Deletion of IFT20 exclusively in the RPE ablates primary cilia and leads to retinal degeneration.

Vision impairment places a serious burden on the aging society, affecting the lives of millions of people. Many retinal diseases are of genetic origin, of which over 50% are due to mutations in cilia-associated genes. Most research on retinal degeneration has focused on the ciliated photoreceptor cells of the retina. However, the contribution of primary cilia in other ocular cell types has largely been ignored. The retinal pigment epithelium (RPE) is a monolayer epithelium at the back of the eye intricately associated with photoreceptors and essential for visual function. It is already known that primary cilia in the RPE are critical for its development and maturation; however, it remains unclear whether this affects RPE function and retinal tissue homeostasis. We generated a conditional knockout mouse model, in which IFT20 is exclusively deleted in the RPE, ablating primary cilia. This leads to defective RPE function, followed by photoreceptor degeneration and, ultimately, vision impairment. Transcriptomic analysis offers insights into mechanisms underlying pathogenic changes, which include transcripts related to epithelial homeostasis, the visual cycle, and phagocytosis. Due to the loss of cilia exclusively in the RPE, this mouse model enables us to tease out the functional role of RPE cilia and their contribution to retinal degeneration, providing a powerful tool for basic and translational research in syndromic and non-syndromic retinal degeneration. Non-ciliary mechanisms of IFT20 in the RPE may also contribute to pathogenesis and cannot be excluded, especially considering the increasing evidence of non-ciliary functions of ciliary proteins.

Anastomotic Leakage in Relation to Type of Mesorectal Excision and Defunctioning Stoma Use in Anterior Resection for Rectal Cancer.

BACKGROUND: Anastomotic leakage after anterior resection for rectal cancer is more common after total mesorectal excision compared to partial mesorectal excision but might be mitigated by a defunctioning stoma. OBJECTIVE: The aim is to assess how anastomotic leakage is affected by type of mesorectal excision and defunctioning stoma use. DESIGN: This is a retrospective multicenter cohort study evaluating anastomotic leakage after anterior resection. Multivariable Cox regression with HRs and 95% CIs was used to contrast mesorectal excision types and defunctioning stoma use with respect to anastomotic leakage, with adjustment for confounding. SETTINGS: This multicenter study included patients from 11 Swedish hospitals between 2014 and 2018. PATIENTS: Patients who underwent anterior resection for rectal cancer were included. MAIN OUTCOMES MEASURES: Anastomotic leakage rates within and after 30 days of surgery are described up to 1 year after surgery. RESULTS: Anastomotic leakage occurred in 24.2% and 9.0% of 1126 patients operated with total and partial mesorectal excision, respectively. Partial compared to total mesorectal excision was associated with a reduction in leakage, with an adjusted HR of 0.46 (95% CI, 0.29-0.74). Early leak rates within 30 days were 14.9% with and 12.5% without a stoma, whereas late leak rates after 30 days were 7.5% with and 1.9% without a stoma. After adjustment, defunctioning stoma was associated with a lower early leak rate (HR 0.47; 95% CI, 0.28-0.77). However, the late leak rate was nonsignificantly higher in patients with defunctioning stomas (HR 1.69; 95% CI, 0.59-4.85). LIMITATIONS: This study was limited by its retrospective observational study design. CONCLUSIONS: Anastomotic leakage is common up to 1 year after anterior resection for rectal cancer, where partial mesorectal excision is associated with a lower leak rate. Defunctioning stomas seem to decrease the occurrence of leakage, although partially by only delaying the diagnosis. See Video Abstract . FUGA ANASTOMTICA SEGN EL TIPO DE EXCISIN MESORRECTAL Y LA CONFECCIN DE OSTOMA DE PROTECCIN EN LA RESECCIN ANTERIOR POR CNCER DE RECTO: ANTECEDENTES:La fuga anastomótica después de una resección anterior por cáncer de recto es más frecuente después de la excisión total del mesorrecto comparada con la excisión parcial del mismo, pero podría mitigarse con la confección de ostomías de protección.OBJETIVO:El objetivo es evaluar cómo la fuga anastomótica se ve afectada según el tipo de excisión mesorrectal y la confección de una ostomía de protección.DISEÑO:Estudio de cohortes multicéntrico y retrospectivo que evalúa la fuga anastomótica después de la resección anterior. Se aplicó la regresión multivariada de Cox con los índices de riesgo (HR) y los intervalos de confianza (IC) al 95% para contrastar los tipos de excisión mesorrectal y el uso de otomías de protección con respecto a la fuga anastomótica, realizando ajustes respecto a las variables de confusión.AJUSTES:El presente estudio multicéntrico incluyó pacientes de 11 hospitales suecos entre 2014 y 2018.PACIENTES:Se incluyeron todos aquellos sometidos a resección anterior por cáncer de recto.PRINCIPALES MEDIDAS DE RESULTADOS:Las tasas de fuga anastomótica dentro y después de los 30 días de la cirugía fueron descritos hasta un año mas tarde al acto quirúrgico.RESULTADOS:La fuga anastomótica ocurrió en el 24,2% y el 9,0% de 1126 pacientes operados por excisión total y parcial del mesorrecto respectivamente.La excisión parcial del mesorrecto en comparación con la total se asoció con una reducción de la fuga, HR ajustado de 0,46 (IC del 95 %: 0,29 a 0,74). Las tasas de fuga temprana dentro de los 30 días fueron del 14,9 % con y el 12,5 % sin estoma, mientras que las tasas de fuga tardía después de 30 días fueron del 7,5 % con y el 1,9 % sin estoma.Después del ajuste de variables de confusión, las ostomías de protección se asociaron con una tasa de fuga temprana más baja (HR 0,47; IC 95 %: 0,28-0,77). Sin embargo, la tasa de fuga tardía no fue significativamente mayor en pacientes ostomizados (HR 1,69; IC 95%: 0,59-4,85).LIMITACIONES:Las limitaciones del presente estudio estuvieron vinculadas con el diseño de tipo observacional y retrospectivo.CONCLUSIONES:La fuga anastomótica es común hasta un año después de la resección anterior por cáncer de recto, donde la excisión parcial del mesorrecto se asocia con una menor tasa de fuga. La confección de ostomías de protección parece disminuir la aparición de fuga anastomótica, aunque en parte sólo retrasen el diagnóstico. (Traducción-Dr. Xavier Delgadillo ).

