Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis.

AIM: The aim was to assess the benefit of adjuvant chemotherapy in high-risk Stage II colorectal cancer. METHOD: A systematic literature review and meta-analysis was performed comparing survival in patients with resected Stage II colorectal cancer and high-risk features having postoperative chemotherapy vs no chemotherapy. RESULTS: Of 1031 articles screened, 29 were included, reporting on 183 749 participants. Adjuvant chemotherapy significantly improved overall survival [hazard ratio (HR) 0.61, P < 0.0001], disease-specific survival (HR = 0.73, P = 0.05) and disease-free survival (HR = 0.59, P < 0.0001) compared to no chemotherapy. Adjuvant chemotherapy significantly increased 5-year overall survival (OR = 0.53, P = 0.0008) and 5-year disease-free survival (OR = 0.50, P = 0.001). Overall survival and disease-free survival remained significantly prolonged during subgroup analysis of studies published from 2015 onwards (HR = 0.60, P < 0.0001; HR = 0.65, P = 0.0001; respectively), in patients with two or more high-risk features (HR = 0.59, P = 0.0001; HR = 0.70, P = 0.03; respectively) and in colon cancer (HR = 0.61, P < 0.0001; HR = 0.51, P = 0.0001; respectively). Overall survival, disease-specific survival and disease-free survival during subgroup analysis of individual high-risk features were T4 tumour (HR = 0.58, P < 0.0001; HR = 0.50, P = 0.003; HR = 0.75, P = 0.05), < 12 lymph nodes harvested (HR = 0.67, P = 0.0002; HR = 0.80, P = 0.17; HR = 0.72, P = 0.02), poor differentiation (HR = 0.84, P = 0.35; HR = 0.85, P = 0.23; HR = 0.61, P = 0.41), lymphovascular or perineural invasion (HR = 0.55, P = 0.05; HR = 0.59, P = 0.11; HR = 0.76, P = 0.05) and emergency surgery (HR = 0.60, P = 0.02; HR = 0.68, P = 0.19). CONCLUSION: Adjuvant chemotherapy in high-risk Stage II colorectal cancer results in a modest survival improvement and should be considered on an individual patient basis. Due to potential heterogeneity and selection bias of the included studies, and lack of separate rectal cancer data, further large randomized trials with predefined inclusion criteria and standardized chemotherapy regimens are required.

Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer.

BACKGROUND: The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. OBJECTIVE: To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. METHODS: IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. RESULTS: IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. CONCLUSIONS: Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.

Obstructed defaecation syndrome: European consensus guidelines on the surgical management.

Clinical decision-making in the treatment of patients with obstructed defaecation remains controversial and no international guidelines have been provided so far. This study reports a consensus among European opinion leaders on the management of obstructed defaecation in different possible clinical scenarios.

Meta-analysis of the predictive value of C-reactive protein for infectious complications in abdominal surgery.

BACKGROUND: The aim of this analysis was to assess the predictive value of C-reactive protein (CRP) for the early detection of postoperative infectious complications after a variety of abdominal operations. METHODS: A meta-analysis of seven cohort studies from a single institution was performed. Laparoscopic gastric bypass and colectomies, as well as open resections of cancer of the colon, rectum, pancreas, stomach and oesophagus, were included. The predictive value of CRP was assessed by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Of 1986 patients, 577 (29·1 (95 per cent c.i. 27·1 to 31·3) per cent) had at least one postoperative infectious complication. Patients undergoing laparoscopic gastric bypass (383 patients) or colectomy (285), and those having open gastric (97) or colorectal (934) resections were combined in a meta-analysis. Patients who had resection for cancer of the oesophagus (41) or pancreas (246) were analysed separately owing to heterogeneity. CRP levels 4 days after surgery had the highest diagnostic accuracy (AUC 0·76, 95 per cent c.i. 0·73 to 0·78). Sensitivity and specificity were 68·5 (60·6 to 75·5) and 71·6 (66·6 to 76·0) per cent respectively. Positive and negative predictive values were 50·4 (46·0 to 54·8) and 84·3 (80·8 to 87·3) per cent. The threshold CRP varied according to the procedure performed. CONCLUSION: The negative predictive value of serum CRP concentration on day 4 after surgery facilitates reliable exclusion of postoperative infectious complications.

Anal fistula plug: a prospective evaluation of success, continence and quality of life in the treatment of complex fistulae.

