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1.	Acosta, Stefan, et al. (författare) Epidemiology and Prognostic Factors in Acute Superior Mesenteric Artery Occlusion. 2010 Ingår i: Journal of Gastrointestinal Surgery. - : Springer Science and Business Media LLC. - 1873-4626 .- 1091-255X. ; 14, s. 628-635 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Reports on trends in incidence and mortality of acute superior mesenteric artery (SMA) occlusion and evaluation of prognostic factors in recent years are lacking. METHODS: Patients with acute SMA occlusion were identified through the in-patient and autopsy registry between 1970 and 1982 (n = 270), 1987 to 1996 (n = 135), and 2000 and 2006 (n = 100) in Malmö, Sweden. RESULTS: The overall incidence rate decreased from 8.6 to 5.4/100,000 person years and the autopsy rate from 87% to 25% over time. A higher serum creatinine level was associated with a lower probability of undergoing multi-detector row computed tomography with intravenous contrast (MDCTiv) (p = 0.006). Not performing a MDCTiv (odds ratio 4.0; 95% confidence interval [1.0-16.0]) remained as independent prognostic factor for in-hospital mortality. General and vascular surgeons collaborated in 25 out of 61 patients that underwent an intervention, of which 21 (84%) (p < 0.001) survived. CONCLUSIONS: A close collaboration between radiologists and general and vascular surgeons seems to be most important to lower the mortality in patients with acute SMA occlusion.
2.	Agren, Magnus S., et al. (författare) Action of matrix metalloproteinases at restricted sites in colon anastomosis repair: an immunohistochemical and biochemical study 2006 Ingår i: Surgery. - : Elsevier BV. - 1532-7361 .- 0039-6060. ; 140:1, s. 72-82 Tidskriftsartikel (refereegranskat)abstract Background. Dehiscence of colon anastomosis is a common, serious and potentially life-threatening complication after colorectal operation. In experimental models, impaired biomechanic strength of colon anastomoses is preventable by general inhibitors of matrix metalloproteinases (MMPs) and associated with collagen loss, which indicates a possible link between MMP-mediated collagen degradation and dehiscence. The precise localization of collagen degradation within the anastomotic area and the specific MMPs responsible are unknown. Methods. We have analyzed distinct zones within anastomoses using a novel microdissection technique for collagen levels, collagenolytic activity exerted directly by endogenous proteinases, and MMP-8 and MMP-9 immunoreactivity and their collagenolytic activity. Results. The most pronounced collagen loss was observed in the suture-holding zone, showing a 29% drop compared with adjacent micro-areas of 3-day-old anastomoses. Only this specific tissue compartment underwent a dramatic and significant increase in collagenolysis, amounting to a loss of 10% of existing collagen molecules in 24 hours, and was abolished by metalloproteinase inhibitors. The tissue surrounding suture channels was heavily infiltrated with CD68-positive histiocytes that expressed MMP-8 and to a lesser extent MMP-9. The collagenolytic effect of the interstitial collagenase MMP-8 was synergistically potentiated by the gelatinase MMP-9 when added to colon biopsies incubated in vitro. Conclusions. The unique finding of this study was that the specific tissue holding the sutures of a colon anastomosis lost the most collagen presumably through induction and activation of multiple MMPs that may explain the beneficial effects of treatment with non-selective MMP antagonists.
3.	Akesson, Oscar, et al. (författare) Morbidity related to defunctioning loop ileostomy in low anterior resection 2012 Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 27:12, s. 1619-1623 Tidskriftsartikel (refereegranskat)abstract Aim A defunctioning loop ileostomy in low anterior resection reduces the incidence and morbidity of an anastomotic leakage, but complications related to the stoma may occur. We explored stoma-associated complications during the stoma period and after stoma reversal. Methods A retrospective analysis of rectal cancer patients operated with low anterior resection and a defunctioning loop ileostomy at Helsingborg Hospital and Malmo University Hospital from January 2007 to June 2009 was undertaken. Results Ninety-two patients were included, of whom 82 (89 %) underwent stoma reversal. The median stoma period was 6.2 +/- 3.2 months. Sixty-six percent of the patients suffered from minor or major stoma-associated morbidity. The complication rate was significantly related to the stoma time (p < 0.01). Twenty-nine percent (27/92) had at least one episode of dehydration, leading to readmittance in half of the cases. Elderly patients were more prone to develop dehydration. Dehydration most commonly occurred early in the postoperative period (mean, 5.8 weeks). The mean hospital stay for stoma reversal was 6.5 +/- 4.0 days. Forty percent (33/82) had some complication associated with the reversal. Conclusion This study indicates high morbidity associated with defunctioning loop ileostomy. Our data suggest that the stoma time should be limited to reduce complications. Monitoring and early stoma reversal should be considered in elderly patients. Furthermore, stoma reversal is not uneventful, and more studies are needed to address how to minimize complications.
4.	Al-Haidari, Amr A., et al. (författare) MiR-155-5p positively regulates CCL17-induced colon cancer cell migration by targeting RhoA 2017 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:9, s. 14887-14896 Tidskriftsartikel (refereegranskat)abstract Colorectal cancer is the second most common cause of cancer-related death, which is due to migration of tumor cells to distant sites of metastasis. Accumulating data indicate that mciroRNAs play an important role in several aspects of colon cancer cell biology. Herein, we examined the role of miR-155-5p in colon cancer cell migration induced by the CCL17-CCR4 axis in HT-29 colon cancer cells. We found that miR-155-5p knockdown in serum starved colon cancer cells decreased CCL17-induced cell chemotaxis. Moreover, knocking down miR-155-5p markedly decreased CCL17-provoked activation of RhoA in colon cancer cells. Bioinformatics analysis predicted two putative binding sites in the AU-rich element at the 3'-UTR of RhoA mRNA. MiR-155-5p binding to RhoA mRNA was verified using a target site blocker and functionally validated by RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of RhoA mRNA is mediated by AU-rich elements present in the 3'-UTR region. Taken together, these results show that miR-155-5p positively regulates RhoA mRNA levels and translation as well as cell migration in serum starved colon cancer cells and indicate that targeting miR-155-5p might be a useful strategy to antagonize colon cancer metastasis.
5.	Al-Haidari, Amr, et al. (författare) HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation. 2014 Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 446:1, s. 68-72 Tidskriftsartikel (refereegranskat)abstract Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects.
6.	Al-Haidari, Amr, et al. (författare) MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R (HuR) 2018 Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 421, s. 145-151 Tidskriftsartikel (refereegranskat)abstract Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the worst prognostic factor for patients with CRC. HuR (ELAVL1) is overexpressed in CRC and has been reported to promote colon cancer growth by targeting RNA in the cell cytoplasm. Herein, the role of miR-155-5p in regulating HuR expression and cell migration was examined in colon cancer cells. MiR-155-5p knockdown in serum-starved colon cancer cells decreased both colon cancer cell chemotaxis and cytoplasmic expression of HuR. Bioinformatics analysis predicted two putative binding sites in the AU-rich elements (AREs) at the 3′-UTR of HuR mRNA. MiR-155-5p binding to HuR was verified using specific target site blockers and functionally validated by use of RNA immunoprecipitation assays, showing that miR-155-5p-dependent regulation of HuR expression is mediated by AREs. Targeting AREs with a specific blocker inhibited colon cancer cell migration. Taken together, these novel findings demonstrate that AREs mediate miR-155-5p positive regulation of HuR mRNA levels and translation as well as migration in colon cancer cells, suggesting that targeting miR-155-5p and/or Hur might be useful therapeutic strategies against colon cancer metastasis.
