Association Between RAS/BRAF Mutations and Complete Response Following Total Neoadjuvant Therapy in Patients with Rectal Cancer: A Prospective Multicentered Study.

BACKGROUND: The impact of RAS/BRAF mutation on primary response rates after total neoadjuvant therapy (TNT) in patients with advanced rectal cancer is unclear. The aim of this study was to assess complete response rates after TNT according to RAS/BRAF mutation status. METHODS: A prospective observational study was performed in patients with rectal cancer who underwent TNT with curative intent at three South Australian hospitals between 2019 and 2023. Patients were classified according to their mutation status: mutant RAS/BRAF (mutRAS) or wild-type RAS/BRAF (wtRAS). The primary endpoint was overall complete response (oCR) rate, defined as the proportion of patients who achieved clinical complete response (cCR) and/or pathological complete response (pCR). RESULTS: Of the 150 patients eligible for inclusion, 80 patients with RAS/BRAF status available were identified. Of these, 43 (53.8%) patients were classified as mutRAS and 37 (46.3%) patients as wtRAS. Patients with mutRAS had significantly lower cCR and oCR rates after TNT than patients with wtRAS (14% vs. 37.8%, p = 0.014; 11.6% vs. 43.2%, p = 0.001, respectively). There was no significant difference in pCR rate between the groups. Of the 80 rectal cancer patients tested, 35 (43.8%) had metastatic disease (M1). There was no significant difference in complete M1 response rates between the groups (17.6% vs. 38.9%, p = 0.254). CONCLUSION: RAS/BRAF mutations negatively impact primary tumor response rates after TNT in patients with advanced rectal cancer. Large-scale national studies are needed to determine whether RAS/BRAF status could be used to select optimal oncologic therapy in rectal cancer patients.

Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal surgery (PyRICo-RCT): randomized clinical trial.

BACKGROUND: Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. METHODS: This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. RESULTS: Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. CONCLUSION: Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).

Use of Acetylcholinesterase Inhibitors in Reducing Time to Gastrointestinal Function Recovery following Abdominal Surgery: A Systematic Review.

INTRODUCTION: Postoperative ileus (POI) is a significant complication following abdominal surgery, increasing morbidity and mortality. The cholinergic anti-inflammatory response is one of the major pathways involved in developing POI, but current recommendations to prevent POI do not target this. This review aims to summarise evidence for the use of acetylcholinesterase inhibitors, neostigmine and pyridostigmine, to reduce the time to return of gastrointestinal function (GI) following abdominal surgery. METHODS: A systematic search of various databases was performed from 1946 to May 2023. Randomised controlled trials (RCTs) on acetylcholinesterase inhibitors in intra-abdominal surgery were included. Data on time to flatus and/or stool and side effects were extracted. RESULTS: Among 776 screened manuscripts, 8 RCTs (703 patients) investigating acetylcholinesterase inhibitors in intra-abdominal surgery were analysed. Five studies showed a significant reduction in time to flatus and/or stool by 17-47.6 h. Methodological variations, differing procedure types, and potential bias were observed. Limited studies reported side effects or length of stay. CONCLUSION: Acetylcholinesterase inhibitors may reduce the time for GI to return. However, current evidence is limited and biased. Further studies incorporating acetylcholinesterase inhibitors in an enhanced recovery protocol are required to address this question, especially for patients undergoing colorectal surgery.

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. METHODS: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. RESULTS: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor ß was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis. CONCLUSIONS: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

Does Sarcopenia Predict Local Response Rates After Chemoradiotherapy for Locally Advanced Rectal Cancer?