AIM: Curing complex anal fistula without compromising continence can be extremely challenging. This study investigated the healing rate, continence and quality of life of patients after treatment of complex anal fistula of cryptoglandular origin with a bioprosthetic plug. METHOD: Consecutive patients were prospectively followed in four referral centres. Following seton conditioning, a bioprosthetic plug was inserted into the fistula and sutured to the anal sphincter. Clinical evaluation was performed at 10 days, 6 weeks and 6 months after surgery, and was completed by telephone interviews. Anal continence and quality of life were evaluated using the Fecal Incontinence Score Index and the Short Form-36 Health Survey, version 2 (SF-36 v2) questionnaire. RESULTS: Forty-six patients presenting with a complex anal fistula and a median of three previous fistula surgeries were included. The 6-month recurrence rate was 30.7% (95% CI: 15.9-42.8%), increasing to 48.0% (95% CI: 30.6-61.1%) after 2 years. Follow up was continued for a median of 68.1 months, and 26 (56.5%) recurrences were identified. Anal continence improved from a median of 19 points to 12 points at 6 months of follow up (P = 0.008). Quality of life markedly improved in all scales. The physical summary score increased from 47.2 to 56.2 (P < 0.001), and the mental summary score increased from 48.5 to 55.3 (P = 0.013). CONCLUSION: The bioprosthetic fistula plug demonstrated a healing rate close to 50% in complex cryptoglandular fistula. Also, it markedly improved anal continence and quality of life. These data support the use of a bioprosthetic plug as first-line therapy for complex fistula instead of more aggressive and potentially debilitating surgical options.

Contemporary perioperative care strategies.

BACKGROUND: Historically, the preoperative and postoperative care of patients with gastrointestinal cancer was provided by surgeons. Contemporary perioperative care is a truly multidisciplinary endeavour with implications for cancer-specific outcomes. METHODS: A literature review was performed querying PubMed and the Cochrane Library for articles published between 1966 to 2012 on specific perioperative interventions with the potential to improve the outcomes of surgical oncology patients. Keywords used were: fast-track, enhanced recovery, accelerated rehabilitation, multimodal and perioperative care. Specific interventions included normothermia, hyperoxygenation, surgical-site infection, skin preparation, transfusion, non-steroidal anti-inflammatory drugs, thromboembolism and antibiotic prophylaxis, laparoscopy, radiotherapy, perioperative steroids and monoclonal antibodies. Included articles had to be randomized controlled trials, prospective or nationwide series, or systematic reviews/meta-analyses, published in English, French or German. RESULTS: Important elements of modern perioperative care that improve recovery of patients and outcomes in surgical oncology include accelerated recovery pathways, thromboembolism and antibiotic prophylaxis, hyperoxygenation, maintenance of normothermia, avoidance of blood transfusion and cautious use of non-steroidal anti-inflammatory drugs, promotion of laparoscopic surgery, chlorhexidine-alcohol skin preparation and multidisciplinary meetings to determine multimodal therapy. CONCLUSION: Multidisciplinary management of perioperative patient care has improved outcomes.

Randomized clinical trial comparing the cost and effectiveness of bipolar vessel sealers versus clips and vascular staplers for laparoscopic colorectal resection.

BACKGROUND: The widespread use of laparoscopy has resulted in a variety of instruments being used routinely for vascular control. This randomized controlled trial evaluated the cost-effectiveness of bipolar vessel sealer (BVS) compared with clips and vascular stapler (CVS) in straight laparoscopic colorectal resection. METHODS: Patients scheduled for elective colorectal resection, including benign and malignant diseases, were randomized to either BVS or CVS for vascular control. Patients whose operation was converted to an open approach before pedicle ligation were excluded. The primary endpoints were duration of operation, including time taken to control vascular pedicles, and cost of disposable instruments for vascular control. RESULTS: Of 114 patients randomized to BVS (60 patients) or CVS (54), 14 did not receive the allocated vascular control device, leaving 55 and 45 respectively for analysis. The BVS reduced the time spent for vascular control by a mean of 6·9 min (P = 0·031) and reduced the cost of disposable instruments for vascular control by US $ 80·7 per patient (P = 0·043). For total colectomy, the BVS reduced the operating time by 103·6 min (P = 0·023) and the time taken for vascular control by 16·8 min (P = 0·022). For left colectomy, it decreased the time to vascular control by 9·3 min (P = 0·021). In multivariable analysis, the cost of disposable instruments for vascular control was independently reduced by randomization to BVS, type of procedure, female sex and estimated blood loss. The mean cost reduction was $ 88·2 for left colectomy (P = 0·037), $ 377·7 (P = 0·005) for total colectomy and $ 366·9 (P = 0·012) for proctectomy. Conversely, use of the BVS increased the cost of instruments used for vascular control in right colectomy by $ 92·6 (P = 0·012). CONCLUSION: BVS devices are expedient and cost-efficient in proctectomy, left and total colectomy procedures.