Evolution of surgical approach to rectal cancer resection: A multinational registry assessment.

PURPOSE: Surgical approach to rectal cancer has evolved in recent decades, with introduction of minimally invasive surgery (MIS) techniques and local excision. Since implementation might differ internationally, this study is aimed at evaluating trends in surgical approach to rectal cancer across different countries over the last 10 years and to gain insight into patient, tumour and treatment characteristics. METHODS: Pseudo-anonymised data of patients undergoing resection for rectal cancer between 2010 and 2019 were extracted from clinical audits in the Netherlands (NL), Sweden (SE), England-Wales (EW) and Australia-New Zealand (AZ). RESULTS: Ninety-nine thousand five hundred ninety-seven patients were included (38,413 open, 55,155 MIS and 5416 local excision). An overall increase in MIS was observed from 29.9% in 2010 to 72.1% in 2019, with decreasing conversion rates (17.5-9.0%). The MIS proportion was highly variable between countries in the period 2010-2014 (54.4% NL, 45.3% EW, 39.8% AZ, 14.1% SE, P < 0.001), but variation reduced over time (2015-2019 78.8% NL, 66.3% EW, 64.3% AZ, 53.2% SE, P < 0.001). The proportion of local excision for the two periods was highly variable between countries: 4.7% and 11.8% in NL, 3.9% and 7.4% in EW, 4.7% and 4.6% in AZ, 6.0% and 2.9% in SE. CONCLUSIONS: Application and speed of implementation of MIS were highly variable between countries, but each registry demonstrated a significant increase over time. Local excision revealed inconsistent trends over time.

Implications of pretreatment extramural venous invasion in rectal cancer patients: A population-based study.