BACKGROUND: The predictive value of sarcopenia for tumor response to neoadjuvant chemoradiotherapy is unclear. OBJECTIVE: This study aimed to investigate the association between sarcopenia and pathological tumor regression grade after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN: Retrospective cohort study from a prospectively collected database. Univariate logistic regression was performed to assess the association between sarcopenia and tumor response. SETTINGS: This study was conducted at 2 tertiary care centers. PATIENTS: Participants were patients undergoing neoadjuvant chemoradiotherapy for locally advanced rectal cancer (T3/4, N0/+) between 2007 and 2018. INTERVENTION: Sarcopenia was diagnosed using sex-specific cutoffs of lean muscle mass. Using the initial staging CT, lean muscle mass was estimated using the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra, normalized for patient height. MAIN OUTCOME MEASURES: The primary end point was pathological tumor regression grade, defined as good (tumor regression grade 0/1) vs poor (tumor regression grade 2/3). RESULTS: The study included 167 patients with locally advanced rectal cancer with a median age of 60 (20-91) years, with 132 in the nonsarcopenia group and 35 in the sarcopenia group. Eighty-nine percent of patients had stage 3 cancer. Nine patients (5.4%) had a complete clinical response, 1 patient did not respond to treatment and opted for nonoperative management, and the remaining 157 patients (94.0%) proceeded to surgery. Pathological data revealed no significant difference between good tumor regression grade patients in the sarcopenia group compared with the nonsarcopenia group. Univariate analysis revealed BMI ≥25 kg/m 2 to be a risk factor for good tumor regression grade ( p = 0.002). LIMITATIONS: This study was limited by its retrospective design and small sample size. CONCLUSIONS: Sarcopenia is not a predictor of poor neoadjuvant chemoradiotherapy response in patients with locally advanced rectal cancer. Increasing BMI was associated with good tumor regression grade. Future multicentered studies are warranted to validate this finding. See Video Abstract at http://links.lww.com/DCR/C78 . LA SARCOPENIA PREDICE LAS TASAS DE RESPUESTA LOCAL DESPUS DE LA QUIMIORRADIOTERAPIA PARA EL CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El valor predictivo de la sarcopenia para la respuesta tumoral a la quimiorradioterapia neoadyuvante no está claro.OBJETIVO:Este estudio investiga la asociación entre la sarcopenia y el grado de regresión tumoral patológica después de la quimiorradioterapia neoadyuvante en pacientes con cáncer de recto localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo a partir de una base de datos recolectada prospectivamente. Se realizó una regresión logística univariante para evaluar la asociación entre la sarcopenia y la respuesta tumoral.ENTORNO CLINICO:Este estudio se realizó en dos centros de atención terciaria.PACIENTES:Pacientes sometidos a quimiorradioterapia neoadyuvante por cáncer de recto localmente avanzado (T3/4, N0/+) entre 2007-2018.INTERVENCIÓNES:La sarcopenia se diagnosticó utilizando puntos de corte de masa muscular magra específicos por género. Utilizando la tomografía computarizada de estadificación inicial, se estimó la masa muscular magra utilizando el área transversal del músculo psoas a nivel de la tercera vértebra lumbar, normalizada para la altura del paciente.PRINCIPALES MEDIDAS DE VALORACIÓN:El criterio principal de valoración fue el grado de regresión tumoral patológica, definido como bueno (grado de regresión tumoral 0/1) frente a malo (grado de regresión tumoral 2/3).RESULTADOS:El estudio incluyó a 167 pacientes con cáncer de recto localmente avanzado con una mediana de edad de 60 años (20-91), 132 en el grupo sin sarcopenia y 35 en el grupo con sarcopenia. Ochenta y nueve por ciento estaban en etapa III. Seis pacientes (5,4%) tuvieron respuesta clínica completa sostenida, un paciente no respondió al tratamiento y optó por manejo conservador, los 157 restantes (94,0%) procedieron a cirugía. Los datos patológicos no revelaron diferencias significativas entre los pacientes con buen grado de regresión tumoral en el grupo de sarcopenia en comparación con el grupo sin sarcopenia. El análisis univariado reveló que un IMC ≥25 kg/m2 era un factor de riesgo para un buen grado de regresión tumoral (p = 0,002).LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo y tamaño de muestra pequeño.CONCLUSIÓNES:La sarcopenia no es un predictor de mala respuesta a la quimiorradioterapia neoadyuvante en pacientes con cáncer de recto localmente avanzado. El aumento del IMC se asoció con un buen grado de regresión tumoral. Se justifican futuros estudios multicéntricos para validar este hallazgo. Consulte Video Resumen en http://links.lww.com/DCR/C78 . (Traducción-Dr. Ingrid Melo ).

Can sarcopenia predict complete response after total neoadjuvant therapy in advanced rectal cancer? A multicentre observational cohort study.

BACKGROUND: The association between sarcopenia and response to neoadjuvant treatment remains unclear. This study investigates sarcopenia as a predictor of overall complete response (oCR) after Total Neoadjuvant Therapy (TNT) for advanced rectal cancer. METHOD: A prospective observational study was performed of patients with rectal cancer undergoing TNT at three South Australian hospitals between 2019 and 2022. Sarcopenia was diagnosed by pretreatment computed tomography measurement of psoas muscle cross-sectional area at the third lumbar vertebra level, normalised for patient height. The primary endpoint was oCR rate defined as the proportion of patients who achieved either clinical complete response (cCR) or pathological complete response. RESULTS: This study included 118 rectal cancer patients with an average age of 59.5 years, 83 (70.3%) of whom formed the non-sarcopenic group (NSG) and 35 (29.7%) the sarcopenic group (SG). The oCR rate was significantly higher in NSG compared with the SG (p < 0.001). cCR rate was significantly greater in NSG compared with the SG (p = 0.001). Multivariate analysis revealed sarcopenia (p = 0.029) and hypoalbuminemia (p = 0.040) were risk factors for cCR and sarcopenia was an independent risk factor for oCR (p = 0.020). CONCLUSION: Sarcopenia and hypoalbuminemia were negatively associated with tumour response following TNT in advanced rectal cancer patients.

Incidence and associated morbidity of sarcopenia in non-malignant small and large bowel anastomosis: propensity score-matched analysis.

