| 1. |
- Nilsson, Emelie, et al.
(författare)
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Risk of recurrence in high-risk T1 colon cancer following endoscopic and surgical resection : registry-based cohort study
- 2024
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Ingår i: BJS Open. - 2474-9842. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Endoscopic resection of T1 colon cancer (CC) is currently limited by guidelines related to risk of lymph node metastases. However, clinical outcome following endoscopic and surgical resection is poorly investigated. Method: A retrospective multicentre national cohort study was conducted on prospectively collected data from the Swedish colorectal cancer registry on all non-pedunculated T1 CC patients undergoing surgical and endoscopic resection between 2009 and 2021. Patients were categorized on the basis of deep submucosal invasion (Sm2–3), lymphovascular invasion (LVI), poor tumour differentiation, and R1/Rx into low- and high-risk cases. The primary outcomes of interest were recurrence rates and disease-free interval (DFI, defined as time from treatment to date of recurrence) according to resection methods and risk factors (sex, age at diagnosis, histologic grade, LVI, perineural invasion, mucinous subtype, submucosal invasion, tumour location, resection margin and nodal positivity in the surgical group). Results: In total, 1805 patients undergoing endoscopic (488) and surgical (1317) resection with 60.0 months median follow-up were included. Recurrence occurred in 18 (3.7%) endoscopically and 48 (3.6%) surgically resected patients. Adjuvant treatment was administered in 7.4% and 0.2% of the cases respectively in the surgical and endoscopically treated patients. Five-year DFI was 95.6% after endoscopic and 96.2% after surgical resection, with no significant difference when adjusting for confounding factors (HR 1.03, 95% c.i. 0.56 to 1.91, P = 0.920). There were no statistically significant differences in recurrence comparing endoscopic (1.7%) versus surgical (3.6%) low-risk and endoscopic (5.4%) versus surgical (3.8%) high-risk cases. LVI was the only significant risk factor for recurrence in multivariate Cox regression (HR 3.73, 95% c.i. 1.76 to 7.92, P < 0.001). Conclusions: This study shows no difference in recurrence after endoscopic and surgical resection in high-risk T1 CC. Although it was not possible to match groups according to treatment, the multivariate analysis showed that lymphovascular invasion was the only independent risk factor for recurrence.
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| 2. |
- Du, Feifei, et al.
(författare)
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E3 Ubiquitin Ligase Midline 1 Regulates Endothelial Cell ICAM-1 Expression and Neutrophil Adhesion in Abdominal Sepsis
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Septic lung damage is associated with endothelial cell and neutrophil activation. This study examines the role of the E3 ubiquitin ligase midline 1 (Mid1) in abdominal sepsis. Mid1 expression was increased in endothelial cells derived from post-capillary venules in septic mice and TNF-α challenge increased Mid1 levels in endothelial cells in vitro. The siRNA-mediated knockdown of Mid1 decreased TNF-α-induced upregulation of ICAM-1 and neutrophil adhesion to endothelial cells. Moreover, Mid1 silencing reduced leukocyte adhesion in post-capillary venules in septic lungs in vivo. The silencing of Mid1 not only decreased Mid1 expression but also attenuated expression of ICAM-1 in lungs from septic mice. Lastly, TNF-α stimulation decreased PP2Ac levels in endothelial cells in vitro, which was reversed in endothelial cells pretreated with siRNA directed against Mid1. Thus, our novel data show that Mid1 is an important regulator of ICAM-1 expression and neutrophil adhesion in vitro and septic lung injury in vivo. A possible target of Mid1 is PP2Ac in endothelial cells. Targeting the Mid1-PP2Ac axis may be a useful way to reduce pathological lung inflammation in abdominal sepsis.
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| 3. |
- Wetterholm, Erik, et al.
(författare)
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CT is unreliable in locoregional staging of early colon cancer : A nationwide registry-based study
- 2023
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Ingår i: Scandinavian Journal of Surgery. - : SAGE Publications. - 1799-7267 .- 1457-4969. ; 112:1, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVE: The option to treat early colon cancer (CC) with local resection, as well as trials investigating neoadjuvant treatment, has increased the importance of identifying early-stage disease in the workup. Most CC patients are T- and N-staged preoperatively with CT, although its reliability in staging early CC remains elusive. The aim of this study was to investigate CT-staging accuracy in early CC by evaluating pT and pN stages in patients staged as cT1-2, and cT and cN stages in patients with pT1 tumors.METHODS: Retrospective population-based cohort study on data from the nationwide Swedish colorectal cancer registry on all CC patients staged as cT1-2 and all patients with pT1 undergoing surgical resection 2009-2018. CT-acquired T- and N-stages were compared with final histopathology. Factors potentially influencing accuracy were analyzed with uni- and multivariate logistic regression.RESULTS: Computed tomography (CT) staged 4849 patients as cT1-2, whereas 2445 (50%) were pT3 and 453 (9%) pT4. Positive predictive value of the cT1-2 stage was 40%. Of 1401 pT1 patients, 624 (45%) were staged as cT1-2, 139 (10%) as cT3, 15 (1%) as cT4 and 623 (44%) as cTx. In all, 1474 (30%) of the cT1-2 patients were pN+, whereas CT staged 1062 (72%) as cN0. A total of 771 patients were staged as cN+, whereas 403 (52%) were pN0. Overall accuracy in determining N+ was 67%, with 26% sensitivity and 88% specificity. Positive and negative predictive values in determining N+ were 48% and 73%, respectively.CONCLUSIONS: This nationwide population-based study shows that CT-staging carries a substantial risk of understaging locally advanced tumors as cT1-2 and pT1 tumors as cTx, in addition to poor N-staging. Thus, CT obtained T- and N-staging should not be used for deciding treatment strategies in early CC.