AIM: Extramural venous invasion detected by MRI (mrEMVI) has in several expert centre studies been identified as an important prognostic factor in rectal cancer, and in guiding neoadjuvant therapy. However, population-based evidence for mrEMVI as a predictor for recurrent disease is lacking. METHOD: This was a multicentre retrospective study based on the Swedish Colorectal Cancer Registry. The study period encompassed patients operated with abdominal resection for rectal cancer 2017-2021, with follow-up until January 2023. Patients diagnosed at hospitals with radiological registry data coverage <90% or with metastatic disease were excluded. Pretreatment mrEMVI constituted exposure, while recurrence-free survival was the main outcome. Distant and local recurrence, and overall survival were secondary outcomes, and pretreatment and postoperative scenarios were explored using multivariable Cox regression with multiple imputation. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. RESULTS: A total of 2737 patients from 13 hospitals were eligible for analysis. Pretreatment mrEMVI was reported in 14.5% of patients, while 71.9% had negative findings and 13.6% had missing data. In the pretreatment scenario, mrEMVI was an independent predictor for worse recurrence-free survival with an adjusted HR of 1.64 (95% CI: 1.31-2.06). In the postoperative MDT setting, the influence of mrEMVI on recurrence-free survival decreased with an adjusted HR of 1.27 (95% CI: 1.00-1.61). CONCLUSION: mrEMVI at diagnosis is an independent predictor of recurrence-free survival in an unselected population of rectal cancer patients undergoing abdominal resection.

Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

Short-term results in a population based study indicate advantage for minimally invasive rectal cancer surgery versus open.

BACKGROUND: The aim of this study was to determine if minimally invasive surgery (MIS) for rectal cancer is non-inferior to open surgery (OPEN) regarding adequacy of cancer resection in a population based setting. METHODS: All 9,464 patients diagnosed with rectal cancer 2012-2018 who underwent curative surgery were included from the Swedish Colorectal Cancer Registry. PRIMARY OUTCOMES: Positive circumferential resection margin (CRM < 1 mm) and positive resection margin (R1). Non-inferiority margins used were 2.4% and 4%. SECONDARY OUTCOMES: 30- and 90-day mortality, clinical anastomotic leak, re-operation < 30 days, 30- and 90-day re-admission, length of stay (LOS), distal resection margin < 1 mm and < 12 resected lymph nodes. Analyses were performed by intention-to-treat using unweighted and weighted multiple regression analyses. RESULTS: The CRM was positive in 3.8% of the MIS group and 5.4% of the OPEN group, risk difference -1.6% (95% CI -1.623, -1.622). R1 was recorded in 2.8% of patients in the MIS group and in 4.4% of patients in the OPEN group, risk difference -1.6% (95% CI -1.649, -1.633). There were no differences between the groups in adjusted unweighted and weighted analyses. All analyses demonstrated decreased mortality and re-admissions at 30 and 90 days as well as shorter LOS following MIS. CONCLUSIONS: In this population based setting MIS for rectal cancer was non-inferior to OPEN regarding adequacy of cancer resection with favorable short-term outcomes.

CRCBaSe: a Swedish register-based resource for colorectal adenocarcinoma research.

OBJECTIVES: To facilitate high-quality register-based research on colorectal cancer (CRC) in Sweden by constructing a database consisting of CRC patients, matched comparators, and relatives. MATERIAL AND METHODS: Patients with adenocarcinoma in the colon and/or rectum were identified in the Swedish Colorectal Cancer Register, a nationwide quality-of-care register. For each patient, six comparators from the general population were matched on birth year, sex, year of CRC diagnosis, and county. Comparators were free from CRC at the time of matching, but could later become cases. For both patients and comparators, first-degree relatives (parents, siblings, and children) were identified. Information from nationwide population-based registers was retrieved and linked to each individual in the database using the personal identification number unique to all Swedish residents. RESULTS: A total of 76,831 CRC patients diagnosed between 1995 and 2016 were identified (51% colon, 49% rectal; before 2007 only rectal cancer patients were included). Among all patients, 37% were stage I-II, 22% stage III, and 22% stage IV. The median follow-up time was 11.9 years (inter-quartile range, IQR: 8.6-15.3). Together with comparators and relatives, the database contains 2,413,139 individuals with information on demographics, dates and causes of death, in- and outpatient healthcare records, cancer diagnoses, prescribed and dispensed drugs, childbirths (among women), and social security information (such as sick leave and early retirement). CONCLUSION: The Colorectal Cancer Database Sweden (CRCBaSe) is a large and unique register-based data research platform, which opens up for clinically important, large epidemiological studies with innovative design in the field of colorectal adenocarcinoma.

The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Preoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment. METHODS: Patients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models. RESULTS: A total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most. DISCUSSION: Preoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.

Long-term oncological outcomes for minimally invasive surgery versus open surgery for colon cancer-a population-based nationwide study with a non-inferiority design.

