Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study.

Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.

Survival, surveillance, and genetics in patients with Peutz-Jeghers syndrome: A nationwide study.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed.

Implementation of a standardized surgical technique in robot-assisted restorative rectal cancer resection: a single center cohort study.

BACKGROUND: Despite increasing focus on the technical performance of total mesorectal excision over recent decades, anastomotic leakage (AL) continues to be a serious complication for many patients, even in the hands of experienced surgical teams. This study describes implementation of standardized surgical technique in an effort to reduce variability, decrease the risk of anastomotic leakage, and improve associated short-term outcomes for rectal cancer patients undergoing robot-assisted restorative rectal resection (RRR). METHODS: We evaluated all rectal cancer patients undergoing robot-assisted RRR at Aarhus University Hospital between 2017 and 2020. Six standardized surgical steps directed to improve anastomotic healing were mandatory for all RRR. Additional changes were made during the period with prohibition of systemic dexamethasone and limiting the use of endoscopic stapling devices. RESULTS: The use of the full standardization, including all six surgical steps, increased from 40.3% (95% CI, 0.28-0.54) to 86.2% (95% CI, 0.68-0.95). The incidence of AL decreased from 21.0% (95% CI, 0.12-0.33) to 6.9% (95% CI, 0.01-0.23). Length of hospital stay (LOS) decreased from 6 days (range 2-50) to 5 days (range 2-26). The rate of patients readmitted within 90 days decreased from 21.0% (95% CI, 0.12-0.33), to 6.9% (95% CI, 0.01-0.23). CONCLUSION: The full standardization was effectively implemented for rectal cancer patients undergoing robot-assisted RRR. The risk of AL, LOS and readmission decreased during the study period. A team focus on high-reliability and peri-operative complications can improve patient outcomes.

Familial colorectal cancer and tooth agenesis caused by an AXIN2 variant: how do we detect families with rare cancer predisposition syndromes?

We present a three-generation family with an AXIN2 variant and a family history of colorectal cancer (CRC), colon polyps and tooth agenesis. A likely pathogenic variant was detected in the AXIN2 gene (c.1994dup; p.(Asn666Glnfs*41)). This variant has previously been associated with tooth agenesis and polyposis, only. In this case report we describe eight carriers with tooth agenesis and variable clinical findings, including polyps and CRC. Our case provides additional knowledge to the sparse data on genotype-phenotype association related to AXIN2 associated cancer syndrome. Further, our case highlights the importance of analysing an extended CRC and oligodontia/ectodermal dysplasia gene panel including AXIN2 but also raises awareness and discussion about appropriate surveillance program.

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.

BACKGROUND: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. METHODS: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. RESULTS: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). CONCLUSIONS: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

[Rectal carcinoma in a 24-year-old man with Hirschsprung's disease].

This case report presents an incident of rectal carcinoma in a 24-year-old man with Hirschsprung's disease, for which he was operated in his early childhood, with a Soave pull-through procedure. No direct association between Hirschsprung's disease and rectal cancer was found in our review of the literature. However, several case reports of rectal cancers following pull-through procedures exist. A low threshold for further clinical investigations is recommended, if these patients are presenting with gastrointestinal symptoms.

Is the accuracy of preoperative MRI stage in rectal adenocarcinoma influenced by tumour height?

AIM: To our knowledge, no prior studies have addressed the possible effects of tumour height on the accuracy of preoperative magnetic resonance imaging (MRI)-based staging relative to postoperative histopathological assessments in patients with adenocarcinoma of the rectum (RC). This study aimed to investigate whether the accuracy of preoperative MRI stage in RC is influenced by tumour height. METHODS: A total of 489 consecutive RC patients scheduled for curative treatment between 2009 and 2013 were included. Of the 489 patients, 133 patients had preoperative chemoradiotherapy (CRT), and 356 patients underwent primary surgery. Low, mid and high RC were defined as a tumour <5 cm, 5-10 cm and >10 cm from the anal verge, respectively. Diagnostic MRI and, for patients with CRT, re-staging MRI features including tumour T-stage (mrT), distance between the tumour border and the distance to the mesorectal fascia (mrMRF), extramural tumour depth (mrEMD), extramural vascular invasion (mrEMVI) and nodal involvement (mrN) were correlated with the corresponding postoperative histopathological findings. RESULTS: There were 115, 186 and 188 patients with low RC, mid RC and high RC, respectively. For all patients, the correlations between mrT and pT and between mrMRF and pCRM were not influenced by tumour height. None of the correlations between mrEMD, mrEMVI and mrN and the corresponding postoperative histopathological findings significantly differed for tumours of different heights. For patients with CRT, a remarkable proportion with low RC were overstaged as ymrT3 compared to ypT0-2. CONCLUSIONS: The ability to preoperatively use MRI to accurately stage is not influenced by tumour height. For patients with preoperative CRT, low RC may be MRI overstaged due to post-radiation fibrosis. We found that mrEMD predicts pEMD reliably and should therefore be considered in treatment decisions. Although new MRI techniques are emerging, preoperative RC staging remains incompletely definitive in daily clinical practice.

