files. Result: During the period 2008-2015, the average completeness of the SCRCR was 98.5% for colon cancer and 98.8% for rectal cancer. Timeliness improved between the years 2008 and 2015, with 98% of the patients registered within 12 months for the year 2015. For most of the variables, comparability was estimated to be reproducible and comparable with other registries. Regarding the validity of the registry, when comparing reabstracted data with the original SCRCR data, average agreement was 90%. Conclusion: The SCRCR can be considered a reliable registry useful for quality assurance and research. Standardization and improvements in journal documentation are needed to improve future evaluation of the source documents.
49.	Nunes, Luís, 1995-, et al. (författare) Prognostic whole-genome and transcriptome signatures in colorectal cancers Annan publikation (övrigt vetenskapligt/konstnärligt)
50.	Padhan, Narendra, et al. (författare) High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer 2016 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16 Tidskriftsartikel (refereegranskat)abstract Background: The progression of colorectal cancer (CRC) involves recurrent amplifications/mutations in the epidermal growth factor receptor (EGFR) and downstream signal transducers of the Ras pathway, KRAS and BRAF. Whether genetic events predicted to result in increased and constitutive signaling indeed lead to enhanced biological activity is often unclear and, due to technical challenges, unexplored. Here, we investigated proliferative signaling in CRC using a highly sensitive method for protein detection. The aim of the study was to determine whether multiple changes in proliferative signaling in CRC could be combined and exploited as a "complex biomarker" for diagnostic purposes. Methods: We used robotized capillary isoelectric focusing as well as conventional immunoblotting for the comprehensive analysis of epidermal growth factor receptor signaling pathways converging on extracellular regulated kinase 1/2 (ERK1/2), AKT, phospholipase C gamma 1 (PLC gamma 1) and c-SRC in normal mucosa compared with CRC stage II and IV. Computational analyses were used to test different activity patterns for the analyzed signal transducers. Results: Signaling pathways implicated in cell proliferation were differently dysregulated in CRC and, unexpectedly, several were downregulated in disease. Thus, levels of activated ERK1 (pERK1), but not pERK2, decreased in stage II and IV while total ERK1/2 expression remained unaffected. In addition, c-SRC expression was lower in CRC compared with normal tissues and phosphorylation on the activating residue Y418 was not detected. In contrast, PLC gamma 1 and AKT expression levels were elevated in disease. Immunoblotting of the different signal transducers, run in parallel to capillary isoelectric focusing, showed higher variability and lower sensitivity and resolution. Computational analyses showed that, while individual signaling changes lacked predictive power, using the combination of changes in three signaling components to create a "complex biomarker" allowed with very high accuracy, the correct diagnosis of tissues as either normal or cancerous. Conclusions: We present techniques that allow rapid and sensitive determination of cancer signaling that can be used to differentiate colorectal cancer from normal tissue.

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