AIM: The study aimed to compare 5-year overall survival in a national cohort of patients undergoing curative abdominal resection for colon cancer by minimally invasive surgery (MIS) or by the open (OPEN) technique. METHODS: All patients diagnosed between 2010 and 2016 in Sweden with pathological Union International Contre le Cancer Stages I-III colon cancer localized in the caecum, ascending colon, hepatic flexure or sigmoid colon and those who underwent curative right sided hemicolectomy, sigmoid resection or high anterior resection by MIS or OPEN were included. Patients were identified in the Swedish Colorectal Cancer Registry from which all data were retrieved. The analyses were performed as intention-to-treat and the relationship between surgical technique (MIS or OPEN) and overall mortality within 5 years was analysed. For the primary research question a non-inferiority hypothesis was assumed with a statistical power of 90%, a one-side type I error of 2.5% and a non-inferiority margin of 2%. For the secondary analyses, multilevel survival regression models with the patients matched by propensity scores were employed, adjusted for patient- and tumour-related variables. RESULTS: A total of 11 605 pathological Union International Contre le Cancer Stages I-III patients were included with 3297 MIS (28.4%) and 8308 OPEN (71.6%) and were followed until 31 December 2020. The primary analysis demonstrated superiority for MIS compared to OPEN. The multilevel survival regression analyses confirmed that 5-year overall survival was higher in MIS with a hazard ratio of 0.874 (95% confidence interval 0.791-0.965), and if excluding pT4 the outcome was similar, with a hazard ratio of 0.847 (95% confidence interval 0.756-0.948). CONCLUSION: This observational study demonstrated that MIS was favourable to OPEN with regard to 5-year overall survival. These results support the use of laparoscopic colon cancer surgery in routine practice.

Statin Therapy Is Associated With Decreased 90-Day Postoperative Mortality After Colon Cancer Surgery.

BACKGROUND: There have been conflicting reports regarding a protective effect of statin therapy after colon cancer surgery. OBJECTIVE: This study aimed to evaluate the association between statin therapy and the postoperative mortality following elective colon cancer surgery. DESIGN: This population-based cohort study is a retrospective analysis of prospectively collected data from the Swedish Colorectal Cancer Register. SETTINGS: Patient inclusion was achieved through a nationwide register. PATIENTS: All adult patients undergoing elective surgery for colon cancer between January 2007 and September 2016 were included in the study. Patients who had received and collected a prescription for statins pre- and postoperatively were allocated to the statin-positive cohort. MAIN OUTCOME MEASURES: The primary and secondary outcomes of interest were 90-day all-cause mortality and 90-day cause-specific mortality. RESULTS: A total of 22,337 patients underwent elective surgery for colon cancer during the study period, of whom 6,494 (29%) were classified as statin users. Statin users displayed a significant survival benefit despite being older, having a higher comorbidity burden, and being less fit for surgery. Multivariate analysis illustrated significant reductions in the incidence risk for 90-day all-cause mortality (Incidence Rate Ratio = 0.12, p < 0.001) as well as 90-day cause-specific deaths due to sepsis, due to multiorgan failure, or resulting from a cardiovascular and respiratory origin. LIMITATIONS: The limitations of this study include its observational retrospective design, restricting the ability to perform standardized follow-up of statin therapy. Confounding from other uncontrolled variables cannot be excluded. CONCLUSIONS: Statin users had a significant postoperative benefit regarding short-term mortality following elective colon cancer surgery in the current study; however, further research is needed to ascertain whether this relationship is causal. See Video Abstract at http://links.lww.com/DCR/B738. LA TERAPIA CON ESTATINAS SE ASOCIA CON UNA DISMINUCIN DE LA MORTALIDAD POSOPERATORIA A LOS DAS DESPUS DE LA CIRUGA DE CNCER DE COLON: ANTECEDENTES:Ha habido informes contradictorios con respecto al efecto protector de la terapia con estatinas después de la cirugía de cáncer de colon.OBJETIVO:Este estudio tuvo como objetivo evaluar la asociación entre la terapia con estatinas y la mortalidad postoperatoria después de la cirugía electiva por cáncer de colon.DISEÑO:Este estudio de cohorte poblacional es un análisis retrospectivo de datos recopilados prospectivamente del Registro Sueco de Cáncer Colorrectal.AJUSTES:La inclusión de pacientes se logró mediante la inclusión a través de un registro a nivel nacional.PACIENTES:Se incluyeron en el estudio todos los pacientes adultos sometidos a cirugía electiva por cáncer de colon en el período de enero de 2007 y septiembre de 2016. Los pacientes que habían recibido y recogido una receta de estatinas antes y después de la operación fueron asignados a la cohorte positiva de estatinas.PRINCIPALES MEDIDAS DE DESENLACES:Los desenlaces primarios y secundarios de interés fueron la mortalidad por cualquier causa a los 90 días y la mortalidad por causas específicas a los 90 días.RESULTADOS:Un total de 22.337 pacientes se sometieron a cirugía electiva por cáncer de colon durante el período de estudio, de los cuales 6.494 (29%) se clasificaron como usuarios de estatinas. Los usuarios de estatinas mostraron un beneficio significativo en la supervivencia a pesar de ser mayores, de tener una mayor carga de comorbilidad y de estar menos acondicionado para la cirugía. El análisis multivariado ilustró reducciones significativas en el riesgo de incidencia de mortalidad por cualquier causa a 90 días (índice de tasa de incidencia = 0,12, p < 0,001), así como muertes específicas ena 90 días debidas a sepsis, falla multiorgánica o dea enfermedades de origen cardiovascular y respiratorio.LIMITACIONES:Las limitaciones de este estudio incluyen su diseño observacional retrospectivo, que restringe la capacidad de realizar un seguimiento estandarizado de la terapia con estatinas. No se puede excluir confusión a partir de otras variables no controladas.CONCLUSIONES:Los usuarios de estatinas tuvieron un beneficio posoperatorio significativo con respecto a la mortalidad a corto plazo después de cirugía electiva por cáncer de colon en el estudio actual, sin embargo, se necesita más investigación para confirmar si eexiste una relación es causal. Consulte Video Resumen en http://links.lww.com/DCR/B738.

