The Mesentery-Past, Present, and Future.

This article summarizes the events that shaped our current understanding of the mesentery and the abdomen. The story of how this evolved is intriguing at several levels. It speaks to considerable personal commitment on the part of the pioneers involved. It explains how scientific and clinical fields went different directions with respect to anatomy and clinical practice. It demonstrates that it is no longer acceptable to adhere unquestioningly to models of abdominal anatomy and surgery. The article concludes with a brief description of the Mesenteric Model of abdominal anatomy, and of how this now presents an opportunity to unify scientific and clinical approaches to the latter.

European consensus on the standardization of robotic total mesorectal excision for rectal cancer.

AIM: Surgery for rectal cancer is challenging for both technical and anatomical reasons. The European Academy of Robotic Colorectal Surgery (EARCS) provides a competency-based training programme through a standardized approach. However, there is no consensus on technical standards for robotic surgery when used during surgery for rectal cancer. The aim of this consensus study was to establish operative standards for anterior resection incorporating total mesorectal excision (TME) using robotic techniques, based on recommendations of expert European colorectal surgeons. METHOD: A Delphi questionnaire with a 72-item statement was sent through an electronic survey tool to 24 EARCS faculty members from 10 different countries who were selected based on expertise in robotic colorectal surgery. The task was divided into theatre setup, colonic mobilization and rectal dissection, and each task area was further divided into several subtasks. The levels of agreement (A* > 95% agreement, A > 90%, B > 80% and C > 70%) were considered adequate while agreement of < 70% was considered inadequate. Once consensus was reached, a draft document was compiled and sent out for final approval. RESULTS: The average length of experience of robotic colorectal surgery for participants in this study was 6 years. Initial agreement was 87%; in nine items, it was < 70%. After suggested modifications, the average level of agreement for all items reached 94% in the second round (range 0.75-1). CONCLUSION: This is the first European consensus on the standardization of robotic TME. It provides a baseline for technical standards and structured training in robotic rectal surgery.

A personal perspective of the development of MRI for Total Mesorectal Excision surgery.

In this personal account Professor Heald discusses the international implementation of total mesorectal excision for rectal cancer and the development of a generation of "specimen-orientated" surgeons. He describes the importance of the surgeon, radiologist and pathologist working together to improve techniques in all three disciplines and the research challenges for the future.

Adjuvant chemotherapy may improve disease-free survival in patients with rectal cancer positive for MRI-detected extramural venous invasion following chemoradiation.

AIM: MRI-detected extramural venous invasion (mrEMVI) is a poor prognostic factor in rectal cancer. Preoperative chemoradiotherapy (CRT) can cause regression in the severity of EMVI and subsequently improve survival whereas mrEMVI persisting after CRT confers an increased risk of recurrence. The effect of adjuvant chemotherapy (AC) following CRT on survival in rectal cancer remains unclear. The aim of this study was to determine whether there is a survival advantage for AC given to patients with mrEMVI persisting after CRT. METHOD: A prospective analysis was conducted of consecutive patients with locally advanced rectal cancer between 2006 and 2013. All patients underwent CRT followed by surgery. AC was given to selected patients based on the presence of specific 'high-risk' features. Comparison was made between patients offered AC with observation alone. The primary outcome was 3-year disease-free survival (DFS). RESULTS: Of 631 patients, 227 (36.0%) demonstrated persistent mrEMVI following CRT. Patients were grouped on the basis of AC or observation and were matched for age, performance status and final histopathological staging. Three-year DFS in the AC group was 74.6% compared with 53.7% in the observation only group. AC had a survival benefit on multivariate analysis (hazard ratio 0.458; 95% CI: 0.271-0.775, P = 0.004). CONCLUSION: Patients with persistent mrEMVI following CRT who receive AC may have a decreased risk of recurrence and an improved 3-year DFS compared with patients not receiving AC, irrespective of age and performance status.

A collaborative review of the current concepts and challenges of anastomotic leaks in colorectal surgery.