7.	Al-Haidari, Amr, et al. (författare) Neutrophil extracellular traps promote surgery-induced peritoneal carcinosis of metastatic colorectal cancer via modulation of CXCR2 and αv integrin 2017. - Suppl 3 Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 28, s. 87-88 Konferensbidrag (refereegranskat)abstract Introduction: Peritoneal carcinosis (PC) is the third common site of metastatic colorectal cancer which characterized by a very low survival rate. Surgical trauma has been identified as an important factor in the progression of PC, postulated to be caused by the inflammatory response to tissue injury. The mechanism behind tumor metastasis remains poorly understood. However, existing evidence indicates that neutrophils, via Neutrophil Extracellular Traps (NETs), are implicated in the development of metastatic disease and recently identified as one of the most significant key players in promoting tumor progression. In this study, we highlight the mechanism by which NETs promote surgery-induced colon cancer cell peritoneal metastasis through regulation of key receptors, CXCR2 and αvβ3 integrin.Methods: We developed a murine model of surgical stress-induced PC by post-surgery inoculation of CT-26 murine colon cancer cell line. Surface expression of CXCR2 and αvβ3 on CT-26 cells were evaluated by flow cytometry live staining. Gene expression of extracellular matrix (ECM) proteins from wound incision wall was quantified using qRT-PCR. Function of CXCR2 and αvβ3 in tumor cell migration, proliferation, and adhesion were assessed by blocking assays using CXCR2 antagonist SB225002 and anti-CD51 in vitro and in vivo. Role of neutrophils in promoting cancer cell migration and adhesion was demonstrated using in vitro co-cultured migration and adhesion assays. NET formation was measured using modified ELISA technique of Histone-DNA complex. Depletion of NETs were achieved by daily intraperitoneal administration of 2mg/kg DNase I to mice for 10 days and tumor growth was evaluated by counting macroscopic nodules number on the peritoneum.Results: Blocking CXCR2 and Targeting αv integrin reduced tumor nodules number in vivo by 70% and 65% respectively and decreased cancer cell migration, proliferation, and adhesion in vitro. Incision wound tissue displayed pronounced reduction in ECM proteins mRNAs in treated mice with both CXCR2 antagonist and αv antibody. Mice treatment with DNase I significantly reduced tumor nodules number more than 90% compared to tumor control. Anti-CD51 decreased NET-induced CT-26 cell adhesion. Neutrophils stimulation with MIP-2 exhibits dose-dependent increase of NETosis. Co-culture of neutrophils and cancer cells provoked NETs formation and increased capacity of colon cancer cell migration while DNase I treatment abolished neutrophils NETs-induced tumor cell migration in vitroConclusion: Our novel findings implicate NETs in the development of PC due to surgical stress, suggesting that blocking NET formation might be an interesting potential therapeutic approach.
8.	Algaber, Anwar, et al. (författare) MicroRNA-340-5p inhibits colon cancer cell migration via targeting of RhoA 2020 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 16934-16934 Tidskriftsartikel (refereegranskat)abstract Colon cancer is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the most insidious aspect of cancer progression. Convincing data suggest that microRNAs (miRs) play a key function in colon cancer biology. We examined the role of miR-340-5p in regulating RhoA expression as well as cell migration and invasion in colon cancer cells. Levels of miR-340-5p and RhoA mRNA varied inversely in serum-free and serum-grown HT-29 and AZ-97 colon cancer cells. It was found transfection with miR-340-5p not only decreased expression of RhoA mRNA and protein levels in HT-29 cells but also reduced colon cancer cell migration and invasion. Bioinformatics analysis predicted one putative binding sites at the 3'-UTR of RhoA mRNA. Targeting this binding site with a specific blocker reversed mimic miR-340-5p-induced inhibition of RhoA activation and colon cancer cell migration and invasion. These novel results suggest that miR-340-5p is an important regulator of colon cancer cell motility via targeting of RhoA and further experiments are warranted to evaluate the role of miR-340-5p in colon cancer metastasis.
9.	Arnarson, Örvar, et al. (författare) Short- and long-term outcomes following bridge to surgery and emergency resection in acute malignant large bowel obstruction 2023 Ingår i: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 25:4, s. 669-678 Tidskriftsartikel (refereegranskat)abstract Aim: Bridge to surgery (BtS) aims to decrease perioperative morbidity and mortality in emergency resection (ER) of the colon. Previous results are inconsistent, and long-term comparisons are scarce. The aim of this study was to compare the short- and long-term outcomes of BtS and ER. Method: This retrospective study examined data from the Swedish Colorectal Cancer Registry for patients treated for acute malignant large bowel obstruction from 2007 to 2009. Patients were grouped by treatment strategy: BtS (using a self-expanding metallic stent or diverting stoma) or ER. Medical records were scrutinized for all patients in the BtS group. The primary endpoints were 5-year overall survival (OS) and 3-year recurrence-free survival (RFS). The secondary endpoints were postoperative mortality and morbidity rates and stoma permanence. Results: Overall, 143 patients were treated using BtS versus 1302 patients treated with ER. The 5-year OS was higher in the BtS group than in the ER group (53.8% vs. 37.4%; p < 0.05). No difference was noted in the 3-year RFS (75.7% vs. 75.0%; p = 0.38). The postoperative mortality rate was lower in the BtS group than in the ER group (0.7% vs. 7.3%; p < 0.05). Complications occurred in 46.9% of patients in the BtS group (both procedures) versus 35.9% of patients in the ER group (p < 0.05); the rate of severe complications was 23.1% and 16.9%, respectively (p = 0.07). Conclusion: This retrospective population-based registry study showed higher long-term survival and lower postoperative mortality rates among patients treated with BtS versus ER for acute malignant large bowel obstruction.
10.	Arnarson, Örvar, et al. (författare) Who should operate patients presenting with emergent colon cancer? A comparison of short- and long-term outcome depending on surgical sub-specialization 2023 Ingår i: World Journal of Emergency Surgery. - : Springer Science and Business Media LLC. - 1749-7922. ; 18:1 Tidskriftsartikel (refereegranskat)abstract Background: Colorectal cancer presents as emergencies in 20% of the cases. Emergency resection is associated with high postoperative morbidity and mortality. The specialization of the operating team in the emergency settings differs from the elective setting, which may have an impact on outcome. The aim of this study was to evaluate short- and long-term outcomes following emergent colon cancer surgery depending on sub-specialization of the operating team. Methods: This is a retrospective population study based on data from the Swedish Colorectal Cancer Registry (SCRCR). In total, 656 patients undergoing emergent surgery for colon cancer between 2011 and 2016 were included. The cohort was divided in groups according to specialization of the operating team: (1) colorectal team (CRT); (2) emergency surgical team (EST); (3) general surgical team (GST). The impact of specialization on short- and long-term outcomes was analyzed. Results: No statistically significant difference in 5-year overall survival (CRT 48.3%; EST 45.7%; GST 42.5%; p = 0.60) or 3-year recurrence-free survival (CRT 80.7%; EST 84.1%; GST 77.7%21.1%; p = 0.44) was noted between the groups. Neither was any significant difference in 30-day mortality (4.4%; 8.1%; 5.5%, p = 0.20), 90-day mortality (8.8; 11.9; 7.9%, p = 0.37) or postoperative complication rate (35.5%, 35.9 30.7, p = 0.52) noted between the groups. Multivariate analysis adjusted for case-mix showed no difference in hazard ratios for long-term survival or postoperative complications. The rate of permanent stoma after 3 years was higher in the EST group compared to the CRT and GST groups (34.5% vs. 24.3% and 23.9%, respectively; p < 0.0.5). Conclusion: Surgical sub-specialization did not significantly affect postoperative complication rate, nor short- or long-term survival after emergent operation for colon cancer. Patients operated by emergency surgical teams were more likely to have a permanent stoma after 3 years.