Long term oncological outcomes for laparoscopic versus open surgery for rectal cancer - A population-based nationwide noninferiority study.

AIM: The aim of this work was to compare the 5-year overall survival in a national cohort of patients undergoing curative abdominal resection for rectal cancer by laparoscopic (LAP) or open (OPEN) surgery. METHOD: All patients diagnosed with clinical Stage I-III rectal cancer and who underwent LAP or OPEN abdominal curative surgery in Sweden between 2010 and 2016 were retrieved from the Swedish Colorectal Cancer Registry. A noninferiority study design was employed with a statistical power of 90%, a one-side type I error of 2.5% and a noninferiority margin of 2%. The analyses were performed as intention-to-treat and the relationship between surgical technique and overall mortality within 5 years was analysed. Multilevel regression models with the patients matched by propensity scores adjusted for patient- and tumour-related variables were used. RESULTS: A total of 8410 Stage I-III cancer patients were included. This group underwent 2094 LAP (24.9%) and 6316 OPEN (75.1%) procedures and were followed until 31 December 2020. Multivariable Cox regression demonstrated that 5-year overall survival was higher in the LAP group [hazard ratio (HR) 0.877; 95% CI 0.775-0.993]. [Correction added on 21 November 2022, after first online publication: In the preceding sentence, the CI value for LAP group has been corrected from "0.877" to "0.775" in this version.] The outcome was similar when multiple imputation and propensity score matching were employed. When cT4 patients were excluded there was no difference (HR 0.885; 95% CI 0.790-1.033). At 5-years' follow-up local recurrence was not different, at 2.9% for the LAP group and 3.6% for the OPEN group (p = 0.075), while metastatic disease was more frequent in the OPEN group (19.6% compared with 15.6% for LAP; p < 0.001). CONCLUSION: This study demonstrated that the LAP technique was not inferior to OPEN surgery with regard to overall 5-year survival. These results support the use of laparoscopic surgery.

Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer.