PURPOSE: Sarcopenia is a prognostic factor for poor outcomes in colorectal cancer, but data are scarce in colorectal surgery for benign conditions where patients could benefit from a deferral of surgery to enter a prehabilitation programme. We assessed the incidence of sarcopenia and complications in patients with benign colorectal disease. METHODS: Patients who underwent elective non-malignant colorectal surgery during 2018-2022 were retrospectively identified. The cross-sectional psoas area was calculated using computed tomography (CT) imaging mid-3rd lumbar vertebrae. Sarcopenia was determined using gender-specific cut-offs. The primary outcome was complications measured by the comprehensive complication index (CCI). RESULTS: Of 188 patients identified, 39 (20.7%) were sarcopenic. Patients diagnosed with sarcopenia were older (63 vs. 58 years, p = 0.047) and had a reduced BMI (24.7 vs. 27.38 kg/m2, p = 0.001). Sarcopenic patients had more complications (82.1 vs. 64.4%, p = 0.036), and CCI was statistically but not clinically higher (20.9 vs. 20.9, p = 0.047). On univariate linear regression analysis, age ≥ 65 years old, ASA grade ≥ 3, active smokers, sarcopenia, and preoperative anaemia were predictive of CCI. Propensity score-matched analysis was performed, matching 78 cases to remove selection bias, which demonstrated sarcopenia had no impact on postoperative complications. On multivariate analysis, age (p = 0.022), smoking (p = 0.005), and preoperative anaemia (p = 0.008) remained predictive of CCI. CONCLUSION: Sarcopenia is prevalent in one-fifth of patients undergoing benign colorectal surgery. Taking advantage of the longer preoperative waiting periods, sarcopenia could be explored as a target for prehabilitation programmes to improve outcomes.

Is preoperative sarcopenia associated with postoperative complications after pelvic exenteration surgery?

PURPOSE: Pelvic exenteration (PE) involves radical surgical resection of pelvic organs and is associated with considerable morbidity. Sarcopenia is recognised as a predictor of poor surgical outcomes. This study aimed to determine if preoperative sarcopenia is associated with postoperative complications after PE surgery. METHODS: This retrospective study included patients who underwent PE with an available preoperative CT scan between May 2008 and November 2022 at the Royal Adelaide Hospital and St. Andrews Hospital in South Australia. Total Psoas Area Index (TPAI) was estimated by measuring the cross-sectional area of the psoas muscles at the level of the third lumbar vertebra on abdominal CT, normalised for patient height. Sarcopenia was diagnosed based on gender-specific TPAI cut-off values. Logistic regression analyses were performed to identify risk factors for major postoperative complications with a Clavien-Dindo (CD) grade ≥ 3. RESULTS: In total, 128 patients who underwent PE were included, 90 of whom formed the non-sarcopenic group (NSG) and 38 the sarcopenic group (SG). Major postoperative complications (CD grade ≥ 3) occurred in 26 (20.3%) patients. There was no detectable association with sarcopenia and an increased risk of major postoperative complications. Preoperative hypoalbuminemia (P = 0.01) and a prolonged operative time (P = 0.002) were significantly associated with a major postoperative complication on multivariate analysis. CONCLUSION: Sarcopenia is not a predictor of major postoperative complications in patients undergoing PE surgery. Further efforts aimed specifically at optimising preoperative nutrition may be warranted.

Outcomes of open vs laparoscopic vs robotic vs transanal total mesorectal excision (TME) for rectal cancer: a network meta-analysis.

