qRT-PCR analysis of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN in colon cancer lymph nodes-An improved method for assessment of tumor stage and prognosis.

One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, -1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, -1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P = .01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.

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 ).

Minor impact of anastomotic leakage in anterior resection for rectal cancer on long-term male urinary and sexual function.

PURPOSE: Anastomotic leakage after anterior resection for rectal cancer induces bowel dysfunction, but the influence on urinary and sexual function is largely unknown. This cross-sectional cohort study evaluated long-term effect of anastomotic leakage on urinary and sexual function in male patients. METHODS: Patients operated with anterior resection for rectal cancer in 15 Swedish hospitals 2007-2013 were identified. Anastomotic leakage and other clinical variables were retrieved from the Swedish Colorectal Cancer Registry and medical records. Urinary and sexual dysfunction were evaluated at 4 to 11 years after surgery using the International Prostate Symptom Score, International Index of Erectile Function, and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire CR29. The effect of anastomotic leakage on average scores of urinary and sexual dysfunction was evaluated as a primary outcome, and the single items permanent urinary catheter and sexual inactivity as secondary outcomes. The association of anastomotic leakage and functional outcomes was analyzed using regression models with adjustment for confounders. RESULTS: After a median follow-up of 84 months (interquartile range: 67-110), 379 out of 864 eligible men were included. Fifty-nine (16%) patients had anastomotic leakage. Urinary incontinence was more common in the leakage group, with an adjusted mean score difference measured by EORTC QLQ ColoRectal-29 of 8.69 (95% confidence interval: 0.72-16.67). The higher risks of urinary frequency, permanent urinary catheter, and sexual inactivity did not reach significance. CONCLUSION: Anastomotic leakage after anterior resection had a minor negative impact on urinary and sexual function in men.

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.

Peritoneal infection after colorectal cancer surgery induces substantial alterations in postoperative protein levels: an exploratory study.

PURPOSE: Peritoneal infection, due to anastomotic leakage, after resection for colorectal cancer have been shown to associate with increased cancer recurrence and mortality, as well as cardiovascsular morbidity. Alterations in circulating protein levels could help shed light on the underlying mechanisms, prompting this exploratory study of 64 patients operated for colorectal cancer with anastomosis. METHODS: Thirty-two cases who suffered a postoperative peritoneal infection were matched with 32 controls who had a complication-free postoperative stay. Proteins in serum samples at their first postoperative visit and at one year after surgery were analysed using proximity extension assays and enzyme-linked immunosorbent assays. Multivariate projection methods, adjusted for multiple testing, were used to compare levels between groups, and enrichment and network analyses were performed. RESULTS: Seventy-seven proteins, out of 270 tested, were differentially expressed at a median sampling time of 41 days postoperatively. These proteins were all normalised one year after surgery. Many of the differentially expressed top hub proteins have known involvement in cancer progression, survival, invasiveness and metastasis. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K-Akt) and transforming growth factor beta (TGF-ß) signaling. CONCLUSION: These affected proteins and pathways could provide clues as to why patients with peritoneal infection might suffer increased cancer recurrence, mortality and cardiovascular morbidity.

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

OBJECTIVE: To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL). BACKGROUND: AL after RC resection often results in a permanent stoma. METHODS: This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated. RESULTS: This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76). CONCLUSIONS: The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies.

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients.

BACKGROUND: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. METHODS: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2 : 1). RESULTS: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). CONCLUSION: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding.

Defunctioning stoma before neoadjuvant treatment or resection of endoscopically obstructing rectal cancer.

