Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Surgical management of complex ileocolonic Crohn's disease: a survey of IBD colorectal surgeons to assess variability in operative strategy.

INTRODUCTION: To explore the reported variability in the surgical management of ileocolonic Crohn' s disease and identify areas of standard practice, we present this study which aims to assess how different colorectal surgeons with a subspecialty interest in inflammatory bowel disease (IBD) surgery may act in different clinical scenarios of ileocolonic Crohn's disease. METHODS: Anonymous videos demonstrating the small bowel walkthrough and anonymised patients' clinical data, imaging and pathological findings were distributed to the surgeons using an electronic tool. Surgeons answered on operative strategy, bowel resections, management of small bowel mesentery, type of anastomosis and use of stomas. RESULTS: Eight small bowel walkthrough videos were registered and 12 assessors completed the survey with a questionnaire completion rate of 87.5%. There was 87.7% agreement in the need to perform an ileocolonic resection. However, the agreement for the need to perform associated surgical procedures such as strictureplasties or further bowel resections was only 57.4%. When an anastomosis was fashioned, the side to side configuration was the most commonly used. The preferred management of the mesentery was dissection close to the bowel. CONCLUSIONS: The decision on the main procedure to be performed had a high agreement amongst the different assessors, but the treatment of multifocal disease was highly controversial, with low agreement on the need for associated procedures to treat internal fistulae and the use of strictureplasties. At the same time, there was significant heterogeneity in the decision on when to anastomose and when to fashion an ileostomy.

Video-laparoscopic assessment of the small bowel in Crohn's disease: a comparative study to evaluate surgeons' inter-observer variability.

BACKGROUND: Assessment of the entire small bowel is advocated during Crohn's disease (CD) surgery, as intraoperative detection of new lesions may lead to change in the planned procedure. The aim of this study was to evaluate the inter-observer variability in the assessment of extent and severity of CD at the small bowel laparoscopic "walkthrough". METHODS: A survey on laparoscopic assessment of the small bowel in patients with CD, including items adapted from the MREnterography or ultrasound in Crohn's disease (METRIC) study and from the classification of severity of mesenteric disease was developed by an invited committee of colorectal surgeons. Anonymous laparoscopic videos demonstrating the small bowel "walkthrough" in ileocolonic resection for primary and recurrent CD were distributed to the committee members together with the anonymous survey. The primary outcome was the rate of inter-observer variability on assessment of strictures, dilatations, complications and severity of mesenteric inflammation. RESULTS: 12 assessors completed the survey on 8 small bowel walkthrough videos. The evaluation of the small bowel thickening and of the mesenteric fat wrapping were the most reliable assessments with an overall agreement of 87.1% (k = 0.31; 95% CI - 0.22, 0.84) and 82.7% (k = 0.35; 95% CI - 0.04, 0.73), respectively. The presence of strictures and pre-stenotic dilatation demonstrated agreement of 75.2% (k = 0.06: 95% CI - 0.33, 0.45) and 71.2% (k = 0.33; 95% CI 0.15, 0.51), respectively. Evaluation of fistulae had an overall agreement of 75.3%, while there was a significant variation in the evaluation of mild, moderate and severe mesenteric disease with overall agreement ranging from 33.3 to 100%. CONCLUSION: Laparoscopic assessment of the small bowel thickening and of the presence of mesenteric fat wrapping is reliable for the intraoperative evaluation of CD with high inter-rater agreement. There is significant heterogeneity in the assessment of the severity of the mesenteric disease involvement.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Correction to: Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication. The complete correct affiliation should read as follows.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of ulcerative colitis management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of ulcerative colitis. The committee was able to identify some points of major disagreement and suggested strategies to improve the quality of available data and acceptance of guidelines.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a position statement of Italian colorectal surgeons to address the surgical aspects of Crohn's disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of Crohn's disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of inflammatory bowel disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the general principles of surgical treatment of inflammatory bowel disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Influence of short-term selenium supplementation on the natural course of Hashimoto's thyroiditis: clinical results of a blinded placebo-controlled randomized prospective trial.

BACKGROUND: The real efficacy of selenium supplementation in Hashimoto's thyroiditis (HT) is still an unresolved issue. OBJECTIVES: We studied the short-term effect of L-selenomethionine on the thyroid function in euthyroid patients with HT. Our primary outcome measures were TSH, thyroid hormones, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb) levels and thyroid echogenicity after 6 months of L-selenomethionine treatment. The secondary outcome measure was serum CXCL10 levels. METHODS: In a placebo-controlled randomized prospective study, we have enrolled untreated euthyroid patients with HT. Seventy-six patients were randomly assigned to receive L-selenomethionine 166 µg/die (SE n = 38) or placebo (controls n = 38) for 6 months. TSH, free T4 (FT4), free T3 (FT3), TPOAb and CXCL10 serum levels were assayed at time 0, after 3 and 6 months. An ultrasound examination of the left and right thyroid lobe in transverse and longitudinal sections was performed. A rectangular region, the region of interest, was selected for analysis. RESULTS: TSH, FT4, FT3, TPOAb, thyroid echogenicity and CXCL10 were not statistically different between SE and control groups at time 0, after 3 and 6 months. In the SE group, FT4 levels were significantly decreased (P < 0.03) after 3 months, while FT3 increased (P < 0.04) after 3 and 6 months versus baseline values. In the control group, the FT3 decreased after 3 and 6 months (P < 0.02) compared to baseline. CONCLUSION: The short-term L-selenomethionine supplementation has a limited impact on the natural course in euthyroid HT. Our results tip the balance toward the ineffectiveness of short-term L-selenomethionine supplementation in HT.