The reduction of the incidence, detection and treatment of anastomotic leakage (AL) continues to challenge the colorectal surgical community. AL is not consistently defined and reported in clinical studies, its occurrence is variably reported and its impact on longterm morbidity and health-care resources has received relatively little attention. Controversy continues regarding the best strategies to reduce the risk. Diagnostic tests lack sensitivity and specificity, resulting in delayed diagnosis and increased morbidity. Intra-operative fluorescence angiography has recently been introduced as a means of real-time assessment of anastomotic perfusion and preliminary evidence suggests that it may reduce the rate of AL. In addition, concepts are emerging about the role of the rectal mucosal microbiome in AL and the possible role of new prophylactic therapies. In January 2016 a meeting of expert colorectal surgeons and pathologists was held in London, UK, to identify the ongoing controversies surrounding AL in colorectal surgery. The outcome of the meeting is presented in the form of research challenges that need to be addressed.

The rationale behind complete mesocolic excision (CME) and a central vascular ligation for colon cancer in open and laparoscopic surgery : proceedings of a consensus conference.

BACKGROUND: It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors. METHOD: There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354-365, 2009; West et al., J Clin Oncol 28:272-278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction. RESULT: The oncological rationale for CME and various technical aspects of the surgical management will be explored. CONCLUSION: The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.

Comparative quality of life in patients following abdominoperineal excision and low anterior resection for low rectal cancer.

BACKGROUND: It is widely believed that quality of life is worse after abdominoperineal excision then after low anterior resection. However, this view is not supported unequivocally. OBJECTIVE: The aim of this study was to compare quality of life in patients 1 year following low anterior resection and abdominoperineal excision for low rectal cancer. DESIGN: Data were collected prospectively on 62 patients undergoing low anterior resection (32) and abdominoperineal excision (30) for low rectal adenocarcinoma within 6 cm of the anal verge. Patients with metastatic disease were excluded. Quality of life was assessed by the use of the European Organization for Research and Treatment of Cancer's QLQ-C30 and QLQ-CR38 modules and Coloplast stoma quality-of-life questionnaire. Bowel function was assessed by using the St Mark's bowel function questionnaire. Quality of life in patients who had low anterior resection was compared with those who had abdominoperineal excision both preoperatively and 1 year after surgery. SETTINGS: This study was conducted at 3 centers in the United Kingdom and 1 center in Europe. PATIENTS: Included were consecutive patients with rectal cancer within 6 cm of the anal verge, all of whom provided written consent for participation. MAIN OUTCOME MEASURES: Mann-Whitney U test comparisons of QLQ-C30 and QLQ-CR38 module scores for patients undergoing low anterior resection and abdominoperineal excision were the main outcomes measured. RESULTS: Patients undergoing low anterior resection were younger (median age, 59.5 vs 67, p = 0.03) with higher tumors (4 vs 3, p < 0.001) and less likely to receive neoadjuvant therapy (p = 0.02). At 1 year postoperatively, global quality-of-life ratings were comparable, but patients undergoing abdominoperineal excision reported better cognitive (100 vs 83, p = 0.018) and social (100 vs 67, p = 0.012) function, and less symptomatology with respect to pain (0 vs 17, p = 0.027), sleep disturbance (0 vs 33, p = 0.013), diarrhea (0 vs 33, p = 0.017), and constipation (p = 0.021). Patients undergoing low anterior resection reported better sexual function (33 vs 0, p = 0.006), but 72% experienced a degree of fecal incontinence. LIMITATIONS: This study was limited by its relatively small sample size. CONCLUSION: Abdominoperineal excision should not be regarded as an operation that is inferior to low anterior resection in the management of low rectal cancer on the basis of quality of life alone.

A pictorial description of extralevator abdominoperineal excision for low rectal cancer.

AIM: Extralevator abdominoperineal excision in the prone position has been reported as a method to improve the poor outcome sometimes observed after abdominoperineal excision (APE) for low rectal cancer. In this paper a pictorial guide is presented describing the key anatomical steps and landmarks of the operation. METHOD: Intraoperative footage of five APE operations filmed in high definition was reviewed and key stages of the operation were identified. Still frames were captured from these sequences to illustrate this guide. An edited video sequence was produced from one of these operations to accompany this paper. CONCLUSION: The prone APE allows improved visualization of the perineal portion of the operation by the surgeon, assistants and observers. It permits clear demonstration for teaching. Prospective evaluation is still required to identify patients who would benefit from extralevator APE.

Outcomes following a limited approach to radiotherapy in rectal cancer.