Pelvic Pain and Quality of Life Before and After Laparoscopic Bowel Resection for Rectosigmoid Endometriosis: A Prospective, Observational Study.

BACKGROUND: Surgery for rectosigmoid endometriosis carries a substantial risk of short- and long-term complications, which has to be counterbalanced against the potential effect of the procedure. Prospective data are scarce in the field of deep infiltrating endometriosis surgery. OBJECTIVE: The study aimed to assess pelvic pain and quality of life before and after laparoscopic bowel resection for rectosigmoid endometriosis. DESIGN: The study involved prospectively collected data regarding pelvic pain and quality of life before and after surgery. SETTINGS: It was conducted at a tertiary endometriosis referral unit at Aarhus University Hospital. PATIENTS: A total of 175 women were included. INTERVENTION: Patients underwent laparoscopic bowel resection for endometriosis. MAIN OUTCOME MEASURES: Questionnaires for pain (Numerical Rating Scale) and quality of life (RAND Short Form-36) were answered before and 1 year after surgery. Data on analgesic and hormone treatment were collected. Preoperative and postoperative pelvic pain and quality-of-life scores were compared, and risk factors for improvement/worsening were identified. RESULTS: A total of 97.1% of the women completed the 1-year follow up. A significant decrease (p = 0.0001) was observed on all pelvic pain parameters. Most profound was the decrease in dyschezia. A significant improvement on all quality-of-life scores was observed (p = 0.0001). A surgical complication did not have a negative impact on outcome 1 year after surgery. The postoperative outcome was not related to the type of surgery. LIMITATIONS: This is an observational study without a control group. Risk factor data should be interpreted with caution, because the study was relatively underpowered for some of the rare outcomes. CONCLUSIONS: A significant and clinically relevant improvement in pelvic pain and quality of life 1 year after laparoscopic bowel resection for endometriosis was found. We strongly recommend surgery for rectosigmoid endometriosis that is unresponsive to conservative treatment. See Video Abstract at http://links.lww.com/DCR/A472.

Diagnostic Value of Serial Measurement of C-Reactive Protein in the Detection of a Surgical Complication after Laparoscopic Bowel Resection for Endometriosis.

AIMS: The study aimed to assess the diagnostic value of serial monitoring of biochemical inflammatory markers (C-reactive protein (CRP) and white blood cell (WBC) count) in the postoperative diagnosis of anastomotic leakage or ureteral injury after bowel resection for deep infiltrating endometriosis. METHODS: This is a review of prospectively collected data from 217 patients who underwent laparoscopic bowel resection for endometriosis from January 2009 to April 2015. Patients with an anastomotic leakage or ureteral injury were identified and classified. RESULTS: The frequency of anastomotic leakage requiring reoperation was 8.3%. The frequency of ureteral injury was 4.6%. Median time to diagnosis was 6 days for anastomotic leakage and 8 days for ureteral injury. The daily mean values of serum CRP were significantly higher in patients with a surgical complication starting at the second postoperative day (POD 2, p = 0.004). WBC was significantly higher (p < 0.05) on POD 2 and 3 in patients with a surgical complication. A decrease in CRP from POD 1 to 3 predicted an uncomplicated course in 92.1% of the cases. CONCLUSION: A decrease in CRP from POD 1 to 3 was an indicator of uncomplicated subsequent postoperative course. The test is recommended when early discharge after rectal resection for deep infiltrating endometriosis is considered.

Diagnosis and treatment of haemorrhoids.

These guidelines provide a review of diagnosis, conservative and surgical treatment of haemorrhoids with primary focus on the surgical treatment. In symptomatic hemorrhoids it is recommended, that conservative treatment is used as basic treatment regardless of grading. The vast majority of grade II haemorrhoids are treated conservatively, but surgery may be considered in a few cases with pronounced symptoms. In these cases chirurgia minor, Doppler guided dearterilization procedures or stapled haemorrhoidopexy are recommended. In grade III and IV Doppler guided dearterilization procedures, stapled haemorrhoidopexy (Grade III) or conventional Milligan Morgan haemorrhoidectomy are recommended.