Vascular anomalies of the large bowel.

Vascular anomalies of the large bowel, commonly known as vascular malformations of the colon (VMC), constitute a rare but important condition, potentially causing significant morbidity and mortality. Our aim is to provide an up-to-date, practical summary evaluating this disease entity, focussing on pathogenesis, as well as diagnostic and therapeutic modalities. We reviewed available data in the literature, and discussed it in the form of a narrative, readily applicable review. Most VMC (over 70%) are detected in the caecum and ascending colon, and affect people aged over 50 years. VMC are almost always symptomatic, presenting with lower bleeding. Endoscopy is crucial to identify and locate VMC, and to treat the lesions. In patients who fail or do not fit endoscopic treatment, aggressive approaches (interventional angiology or surgery) are mandatory. Up to 40% of patients may have relapse in the long term. VMC are rare but potentially life-threatening. Advances in endoscopic imaging and therapy have improved the results of treatment. Long-term follow-up after treatment is recommended.

Predictors of Venous Thromboembolism after Colorectal Surgery in a Single Unit.

BACKGROUND: Patients undergoing colorectal surgery are at risk of developing venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). Knowing predictors of VTE could help preventing this life-threatening complication. METHODS: We collected data of patients undergoing colorectal surgery at our Unit between 2009 and 2014. Baseline characteristics, type of surgery, and postoperative complications were gathered. A univariate regression analysis was performed with symptomatic VTE as outcome. Pre-, intra- and postoperative clinical factors were separately tested. All variables significantly associated with VTE occurring within three months from the discharge were entered in the final multivariate regression model. RESULTS: A total of 476 patients were included. Symptomatic VTE occurred in 13 patients (2.7%). Six (46.1%) occurred after hospital discharge. Preoperative variables associated with VTE were: advanced age at surgery (OR 2.3, 95%CI 1.8-5.6), smoking (OR 1.7, 95%CI 1.2-2.5), inflammatory bowel diseases (OR 2.1, 95%CI 1.5-4.3), advanced pelvic malignancies (OR 2.4, 95%CI 2.0-4.2), and obesity (OR 1.5, 95%CI 1.1-2.1). Prolonged pelvic manipulation (OR 1.8, 95%CI 1.1-4.3) and steep Trendelenburg position (OR 2.4, 95%CI 1.9-5.0) were intraoperative predictors of VTE, while stockings significantly reduced the risk (OR 0.8, 95%CI 0.4-0.9). Late mobilization (OR 2.5, 95%CI 2.0-4.6) and septic complications (OR 1.4, 95%CI 1.2-3.7) were postoperative predictors of VTE, whereas anticoagulants administered for at least 3 weeks after discharge were associated with lower VTE risk (OR 0.5, 95%CI 0.2-0.8). CONCLUSIONS: We observed several modifiable predictors of VTE. Patients with ≥2 risk factors undergoing colorectal surgery could benefit from a more intensive VTE preventive pathway.

A think tank of the Italian society of colorectal surgery (SICCR) on the surgical treatment of inflammatory bowel disease using the Delphi method: Crohn's disease.

The management of Crohn's disease (CD) requires extensive expertise. Many treatment options are available, and surgery still plays a crucial role. In recent years, many medical societies have provided surgeons and gastroenterologists dealing with CD with authoritative guidelines. However, a certain degree of variation can be observed in these papers, and application of guidelines in clinical practice should be improved. The Italian society of colorectal surgery (SICCR) promoted the project reported here, which consists of a think tank of Italian colorectal surgeons to address the surgical aspects of CD management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of CD. The management of CD is, by necessity, patient-tailored, and it is based on clinical data and surgeon's preference, but the committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

A think tank of the Italian Society of Colorectal Surgery (SICCR) on the surgical treatment of inflammatory bowel disease using the Delphi method: ulcerative colitis.

The majority of patients suffering from ulcerative colitis (UC) are managed successfully with medical treatment, but a relevant number of them will still need surgery at some point in their life. Medical treatments and surgical techniques have changed dramatically in recent years, and available guidelines from relevant societies are rapidly evolving, providing UC experts with updated and valid practical recommendations. However, some aspects of the management of UC patients are still debated, and the application of guidelines in clinical practice may be suboptimal. The Italian Society of Colorectal Surgery (SICCR) sponsored the think tank in order to identify critical aspects of the surgical management of UC in Italy. The present paper reports the results of a think tank of Italian colorectal surgeons concerning surgery for UC and was not developed as an alternative to authoritative guidelines currently available. Members of the SICCR voted on several items proposed by the writing committee, based on evidence from the literature. The results are presented, focusing on points to be implemented. UC management relies on evaluations that need to be individualized, but points of major disagreement reported in this paper should be considered in order to develop strategies to improve the quality of the evidence and the application of guidelines in a clinical setting.