BACKGROUND: Total mesorectal excision (TME) for rectal cancer can be achieved using open (OpTME), laparoscopic (LapTME), robotic (RoTME), or transanal techniques (TaTME). However, the optimal approach for access remains controversial. The aim of this network meta-analysis was to assess operative and oncological outcomes of all four surgical techniques. METHODS: Ovid MEDLINE, EMBASE, and PubMed databases were searched systematically from inception to September 2020, for randomised controlled trials (RCTs) comparing any two TME surgical techniques. A network meta-analysis using a Bayesian random-effects framework and mixed treatment comparison was performed. Primary outcomes were the rate of clear circumferential resection margin (CRM), defined as > 1 mm from the closest tumour to the cut edge of the tissue, and completeness of mesorectal excision. Secondary outcomes included radial and distal resection margin distance, postoperative complications, locoregional recurrence, disease-free survival, and overall survival. Surface under cumulative ranking (SUCRA) was used to rank the relative effectiveness of each intervention for each outcome. The higher the SUCRA value, the higher the likelihood that the intervention is in the top rank or one of the top ranks. RESULTS: Thirty-two RCTs with a total of 6151 patients were included. Compared with OpTME, there was no difference in the rates of clear CRM: LapTME RR = 0.99 (95% (Credible interval) CrI 0.97-1.0); RoTME RR = 1.0 (95% CrI 0.96-1.1); TaTME RR = 1.0 (95% CrI 0.96-1.1). There was no difference in the rates of complete mesorectal excision: LapTME RR = 0.98 (95% CrI 0.98-1.1); RoTME RR = 1.1 (95% CrI 0.98-1.4); TaTME RR = 1.0 (95% CrI 0.91-1.2). RoTME was associated with improved distal resection margin distance compared to other techniques (SUCRA 99%). LapTME had a higher rate of conversion to open surgery when compared with RoTME: RoTME RR = 0.23 (95% CrI 0.034-0.70). Length of stay was shortest in RoTME compared to other surgical approaches: OpTME mean difference in days (MD) 3.3 (95% CrI 0.12-6.0); LapTME MD 1.7 (95% CrI - 1.1-4.4); TaTME MD 1.3 (95% CrI - 5.2-7.4). There were no differences in 5-year overall survival (LapTME HR 1.1, 95% CrI 0.74, 1.4; TaTME HR 1.7, 95% CrI 0.79, 3.4), disease-free survival rates (LapTME HR 1.1, 95% CrI 0.76, 1.4; TaTME HR 1.1, 95% CrI 0.52, 2.4), or anastomotic leakage (LapTME RR = 0.92 (95% CrI 0.63, 1.1); RoTME RR = 1.0 (95% CrI 0.48, 1.8); TaTME RR = 0.53 (95% CrI 0.19, 1.2). The overall quality of evidence as per Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments across all outcomes including primary and secondary outcomes was deemed low. CONCLUSIONS: In selected patients eligible for a RCT, RoTME achieved improved distal resection margin distance and a shorter length of hospital stay. No other differences were observed in oncological or recovery parameters between (OpTME), laparoscopic (LapTME), robotic (RoTME), or trans-anal TME (TaTME). However, the overall quality of evidence across all outcomes was deemed low.

LekCheck: A Prospective Study to Identify Perioperative Modifiable Risk Factors for Anastomotic Leakage in Colorectal Surgery.

OBJECTIVE: To assess potentially modifiable perioperative risk factors for anastomotic leakage in adult patients undergoing colorectal surgery. SUMMARY BACKGROUND DATA: Colorectal anastomotic leakage (CAL) is the single most important denominator of postoperative outcome after colorectal surgery. To lower the risk of CAL, the current research focused on the association of potentially modifiable risk factors, both surgical and anesthesiological. METHODS: A consecutive series of adult patients undergoing colorectal surgery with primary anastomosis was enrolled from January 2016 to December 2018. Fourteen hospitals in Europe and Australia prospectively collected perioperative data by carrying out the LekCheck, a short checklist carried out in the operating theater as a time-out procedure just prior to the creation of the anastomosis to check perioperative values on 1) general condition 2) local perfusion and oxygenation, 3) contamination, and 4) surgery related factors. Univariate and multivariate logistic regression analysis were performed to identify perioperative potentially modifiable risk factors for CAL. RESULTS: There were 1562 patients included in this study. CAL was reported in 132 (8.5%) patients. Low preoperative hemoglobin (OR 5.40, P < 0.001), contamination of the operative field (OR 2.98, P < 0.001), hyperglycemia (OR 2.80, P = 0.003), duration of surgery of more than 3 hours (OR 1.86, P = 0.010), administration of vasopressors (OR 1.80, P = 0.010), inadequate timing of preoperative antibiotic prophylaxis (OR 1.62, P = 0.047), and application of epidural analgesia (OR, 1.81, P = 0. 014) were all associated with CAL. CONCLUSIONS: This study identified 7 perioperative potentially modifiable risk factors for CAL. The results enable the development of a multimodal and multidisciplinary strategy to create an optimal perioperative condition to finally lower CAL rates.

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. METHODS: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. RESULTS: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor ß and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. CONCLUSIONS: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Malignant Features in Pretreatment Metastatic Lateral Lymph Nodes in Locally Advanced Low Rectal Cancer Predict Distant Metastases.

INTRODUCTION: Pretreatment enlarged lateral lymph nodes (LLN) in patients with locally advanced low rectal cancer are predictive for local recurrences after neoadjuvant (chemo)radiotherapy (n(C)RT) followed by total mesorectal excision (TME). Not much is known of the impact on oncological outcomes when in addition malignant features are present in enlarged LLN. PATIENTS AND METHODS: A multicenter retrospective cohort study was conducted at five tertiary referral centers in the Netherlands and Australia. All patients were diagnosed with locally advanced low rectal cancer with LLN on pretreatment magnetic resonance imaging (MRI) and underwent n(C)RT followed by TME. LLN were considered enlarged with a short axis of ≥ 5 mm. Malignant features were defined as nodes with internal heterogeneity and/or border irregularity. Outcomes of interest were local recurrence-free survival (LRFS), distant metastatic-free survival (DMFS), and overall survival (OS). RESULTS: Out of 115 patients, the majority was male (75%) and the median age was 64 years (range 26-85 years). Median pretreatment LLN short axis was 7 mm (range 5-28 mm), and 60 patients (52%) had malignant features. After a median follow-up of 47 months, patients with larger LLN (7 + mm) had a worse LRFS (p = 0.01) but no difference in DMFS (p = 0.37) and OS (p = 0.54) compared with patients with smaller LLN (5-6 mm). LLN patients with malignant features had no difference in LRFS (p = 0.20) but worse DMFS (p = 0.004) and OS (p = 0.006) compared with patients without malignant features in the LLN. Cox regression analysis identified LLN short axis as an independent factor for LR. Malignant features in LLN were an independent factor for DMFS. CONCLUSION: The current study suggests that pretreatment enlarged LLN that also harbor malignant features are predictive of a worse DMFS. More studies will be required to further explore the role of malignant features in LLN.