AIM: To investigate whether patients with endoscopically untraversable rectal cancer may benefit from a defunctioning stoma created before neoadjuvant therapy or resectional surgery. METHODS: This retrospective study comprise patients diagnosed with rectal cancer during 2007-2020 in Region Västerbotten, Sweden. The primary outcome was time between diagnosis and any treatment, while survival and the incidence of complications were secondary outcomes. Excluded were patients without endoscopic obstruction, patients already having a stoma, patients with recurrent disease, palliative patients, and patients receiving a stoma shortly after diagnosis due to any urgent bowel-related complication. Data were obtained from the Swedish Colorectal Cancer Registry and medical records. Kaplan-Meier failure curves were drawn, and a multivariable Cox regression model was employed for confounding adjustment. RESULTS: Out of 843 patients, 57 remained after applying exclusion criteria. Some 12/57 (21%) patients received a planned stoma before treatment, and the remainder received upfront neoadjuvant therapy or surgery. Median time to any treatment was 51 days for the planned stoma group and 36 days for the control group, with an adjusted hazard ratio of 0.28 (95% confidence interval: 0.12-0.64). Complications occurred at a rate of 5/12 (42%) and 7/45 (16%) in the planned stoma group and control group, respectively. Survival was similar between groups. CONCLUSION: A planned stoma results in treatment delay, but it remains unclear whether this is clinically relevant. Complications were more common in the planned stoma group, although the data are limited. While larger studies are needed, it seems feasible to avoid defunctioning stomas even in endoscopically obstructing rectal cancers.

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.

Oral antibiotics and mechanical bowel preparation for colorectal surgery: A prospective observational study of surgical site infection and microbial analysis.

PURPOSE: Surgical site infections (SSIs) are common in colorectal surgery. Mechanical bowel preparation (MBP) in conjunction with oral antibiotics (OABs) have been shown to reduce SSI rates. It however is still unclear which OABs to use, and how this can be implemented in practice. METHODS: This is a prospective observational study carried out in Swansea Bay University Health Board during 2019-2021, evaluating the introduction of OABs in a stepwise manner on the incidence of SSI in major colorectal surgery. A control group having MBP only was compared to two OAB groups: one group had MBP plus metronidazole only and the second MBP plus metronidazole and neomycin. A 30-day follow-up after surgery was ascertained via chart review and telephone contact. Logistic regression was performed to estimate the relation between OAB use and SSI, with adjustment for confounding. In a subset of patients, faecal samples were analysed through 16S rRNA amplicon sequencing before and after OAB treatment, depicting the impact of the gut microbiome. RESULTS: In total 160 patients were analysed: 46 patients had MBP only, whilst 76 patients had MBP plus metronidazole only and 38 patients had MBP with metronidazole/neomycin. The SSI rate in the entire cohort was 33.8%, whilst the adjusted ORs for the single- and dual-OAB groups were 0.76 (95% CI: 0.17-1.81) and 0.50 (95% CI: 0.17-1.52). The microbial analysis demonstrated that the relative abundance for many bacterial genera was changed before and after OAB treatment, but no link with SSI development could be shown. CONCLUSIONS: Introduction of OABs in conjunction with MBP in colorectal surgery is feasible, and may potentially lead to lower rates of SSI, as well as altering the community structure of the faecal microbiome. More research is needed, especially considering different OABs and mechanistic studies of the gut microbiome in the context of colorectal surgery.

The impact of the anastomotic configuration on low anterior resection syndrome 3 years after total mesorectal excision for rectal cancer: a national cohort study.

AIM: After low anterior resection, the bowel can be anastomosed in different ways. It is not clear which configuration is optimal from a functional and complication point of view. The primary aim was to investigate the impact of the anastomotic configuration on bowel function evaluated by the low anterior resection syndrome (LARS) score. Secondarily, the impact on postoperative complications was evaluated. METHOD: All patients who had undergone low anterior resection from 2015 to 2017 were identified in the Swedish Colorectal Cancer Registry. Three years after surgery, patients were sent an extensive questionnaire and were analysed based on anastomotic configuration ('J-pouch/side-to-end anastomosis' or 'straight anastomosis'). Inverse probability weighting by propensity score was used to adjust for confounding factors. RESULTS: Among 892 patients, 574 (64%) responded, of whom 494 patients were analysed. After weighting, the anastomotic configuration had no significant impact on the LARS score (J-pouch/side-to-end OR 1.05, 95% confidence interval [CI] 0.82-1.34). The J-pouch/side-to-end anastomosis was significantly associated with overall postoperative complications (OR 1.43, 95% CI 1.06-1.95). No significant difference was seen regarding surgical complications (OR 1.14, 95% CI 0.78-1.66). CONCLUSION: This is the first study investigating the impact of the anastomotic configuration on long-term bowel function, evaluated by the LARS score, in an unselected national cohort. Our results suggested no benefit for J-pouch/side-to-end anastomosis on long-term bowel function and postoperative complication rates. The anastomotic strategy may be based upon the anatomical conditions of the patient and surgical preference.