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| 4. |
- Arthursson, Victoria, et al.
(författare)
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Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer
- 2022
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Ingår i: Endoscopy. - : Georg Thieme Verlag KG. - 1438-8812 .- 0013-726X. ; 54:11, s. 1071-1077
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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.
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| 5. |
- Ding, Zhiyi, et al.
(författare)
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Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis
- 2022
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Ingår i: American Journal of Physiology - Lung Cellular and Molecular Physiology. - 1040-0605. ; 322:5, s. 662-672
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.
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| 6. |
- Du, Feifei, et al.
(författare)
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S100A9 induces reactive oxygen species-dependent formation of neutrophil extracellular traps in abdominal sepsis
- 2022
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 421:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes in S100A9-stimulated neutrophils. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Administration of the S100A9 inhibitor ABR-238901 decreased CLP-induced formation of NETs in lungs and DNA-histone complexes in plasma. In addition, transmission electron microscopy revealed that S100A9 was abundantly expressed on NETs in the lungs in CLP mice. By use of intravital microscopy, we found that local injection of NETs increased leukocyte adhesion and migration in the mouse cremaster muscle microvasculature. Notably, treatment with ABR-238901 attenuated NET-induced leukocyte adhesion and extravasation in the cremaster muscle, suggesting that NET-associated S100A9 promotes leukocyte recruitment in vivo. Taken together, these novel findings suggest that S100A9 triggers ROS-dependent formation of NETs via TLR4 and RAGE signaling in neutrophils. Moreover, S100A9 regulates both formation of NETs and NET-induced leukocyte recruitment in vivo. Thus, targeting S100A9 might be useful to ameliorate lung damage in abdominal sepsis.
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| 7. |
- Rosén, Roberto, et al.
(författare)
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Accuracy of MRI in early rectal cancer: national cohort study
- 2022
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323.
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Tidskriftsartikel (refereegranskat)abstract
- Radiological staging of rectal cancer dictates subsequent patienttreatment. In early-stage disease, local excision is associatedwith reduced morbidity, mortality, and costs, and maintainsbowel continuity compared with surgery, where the whole orpart of the rectum is resected1–3. Nearly 90 per cent of patientswith T1 rectal cancer have N0 disease and are therefore potentially curable with local resection, yet the majority undergo major resection4–6. MRI is the primary staging investigation used to predictlocal stage in rectal cancer7, mainly owing to its ability to allocatepatients in need of neoadjuvant treatment8–10. There is potentially inaccuracy in MRI staging for nodal involvement and differentiation of T1 from T2 tumours6,7,11. Consequently, cT1 and cT2 areoften combined and comprice tumours considered for local resection. Apart from a recent study6 reporting 54 per cent accuracy forMRI cT1–2 category, combined cT1–2 status has not beeninvestigated.The aim of this large nationwide retrospective cohort study wasto investigate the staging accuracy of MRI, from a clinical perspective, in early rectal cancer when combining cT1 and cT2 categories.
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| 8. |
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| 9. |
- Algaber, Anwar, et al.
(författare)
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Targeting FHL2-E-cadherin axis by miR-340-5p attenuates colon cancer cell migration and invasion
- 2021
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- Convincing data has suggested that four and a half LIM domain 2 protein (FHL2) serves a key function in cancer cell metastasis and that microRNA (miR)-340-5p can regulate cancer cell migration. The current study hypothesized that targeting FHL2 expression by miR-340-5p in colon cancer may attenuate colon cancer cell migration and invasion. FHL2 expression was therefore assessed in colon cancer microarray datasets using Qlucore omics explorer as well as in HT-29 and AZ-97 colon cancer cell lines via reverse transcription-quantitative PCR (RT-qPCR). Colon cancer cell migration and invasion were evaluated in the presence of miR-340-5p mimic, mimic control or mimic with a target site blocker. Confocal microscopy and RT-qPCR were subsequently performed to assess FHL2, E-cadherin (E-cad) protein and mRNA expression in colon cancer cells. Microarray dataset analysis revealed that FHL2 expression was lower in primary colon cancer cells compared with normal colonic mucosa. It was revealed that the expression of miR-340-5p and FHL2 were inversely related in serum-grown and low-serum conditions in HT-29 and AZ-97 cells. Short-time serum exposure to low-serum grown cells induced FHL2 expression. Transfection of HT-29 cells with miR-340-5p mimic not only decreased serum-induced expression of FHL2 but also decreased cancer cell migration and invasion. Bioinformatics analysis revealed that FHL2 mRNA had one putative binding site for miR-340-5p at the 3-untranslated region. Blocking of the target site using a specific blocker reverted miR-340-5p mimic-induced inhibition of FHL2 expression and cancer cell migration and invasion. Confocal microscopy confirmed that the reduction of FHL2 expression by miR-340-5p mimic also reversed serum-induced E-cad disruption and that the target site blocker abrogated the effect of miR-340-5p. The current results suggested that miR-340-5p could be used to antagonize colon cancer cell metastasis by targeting the FHL2-E-cad axis.
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| 10. |
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