Topical Versus Oral Metronidazole After Excisional Hemorrhoidectomy: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Both topical and oral metronidazole have been shown to reduce pain after excisional hemorrhoidectomy. Although recent meta-analyses have demonstrated efficacy against placebo, there has been no comparison between the 2 routes. OBJECTIVE: This study aims to investigate whether topical or oral metronidazole provides the most analgesic properties after excisional hemorrhoidectomy. DESIGN: A prospective, double-blind, randomized controlled trial was performed. SETTING: This trial was conducted at 2 hospitals in New Zealand between March 2019 and February 2020. PATIENTS: Adults undergoing elective excisional hemorrhoidectomy for grade III/IV hemorrhoids were randomized. INTERVENTIONS: Participants were randomized to receive either topical metronidazole ointment and an oral placebo versus oral metronidazole with a placebo ointment for 7 days. MAIN OUTCOME MEASURES: The primary outcome was daily pain scores for 7 days, estimated using a generalized linear mixed model fitted with time and treatment arm and tested for interaction with time and treatment arm. Secondary outcomes included additional analgesia, return to normal activity, recovery scores, and adverse effects. RESULTS: A total of 120 participants were included, with 60 in each group. A unimodal peak of pain was recorded with the maximum at days 3 and 4, but there was no significant difference in resting pain scores, with a mean difference at day 3 of 0.47 (-0.48, 1.42). There were no significant differences for secondary outcomes. Fourteen (11.7%) participants were readmitted, without significant difference between groups. Fifty-nine percent of participants preferred topical analgesic compared with 31% who preferred oral and 9.7% who had no preference. LIMITATIONS: This was a pragmatic study in which we could not have stopped participants seeking other analgesics and with less than perfect complete compliance. CONCLUSION: Postoperative oral and topical metronidazole provide similar analgesia after excisional hemorrhoidectomy. The route should depend on patient preference, with topical administration potentially benefiting from improved antimicrobial stewardship and having less effect on the gut microbiome. See Video Abstract at http:/links.lww.com/DCR/B853 .METRONIDAZOL TÓPICO VERSUS ORAL DESPUÉS DE UNA HEMORROIDECTOMÍA POR ESCISIÓN: UN ENSAYO CONTROLADO ALEATORIO DOBLE CIEGO. ANTECEDENTES: Se ha demostrado que tanto el metronidazol tópico como el oral reducen el dolor después de una hemorroidectomía por escisión. Aunque los metaanálisis más recientes han demostrado eficacia frente al placebo, no ha habido comparación entre las dos vías. OBJETIVO: Este estudio tiene como objetivo investigar si el metronidazol tópico u oral proporciona las propiedades más analgésicas después de una hemorroidectomía por escisión. DISEO: Se realizó un ensayo prospectivo, controlado, aleatorio, a doble ciego. AJUSTE: Este ensayo fue realizado en dos hospitales de Nueva Zelanda entre marzo de 2019 y febrero de 2020. PACIENTES: Se asignaron al azar pacientes adultos sometidos a hemorroidectomía por escisión electiva por hemorroides de grado III / IV. INTERVENCIONES: Los participantes fueron asignados al azar para recibir un ungüento de metronidazol tópico y un placebo oral versus metronidazol oral con un ungüento de placebo durante siete días. PRINCIPALES MEDIDAS DE RESULTADO: El resultado primario fueron las puntuaciones diarias de dolor durante siete días, estimadas mediante un modelo lineal mixto generalizado ajustado tanto con el tiempo y el brazo de tratamiento y probado para la interacción con el tiempo y el brazo de tratamiento. Los resultados secundarios incluyen analgesia adicional, retorno a la actividad normal, puntuaciones de recuperación y efectos adversos. RESULTADOS: Se incluyó un total de 120 participantes, 60 en cada grupo. Se registró un pico de dolor unimodal con el máximo en los días 3 y 4, pero no hubo diferencias significativas en las puntuaciones de dolor en reposo, con una diferencia media en el día 3 de 0,47 (-0,48, 1,42). No hubo diferencias significativas para los resultados secundarios. Catorce (11,7%) participantes fueron readmitidos, sin diferencias significativas entre los grupos. El cincuenta y nueve por ciento de los participantes prefirió el tópico, en comparación con el 31% por vía oral y el 9,7% sin preferencia. LIMITACIONES: Este fue un estudio pragmático en el que no pudimos haber impedido que los participantes buscaran otros analgésicos, con un cumplimiento completo menos que perfecto. CONCLUSINES: El metronidazol posoperatorio por vía oral o tópica proporciona una analgesia similar después de una hemorroidectomía por escisión. La vía debe depender de la preferencia del paciente, y la administración tópica se beneficia potencialmente por una mejor protección de los antimicrobianos y un menor efecto sobre el microbioma intestinal. Consulte Video Resumen en http://links.lww.com/DCR/B853 . (Traducción-Dr Osvaldo Gauto).