Exposure to oestrogen and risk of anastomotic leakage after colorectal cancer surgery - A clue to the different leak rates in men and women.

BACKGROUND: Colorectal anastomotic leakage is consistently more common in men, regardless of tumour location. This fact is largely unexplained but might be a consequence of biological differences including hormonal exposure and not only related to anatomy. METHODS: This was a retrospective, nationwide registry-based observational study of post-menopausal women operated for colorectal cancer with an anastomosis between 2007 and 2016. Hormonal exposure before surgery, as defined by prescribed drugs affecting oestrogen levels, was related to postoperative anastomotic leakage, using mixed-effects logistic regression models with adjustment for confounding. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were derived. In addition, separate estimates according to tumour location were computed, and a sensitivity analysis excluding topical oestrogen hormone exposure was conducted. RESULTS: Some 16,535 post-menopausal women were included, of which 16.2% were exposed to drugs increasing oestrogen levels before surgery. In this exposed group compared to the unexposed, leak rates were 3.1 and 3.8%, respectively. After adjustment, a reduction of anastomotic leakage in the exposed group was detected (OR: 0.77; 95% CI: 0.59-0.99). This finding was largely attributed to the rectal cancer subgroup (OR: 0.55; 95% CI: 0.36-0.85), while the exclusion of topical oestrogen drugs further reduced the estimates of the main analysis (OR: 0.63; 95% CI: 0.38-1.02). CONCLUSIONS: Anastomotic leakage rates are lower in women exposed to hormone replacement therapy before surgery for colorectal cancer, which might explain some of the difference in leak rates between men and women, especially regarding rectal cancer.

High Risk of Low Anterior Resection Syndrome in Long-term Follow-up After Anastomotic Leakage in Anterior Resection for Rectal Cancer.