AIM: The aim of this work was to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be beneficial or harmful when used perioperatively for colorectal cancer patients, as inflammation may affect occult disease and anastomotic healing. METHOD: This is a protocol-based retrospective cohort study on colorectal cancer patients operated on between 2007 and 2012 at 21 hospitals in Sweden. NSAID exposure was retrieved from postoperative analgesia protocols, while outcomes and patient data were retrieved from the Swedish Colorectal Cancer Registry. Older or severely comorbid patients, as well as those with disseminated or nonradically operated tumours were excluded. Multivariable regression with adjustment for confounders was performed, estimating hazard ratios (HRs) for long-term outcomes and odds ratios (ORs) for short-term outcomes, including 95% confidence intervals (CIs). RESULTS: Some 6945 patients remained after exclusion, of whom 3996 were treated at hospitals where a NSAID protocol was in place. No association was seen between NSAIDs and recurrence-free survival (HR 0.97, 95% CI 0.87-1.09). However, a reduction in cancer recurrence was detected (HR 0.83, 95% CI 0.72-0.95), which remained significant when stratifying into locoregional (HR 0.68, 95% CI 0.48-0.97) and distant recurrences (HR 0.85, 95% CI 0.74-0.98). Anastomotic leakage was less frequent (HR 0.69%, 95% CI 0.51-0.94) in the NSAID-exposed, mainly due to a risk reduction in colo-rectal and ileo-rectal anastomoses (HR 0.47, 95% CI 0.33-0.68). CONCLUSION: There was no association between NSAID exposure and recurrence-free survival, but an association with reduced cancer recurrence and the rate of anastomotic leakage was detected, which may depend on tumour site and anastomotic location.

Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer: A Nationwide Cohort Study.

OBJECTIVE: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery. SUMMARY BACKGROUND DATA: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent. METHODS: All stage I-III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs). RESULTS: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79-1.07) or overall (HR 0.98, 95% CI 0.89-1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59-1.23) or distant (HR 1.01, 95% CI 0.88-1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85-1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72). CONCLUSION: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.

Defunctioning stoma and short- and long-term outcomes after low anterior resection for rectal cancer-a nationwide register-based cohort study.

PURPOSE: A defunctioning stoma reduces the risk of symptomatic anastomotic leakage after low anterior resection for rectal cancer and mitigates the consequences when a leakage occurs, but the impact on mortality and oncological outcomes is unclear. The aim was to investigate the associations of a defunctioning stoma with short- and long-term outcomes in patients undergoing low anterior resection for rectal cancer. METHODS: Data from all patients who underwent curative low anterior resection for rectal cancer between 1995 and 2010 were obtained from the Swedish Colorectal Cancer Register. A total of 4130 patients, including 2563 with and 1567 without a defunctioning stoma, were studied. Flexible parametric models were used to estimate hazard ratios for all-cause mortality, 5-year local recurrence, and distant metastatic disease in relation to the use of defunctioning stoma, adjusting for confounding factors and accounting for potential time-dependent effects. RESULTS: During a median follow-up of 8.3 years, a total of 2169 patients died. In multivariable analysis, a relative reduction in mortality was observed up to 6 months after surgery (hazard ratio = 0.82: 95% CI 0.67-0.99), but not thereafter. After 5 years of follow-up, 4.2% (173/4130) of the patients had a local recurrence registered and 17.9% (741/4130) had developed distant metastatic disease, without difference between patients with and without defunctioning stoma. CONCLUSION: A defunctioning stoma is associated with a short-term reduction in all-cause mortality in patients undergoing low anterior resection for rectal cancer without any difference in long-term mortality and oncological outcomes, and should be considered as standard of care.

Comparison between epidural and intravenous analgesia effects on disease-free survival after colorectal cancer surgery: a randomised multicentre controlled trial.

BACKGROUND: Thoracic epidural analgesia (TEA) has been suggested to improve survival after curative surgery for colorectal cancer compared with systemic opioid analgesia. The evidence, exclusively based on retrospective studies, is contradictory. METHODS: In this prospective, multicentre study, patients scheduled for elective colorectal cancer surgery between June 2011 and May 2017 were randomised to TEA or patient-controlled i.v. analgesia (PCA) with morphine. The primary endpoint was disease-free survival at 5 yr after surgery. Secondary outcomes were postoperative pain, complications, length of stay (LOS) at the hospital, and first return to intended oncologic therapy (RIOT). RESULTS: We enrolled 221 (110 TEA and 111 PCA) patients in the study, and 180 (89 TEA and 91 PCA) were included in the primary outcome. Disease-free survival at 5 yr was 76% in the TEA group and 69% in the PCA group; unadjusted hazard ratio (HR): 1.31 (95% confidence interval [CI]: 0.74-2.32), P=0.35; adjusted HR: 1.19 (95% CI: 0.61-2.31), P=0.61. Patients in the TEA group had significantly better pain relief during the first 24 h, but not thereafter, in open and minimally invasive procedures. There were no differences in postoperative complications, LOS, or RIOT between the groups. CONCLUSIONS: There was no significant difference between the TEA and PCA groups in disease-free survival at 5 yr in patients undergoing surgery for colorectal cancer. Other than a reduction in postoperative pain during the first 24 h after surgery, no other differences were found between TEA compared with i.v. PCA with morphine.