Cost of postoperative ileus following colorectal surgery: A cost analysis in the Australian public hospital setting.

AIM: Postoperative ileus (POI) following surgery results in significant morbidity, drastically increasing hospital costs. As there are no specific Australian data, this study aimed to measure the cost of POI after colorectal surgery in an Australian public hospital. METHODS: A cost analysis was performed, for major elective colorectal surgical cases between 2018 and 2021 at the Royal Adelaide Hospital. POI was defined as not achieving GI-2, the validated composite measure, by postoperative day 4. Demographics, length of stay and 30-day complications were recorded retrospectively. Costings in Australian dollars were collected from comprehensive hospital billing data. Univariate and multivariate analyses were performed. RESULTS: Of the 415 patients included, 34.9% (n = 145) developed POI. POI was more prevalent in males, smokers, previous intra-abdominal surgery, and converted laparoscopic surgery (p < 0.05). POI was associated with increased length of stay (8 vs. 5 days, p < 0.001) and with higher rates of complications such as pneumonia (15.2% vs. 8.1%, p = 0.027). Total cost of inpatient care was 26.4% higher after POI (AU$37,690 vs. AU$29,822, p < 0.001). POI was associated with increased staffing costs, as well as diagnostics, pharmacy, and hospital services. On multivariate analysis POI, elderly patients, stoma formation, large bowel surgery, prolonged theatre time, complications and length of stay were predictive of increased costs (p < 0.05). CONCLUSION: In Australia, POI is significantly associated with increased complications and higher costs due to prolonged hospital stay and increased healthcare resource utilisation. Efforts to reduce POI rates could diminish its morbidity and associated expenses, decreasing the burden on the healthcare system.

Pelvic Radiation Disease.

Pelvic radiation is increasingly being used for the neoadjuvant and definitive treatment of pelvic organ malignancy. While this treatment can be highly effective, and may assist in organ sparing, it is also associated with significant toxicity and devastating adverse events that need to be considered. In broad terms, pelvic radiation disease affects both the primary target organ as well as adjacent organs and soft tissue structures, with complications that can be classified and graded according to consensus criteria. The complication grade is often modality, dose, and area dependent. The most common manifestations are proctitis, cystitis, recto-urethral fistula, ureteric stricture, and bone involvement. Toxicity can be misdiagnosed for many years, resulting in significant management delays. Complications can be difficult to prevent and challenging to treat, requiring specialized multi-disciplinary input to achieve the best possible strategy to minimize impact and improve patient quality of life.

Artificial intelligence for pre-operative lymph node staging in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Artificial intelligence (AI) is increasingly being used in medical imaging analysis. We aimed to evaluate the diagnostic accuracy of AI models used for detection of lymph node metastasis on pre-operative staging imaging for colorectal cancer. METHODS: A systematic review was conducted according to PRISMA guidelines using a literature search of PubMed (MEDLINE), EMBASE, IEEE Xplore and the Cochrane Library for studies published from January 2010 to October 2020. Studies reporting on the accuracy of radiomics models and/or deep learning for the detection of lymph node metastasis in colorectal cancer by CT/MRI were included. Conference abstracts and studies reporting accuracy of image segmentation rather than nodal classification were excluded. The quality of the studies was assessed using a modified questionnaire of the QUADAS-2 criteria. Characteristics and diagnostic measures from each study were extracted. Pooling of area under the receiver operating characteristic curve (AUROC) was calculated in a meta-analysis. RESULTS: Seventeen eligible studies were identified for inclusion in the systematic review, of which 12 used radiomics models and five used deep learning models. High risk of bias was found in two studies and there was significant heterogeneity among radiomics papers (73.0%). In rectal cancer, there was a per-patient AUROC of 0.808 (0.739-0.876) and 0.917 (0.882-0.952) for radiomics and deep learning models, respectively. Both models performed better than the radiologists who had an AUROC of 0.688 (0.603 to 0.772). Similarly in colorectal cancer, radiomics models with a per-patient AUROC of 0.727 (0.633-0.821) outperformed the radiologist who had an AUROC of 0.676 (0.627-0.725). CONCLUSION: AI models have the potential to predict lymph node metastasis more accurately in rectal and colorectal cancer, however, radiomics studies are heterogeneous and deep learning studies are scarce. TRIAL REGISTRATION: PROSPERO CRD42020218004 .