BACKGROUND: Low anterior resection syndrome is common after sphincter-sparing surgery, but it is unclear to what extent anastomotic leakage after anterior resection contributes to this condition. OBJECTIVE: The aim of this study is to assess the long-term effect of anastomotic leakage on the occurrence of major low anterior resection syndrome. DESIGN: This is a retrospective observational cohort study evaluating low anterior resection syndrome 4 to 11 years after index surgery. After propensity score-matching using the covariates sex, age, tumor stage, comorbidity, neoadjuvant treatment, extent of mesorectal excision, and defunctioning stoma at index surgery, the effect of anastomotic leakage on low anterior resection syndrome was investigated using relative risk and 95% CI. SETTINGS: This multicenter study included patients from 15 Swedish hospitals between 2007 and 2013. PATIENTS: Patients who underwent anterior resection for rectal cancer were included. MAIN OUTCOME MEASURES: Outcome measures included patient-reported major low anterior resection syndrome, obtained via a postal questionnaire that included a question on stoma status. RESULTS: Among 1099 patients, 653 (59.4%) responded in at a median of 83.5 (interquartile range 66 to 110) months postoperatively. After excluding patients with residual stoma or incomplete responses, 544 remained; of these, 42 had anastomotic leakage. Patients with anastomotic leakage were more likely to have major low anterior resection syndrome (66.7% [28/42]) than patients without leakage (45.8% [230/502]). After matching, anastomotic leakage was significantly related to major low anterior resection syndrome (relative risk 2.3; 95% CI 1.4-3.9) and the individual symptom of urgency (relative risk 2.1; 95% CI 1.1-4.1). LIMITATIONS: This study was limited by its retrospective observational study design. CONCLUSIONS: In long-term follow-up, major low anterior resection syndrome is common after anterior resection for rectal cancer. Anastomotic leakage appears to increase the risk of major low anterior resection syndrome, with urgency as a major contributing symptom. See Video Abstract at http://links.lww.com/DCR/B868 . ALTO RIESGO DE SNDROME DE RESECCIN ANTERIOR BAJA EN EL SEGUIMIENTO A LARGO PLAZO TRAS FUGA ANASTOMTICA EN RESECCIN ANTERIOR POR CNCER DE RECTO: ANTECEDENTES:El síndrome de resección anterior baja es común después de una cirugía con preservación de esfínter pero no está claro hasta qué punto contribuye a esta condición la fuga anastomótica después de una resección anterior.OBJETIVO:El objetivo de este estudio es evaluar el efecto a largo plazo de la fuga anastomótica sobre la aparición de un síndrome de resección anterior baja mayor.DISEÑO:Se trata de un estudio de cohorte observacional retrospectivo que evalúa el síndrome de resección anterior baja 4-11 años después de la cirugía índice. Después del apareamiento por puntuación de propensión utilizando las covariables sexo, edad, estadio del tumor, comorbilidad, tratamiento neoadyuvante, extensión de la escisión mesorrectal y estoma de derivación en la cirugía índice, se investigó el efecto de la fuga anastomótica en el síndrome de resección anterior baja utilizando el riesgo relativo y intervalos de confianza de 95%.AJUSTES:Este estudio multicéntrico incluyó pacientes de 15 hospitales suecos entre 2007 y 2013.PACIENTES:Se incluyeron pacientes que fueron sometidos a resección anterior por cáncer de recto.PRINCIPALES MEDIDAS DE DESENLACE:Síndrome de resección anterior baja mayor informado por el paciente, obtenido a través de un cuestionario postal que incluye una pregunta sobre el estado de estomas.RESULTADOS:De 1099 pacientes, 653 (59,4%) respondieron una mediana de 83,5 meses después de la operación (rango intercuartílico 66-110).Después de excluir a los pacientes con estoma residual o respuestas incompletas, quedaron 544; de estos, 42 tuvieron fuga anastomótica. Los pacientes con fuga anastomótica tenían síndrome de resección anterior baja mayor en el 66,7% (28/42) en comparación con el 45,8% (230/502) de los pacientes sin fuga. Después del apareamiento, la fuga anastomótica se relacionó significativamente con el síndrome de resección anterior baja mayor (riesgo relativo 2,3; intervalo de confianza del 95%: 1,4-3,9) y con el síntoma individual de urgencia (riesgo relativo 2,1; intervalo de confianza del 95% 1,1-4,1).LIMITACIONES:Este estudio estuvo limitado por su diseño de estudio observacional retrospectivo.CONCLUSIONES:En el seguimiento a largo plazo, el síndrome de resección anterior baja mayor es común después de la resección anterior por cáncer de recto. La fuga anastomótica parece aumentar el riesgo de síndrome de resección anterior baja mayor, siendo la urgencia uno de los principales síntomas contribuyentes. Consulte Video Resumen en http://links.lww.com/DCR/B868 . (Traducción-Dr. Juan Carlos Reyes ).

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.

Early postoperative pain as a marker of anastomotic leakage in colorectal cancer surgery.

PURPOSE: Even though anastomotic leakage after colorectal surgery is a major clinical problem in need of a timely diagnosis, early indicators of leakage have been insufficiently studied. We therefore conducted a population-based observational study to determine whether the patient's early postoperative pain is an independent marker of anastomotic leakage. METHODS: By combining the Swedish Colorectal Cancer Registry and the Swedish Perioperative Registry, we retrieved prospectively collected data on 3084 patients who underwent anastomotic colorectal surgery for cancer in 2014-2017. Postoperative pain, measured with the numerical rating scale (NRS), was considered exposure, while anastomotic leakage and reoperation due to leakage were outcomes. We performed logistic regression to evaluate associations, estimating odds ratios (ORs) and 95% confidence intervals (CIs), while multiple imputation was used to handle missing data. RESULTS: In total, 189 patients suffered from anastomotic leakage, of whom 121 patients also needed a reoperation due to leakage. Moderate or severe postoperative pain (NRS 4-10) was associated with an increased risk of anastomotic leakage (OR 1.69, 95% CI 1.21-2.38), as well as reoperation (OR 2.17, 95% CI 1.41-3.32). Severe pain (NRS 8-10) was more strongly related to leakage (OR 2.38, 95% CI 1.44-3.93). These associations were confirmed in multivariable analyses and when reoperation due to leakage was used as an outcome. CONCLUSION: In this population-based retrospective study on prospectively collected data, increased pain in the post-anaesthesia care unit is an independent marker of anastomotic leakage, possibly indicating a need for further diagnostic measures.

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.

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.

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.