Laparoscopic total mesorectal excision for low rectal cancer.

BACKGROUND: Laparoscopic total mesorectal excision for rectal cancer is coming out of age with recent publications highlighting its safety, feasibility, sound oncological outcomes, and improved quality of life. Nevertheless, laparoscopic proctectomy remains a challenging procedure. An embedded didactic video demonstrates a step-by-step laparoscopic total mesorectal excision with coloanal anastomosis for a low rectal cancer. METHODS: A five-trocar technique is shown. The key steps demonstrated are: high division of the inferior mesenteric artery, medial-to-lateral mobilization of the descending colon, high division of the inferior mesenteric vein, take-down of the splenic flexure, total mesorectal excision with division of the rectum at the pelvic floor, and side-to-end coloanal anastomosis. Principles of a good anastomosis and potential pitfalls are described, including protection of the ureter and pelvic autonomic nerves. RESULTS: A series of ten consecutive patients operated for low rectal cancer with total mesorectal excision is reported. Median (range) operative time and estimated blood loss were 274 (135-360) minutes and 25 (10-50) ml. Median tumor height from the anal verge was 7 (4-10) cm. Reconstruction included three coloanal J-pouch and seven side-to-end anastomosis. Nine anastomoses were performed by using a double-stapled technique. One patient with an intersphincteric dissection required a handsewn anastomosis. A diverting ileostomy protected all coloanal anastomosis. Median length of stay was 3 (range, 2-7) days. One of ten patients was readmitted for a small bowel obstruction. The embedded video demonstrates a total mesorectal excision down to the pelvic floor in a patient who had a T2 cancer 6 cm from the anal verge with prior open cholecystectomy and hysterectomy. CONCLUSIONS: Laparoscopic total mesorectal excision is a safe and effective procedure. Patient selection and advanced laparoscopic skills are paramount. It is hoped that this didactic video will contribute to a wider and safer practice of laparoscopic total mesorectal excision for low rectal cancer.

Population-based trend analysis of 2813 patients undergoing laparoscopic sigmoid resection.

BACKGROUND: The use of laparoscopic sigmoid resection for diverticular disease has become increasingly popular. The objective of this trend analysis was to assess whether clinical outcomes following laparoscopic sigmoid resection for diverticular disease have improved over the past 10 years. METHODS: The analysis was based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery. Some 2813 patients undergoing elective laparoscopic sigmoid resection for diverticular disease from 1995 to 2006 were included. Unadjusted and risk-adjusted analyses were performed. RESULTS: Over time, there was a significant reduction in the conversion rate (from 27.3 to 8.6 per cent; P(trend) < 0.001), local postoperative complication rate (23.6 to 6.2 per cent; P(trend) = 0.004), general postoperative complication rate (14.6 to 4.9 per cent; P(trend) = 0.024) and reoperation rate (5.5 to 0.6 per cent; P(trend) = 0.015). Postoperative median length of hospital stay significantly decreased from 11 to 7 days (P(trend) < 0.001). CONCLUSION: This first trend analysis in the literature of clinical outcomes after laparoscopic sigmoid resection, based on almost 3000 patients, has provided compelling evidence that rates of postoperative complications, conversion and reoperation, and length of hospital stay have decreased significantly over the past 10 years.

Inflammatory Bowel Disease Management During the COVID-19 Outbreak: The Ten Do's and Don'ts from the ECCO-COVID Taskforce.

Our knowledge of COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and on appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as inflammatory bowel disease [IBD]. In this review, we have compiled existing evidence on the impact of COVID-19 in IBD patients and provide guidance on the most appropriate care to adopt during the pandemic. Our review highlights that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management should be carefully adapted: [i] in SARS-CoV-2-positive IBD patients, medical treatments should be re-evaluated [with a particular focus on corticosteroids] always with the purpose of treating active disease and maintaining remission; [ii] non-urgent surgeries and endoscopic procedures should be postponed for all patients; [iii] online consultancy should be implemented; and [iv] hospitalization and surgery should be limited to life-threatening situations.

Anatomy and mechanical properties of the anal sphincter muscles in healthy senior volunteers.