BACKGROUND: Variation in the use of neoadjuvant and adjuvant radiotherapy for rectal cancer suggests an opportunity to avoid it in all but patients at highest risk of local recurrence. METHODS: Between 1 July 1999 and 1 February 2006, patients with primary rectal cancer were treated by a single surgeon operating at McMaster University, Hamilton, Ontario, Canada. Digital rectal examination and pelvic computed tomography were used to determine whether the mesorectal margin was threatened by tumour and thus whether preoperative radiotherapy would be needed. The study outcome was local tumour recurrence. RESULTS: Forty-six (48 per cent) of 96 patients received preoperative radiation therapy. The median follow-up was 4·2 years. Tumours were fixed or tethered in 31 (67 per cent) of the 46 irradiated patients. In contrast, no tumour was fixed in unirradiated patients and only ten (20 per cent) of the 50 tumours were tethered. The proportion of patients with stage I or II tumours based on final pathology was similar: 61 per cent (28 of 46) and 56 per cent (28 of 50) in irradiated and unirradiated groups respectively (P = 0·287). There were four (9 per cent) and two (4 per cent) local recurrences among irradiated and unirradiated patients respectively (P = 0·422). CONCLUSION: Limiting preoperative radiotherapy in rectal cancer to patients with a threatened circumferential margin does not compromise patient outcome.

One millimetre is the safe cut-off for magnetic resonance imaging prediction of surgical margin status in rectal cancer.

BACKGROUND: A pathologically involved margin in rectal cancer is defined as tumour within 1 mm of the surgical resection margin. There is no standard definition of a predicted safe margin on magnetic resonance imaging (MRI). The aim of this study was to assess which cut-off (1, 2 or 5 mm) was the best predictor of local recurrence based on preoperative MRI assessment of the circumferential resection margin (CRM). METHODS: Data were collected prospectively on the distance between the tumour and mesorectal fascia for patients with documented radiological margin status in the MERCURY study. Positive margin and local recurrence rates were compared for MRI distances from the tumour to the mesorectal fascia of 1 mm or less, more than 1 mm up to 2 mm, more than 2 mm up to 5 mm, and more than 5 mm. The Cox proportional hazard regression method was used to determine the effect of level of margin involvement on time to local recurrence. RESULTS: Univariable analysis showed that, relative to a distance measured by MRI of more than 5 mm, the hazard ratio (HR) for local recurrence was 3·90 (95 per cent confidence interval 1·99 to 7·63; P < 0·001) for a margin of 1 mm or less, 0·81 (0·36 to 1·85; P = 0·620) for a margin of more than 1 mm up to 2 mm, and 0·33 (0·10 to 1·08; P = 0·067) for a margin greater than 2 mm up to 5 mm. Multivariable analysis of the effect of MRI distance to the mesorectal fascia and preoperative treatment on local recurrence showed that a margin of 1 mm or less remained significant regardless of preoperative treatment (HR 3·72, 1·43 to 9·71; P = 0·007). CONCLUSION: For preoperative staging of rectal cancer, the best cut-off distance for predicting CRM involvement using MRI is 1 mm. Using a cut-off greater than this does not appear to identify patients at higher risk of local recurrence.

Relevance of magnetic resonance imaging-detected pelvic sidewall lymph node involvement in rectal cancer.

BACKGROUND: The significance of magnetic resonance imaging (MRI)-suspected pelvic sidewall (PSW) lymph node involvement in rectal cancer is uncertain. METHODS: Magnetic resonance images were reviewed retrospectively by specialist gastrointestinal radiologists for the presence of suspicious PSW nodes. Scans and outcome data were from patients with biopsy-proven rectal cancer and a minimum of 5 years' follow-up in the Magnetic Resonance Imaging and Rectal Cancer European Equivalence Study. Overall disease-free survival (DFS) was analysed using the Kaplan-Meier product-limit method and stratified according to preoperative therapy. Binary logistic regression was used to match patients for propensity of clinical and staging characteristics, and further survival analysis was carried out to determine associations between suspicious PSW nodes on MRI and survival outcomes. RESULTS: Of 325 patients, 38 (11·7 per cent) had MRI-identified suspicious PSW nodes on baseline scans. Such nodes were associated with poor outcomes. Five-year DFS was 42 and 70·7 per cent respectively for patients with, and without suspicious PSW nodes (P < 0·001). Among patients undergoing primary surgery, MRI-suspected PSW node involvement was associated with worse 5-year DFS (31 versus 76·3 per cent; P = 0·001), but the presence of suspicious nodes had no impact on survival among patients who received preoperative therapy. After propensity matching for clinical and tumour characteristics, the presence of suspicious PSW nodes on MRI was not an independent prognostic variable. CONCLUSION: Patients with suspicious PSW nodes on MRI had significantly worse DFS that appeared improved with the use of preoperative therapy. These nodes were associated with adverse features of the primary tumour and were not an independent prognostic factor.