Epidemiology of haemorrhoids and publicly funded excisional haemorrhoidectomies in New Zealand (2007-2016): a population-based cross-sectional study.

AIM: Haemorrhoids are frequently encountered by the general or colorectal surgeon. Although a benign disease, those with symptomatic, advanced grades frequently require excisional haemorrhoidectomy for definitive management. Despite their widespread nature, the epidemiological burden of haemorrhoids and haemorrhoidectomies on populations is not well described. This study seeks to establish the incidence of both haemorrhoids diagnosed and haemorrhoidectomies performed in New Zealand. METHOD: This is a population-based cross-sectional study examining the incidence of all patients who were newly diagnosed with haemorrhoids in New Zealand public hospital outpatient clinics and those who received excisional haemorrhoidectomy in New Zealand public hospitals from 2007 to 2016. Data were extracted and linked using the New Zealand National Minimum Dataset and the National Non-Admitted Patient Collection. Variables collected included age group, sex, ethnicity and geographical location. RESULTS: A total of 46 095 recorded diagnoses of haemorrhoids were made, with a total of 18 739 haemorrhoidectomies in the 10-year period recorded. The incidence rate of diagnosis increased from 84.6 to 120.5 per 100 000 and the incidence rate of haemorrhoidectomies performed from 30.4 to 51.1 per 100 000, a significantly increased annual incidence. There was a unimodal peak prevalence in the fifth decade of life with women more affected. Europeans formed the largest group affected, with Asians showing the highest rate of increased incidence. CONCLUSION: There is an increasing incidence of patients with symptomatic haemorrhoids presenting to the New Zealand public healthcare system, with a preponderance in working age adults, especially women.

Current practice in Australia and New Zealand for defunctioning ileostomy after rectal cancer surgery with anastomosis: Analysis of the Binational Colorectal Cancer Audit.

AIM: This study aimed to investigate the use of defunctioning stomas after rectal cancer surgery in Australia and New Zealand, as current practice is unknown. METHODS: From the Binational Colorectal Cancer Audit database, data on rectal cancer patients who underwent a resection between 2007 and 2019 with the formation of an anastomosis were extracted and analysed. The primary outcome was the rate of defunctioning stoma formation. Secondary outcomes were anastomotic leakage (AL) rates and other postoperative complications, length of hospital stay (LOS), readmissions and 30-day mortality rates between stoma and no-stoma groups. Propensity score matching was performed to correct for differences in baseline characteristics between stoma and no-stoma groups. RESULTS: In total, 2581 (89%) received a defunctioning stoma and 319 (11%) did not. There were more male patients in the stoma group (65.5% vs. 57.7% for the no-stoma group; P = 0.006). The median age was 64 years in both groups. The stoma group underwent more ultra-low anterior resections (79.9% vs. 30.1%; P < 0.0001), included more American Joint Committee on Cancer Stage III patients (53.7% vs. 29.2%; P < 0.0001) and received more neoadjuvant therapy (66.9% vs. 16.3%; P < 0.0001). The AL rate was similar in both groups (5.1% vs. 6.0%; P = 0.52). LOS was longer in the stoma group (8 vs. 6 days; P < 0.0001) with higher 30-day readmission rates (14.9% vs. 8.3%; P = 0.003). After propensity score matching (n = 208 in both groups), AL rates remained similar (2.9% for stoma vs. 5.8% for no-stoma group; P = 0.15), but stoma patients required less reoperations (0% vs. 8%; P = 0.016). The stoma group had higher postoperative ileus rates and an increased LOS. CONCLUSION: In Australia and New Zealand, most patients who underwent rectal cancer resections with the formation of an anastomosis received a defunctioning stoma. A defunctioning stoma does not prevent AL from occurring but is mostly associated with a lower reoperation rate. Patients with a defunctioning stoma experienced a higher postoperative ileus rate and had an increased LOS.

PyRICo-Pilot: pyridostigmine to reduce the duration of postoperative ileus after colorectal surgery - a phase II study.

AIM: Postoperative ileus (POI) is a major problem after colorectal surgery. Acetylcholinesterase inhibitors such as pyridostigmine increase gastrointestinal (GI) motility through a cholinergic anti-inflammatory pathway. The purpose of this phase II pilot study is to determine the safety of oral pyridostigmine after elective colorectal surgery. METHOD: This is a Stage 2b safety study (IDEAL framework). All adult patients undergoing elective colorectal resection or formation or reversal of stoma at the Royal Adelaide Hospital between September 2020 and January 2021 were eligible. The primary outcomes were 30-day postoperative complications, reported adverse events and GI-2 - a validated composite outcome measure of recovery of GI function after surgery, defined as the interval from surgery until first passage of stool and tolerance of a solid intake for 24 h (in whole days) in the absence of vomiting. RESULTS: Fifteen patients were included in the study. The median age was 58 (range 50-82) years and seven (47%) were men. Most participants had an American Society of Anesthesiologists grade ≥2 (53%) and the median body mass index was 27 (24-35) kg/m2 . There were 13 postoperative complications [seven were Clavien-Dindo (CD) 1, five CD 2 and one CD 3]. None appeared directly related to pyridostigmine administration, and none of the patients had any overt symptoms of excessive parasympathetic activity. Median GI-2 was 2 (1-4) days. CONCLUSION: Oral pyridostigmine appears to be safe to use after elective colorectal surgery in a select group of patients. However, considering this is a pilot study with a small sample size, larger controlled studies are needed to confirm this finding and establish efficacy for prevention of POI.