11.	Arthursson, Victoria, et al. (författare) COST COMPARISONS OF ENDOSCOPIC AND SURGICAL RESECTION OF T1 RECTAL CANCER 2021 Ingår i: Endoscopy. - : Georg Thieme Verlag KG. - 1438-8812 .- 0013-726X. ; 53:Suppl 1, s. 253-254 Konferensbidrag (refereegranskat)
12.	Arthursson, Victoria, et al. (författare) Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer 2022 Ingår i: Endoscopy. - : Georg Thieme Verlag KG. - 1438-8812 .- 0013-726X. ; 54:11, s. 1071-1077 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The long-term outcome after local excision of T1 colorectal cancer (CRC) remains unknown. The aim of this study was to examine clinical and histopathological risk factors for recurrence in patients with T1 CRC undergoing endoscopic resection.METHODS: This was a retrospective registry-based population study on prospectively collected data of all patients with nonpedunculated T1 CRC undergoing only local excision (no salvage surgery) in Sweden between 2009 and 2018. Potential risk factors for recurrence, including age, sex, tumor location, resection margins, lymphovascular, perineural, and submucosal invasion, grade of differentiation, and mucinous subtype, were analyzed using univariate and multivariate cox regression.RESULTS: Median follow-up time was 60 months, and 28 /602 patients (4.7 %) had a recurrence (13 local and 18 distant). Recurrence rate stratified by submucosal invasion was: Sm1 3.5 % (14 /397), Sm2 6.0 % (8 /133), and Sm3 8.3 % (6 /72), with no significant differences. Resection margins, lymphovascular and perineural invasion, grade of differentiation, mucinous subtype, and age were not significant risk factors for recurrence. In contrast, rectal location was found to be a significant risk factor for tumor recurrence in multivariate analysis (hazard ratio 3.08, P = 0.006). The 3- and 5-year disease-free survival was 96.2 % and 91.1 %, respectively, in T1 CRC patients undergoing endoscopic resection.CONCLUSION: Tumor recurrence was rare (4.7 %) in this large population-based study on recurrence after local excision of nonpedunculated T1 CRC. Rectal location was an independent risk factor for recurrence, suggesting the need for strict surveillance after endoscopic resection of early rectal cancer.
13.	Awla, Darbaz, et al. (författare) Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis. 2012 Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 91, s. 711-719 Tidskriftsartikel (refereegranskat)abstract MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.
14.	Bjursten, Henrik, et al. (författare) S100B Profiles and Cognitive Function at High Altitude 2010 Ingår i: High Altitude Medicine & Biology. - : Mary Ann Liebert Inc. - 1527-0297 .- 1557-8682. ; 11:1, s. 31-38 Tidskriftsartikel (refereegranskat)abstract Bjursten, Henrik, Per Ederoth, Engilbert Sigurdsson, Magnus Gottfredsson, Ingvar Syk, Orri Einarsson, and Tomas Gudbjartsson. S100B profiles and cognitive function at high altitude. High Alt. Med. Biol. 11:31-38, 2010.-Exposure to high altitude can lead to acute mountain sickness (AMS) and high altitude cerebral edema (HACE). In this study we investigated the effect of high altitude on neurocognitive function and S100B release. Increased S100B release has been hypothesized to signify a loss of integrity in the blood-brain barrier (BBB). Seven healthy volunteers trekked to Capanna Regina Margherita (4554 m above sea level) in the Monte Rosa massif. During ascent and descent, five test events were undertaken; participants underwent neurocognitive testing, Lake Louise scoring (LLS), and blood sampling to measure levels of S100B. The blood tests revealed that S100B levels increased 42% to 122% from baseline, and mean LLS increased from 0.57 to 2.57. A significant correlation was observed between both S100B levels and LLS and S100B and some neurocognitive scores. The study indicates that S100B can be released by a mild hypoxia during AMS. Moreover, an observed correlation between S100B and a lower score on neurocognitive tests suggests that the pathogenetic mechanisms may be linked. The study indicates that a decline in cognitive function is associated with symptoms of AMS.
15.	Buchwald, Pamela, et al. (författare) Standard protocol for assessment of colon cancer improves the quality of pathology. 2011 Ingår i: Colorectal Disease. - : Wiley. - 1462-8910. ; 13, s. 33-36 Tidskriftsartikel (refereegranskat)abstract Aim: Tumour stage is the most important prognostic factor in colon cancer. The aim of this study was to examine the impact on the quality of pathology by the use of a standardized PAD protocol. Method: A standardized PAD protocol for colorectal cancer was developed and all patients subjected to colon resection due to adenocarcinomas between 2004 and 2006 were analyzed concerning lymph node status, circumferential resection margin (CRM), intravascular and perineural growth. Moreover, usage of the PAD protocol and whether a pathologist or biomedicine analytic technician (BMA) performed the lymph node dissection was noted and also if the surgical procedure was elective or acute. Results: During the study period 302 colon resections were carried out. The standard protocol was employed in 68% of the cases varying from 0-100% between pathologists. The median number of investigated lymph nodes was 16 ± 11. When the lymph node dissection was performed by a BMA, significantly more lymph nodes were examined; 22 ± 15 and 14 ± 9 respectively (p<0.01). There was a positive correlation between application of the standard protocol and the number of analyzed lymph nodes (<0.05). Comments on CRM, perineural growth and intravascular growth were also significantly more frequent when the protocol was used. Emergency surgery did not influence the handling of the specimens. Conclusion: Minor efforts in terms of a standard protocol for pathology and specimen dissection by BMAs, leading to an increased quality of the PAD-report may also improve long term outcome for patients.
16.	Cashin, Peter H., et al. (författare) Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases : A randomised trial 2016 Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 53, s. 155-162 Tidskriftsartikel (refereegranskat)abstract Background: First-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm). Methods: Patients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m(2) /d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity. Results: The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27-0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III-IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities. Conclusions: Cytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials. gov nr: NCT01524094).
17.	Cashin, Peter, 1984-, et al. (författare) Peritoneal mesothelioma in Sweden : A population-based study 2019 Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 8:14, s. 6468-6475 Tidskriftsartikel (refereegranskat)abstract The study aim was to report survival and morbidity of all patients in Sweden with peritoneal mesothelioma treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as well as investigate whether the survival has increased on a population level since this treatment was nationalized 2011. Study data were collected from the Swedish HIPEC registry and the Swedish National Cancer Registry. All patients with peritoneal mesothelioma scheduled for CRS/HIPEC treatment in Sweden January 2011 to March 2018 were retrieved from the Swedish HIPEC registry. Clinicopathological and survival data were collected. For population-level analysis, all patients with diffuse malignant peritoneal mesothelioma (DMPM) were identified from the Swedish National Cancer Registry and data were retrieved from two separate 5-year time periods: 1999-2003 and 2011-2015. Thirty-two patients were accepted for CRS/HIPEC. Four were open/close cases. Two-year survival rate was 84% or 59% when excluding borderline peritoneal mesotheliomas (n = 17). Median overall survival was not reached. Grade III-IV Clavien-Dindo events occurred in 22% with no mortality. From the national cancer registry, 102 DMPM cases were retrieved: 40 cases between 1999 and 2003, and 62 cases between 2011 and 2015 (corresponding to an increase from 0.9 to 1.24/million/year, P =.04). Six patients (10%) received CRS/HIPEC in the second period. Median OS increased between periods from 7 to 15 months and 5-year survival from 14% to 29% (P =.03). Peritoneal mesothelioma of both borderline and DMPM subtypes undergoing CRS/HIPEC have good long-term survival. The incidence of DMPM in Sweden has increased. Overall survival has increased alongside the introduction of CRS/HIPEC, which may be a contributing factor.