Intersphincteric approach for rectourethral fistulas following radical prostatectomy.

BACKGROUND: Rectourethral fistula is a challenging complication of radical retropubic prostatectomy. Several treatments have been proposed, with varying outcomes. The available data are difficult to interpret, because patient and disease characteristics differ significantly among reports. Details of long-term follow-up and functional status are rarely provided. We describe a technique of rectourethral fistula repair via an intersphincteric route. METHODS: Preoperative workup included proctoscopy and urethrocystography. All patients already had a stoma at the time of fistula repair. Mechanical cleansing of the bowel distal to the colostomy was routinely performed, and perioperative antibiotic prophylaxis was administered. Patients were placed in the lithotomy position. Under spinal anesthesia, a curvilinear anteanal incision was made, to expose the external sphincter. The anterior portion of the external sphincter was gently displaced along half of its circumference. The anterior rectal wall was sharply dissected free from the urethra, approximately up to 2 cm above the fistula level through the intersphincteric plane. The fistula was identified. The surrounding tissues were mobilized to obtain a tension-free repair of the urethral defect, using a single row of 4-0 polyglactin transverse, interrupted sutures. Transanally, a U-shaped full-thickness rectal flap was advanced and sutured with 3-0 monofilament interrupted sutures to cover the rectal opening, and care was taken to ensure that the two suture lines were in different planes. The catheter was left in place for 4 weeks. Patients were evaluated at 3-month follow-up for stoma closure. RESULTS: We successfully treated five patients. Only one minor complication was observed (surgical site infection). Stomas were taken down uneventfully. After a median follow-up duration of 2 years (range 2-3 years), no patients had fistula recurrence or impaired continence. CONCLUSIONS: Intersphincteric repair should be considered as an effective option in patients with iatrogenic rectourethral fistulas. This technique offers several advantages over alternative procedures that require more extensive approaches or invasive manipulation of the anal sphincters.

Vascular anomalies of the large bowel.

INTRODUCTION: Vascular anomalies of the large bowel, commonly referred to as vascular malformations of the colon (VMC) constitute a rare but important condition, potentially causing significant morbidity and mortality. Our aim is to provide an up-to-date, practical summary evaluating this disease entity, focussing on pathogenesis, as well as diagnostic and therapeutic modalities. MATERIALS AND METHODS: We reviewed available data in the literature, and discussed it in the form of a narrative, readily applicable review. RESULTS: Most VMC (over 70%) are detected in the caecum and ascending colon, and affect people aged over 50 years. VMC are almost always symptomatic, presenting with lower bleeding. Endoscopy is crucial to identify and locate VMC, and to treat the lesions. In patients who fail or do not fit endoscopic treatment, aggressive approaches (interventional angiology or surgery) are mandatory. Up to 40% of patients may have relapse in the long term. CONCLUSIONS: VMC are rare but potentially life-threatening. Advances in endoscopic imaging and therapy have improved the results of treatment. Long-term follow-up after treatment is recommended.

Paediatric ulcerative colitis surgery: Italian survey.

BACKGROUND AND AIMS: Recent epidemiological studies showed an increase in ulcerative colitis among children, especially in its aggressive form, requiring surgical treatment. Although medical therapeutic strategies are standardized, there is still no consensus regarding indications, timing and kind of surgery. This study aimed to define the surgical management of paediatric ulcerative colitis and describe attitudes to it among paediatric surgeons. METHODS: This was a retrospective cohort study. All national gastroenterology units were invited to participate. From January 2009 to December 2013, data on paediatric patients diagnosed with ulcerative colitis that required surgery were collected. RESULTS: Seven units participated in the study. Seventy-one colectomies were performed (77.3% laparoscopically). Main surgical indications were a severe ulcerative colitis attack (33.8%) and no response to medical therapies (56.3%). A three-stage strategy was chosen in 71% of cases. Straight anastomosis was performed in 14% and J-pouch anastomosis in 86% of cases. A reconstructive laparoscopic approach was used in 58% of patients. Ileo-anal anastomosis was performed by the Knight-Griffen technique in 85.4% and by the pull-through technique in 9.1% of patients. Complications after colectomy, after reconstruction and after stoma closure were reported in 12.7, 19.3 and 35% of cases, respectively. CONCLUSIONS: This study shows that there is general consensus regarding indications for surgery. The ideal surgical technique remains under debate. Laparoscopy is a procedure widely adopted for colectomy but its use in reconstructive surgery remains limited. Longer follow-up must be planned to define the quality of life of these patients.