Defunctioning stomas may reduce chances of a stoma-free outcome after anterior resection for rectal cancer.

AIM: To investigate the conflicting consequences of faecal diversion on stoma outcomes and anastomotic leakage in anterior resection for rectal cancer, including interaction effects determined by the extent of mesorectal excision. METHOD: Anterior resections between 2007 and 2016 were identified using the Swedish Colorectal Cancer Registry. National Patient Registry data were added to determine stoma outcome 2 years after surgery. Tumour distance from the anal verge constituted a proxy for extent of mesorectal excision [total mesorectal excision (TME): ≤10 cm; partial mesorectal excision (PME): 13-15 cm]. With confounder-adjusted probit regression, the total effect of defunctioning stoma on permanent stoma, and the interaction effect of extent of mesorectal excision, were estimated together with the indirect effect through anastomotic leakage. Baseline risks, risk differences (RDs) and relative risks (RRs) were reported. RESULTS: The main study cohort included 4529 patients. Defunctioning stomas influenced the absolute permanent stoma risk (TME: RD 0.11 [95% CI 0.09-0.13]; PME: RD 0.15 [95% CI 0.13-0.16]). The baseline risk was higher in TME, with a resulting greater RR in PME (2.23 [95% CI 1.43-3.02] vs 4.36 [95% CI 3.05-5.68]). The indirect reduction in permanent stoma rates, due to the alleviating effect of faecal diversion on anastomotic leakage, was small (TME: 0.89 [95% CI 0.81-0.96]; PME: 0.96 [95% CI 0.91-1.00]). CONCLUSION: In anterior resection for rectal cancer, defunctioning stomas may reduce chances of a stoma-free outcome. Considering leakage reduction benefits, consequences of routine diversion in TME might be fairly balanced, while this seems questionable in PME.

Statin therapy and postoperative short-term mortality after rectal cancer surgery.

AIM: This study aimed to assess the correlation between regular statin therapy and postoperative mortality following surgical resection for rectal cancer. METHOD: This retrospective cohort study included all adult patients undergoing abdominal rectal cancer surgery in Sweden between January 2007 and September 2016. Data were gathered from the Swedish Colorectal Cancer Registry, a large population-based prospectively collected registry. Statin users were defined as patients with one or more collected prescriptions of a statin within 12 months before the date of surgery. The statin-positive and statin-negative cohorts were matched by propensity scores based on baseline demographics. RESULTS: A total of 11 966 patients underwent surgical resection for rectal cancer, of whom 3019 (25%) were identified as statin users. After applying propensity score matching (1:1), 3017 pairs were available for comparison. In the matched groups, statin users demonstrated reduced 90-day all-cause mortality (0.7% vs. 5.5%, p < 0.001) and also showed significantly reduced cause-specific mortality due to cardiovascular and respiratory events, as well as sepsis and multiorgan failure. The significant postoperative survival benefit of statin users was seen despite a higher rate of cardiovascular comorbidity. CONCLUSION: Preoperative statin therapy displays a strong association with reduced postoperative mortality following surgical resection for rectal cancer. The results from the current study warrant further investigation to determine whether a causal relationship exists.

Center-Level Procedure Volume Does Not Predict Failure-to-Rescue After Severe Complications of Oncologic Colon and Rectal Surgery.