18.	Duan, Rui-Dong, et al. (författare) Purification, localization, and expression of human intestinal alkaline sphingomyelinase 2003 Ingår i: Journal of Lipid Research. - 1539-7262. ; 44:6, s. 1241-1250 Tidskriftsartikel (refereegranskat)
19.	Erlandsson, Johan, et al. (författare) Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial 2017 Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 18:3, s. 336-346 Tidskriftsartikel (refereegranskat)abstract Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 x 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 x 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1.7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33.4 months (range 18.2-62.2) in the short-course radiotherapy group and 19.3 months (8.5-39.5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33.3 months (range 17.8-114.3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1.44 [95% CI 0.41-5.11]; long-course radiotherapy with delay 2.24 [0.71-7.10]; p=0.48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (amp;lt;1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0.59 [95% CI 0.36-0.97], long-course radiotherapy with delay 0.63 [0.38-1.04], p=0.075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0.61 [95% CI 0.45-0.83] p=0.001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery.
20.	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.
21.	Hansdotter Andersson, Pernilla, et al. (författare) The COLOFOL trial: study design and comparison of the study population with the source cancer population. 2016 Ingår i: Clinical Epidemiology. - 1179-1349. ; 8, s. 15-21 Tidskriftsartikel (refereegranskat)abstract The COLOFOL trial, a prospective randomized multicenter trial comparing two follow-up regimes after curative surgical treatment for colorectal cancer, focuses on detection of asymptomatic recurrences. This paper aims to describe the design and recruitment procedure in the COLOFOL trial, comparing demographic characteristics between randomized patients and eligible patients not included in the study.
22.	Hansdotter, Pernilla, et al. (författare) Treatment and survival of patients with metachronous colorectal lung metastases 2023 Ingår i: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 127:5, s. 806-814 Tidskriftsartikel (refereegranskat)abstract Introduction: The lungs are the second most common site for metachronous metastases in colorectal cancer. No treatment algorithm is established, and the role of adjuvant chemotherapy is unclear. This study aimed to map pulmonary recurrences in a modern multimodal treated population, and to evaluate survival depending on management.Methods: Retrospective study based on the COLOFOL-trial population of 2442 patients, radically resected for colorectal cancer stage II-III. All recurrences within 5 years were identified and medical records were scrutinized.Results: Of 165 (6.8%) patients developing lung metastases as first recurrence, 89 (54%) were confined to the lungs. Potentially curative treatment was possible in 62 (37%) cases, of which 33 with surgery only and 29 with surgery and chemotherapy combined. The 5-year overall survival (5-year OS) for all lung recurrences was 28%. In patients treated with chemotherapy only the 5-year OS was 7.5%, compared with 55% in patients treated with surgery, and 72% when surgery was combined with chemotherapy. Hazard ratio for mortality was 2.9 (95% confidence interval 1.40-6.10) for chemotherapy only compared to surgery.Conclusion: A high proportion of metachronous lung metastases after colorectal surgery were possible to resect, yielding good survival. The combination of surgery and chemotherapy might be advantageous for survival.
23.	Hasan, Zirak, et al. (författare) Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury 2013 Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 304:4, s. 221-229 Tidskriftsartikel (refereegranskat)abstract Hasan Z, Rahman M, Palani K, Syk I, Jeppsson B, Thorlacius H. Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury. Am J Physiol Lung Cell Mol Physiol 304: L221-L229, 2013. First published December 14, 2012; doi:10.1152/ajplung.00199.2012.-Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-alpha (TNF-alpha), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-alpha, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.
24.	Hasan, Zirak, et al. (författare) Rho-kinase regulates induction of T-cell immune dysfunction in abdominal sepsis. 2013 Ingår i: Infection and Immunity. - 1098-5522. ; 81:7, s. 2499-2506 Tidskriftsartikel (refereegranskat)abstract T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho-kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho-kinase inhibitor Y-27632 (5 mg/kg) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of ELISA. It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T-cells. Inhibition of Rho-kinase activity decreased apoptosis and enhanced proliferation of CD4 T-cells in septic animals. In addition, CLP-evoked induction of regulatory T-cells in the spleen was abolished by Rho-kinase inhibition. CLP reduced the levels of IFN-γ and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-γ but not IL-4 formation in the spleen. CLP increased plasma levels of HMGB1 by 20-fold and IL-6 by 19-fold. Inhibition of Rho-kinase decreased this CLP-evoked increase of HMGB1, IL-6 and IL-17 levels in the plasma by more than 60%, suggesting that Rho-kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho-kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho-kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis.
25.	Hasan, Zirak, et al. (författare) Rho-Kinase Signaling Regulates Pulmonary Infiltration of Neutrophils in Abdominal Sepsis via Attenuation of CXC Chemokine Formation and Mac-1 Expression on Neutrophils. 2012 Ingår i: Shock. - 1540-0514. ; 37:3, s. 282-288 Tidskriftsartikel (refereegranskat)abstract ABSTRACT: Excessive neutrophil infiltration is a major component in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of neutrophils in polymicrobial sepsis remain elusive. Herein, we hypothesized that Rho-kinase activity may play a significant role in pulmonary neutrophil recruitment and tissue damage in abdominal sepsis. Male C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 (0.5 or 5 mg/kg) before cecal ligation and puncture. Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets as well as soluble CD40L and metalloproteinase-9 (MMP-9) in plasma. CLP triggered significant pulmonary damage characterized by neutrophil infiltration, increased levels of CXC chemokines, and edema formation in the lung. Furthermore, CLP up-regulated Mac-1 expression on neutrophils, decreased CD40L on platelets and increased soluble CD40L and MMP-9 in the circulation. Interestingly, inhibition of Rho-kinase dose-dependently decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration and tissue damage in the lung. Moreover, Rho-kinase inhibition significantly reduced sepsis-provoked gene-expression of CXC chemokines in alveolar macrophages. In contrast, Rho-kinase inhibition had no effect on platelet shedding of CD40L or plasma levels of MMP-9 in septic mice. In conclusion, these data demonstrate that the Rho-kinase signaling pathway plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of CXC chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis.