Magnetic resonance imaging-detected lymph nodes close to the mesorectal fascia are rarely a cause of margin involvement after total mesorectal excision.

BACKGROUND: In rectal cancer the management of suspicious magnetic resonance imaging (MRI)-detected lymph nodes lying close to the mesorectal fascia poses an ongoing dilemma. Key decisions in treatment planning are commonly based on the prediction of margin status. However, it is unclear whether a lymph node that appears to contain tumour close to the mesorectal fascia will result in a positive margin. METHODS: Some 396 patients with rectal cancer were included. MRI assessment of mesorectal nodes, the pathologically involved circumferential resection margin (CRM) rate and causes of margin involvement were analysed to establish the clinical significance of MRI-detected suspicious lymph nodes at the resection margin. RESULTS: Fifty (12.6 per cent) of 396 patients had a positive CRM on histopathological analysis, five (10 per cent) solely due to an involved lymph node. Four of the five malignant nodes were not predicted on MRI. Thirty-one of the 396 MRI studies had suspicious nodes 1 mm or less from the CRM. None of these patients had a positive CRM owing to nodal involvement. CONCLUSION: Involvement of the CRM by lymph node metastases alone is uncommon.

Spindles get the ran around.

Despite its fundamental role in cell division, the mitotic spindle remains an enigmatic figure in cell biology. This is due to the complex dynamic behaviour of microtubules, which form the spindle fibres responsible for segregating chromosomes to opposite ends of the cell during mitosis. Recent reports indicate that the small GTPase Ran, which plays a key role in nuclear transport, also has a role in mitosis by regulating microtubule nucleation and/or growth. The race is now on to determine how Ran exerts its effects on spindle assembly.

Regulation of Op18 during spindle assembly in Xenopus egg extracts.

Oncoprotein 18 (Op18) is a microtubule-destabilizing protein that is negatively regulated by phosphorylation. To evaluate the role of the three Op18 phosphorylation sites in Xenopus (Ser 16, 25, and 39), we added wild-type Op18, a nonphosphorylatable triple Ser to Ala mutant (Op18-AAA), and to mimic phosphorylation, a triple Ser to Glu mutant (Op18-EEE) to egg extracts and monitored spindle assembly. Op18-AAA dramatically decreased microtubule length and density, while Op18-EEE did not significantly affect spindle microtubules. Affinity chromatography with these proteins revealed that the microtubule-destabilizing activity correlated with the ability of Op18 to bind tubulin. Since hyperphosphorylation of Op18 is observed upon addition of mitotic chromatin to extracts, we reasoned that chromatin-associated proteins might play a role in Op18 regulation. We have performed a preliminary characterization of the chromatin proteins recruited to DNA beads, and identified the Xenopus polo-like kinase Plx1 as a chromatin-associated kinase that regulates Op18 phosphorylation. Depletion of Plx1 inhibits chromatin-induced Op18 hyperphosphorylation and spindle assembly in extracts. Therefore, Plx1 may promote microtubule stabilization and spindle assembly by inhibiting Op18.

Spindle assembly in Xenopus egg extracts: respective roles of centrosomes and microtubule self-organization.

In Xenopus egg extracts, spindles assembled around sperm nuclei contain a centrosome at each pole, while those assembled around chromatin beads do not. Poles can also form in the absence of chromatin, after addition of a microtubule stabilizing agent to extracts. Using this system, we have asked (a) how are spindle poles formed, and (b) how does the nucleation and organization of microtubules by centrosomes influence spindle assembly? We have found that poles are morphologically similar regardless of their origin. In all cases, microtubule organization into poles requires minus end-directed translocation of microtubules by cytoplasmic dynein, which tethers centrosomes to spindle poles. However, in the absence of pole formation, microtubules are still sorted into an antiparallel array around mitotic chromatin. Therefore, other activities in addition to dynein must contribute to the polarized orientation of microtubules in spindles. When centrosomes are present, they provide dominant sites for pole formation. Thus, in Xenopus egg extracts, centrosomes are not necessarily required for spindle assembly but can regulate the organization of microtubules into a bipolar array.