BACKGROUND: A large proportion of age-related fecal incontinence is attributed to weakness or degeneration of the muscles composing the anal continence organ. However, the individual role of these muscles and their functional interplay remain poorly understood. METHODS: This study employs a novel technique based on the combination of MR imaging and FLIP measurements (MR-FLIP) to obtain anatomical and mechanical information simultaneously. Unlike previous methods used to assess the mechanics of the continence organ, MR-FLIP allows inter-individual comparisons and statistical analysis of the sphincter morpho-mechanical parameters. The anatomy as well as voluntary and involuntary mechanical properties of the anal continence organ were characterized in 20 healthy senior volunteers. RESULTS: Results showed that the external anal sphincter (EAS) forms a funnel-like shape with wall thickness increasing by a factor of 2.5 from distal (6 ± 0 mm) to proximal (15 ± 3 mm). Both voluntary and involuntary mechanical properties in this region correlate strongly with the thickness of the muscle. The positions of least compliance and maximal orifice closing were both located toward the proximal EAS end. In addition, maximal contraction during squeeze maneuvers was reached after 2 s, but high muscle fatigue was measured during a 7 s holding phase, corresponding to about 60% loss of the energy produced by the muscles during the contraction phase. CONCLUSIONS: This work reports baseline parameters describing the morpho-mechanical condition of the sphincter muscle of healthy elderly volunteers. New parameters were also proposed to quantify the active properties of the muscles based on the mechanical energy associated with muscle contraction and fatigue. This information could be used to assess patients suffering from AI or for the design of novel implants.

Prognostic Factors for Enteroatmospheric Fistula in Open Abdomen Treated with Negative Pressure Wound Therapy: a Multicentre Experience.

BACKGROUND: Reductions in mortality were reported with negative pressure wound therapy for laparostomy. However, some authors have voiced concern over an increased risk of enteroatmospheric fistulae. In this retrospective study, we hypothesized that surgical and metabolic derangements could increase the incidence of enteroatmospheric fistulae. We aimed to assess our experience and report long-term outcomes. METHODS: A multicentre review of all patients with a laparostomy managed with negative pressure wound therapy between 2005 and 2015 was undertaken. Features associated with enteroatmospheric fistulae were included in multivariate logistic regression. RESULTS: Fifty-seven patients were treated according to uniform protocol. Fourteen per cent (8/57) presented enteroatmospheric fistulae. Mesenteric ischaemia and preoperative arterial serum lactate >3.5 mmol/L were associated with a significantly increased risk of enteroatmospheric fistulae. Preoperative arterial serum lactate >3.5 mmol/L was an independent predictor of enteroatmospheric fistulae with an odds ratio of 12.41 (95% CI 1.54-99.99). All mesenteric ischaemia patients with anastomosis (5/15) presented enteroatmospheric fistulae. In-hospital mortality was 26.3% (15/57). One-year mortality was 33.3% (19/57). Incisional hernia rate was 5.2% (2/38) after 14.2 (2.4-56.3) months of follow-up. DISCUSSION: Mesenteric ischaemia increases the risk of enteroatmospheric fistulae. Anastomosis should only be created in revascularized patients. When mesenteric vascularization is not restored, diversion is advised.

Phase I/II clinical trial of a nonreplicative vaccinia virus expressing multiple HLA-A0201-restricted tumor-associated epitopes and costimulatory molecules in metastatic melanoma patients.

We performed a phase I/II clinical trial in metastatic melanoma patients with an ultraviolet (UV)-inactivated nonreplicating recombinant vaccinia virus enabling the expression, from a single construct, of endoplasmic reticulum-targeted HLA-A0201-restricted Melan-A/MART-1(27-35), gp100(280-288), and tyrosinase(1-9) epitopes, together with CD80 and CD86 costimulatory proteins. Corresponding soluble peptides were used to boost responses and granulocyte-macrophage colony-stimulating factor was used as systemic adjuvant. Safety and immunogenicity, as monitored with in vitro-restimulated peripheral blood mononuclear cells by cytotoxic T lymphocyte precursor (CTLp) frequency analysis and tetramer staining, were specifically addressed. Of 20 patients entering the protocol, 2 had to withdraw because of rapidly progressing disease. Immune responses were evaluated in 18 patients (stage III, n = 5; stage IV, n = 13) and increases in specific CTLp frequencies were observed in 15. In 16 patients responsiveness against all 3 antigens could be analyzed: 7 (43%), including all stage III cases, showed evidence of induction of CTLs specific for the three epitopes, and 2 (12%) and 4 (25%), respectively, showed reactivity against two or one tumor-associated antigen. In three stage IV patients no specific CTL reactivity could be induced. Increases in CTLp frequency were detected mostly after viral vaccine injections. However, in a majority of patients final CTLp levels were comparable to initial levels. Tetramer characterization of Melan-A/MART-1(27-35)-specific CTLs during the protocol also suggested preferential expansion after recombinant virus administration. Vector-specific humoral responses, frequently undetectable in stage IV patients, did not appear to prevent tumor-associated antigen-specific CTL induction. Aside from a single occurrence of transient grade 3 leukopenia, no major clinical toxicity was reported. Seventeen of 18 patients completed the 3-month trial (one patient died before the last delayed-type hypersensitivity test). Three displayed regression of individual metastases, seven had stable disease, and progressive disease was observed in seven patients. This is the first report on the administration of a UV-inactivated recombinant vaccinia virus coexpressing five transgenes in cancer patients. The results described here, in terms of safety and immunogenicity, support the use of this reagent in active specific immunotherapy.