26.	Hwaiz, Rundk, et al. (författare) Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury. 2015 Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 97:5, s. 975-984 Tidskriftsartikel (refereegranskat)abstract Accumulating evidence suggest that platelets play an important role in regulating neutrophil recruitment in septic lung injury. Herein, we hypothesized that platelet-derived CCL5 might facilitate sepsis-induced neutrophil accumulation in the lung. Abdominal sepsis was induced by CLP in C57BL/6 mice. CLP increased plasma levels of CCL5. Platelet depletion and treatment with the Rac1 inhibitor NSC23766 markedly reduced CCL5 in the plasma of septic mice. Moreover, Rac1 inhibition completely inhibited proteasePAR4-induced secretion of CCL5 in isolated platelets. Immunoneutralization of CCL5 decreased CLP-induced neutrophil infiltration, edema formation, and tissue injury in the lung. However, inhibition of CCL5 function had no effect on CLP-induced expression of Mac-1 on neutrophils. The blocking of CCL5 decreased plasma and lung levels of CXCL1 and CXCL2 in septic animals. CCL5 had no effect on neutrophil chemotaxis in vitro, suggesting an indirect effect of CCL5 on neutrophil recruitment. Intratracheal challenge with CCL5 increased accumulation of neutrophils and formation of CXCL2 in the lung. Administration of the CXCR2 antagonist SB225002 abolished CCL5-induced pulmonary recruitment of neutrophils. Isolated alveolar macrophages expressed significant levels of the CCL5 receptors CCR1 and CCR5. In addition, CCL5 triggered significant secretion of CXCL2 from isolated alveolar macrophages. Notably, intratracheal administration of clodronate not only depleted mice of alveolar macrophages but also abolished CCL5-induced formation of CXCL2 in the lung. Taken together, our findings suggest that Rac1 regulates platelet secretion of CCL5 and that CCL5 is a potent inducer of neutrophil recruitment in septic lung injury via formation of CXCL2 in alveolar macrophages.
27.	Hwaiz, Rundk, et al. (författare) Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation. 2013 Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 183:2, s. 798-807 Tidskriftsartikel (refereegranskat)abstract Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis.
28.	Kodeda, Karl, et al. (författare) Population-based data from the Swedish Colon Cancer Registry 2013 Ingår i: British Journal of Surgery. - : Wiley-Blackwell. - 0007-1323 .- 1365-2168. ; 100:8, s. 1100-1107 Tidskriftsartikel (refereegranskat)abstract Background Evaluating the external validity of clinical trials requires knowledge not only of the study population but also of a relevant reference population. The main aim of this study was to present data from a large, contemporary, population-based cohort of patients with colonic cancer. Methods Data on patients diagnosed between 2007 and 2011 were extracted from the Swedish Colon Cancer Registry. The data, registered prospectively in a national population of almost 10 million, included over 99 per cent of all diagnosed adenocarcinomas of the colon. Results This analysis included 18889 patients with 19526 tumours (3 center dot 0 per cent had synchronous tumours). The sex distribution was fairly equal, and the median age was 74 center dot 1 (interquartile range 65-81) years. The overall and relative (cancer-specific) survival rates after 3 years were 62 center dot 7 and 71 center dot 4 per cent respectively. Some 88 center dot 0 per cent of the patients were operated on, and 83 center dot 8 per cent had tumours resected. Median blood loss during bowel resection was 200 (mean 311) ml, and the median operating time was 160min; 5 center dot 6 per cent of the procedures were laparoscopic. Preoperative chemotherapy was administered to 2 center dot 1 per cent of patients; postoperative chemotherapy was planned in 90 center dot 1 per cent of fit patients aged less than 75 years with stage III disease. In patients operated on in an emergency setting (21 center dot 5 per cent), the preoperative evaluation was less extensive, the proportion of R0 resections was lower, and the outcomes were poorer, in both the short and long term. Conclusion These population-based data represent good-quality reference points.
29.	Krarup, Peter-Martin, et al. (författare) Rapid morphological changes and loss of collagen following experimental acute colonic obstruction 2013 Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 28:3, s. 341-347 Tidskriftsartikel (refereegranskat)abstract Anastomosis of an acutely obstructed colon is associated with an increased risk of dehiscence. In experimental models, acute obstruction decreases collagen in the colonic wall, but the time course and propagation along the colon of the biochemical changes are unknown. Furthermore, there is a paucity of information on the correlation between these biochemical changes and histological features. Forty male Sprague Dawley rats were subjected to partial obstruction by placing a silicone ring around the left colon 30 mm above the reflection. Obstruction was maintained for 0, 1, 2, 3 or 4 days. Samples from five different locations along the colon were analysed on circumference, tissue water content, collagen concentration and histomorphology. Neutrophil and macrophage infiltration was characterized immunohistochemically. The colonic circumference and water content increased (p < 0.001), while the collagen concentration decreased by 48 % (p < 0.01) proximal to the obstruction already after 1 day. The degree of dilation and collagen reduction did not change significantly over the subsequent 3 days of obstruction, whereas the water content normalized by day 3. Mucosal and submucosal oedema and the relative neutrophil infiltration were highest after 1 day in the colonic segment proximal to the stenosis while the macrophage population continued to increase to day 4. Muscular necrosis in addition to ganglionitis and neuritis in the nervous plexus increased with duration of obstruction. The pronounced and rapid changes of the composition of cells and the extracellular matrix of the colonic wall following acute obstruction may be of guidance for present surgical treatments and future pharmacological interventions.
30.	Larsson, Anna H, et al. (författare) Podocalyxin-like protein expression in primary colorectal cancer and synchronous lymph node metastases 2013 Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 8:1, s. 109- Tidskriftsartikel (refereegranskat)abstract Aims: Previous studies have shown that membranous expression of podocalyxin-like protein (PODXL) is associated with poor prognosis in colorectal cancer (CRC). In this study, we compared PODXL expression in primary CRC and synchronous lymph node metastases. We further analyzed whether its expression changed in rectal tumours after neoadjuvant radiation therapy. Methods and results: The studied cohort consists of 73 consecutive patients from the South-Swedish Colorectal Cancer Biobank. Immunohistochemical PODXL expression was examined on full-face sections from all primary tumours and all 140 available lymph node metastases from 31 cases. Membranous PODXL expression was denoted in 18/73 (24,7%) primary tumours, with a high concordance between primary and metastatic lesions. While all negative primary tumours had negative metastases, some PODXL positive primaries had a varying proportion of positive and negative metastatic lymph nodes. PODXL expression was also found to be mainly unaltered in pre- and post-irradiation surgically resected tumour specimens in rectal cancer patients (n=16). Conclusions: The findings in this study suggest that analysis of PODXL expression in the primary tumour is sufficient for its use as a prognostic and treatment predictive biomarker in CRC, also in patients with metastatic disease.
31.	Larsson, Anna, et al. (författare) Water soluble contrast enema examination of the integrity of the rectal anastomosis prior to loop ileostomy reversal may be superfluous 2015 Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 30:3, s. 381-384 Tidskriftsartikel (refereegranskat)abstract Defunctioning loop ileostomy in low anterior resection (LAR) is routinely used to reduce consequences of anastomotic leakage. The purpose of this study was to analyze which examination technique is optimal for evaluating the integrity of the anastomosis prior to loop ileostomy reversal. Retrospective analysis of 95 patients who had been subjected to LAR at Helsingborg Hospital and SkAyenne University Hospital, Sweden, was undertaken between January 2007 and June 2009. The examination techniques of the rectal anastomosis prior to reversal and the clinical outcome after reversal were studied. Radiologic anastomosis control using water soluble contrast enema, digital rectal examination (DRE), and rectoscopy were performed in 53 % (50/95), 98 % (93/95), and 69 % (66/95), respectively. In two patients, no control of the anastomosis was performed before reversal. Fifty-two percent (49/95) of the patients were examined using all techniques. Six patients demonstrated leakage detected before reversal of which two were only radiological leakages. These two patients underwent loop ileostomy reversal after delay without complications. They were the only ones where the three examination techniques did not prove coherence. Four patients had symptomatic leakage; these were detected with rectoscopy and DRE and verified with enema. Three patients developed anastomotic leakage after loop ileostomy reversal despite normal preoperative examinations. Two of these patients had rectovaginal fistulas (AVFs). This retrospective study indicates that contrast enema does not provide additional information if rectoscopy and DRE are normal. Despite negative examinations, three of nine leakages were diagnosed after loop ileostomy reversal. Especially, AVFs seem difficult to diagnose.