[Abdominal cocoon is a rare cause of ileus]. / Abdominal cocoon er en sjælden årsag til ileus.

Partial or total encapsulation of bowel in a membrane-like sac is a rare cause of mechanical bowel obstruction. Three different types of encapsulation have been described: a congenital, a secondary and an idiopathic or "abdominal cocoon". The present case describes a 34-year-old male, who was admitted with small bowel obstruction caused by an "abdominal cocoon", which was successfully treated by surgery. Precise preoperative diagnosis is often missed, but a computed tomography visualizing bowel loops enclosed in a membrane is a characteristic finding.

Diagnosis and treatment of fistulising Crohn's disease.

A fistula is defined as a pathological connection between the intestine and an inner (bladder or other intestine) or outer (vagina or skin) epithelial surface. Fistulas are discovered in up to 25% of all Crohn's disease patients during long-term follow-up examinations. Most are perianal fistulas, and these may be classified as simple or complex. The initial investigation of perianal fistulas includes imaging (MRI of the pelvis and rectum), examination under anaesthesia (EUA) with digital imaging, endoscopy, probing and anal ultrasound. Non-perianal fistulas require contrast imaging and/or CT/MRI for complete anatomical definition. Any abscess should be drained, and the disease extent throughout the entire gastrointestinal tract should be evaluated. Treatment goals for perianal fistulas include reduced fistula secretion or none, evaluated by clinical examination; the absence of abscesses; and patient satisfaction. MR imaging is required to demonstrate definitive fistula closure. Fistulotomy is considered for simple perianal fistulas. In complex perianal fistulas, antibiotics and azathioprine or 6-mercaptopurine, which are often combined with a loose seton, constitute the first-line medical therapy. In cases with persistent secretion, infliximab at 5 mg/kg is given at weeks 0, 2, and 6 and subsequently every 8 weeks. Adalimumab may improve fistula response in both infliximab-naïve patients and following infliximab treatment failure. Local therapy with fibrin glue or fistula plugs is rarely effective. Definitive surgical closure of perianal fistulas using an advancement flap may be attempted, but this procedure is associated with a high risk of relapse. Colostomy and proctectomy are the ultimate surgical treatment options for fistulas. Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas.

[Organisation and early outcome of restorative proctocolectomy and ileal pouch-anal anastomosis]. / Organisation og tidlige operationsresultater efter ileo-pouch-anal-anastomose.

INTRODUCTION: Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) has become the operation of choice for patients with ulcerative colitis and familial polyposis. However, the procedure is complex with a long learning curve, and carries a risk of both early and late complications. The purpose of this study was to evaluate the early outcomes (within 30 days after surgery) and organisation of IPAA surgery in Denmark between January 2001 and December 2005. MATERIALS AND METHODS: IPAA patients >18 years old were drawn from the Danish National Patient Registry from 2001 through 2005. Hospital stay and the primary operation were recorded as well as re-operations and readmissions within the first 30 postoperative days. Mortality was recorded from the National Civic Register. RESULTS: 385 patients underwent IPAA surgery during the study period (77/year) in six centres. One centre performed 31% of the operations. The mean postoperative hospital stay (primary - and readmission within 30 days) was 13.5 days. 24% were readmitted within 30 days and 8% were re-operated. The mortality rate was 0.3%. CONCLUSION: Based upon the limited number of operations, the high risk of early readmissions and re-operations, the well-known steep learning curve and the potential improvement with the technically demanding laparoscopic technique, a reorganisation of the procedure to fewer centres is suggested.

The effect of azathioprine on anastomotic healing: an experimental study in rats.

PURPOSE: The cytotoxic and immunosuppressive effects of azathioprine, which mitigate the disease activity in inflammatory bowel disease, may compromise the healing of intestinal anastomoses leading to an increased risk of anastomotic leakage. The effect of azathioprine treatment on intestinal healing was tested. METHODS: In an experimental study, rats were randomly given one oral dose of azathioprine (5 mg or 20 mg/kg body weight per day) or placebo. After 28 days of treatment, a left colonic anastomosis was performed. After three days of healing, the breaking strengths of the anastomoses were tested, along with measurements of azathioprine major metabolite concentrations: 6-thioguanine and 6-methyl-mercaptopurine. RESULTS: There were no significant differences in the anastomotic breaking strength between the three groups. CONCLUSIONS: Daily treatment for four weeks with high or low azathioprine doses has no inhibitory effect on colonic healing in rats.