BACKGROUND: The relationship between hospital surgical volume and outcome after colorectal cancer surgery has thoroughly been studied. However, few studies have assessed hospital surgical volume and failure-to-rescue (FTR) after colon and rectal cancer surgery. The aim of the current study is to evaluate FTR following colorectal cancer surgery between clinics based on procedure volume. METHODS: Patients undergoing colorectal cancer surgery in Sweden from January 2015 to January 2020 were recruited through the Swedish Colorectal Cancer Registry. The primary endpoint was FTR, defined as the proportion of patients with 30-day mortality after severe postoperative complications in colorectal cancer surgery. Severe postoperative complications were defined as Clavien-Dindo ≥ 3. FTR incidence rate ratios (IRR) were calculated comparing center volume stratified in low-volume (≤ 200 cases/year) and high-volume centers (> 200 cases/year), as well as with an alternative stratification comparing low-volume (< 50 cases/year), medium-volume (50-150 cases/year) and high-volume centers (> 150 cases/year). RESULTS: A total of 23,351 patients were included in this study, of whom 2964 suffered severe postoperative complication(s). Adjusted IRR showed no significant differences between high- and low-volume centers with an IRR of 0.97 (0.75-1.26, p = 0.844) in high-volume centers in the first stratification and an IRR of 2.06 (0.80-5.31, p = 0.134) for high-volume centers and 2.15 (0.83-5.56, p = 0.116) for medium-volume centers in the second stratification. CONCLUSION: This nationwide retrospectively analyzed cohort study fails to demonstrate a significant association between hospital surgical volume and FTR after colorectal cancer surgery. Future studies should explore alternative characteristics and their correlation with FTR to identify possible interventions for the improvement of quality of care after colorectal cancer surgery.

Mucosal blood flow in the remaining rectal stump is more affected by total than partial mesorectal excision in patients undergoing anterior resection: a key to understanding differing rates of anastomotic leakage?

PURPOSE: Anterior resection is the procedure of choice for tumours in the mid and upper rectum. Depending on tumour height, a total mesorectal excision (TME) or partial mesorectal excision (PME) can be performed. Low anastomoses in particular have a high risk of developing anastomotic leakage, which might be explained by blood perfusion compromise. A pilot study indicated a worse blood flow in TME patients in an open setting. The aim of this study was to further evaluate perianastomotic blood perfusion changes in relation to TME and PME in a predominantly laparoscopic context. METHOD: In this prospective cohort study, laser Doppler flowmetry was used to evaluate the perianastomotic colonic and rectal perfusion before and after surgery. The two surgical techniques were compared in terms of mean differences of perfusion units using a repeated measures ANOVA design, which also enabled interaction analyses between type of mesorectal excision and location of measurement. Anastomotic leakage until 90 days after surgery was reported for descriptive purposes. RESULTS: Some 28 patients were available for analysis: 17 TME and 11 PME patients. TME patients had a reduced blood perfusion postoperatively compared to PME patients in the aboral posterior area (mean difference: -57 vs 18 perfusion units; p = 0.010). An interaction between mesorectal excision type and anterior/posterior location was detected at the aboral level (p = 0.007). Two patients developed a minor leakage, diagnosed after discharge. CONCLUSION: Patients operated on using TME have a decreased blood flow in the aboral posterior quadrant of the rectum postoperatively compared to patients operated on using PME. This might explain differing rates of anastomotic leakage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02401100.

Discrepancy between surgeon and radiological assessment of ligation level of the inferior mesenteric artery in patients operated for rectal cancer-impacting registry-based research and surgical practice.

BACKGROUND: The reliability of the registered ligation level of the inferior mesenteric artery (IMA) in the Swedish Colorectal Cancer Registry has been questioned. The primary aim of this study was to evaluate this parameter in the registry by comparing the registered ligation levels with a postoperative computed tomography angiography (CT-angiography) in patients operated for rectal cancer. METHODS: Patients operated for rectal cancer at two Swedish university hospitals were prospectively included between December 2016 and December 2019. At the 1-year postoperative follow-up, an additional CT-angiography was performed and independently examined by two radiologists. The radiological assessment of the ligation level was compared to registry data, using different measures of agreement. RESULTS: A total of 94 patients were included, 55 (59%) were men and 39 (41%) women. All patients underwent abdominal resection: conventional or robot-assisted laparoscopic surgery, n=56 (60%), or open resection, n=38 (40%). The ligation level as assessed on CT-angiography was high in 29 (31%) patients and low in 65 (69%). The registered level of ligation of the IMA and the radiological assessment of the CT-angiographies were consistent in 77/94 cases, demonstrating an 82% agreement and a sensitivity and specificity of 86% and 72%, respectively. The estimated Kappa value was 0.58, reaching 0.64 after prevalence bias adjustment. CONCLUSION: This study showed that CT-angiography can be used to evaluate the reliability of the registered ligation level in the Swedish Colorectal Cancer Registry. The demonstrated agreement between the registry and postoperative CT-angiography was moderate to good. This discrepancy impacts registry-based research using IMA ligation data and may ultimately influence surgical practice. TRIAL REGISTRATION: Clinical Trials identifier NCT03875612.