Outcomes of Minimally Invasive Versus Open Proctectomy for Rectal Cancer: A Propensity-Matched Analysis of Bi-National Colorectal Cancer Audit Data.

BACKGROUND: Minimally invasive surgery is commonly used in the treatment of rectal cancer, despite the lack of evidence to support oncological equivalence or improved recovery compared with open surgery. OBJECTIVE: This study aims to analyze prospectively collected data from a large Australasian colorectal cancer database. DESIGN: This is a retrospective cohort study using propensity score matching. SETTING: This study was conducted using data supplied by the Bi-National Colorectal Cancer Audit. PATIENTS: A total of 3451 patients who underwent open (n = 1980), laparoscopic (n = 1269), robotic (n = 117), and transanal total mesorectal excision (n = 85) for rectal cancer were included in this study. MAIN OUTCOME MEASURE: The primary outcome was positive margin rates (circumferential resection margin and/or distal resection margin) in patients treated with curative intent. RESULTS: Propensity score matching yielded 1132 patients in each of the open and minimally invasive surgery groups. Margin positivity rates and lymph node yields did not differ between groups. The open group had a significantly lower total complication rate (27.6% vs 35.8%, p < 0.0001), including a lower rate of postoperative small-bowel obstruction (1.2% vs 2.5%, p = 0.03). The minimally invasive surgery group had significantly lower wound infection rate (2.9% vs 5.0%, p = 0.02) and a shorter length of hospital stay (8 vs 9 days, p < 0.0001). There was no difference in 30-day mortality. LIMITATIONS: Results are limited by the quality of registry data entries. CONCLUSION: In this patient population, minimally invasive proctectomy demonstrated similar margin rates in comparison with open proctectomy, with a reduced length of stay but a higher overall complication rate. See Video Abstract at http://links.lww.com/DCR/B190. RESULTADOS DE LA PROCTECTOMÍA MÍNIMA INVASIVA VERSUS ABIERTA PARA EL CÁNCER DE RECTO: UN ANÁLISIS DE PROPENSIÓN DE LOS DATOS BINACIONALES DE AUDITORÍA DEL CÁNCER COLORRECTAL: La cirugía mínima invasiva, frecuentemente se utiliza en el tratamiento del cáncer rectal, a pesar de la falta de evidencia que respalde la equivalencia oncológica o la mejor recuperación, en comparación con la cirugía abierta.El estudio tiene como objetivo analizar datos prospectivamente obtenidos, de una gran base de datos de cáncer colorrectal de Australia.Estudio de cohorte retrospectivo utilizando el emparejamiento de puntaje de propensión.Este estudio se realizó utilizando datos proporcionados por la Auditoría Binacional del Cáncer Colorrectal.Se incluyeron en este estudio un total de 3451 pacientes que se trataron de manera abierta (n = 1980), laparoscópica (n = 1269), robótica (n = 117) y taTME (n = 85) para cáncer rectal.Los resultados primarios fueron de tasas de margen positivas (margen de resección circunferencial y/o margen de resección distal) en pacientes con intención curativa.La coincidencia de puntaje de propensión arrojó 1132 pacientes en cada uno de los grupos de cirugía abierta y mínima invasiva. Las tasas de positividad del margen y los rendimientos de los ganglios linfáticos no difirieron entre los dos grupos. El grupo abierto tuvo una tasa de complicaciones totales significativamente menor (27.6% vs 35.8%, p <0.0001), incluida una tasa menor de obstrucción postoperatoria del intestino delgado (1.2% vs 2.5%, p = 0.03). El grupo de cirugía mínimamente invasiva tuvo una tasa de infección de la herida significativamente menor (2.9% frente a 5.0%, p = 0,02) y una estancia hospitalaria más corta (8 frente a 9 días, p <0.0001). No hubo diferencias en la mortalidad a los 30 días.Los resultados están limitados por la calidad de la entrada de datos de registro.En esta población de pacientes, la proctectomía mínima invasiva demostró tasas de margen similares en comparación con la proctectomía abierta, con una estadía reducida pero una tasa más alta de complicaciones en general. Consulte Video Resumen en http://links.lww.com/DCR/B190. (Traducción-Dr. Fidel Ruiz Healy).