Early introduction of laparoscopic sigmoid colectomy during residency.

BACKGROUND: Laparoscopic sigmoid colectomy for benign diseases is becoming the standard of care. However, few residency programmes incorporate the procedure. This study evaluated the safety and feasibility of the early introduction of laparoscopic sigmoid colectomy during residency. METHODS: From a database of consecutive laparoscopic sigmoid colectomies collected prospectively over 6 years, those for cancer and primary open sigmoid colectomies were excluded. Surgeons were categorized into five levels of experience in colonic surgery. Patient demographics, operative data, complications and conversion rates were assessed. RESULTS: A total of 262 sigmoid colectomies were performed by 13 surgeons. American Society of Anesthesiologists grade and diverticular disease classification were similar across the five experience levels. There were no significant differences in morbidity, mortality or readmission rates between experience levels. However, operative time (230 versus 145 min, P < 0.001) intraoperative blood loss (200 versus 100 ml, P < 0.001) and conversion rate (13.6 versus 2.1 per cent, P = 0.002) all decreased with increasing surgical experience (trainee versus trainer). CONCLUSION: It is safe and feasible to introduce laparoscopic sigmoid colectomy to a structured residency.

Propensity scores and the surgeon.

BACKGROUND: Evidence-based surgery has been established as a cornerstone of good clinical practice, promising to improve the treatment of patients and the quality of surgical education. However, evidence-based surgery requires dedicated clinicians trained to perform methodologically sound clinical investigations. Statistical knowledge is therefore invaluable. Surgical studies often cannot be randomized. Propensity scores offer a powerful alternative to multivariable analysis in the assessment of observational, non-randomized surgical studies. Unfortunately, many surgeons are unaware of this important analytical approach that has gained increasing stature in medical research. Thus, propensity score analyses are not used often in surgical studies. OBJECTIVE: The purpose of this paper is to provide a comprehensive overview of propensity score analysis, allowing the surgeon to understand the role, advantages and limitations of propensity scores, boosting their development in surgical investigations.

Encapsulation into sterically stabilised liposomes enhances the immunogenicity of melanoma-associated Melan-A/MART-1 epitopes.

Tumour-associated antigens (TAA)-specific vaccination requires highly immunogenic reagents capable of inducing cytotoxic T cells (CTL). Soluble peptides are currently used in clinical applications despite an acknowledged poor immunogenicity. Encapsulation into liposomes has been suggested to improve the immunogenicity of discrete antigen formulations. We comparatively evaluated the capacity of HLA-A2.1 restricted Melan-A/MART-1 epitopes in soluble form (S) or following inclusion into sterically stabilised liposomes (SSL) to be recognised by specific CTL, to stimulate their proliferation and to induce them in healthy donors' peripheral blood mononuclear cells (PBMC), as well as in melanoma-derived tumour-infiltrating lymphocytes (TIL). HLA-A2.1(+), Melan-A/MART-1-NA-8 melanoma cells served as targets of specific CTL in 51Cr release assays upon pulsing by untreated or human plasma-treated soluble or SSL-encapsulated Melan-A/MART-1 27-35 (M27-35) or 26-35 (M26-35) epitopes. These reagents were also used to stimulate CTL proliferation, measured as 3H-thymidine incorporation, in the presence of immature dendritic cells (iDC), as antigen-presenting cells (APC). Induction of specific CTL upon stimulation with soluble or SSL-encapsulated peptides was attempted in healthy donors' PBMC or melanoma-derived TIL, and monitored by 51Cr release assays and tetramer staining. Na-8 cells pulsing with SSL M27-35 resulted in a five-fold more effective killing by specific CTL as compared with equal amounts of S M27-35. Encapsulation into SSL also provided a partial (50%) protection of M27-35 from plasma hydrolysis. No specific advantages regarding M26-35 were detectable in these assays. However, at low epitope concentrations (