32.	Lepsenyi, Mattias, et al. (författare) CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells 2021 Ingår i: Clinical and Experimental Metastasis. - : Springer Science and Business Media LLC. - 1573-7276 .- 0262-0898. ; 38:4, s. 401-410 Tidskriftsartikel (refereegranskat)abstract Peritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.
33.	Lepsenyi, Mattias, et al. (författare) Self-expanding metal stents in malignant colonic obstruction: experiences from Sweden. 2011 Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 4 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Acute surgery in the management of malignant colonic obstruction is associated with high morbidity and mortality. The use of self-expanding metal stents (SEMS) is an alternative method of decompressing colonic obstruction. SEMS may allow time to optimize the patient and to perform preoperative staging, converting acute surgery into elective. SEMS is also proposed as palliative treatment in patients with contraindications to open surgery. Aim: To review our experience of SEMS focusing on clinical outcome and complications. The method used was a review of 75 consecutive trials at SEMS on 71 patients based on stent-protocols and patient charts. FINDINGS: SEMS was used for palliation in 64 (85%) cases and as a bridge to surgery in 11 (15%) cases. The majority of obstructions, 53 (71%) cases, were located in the recto-sigmoid. Technical success was achieved in 65 (87%) cases and clinical decompression was achieved in 60 (80%) cases. Reasons for technical failure were inability to cannulate the stricture in 5 (7%) cases and suboptimal SEMS placement in 3 (4%) cases. Complications included 4 (5%) procedure-related bowel perforations of which 2 (3%) patients died in junction to post operative complications. Three cases of bleeding after SEMS occurred, none of which needed invasive treatment. Five of the SEMS occluded. Two cases of stent erosion were diagnosed at the time of surgery. Average survival after palliative SEMS treatment was 6 months. CONCLUSION: Our results correspond well to previously published data and we conclude that SEMS is a relatively safe and effective method of treating malignant colonic obstruction although the risk of SEMS-related perforations has to be taken into account.
34.	Loftås, Per, 1964- (författare) Response to neoadjuvant treatment in rectal cancer surgery 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.
35.	Luo, Lingtao, et al. (författare) Pro-inflammatory role of neutrophil extracellular traps in abdominal sepsis. 2014 Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 307:7, s. 586-596 Tidskriftsartikel (refereegranskat)abstract Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with rhDNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity and lung. Blood, peritoneal fluid and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in the plasma, peritoneal cavity and lung. Administration of rhDNAse not only eliminated NET formation in the plasma, peritoneal cavity and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6 and HMGB1 in the plasma as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of pro-inflammatory compounds in abdominal sepsis. Thus, we conclude that NETs exert a pro-inflammatory role in septic lung injury.
36.	Lurvink, R.J, et al. (författare) The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma 2021 Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983. ; 47:1, s. 4-10 Forskningsöversikt (refereegranskat)abstract Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%–100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.
37.	Mangell, Peter, et al. (författare) Lactobacillus plantarum 299v Does Not Reduce Enteric Bacteria or Bacterial Translocation in Patients Undergoing Colon Resection. 2012 Ingår i: Digestive Diseases and Sciences. - : Springer Science and Business Media LLC. - 1573-2568 .- 0163-2116. ; 57:7, s. 1915-1924 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Probiotics may exert beneficial effects in the gastrointestinal tract. This randomized trial investigated the effect of the probiotic Lactobacillus plantarum 299v on the intestinal load of potentially pathogenic bacteria, bacterial translocation, and cell proliferation in elective colon surgery. METHODS: Seventy-five patients were randomized to pre- and postoperative oral intake of Lactobacillus plantarum 299v or placebo. Rectal swabs and mucosal biopsies were taken before the start of intake, after 1 week, at surgery, and after 6 days, weeks, and months. Viable counts were quantified for clostridia, Enterobacteriaceae, Gram-negative anaerobes, and lactobacilli. Bacterial translocation was determined by the analysis of bacterial DNA genes in mesenteric lymph nodes. Ki-67 was used as a marker of cell proliferation in normal mucosa and tumor. RESULTS: Lactobacillus plantarum 299v was given without adverse effects. Lactobacillus plantarum 299v as well as Enterobacteriaceae and Gram-negative anaerobes increased in the colon 1 week after the administration of Lactobacillus plantarum 299v. There were no significant differences between patients receiving Lactobacillus plantarum 299v and placebo in the incidence of bacterial translocation (27 vs. 13 %) and postoperative complications (16 vs. 31 %). CONCLUSIONS: Lactobacillus plantarum 299v was established in the intestine, but no inhibitory effect on enteric bacteria, bacterial translocation, or postoperative complications was found. The mechanism behind the protective effects of probiotics found in animal and some human studies remain elusive and require further explorations. No adverse effects were recorded after the administration of high doses of Lactobacillus plantarum 299v.
38.	Näsvall, Pia, 1967- (författare) Parastomal hernia : investigation and treatment 2015 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract BackgroundParastomal hernia is a common stoma complication causing the patient considerable inconvenience. The patient becomes aware of a bulge around the stoma, but a bulge is not always a parastomal hernia and diagnostics must be performed to enable differential treatment. It is difficult to distinguish between a bulge and a hernia. Results based on clinical examination and computerised tomography (CT) in the supine position, have not been convincing. Three-dimensional intrastomal ultrasonography (3D US) is a novel technique shown to be promising in the assessment of stoma complaints. Two studies were performed to determine inter- and intra-observer reliability as well as the validity of 3D US as an alternative to CT when assessing stoma complaints.There are numerous options for the treatment of parastomal hernia, but none has been shown superior. In the recent decades the use of mesh in the repair of incisional and inguinal hernia has become routine. New materials must be evaluated as there are potential morbidity and even mortality risks with mesh repair. As recurrence of a parastomal hernia is an even greater challenge, the method of choice should have a low risk for recurrence. A prospective multicenter study was performed to evaluate safety and recurrence rate when using Parastomal Hernia Patch BARDTM (PHP), a mesh specially designed for parastomal hernia repair.A stoma has a profound impact on the patient´s daily life, both physical and psychological. A parastomal hernia with its associated risk for leakage and incarceration worsens the situation. Patient driven assessment of healthcare outcome is important if we are to improve medical care. A quality of life (QoL) survey was performed to assess the impact of parastomal bulging and hernia on the patient´s daily life.MethodsForty patients were investigated and the 3D US images were twice evaluated by two or three physicians to assess inter- and intra-observer reliability. Totally 20 patients with stoma complaints requiring surgery were examined with CT and 3D US prior to surgery. The findings were compared with the intraoperative findings – regarded as the true outcome.Fifty patients with parastomal hernia requiring surgery were enrolled from three hospitals. Patients were followed up one month and one year after repair using PHP.Patients still alive in 2008 who had been operated between1996 and 2004 for rectal cancer in Uppsala/Örebro-, Stockholm/Gotland-, and Northern Regions (986 patients) and registered in the Swedish Rectal Cancer Registry (SRCR) were invited to fill in four QoL questionnaires.ResultsInter-observer agreement using 3D US reached 80% for the last 10 patients examined, with a kappa value of 0.70. Intra-observer agreement for two examiners was 80% and 95%. The learning curve levelled out at 30 patients. Both CT and 3D US showed high sensitivity and specificity when compared with intraoperative findings.After surgery for parastomal hernia with a PHP, the complication rate at one month was 30% and recurrence rate at one year was 22%. Twelve patients were reoperated within one year.In the QoL study, 31.5% of the patients with a stoma reported a bulging or a hernia. 11.7% had been operated for parastomal hernia. A hernia or a bulge gave rise to significantly more pain and impaired stoma function. Overall QoL was inferior in patients with a permanent stoma compared to a group without a stoma.
