Diagnosis and Treatment of Transsphincteric Perianal Fistulas

Fistula’ is the Latin word for a reed, pipe or flute. In medicine it implies a chronic granulating track connecting two epithelium lined surfaces. These surfaces may be cutaneous or mucosal. Perianal fistulas run from the anal canal to the perianal skin or perineum. Perianal fistulas are associated with considerable discomfort and morbidity to the patient. The two principal goals in the treatment of perianal fistulas are eradication of the fistulous tract and preservation of sphincter function. In patients with an intersphincteric fistula, these objectives can be achieved by laying open the fistulous tract. Although this procedure affects anal pressure, the functional results are quite satisfactory. The management of fistulas, crossing the upper two-thirds of the external anal sphincter, however, remains a difficult surgical challenge. Treatment of these high transsphincteric fistulas by a traditional laying open technique will lead to an almost complete transsection of a substantial part of the external anal sphincter with wide separation of both ends. To prevent this, several techniques have been developed. Accurate preoperative assessment of perianal fistula is necessary for planning the most suitable surgical procedure and therefore enables the surgeon to inform the patient on the type of surgery and its possible complications. Based on the findings of this thesis, it is concluded that: (1) The results of 3D endoanal sonography enhanced with hydrogen peroxide and endoanal magnetic resonance scanning are comparable. (2) The outcome of transanal mucosal advancement flap repair is successful in 75 percent of all patients. This technique is a worthwhile treatment for perianal fistulas. (3) Fecal incontinence after transanal mucosal advancement flap repair is caused by the use of a Parks’ anal retractor, not by inclusion of fibers of the internal anal sphincter. (4) The anocutaneous advancement flap repair is not a viable alternative to the transanal mucosal advancement flap repair, since the results are moderate to poor. Furthermore, the incidence of impaired continence is comparable to that after transanal mucosal advancement flap repair. (5) Smoking of cigarettes adversely affects the outcome after transanal mucosal advancement flap repair. (6) The healing rate of transanal advancement flap repair of low rectovaginal fistulas is poor (less than 50 percent). (7) The results of transanal advancement flap repair of low rectovaginal fistulas can not be improved by the addition of a labial fat flap transposition

Long-term follow-up of retrograde colonic irrigation for defaecation disturbances

Objective. Irrigation of the distal part of the large bowel is a nonsurgical alternative for patients with defaecation disturbance. In our institution, all patients with defaecation disturbances, not responding to medical treatment and biofeedback therapy, were offered retrograde colonic irrigation (RCI). This study is aimed at evaluating the long-term feasibility and outcome of RCI. Methods. Between 1989 and 2001, a consecutive series of 267 patients was offered RCI. All patients received instructions about RCI by one of our enterostomal therapists. Twenty-eight patients were lost to follow-up. A detailed questionnaire was sent by mail to 239 patients. The total response rate was 79% (190 patients). Based on the returned questionnaires it became clear the 21 (11%) patients never started RCI. The long-term feasibility and outcome of RCI was therefore assessed in the remaining group of 169 patients. Thirty-two patients were admitted with soiling, 71 patints with faecal incontinence, 37 patients with obstructed defaecation and 29 had defaecation disturbance after low anterior resection or pouch surgery. Results. According to the returned questionnaires, RCI was considered effective by 91 (54%) patients. Among patients with soling and faecal incontinence, RCI was found to be effective in, respectively, 47 and 41% of the subjects. Despite of the reported effectiveness, 10 (67%) patients with soiling and 5 (17%) patients with faecal incontinence decide to stop. Among patients with obstructed defaecation and those with defaecation disturbances after low anterior resection or pouch surgery the effectiveness of RCI was found to be 65 and 79%, respectively. None of these patients ceased their therapy. The overall succes-rate of long-term RCI was therefore 45%. Conclusions. Long-term RCI is beneficial for 45% of patients with defaecation disturbance. In the group of patients who considered RCI effective and beneficial, discontinuation of therapy was only observe among those with soiling and faecal incontinence

Confirmation of a metastasis-specific microRNA signature in primary colon cancer

The identification of patients with high-risk stage II colon cancer who may benefit from adjuvant therapy may allow the clinical approach to be tailored for these patients based on an understanding of tumour biology. MicroRNAs have been proposed as markers of the prognosis or treatment response in colorectal cancer. Recently, a 2-microRNA signature (l et-7i and miR-10b) was proposed to identify colorectal cancer patients at risk of developing distant metastasis. We assessed the prognostic value of this signature and additional candidate microRNAs in an independent, clinically well-defined, prospectively collected cohort of primary colon cancer patients including stage I-II colon cancer without and stage III colon cancer with adjuvant treatment. The 2-microRNA signature specifically predicted hepatic recurrence in the stage I-II group, but not the overall ability to develop distant metastasis. The addition of miR-30b to the 2-microRNA signature allowed the prediction of both distant metastasis and hepatic recurrence in patients with stage I-II colon cancer who did not receive adjuvant chemotherapy. Available gene expression data allowed us to associate m iR-30b expression with axon guidance and l et-7i expression with cell adhesion, migration, and motility

Completeness of pathology reports in stage II colorectal cancer

Introduction: The completeness of the pathological examination of resected colon cancer specimens is important for further clinical management. We reviewed the pathological reports of 356 patients regarding the five factors (pT-stage, tumor differentiation grade, lymphovascular invasion, tumor perforation and lymph node metastasis status) that are used to identify high-risk stage II colon cancers, as well as their impact on overall survival (OS). Methods: All patients with stage II colon cancer who were included in the first five years of the MATCH study (1 July 2007 to 1 July 2012) were selected (n = 356). The hazard ratios of relevant risk factors were calculated using Cox Proportional Hazards analyses. Results: In as many as 69.1% of the pathology reports, the desired information on one or more risk factors was considered incomplete. In multivariable analysis, age (HR: 1.07, 95%CI 1.04–1.10, p < .001), moderately- (HR: 0.35, 95%CI 0.18–0.70, p = .003) and well (HR 0.11, 95%CI 0.01–0.89, p = .038) differentiated tumors were significantly associated with OS. Conclusions: Pathology reports should better describe the five high-risk factors, in order to enable proper patient selection for further treatment. Chemotherapy may be offered to stage II patients only in select instances, yet a definitive indication is still unavailable

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer

Background: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. Methods/Study design: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. Discussion: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. Trial registration:NCT02371304, registration date: February 2015

Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study): Study protocol of a European multicenter randomised controlled trial

Background: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. Methods: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. Discussion: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. Trial registration: Netherlands Trial Register, NL7083, 06 July 2018

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

The Prospective Dutch Colorectal Cancer (PLCRC) cohort: real-world data facilitating research and clinical care

Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the “real-world”. Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013–2016 and 2017–Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64–0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017–Aug’19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC’s representativeness and its contribution to a learning healthcare system