39.	Näverlo, Simon, 1991- (författare) Stomas from a rural perspective : an evaluation of characteristics, differences and improvement opportunities 2020 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Introduction: Stoma-related complications are common and consequences for the individual patient may be considerable. In rural areas, competence regarding stoma-related problems is largely absent. Since the aim of a publicly funded healthcare system is good healthcare on equal terms regardless of where one lives, studies evaluating differences and possible areas of improvement in rural areas are important. An evaluation of stoma-related characteristics, geographic differences and improvement opportunities from a rural perspective has not been done previously. The characteristics and differences studied in this thesis are: stoma reversal; occurrence of permanent stoma; and quality-of-life (QoL).Methods: Epidemiological methods applied to register data were used in Study I. Data extracted from the National Rectal Cancer Register together with socioeconomic data from Statistics Sweden were used. Study II was a cross-sectional study using surveys matched with data from the National Rectal Cancer Register. Study III was based on data from a double-blind randomised controlled trial. Patients were randomised to either a prophylactic mesh or no mesh in order to prevent parastomal hernia (PSH). Quality-of-life was assessed by grouping and comparing results of questionnaires answered by the patients included. In Study IV, a qualitative explorative method was applied to describe the quality of life of rural living stoma patients. Qualitative content analysis was used to analyse data.Aims and Results: Study I investigated whether distance by road to hospital had an impact on the following outcomes: stoma reversal rate; time from index operation to stoma reversal; and occurrence of permanent stoma after rectal cancer surgery. Longer distance to hospital had no effect on these outcomes in a multivariate model. In the univariate logistic regression model results indicated the opposite; patients living closest to the operating hospital had a higher likelihood of no reversal (OR 0.3; 95% CI 0.12–0.76). In northern Sweden, 77 % of all stoma reversals were delayed more than 6 months after index surgery. Stoma reversal was performed up to 1557 days after index surgery, and the shortest time to reversal was 82 days (median 287 days).Study II investigated the impact of distance to nearest hospital on the QoL of rectal cancer patients who had received a stoma at index surgery. Patients living in rural areas reported more pain and sore skin compared to those living closer. When only considering patients who still had a stoma, global QoL was reduced and stoma-related problems were also affected negatively in the rural group.Study III Investigated whether a prophylactic mesh when creating an end colostomy affected QoL. No effect on global QoL was seen at one-year follow up. In several other QoL-parameters mesh patients scored superior compared to non-mesh patients, even when excluding those with a parastomal hernia (PSH).Study IV investigated experiences of living with a stoma in a rural setting, how the process of seeking healthcare was experienced and the problems that occur. Results show that living with a stoma was experienced as a process; an initial sense of hopelessness, especially when suffering from stoma-related problems, progressing to the crucial acceptance of their situation. Stoma leakage was frequently described and experienced as unpleasant and unpredictable. Experiences of seeking healthcare in a rural district varied, some spoke warmly about the care given at the cottage hospital while other expressed dissatisfaction.Conclusions: The notably high rate of delayed reversal of a defunctioning stoma in northern Sweden leads to unnecessary suffering for patients. In view of the long delay in reversal times seen, future studies must have considerably longer follow-up. Rural living rectal cancer patients who receives a stoma reported more pain than those living closer to the nearest hospital. Rectal cancer patients who still had a stoma reported an inferior quality-of-life and more stoma-related problems compared to their town counterparts. Results from the studies in this thesis show that the use of a prophylactic mesh when forming an end colostomy has no impact on subsequent global QoL. Rural living stoma patients commonly experience problems related to their stoma that affect their everyday living. Improved patient education shortly after receiving a stoma could help these patients in coming to terms with their situation.
40.	Olofsson, Fredrik, et al. (författare) No benefit of extended mesenteric resection with central vascular ligation in right-sided colon cancer. 2016 Ingår i: Colorectal Disease. - : Wiley. - 1462-8910. Tidskriftsartikel (refereegranskat)abstract The optimal extent of mesenteric resection in colon cancer surgery is not known. We have previously shown an increased mortality associated with wider mesenteric resection in right hemicolectomy. This study compares the short and long-term outcome in three variations of right hemicolectomy based on the position of the vascular ligature in the mesentery.
41.	Olofsson, Fredrik, et al. (författare) Wide Excision In Right-Sided Colon Cancer Is Associated With Decreased Survival. 2013 Ingår i: Scandinavian Journal of Surgery. - : SAGE Publications. - 1799-7267 .- 1457-4969. ; 102:4, s. 241-245 Tidskriftsartikel (refereegranskat)abstract Nodal involvement is the most important prognostic factor in colon cancer. Although theoretically appealing, it is not known if wider mesenteric excision improves the oncological result. The aim of this retrospective study was to investigate whether wider mesenteric excision yields a superior oncological result.
42.	Påhlman, Lars, et al. (författare) Hur ska vi klara av kravet på MDT-konferens för alla? 2011 Ingår i: Svensk Kirurgi. - 0346-847X. ; 69:4, s. 212-213 Tidskriftsartikel (populärvet., debatt m.m.)abstract Modern medicinsk kunskap är idag så omfattande och diversifierad att en enskild läkare i många sammanhang inte kan ta ett lika klokt medicinskt beslut som en grupp av kollegor. Terapikonferenser blir därför allt viktigare för de flesta maligna tillstånd men också för vissa benigna åkommor. Styrgruppen för kolorektala cancerregistret vill här understryka vikten av MDT-konferenser.
43.	Rahman, Milladur, et al. (författare) Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis 2012 Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 61:6, s. 571-579 Tidskriftsartikel (refereegranskat)abstract Abstract in UndeterminedOBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.RESULTS: The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.CONCLUSIONS: We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.
44.	Rahman, Milladur, et al. (författare) Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis. 2013 Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 11:7, s. 1385-1398 Tidskriftsartikel (refereegranskat)abstract Background and objectives: Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase-9 might cleave surface expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis. Methods: Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine, myeloperoxidase levels, neutrophils in the lung as well as plasma levels of CD40L and MMP-9 were quantified. Results: CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease of platelet surface CD40L and increase of soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary MPO activity and neutrophil infiltration in the alveolar space as well as edema formation and lung injury were markedly decreased in septic animals lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock compared to healthy controls although MMP-9 levels did not correlate with organ injury score. Conclusions: Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis. This article is protected by copyright. All rights reserved.
45.	Rehn, Martin, et al. (författare) Collagen levels are normalized after decompression of experimentally obstructed colon 2011 Ingår i: Colorectal Disease. - : Wiley. - 1462-8910. ; 13:7, s. 165-169 Tidskriftsartikel (refereegranskat)abstract Aim Our aim was to define the dynamics in collagen concentrations in the large bowel wall following decompression of experimental obstruction. Method Colonic obstruction was created in 28 male rats by the placement of a silicone ring around the distal colon. The ring was removed after 4 days to mimic endoscopical decompression by stent deployment. Colon circumference and collagen concentration were measured proximal to the obstructed segment immediately and at 3 and 10 days after decompression. The corresponding colonic sites of 23 sham-operated and eight nonoperated control animals were subjected to identical analyses. Results Four days of obstruction resulted in a more than twofold increase in colonic circumference (20 vs 8 mm), with a concomitant 43% reduction (P = 0.001) in collagen concentration in the bowel wall proximal to the obstruction compared with sham animals. Three days after decompression, collagen concentrations remained reduced (P < 0.05), while there was no significant difference after 10 days with either sham-operated or nonoperated controls. Colonic circumference of the obstructed colon remained slightly distended (11 mm) on day 10 and tended to correlate (r(S) = 0.51, P = 0.053) with total matrix metalloproteinase activity. Conclusion The marked reduction in collagen concentration in an experimentally obstructed colon is normalized 10 days after decompression. These findings may have clinical implications for the timing of surgical resection.
46.	Rehn, Martin, et al. (författare) GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization. 2015 Ingår i: Surgical Infections. - : Mary Ann Liebert Inc. - 1557-8674 .- 1096-2964. ; 16:6, s. 702-708 Tidskriftsartikel (refereegranskat)abstract Emergency operations performed on an obstructed colon are accompanied by an increased risk of anastomotic insufficiency. Tissue-destructive matrix metalloproteinase (MMP) activity is elevated in the obstructed colon and contributes to a loss of suture-holding submucosal collagen, which may be mediated by tumor necrosis factor (TNF)-α. Our aim was to study the effect of the non-selective MMP and TNF-α converting enzyme (TACE) inhibitor GM6001 (30 mg/kg) on anastomosis repair in obstructed left colon. GM6001 has been proved to be highly efficacious in elective anastomosis rodent models.
47.	Risberg, Bo, 1941, et al. (författare) Management of aneurysm sac hygroma 2004 Ingår i: Journal of endovascular therapy. - : International Society of Endovascular Specialists. - 1526-6028 .- 1545-1550. ; 11:2, s. 191-5 Tidskriftsartikel (refereegranskat)abstract PURPOSE: To document the management strategies and outcome of patients diagnosed with sac hygroma following open or endovascular abdominal aortic aneurysm (AAA) repair. METHODS: Seven men (median 68 years, range 43-79) with previous open (n=3) or endovascular (n=4) AAA repairs and increasing aneurysm diameters documented on spiral computed tomography (CT) were diagnosed with sac hygroma based on the lack of a demonstrable endoleak on CT imaging; the presence of a gelatinous, clear fluid in the sac; and a nonpulsatile sac pressure that was about one third of the systemic blood pressure. The patients were followed at regular intervals with spiral CT and percutaneous CT-guided translumbar intrasac pressure measurements. Surgical interventions were performed for sac diameter increase >5 mm or expansion-related pain. Blood samples and fluid aspirated from the sac were analyzed to detect activation of the coagulation and fibrinolytic systems. RESULTS: Over a median 21.5-month follow-up, open fenestration with resection of the aneurysm wall or open tight wrapping of the wall around the graft in 4 patients did not prevent hygroma reoccurrence, nor did repeated punctures with aspiration of fluid in the other 3 patients. Aneurysm diameters remained unchanged during the observation period. CONCLUSIONS: Only symptomatic hygromas need be treated, but the treatment of choice remains to be established, since puncture, fenestration, or resection of the sac do not seem to be adequate.
48.	Ronnow, Carl Fredrik, et al. (författare) Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer : Retrospective Population-based Cohort Study on Prospectively Collected Data, including Validation 2022 Ingår i: Annals of Surgery. - 0003-4932. ; 275:1, s. 148-154 Tidskriftsartikel (refereegranskat)abstract Objective: To identify clinical and histopathological risk factors of LNM in T1 CRC. Summary of Background Data: The requisite of additional surgery after locally resected T1 CRC is dependent on the risk of LNM. Depth of submucosal invasion is used as a key predictor of lymphatic metastases although data are conflicting on its actual impact. Methods: Retrospective population-based cohort study on prospectively collected data on all patients with T1 CRC undergoing surgical resection in Sweden, 2009-2017 and Denmark 2016-2018. The Danish cohort was used for validation. Potential risk factors of LNM investigated were; age, sex, tumor location, submucosal invasion, grade of differentiation, mucinous subtype, lymphovascular, and perineural invasion. Results: One hundred fifty out of the 1439 included patients (10%) had LNM. LVI (P < 0.001), perineural invasion (P < 0.001), mucinous subtype (P = 0.006), and age <60 years (P < 0.001) were identified as independent risk factors whereas deep submucosal invasion was only a dependent (P = 0.025) risk factor and not significant in multivariate analysis (P = 0.075). The incidence ofLNMwas 51/882 (6%) in absence of the independent risk factors. The Danish validation cohort, confirmed our findings regarding the role of submucosal invasion, LVI, and age. Conclusions: This is a large study on LNM in T1 CRC, including validation, showing that LVI and perineural invasion, mucinous subtype, and low age constitute independent risk factors, whereas depth of submucosal invasion is not an independent risk factor of LNM. Thus, our findings provide a useful basis for management of patients after local excision of early CRC.
49.	Scherman, Peter, et al. (författare) High resection rates of colorectal liver metastases after standardized follow-up and multimodal management: an outcome study within the COLOFOL trial 2023 Ingår i: Hpb. - : Elsevier BV. - 1365-182X. ; 25:7, s. 766-774 Tidskriftsartikel (refereegranskat)abstract Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS. Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.
50.	Scherman, Peter, et al. (författare) Impact of patient, primary tumor and metastatic pattern including tumor location on survival in patients undergoing ablation or resection for colorectal liver metastases: A population-based national cohort study 2021 Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 47:2, s. 375-383 Tidskriftsartikel (refereegranskat)abstract Introduction Selecting the optimal treatment strategy for patients with colorectal liver metastases (CRLM) aim to improve survival for the total cohort. Following the introduction of laparoscopic resections and ablation, localization may direct choice of method. The aim with this study was to re-evaluate prognostic factors that should be considered at the preoperative multidisciplinary tumor board, based on a national population cohort. Materials and methods A national cohort with radically operated colorectal cancer in 2009-2013, also treated for CRLM was identified in Swedish national registries. Prognostic factors were identified and evaluated in multivariable analyses. Results 1200 patients treated with resection and 125 with ablation only were included in the study cohort. Relative five-year survival was 54.7% (50.9%-58.4%) and 32.0% (22.4%-41.9%), respectively). High age, acute surgery and complications at time of primary tumor resection remained important risk factors at liver surgery, as well as the primary tumor characteristics; vascular invasion and high lymph node ratio. As for metastatic pattern; tumor size, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after preoperative chemotherapy were significant risk factors. In multivariate analyses, ablation therapy doubled the risk of death within 5 years. This strong negative impact was confirmed in a weighted propensity score analysis (HR = 2.1 (95 % CI 1.5 -3.0)). Conclusion Segmental localization and tumor size were prognostic factors but also patient and primary tumor factors significantly impacted survival after intervention for CRLM. Long-term survival was significantly lower after ablation therapy compared to surgical resection.

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