Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles.

OBJECTIVE: Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. DESIGN: We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. RESULTS: We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. CONCLUSIONS: These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

Surgical management and outcome of rectal carcinoids in a university hospital.

BACKGROUND: Rectal carcinoids are an uncommon entity comprising only 1%-2% of all rectal tumors. Rectal carcinoids are frequently diagnosed during colonoscopy, but management after polypectomy is still controversial. The aims of this study were to review the surgical procedures for rectal carcinoids and to compare the outcomes of patients after different treatment modalities in a university hospital in Hong Kong. METHODS: All rectal carcinoids diagnosed between January 2003 and September 2012 were reviewed retrospectively, including clinicopathological characteristics, their management, and surgical outcomes. RESULTS: There were 54 patients with a median age of 60 years, and 32 were males (59.3%). All patients underwent colonoscopy, and the most had rectal bleeding (53.7%). Two patients were diagnosed incidentally in the surgical specimens of rectal tissues. Eighteen patients were diagnosed to have rectal carcinoids after snaring polypectomy, and no further intervention was required. Twenty-five patients had local resection either by means of transanal resection or transanal endoscopic operation. Radical resection was performed in seven patients in which one had T3N1 disease and the others did not have any lymph node metastasis. In the median follow-up of 30 months (10-108 months), there was no recurrence in the "incidental" or post-polypectomy group. However, two patients with transanal resection and two patients with radical resection developed hepatic metastases after 13-24 months post-treatment. The 5-year overall survival was 100% in patients having snaring polypectomy only, 83% for those with local resection, and 63% in patients who underwent radical surgery (p = 0.04). CONCLUSIONS: Our data suggested that that local resection was an effective treatment for small rectal carcinoids and generally brought about good oncological and surgical outcomes. For larger tumors, radical resection seemed to provide acceptable oncological outcomes. Regular surveillance with colonoscopy and endorectal ultrasound is highly recommended for high-risk patients for long-term management. By sharing our experience, we hope to provide more evidence on the management on rectal carcinoids which, together with evidence from further studies, may guide us in the long-term management of these patients in the future.

Detection of colorectal adenoma by narrow band imaging (HQ190) vs. high-definition white light colonoscopy: a randomized controlled trial.

OBJECTIVES: The benefits of narrow band imaging (NBI) on enhancing colorectal adenoma detection remain questionable. We tested whether the new generation of NBI (190-NBI), which is twice as bright as the previous version, would improve adenoma detection when compared with high-definition white light (HD-WL) colonoscopy. METHODS: It was a randomized controlled trial with tandem colonoscopy. We recruited patients who underwent colonoscopy for symptoms, screening, or surveillance. Patients were randomized for the use of either 190-NBI or HD-WL on withdrawal. Tandem colonoscopy was performed by using the same assigned colonoscope and withdrawal method. Lesions detected on first-pass and second-pass examination were used for adenoma detection and miss rates, respectively. The primary outcomes were adenoma and polyp detection rates. RESULTS: A total of 360 patients were randomized to undergo either 190-NBI or HD-WL colonoscopy. Both the adenoma and polyp detection rates were significantly higher in the 190-NBI group compared with the HD-WL group (adenoma: 48.3% vs. 34.4%, P=0.01; polyps: 61.1% vs. 48.3%, P=0.02). The mean number of polyps detected per patient was higher in the 190-NBI group (1.49% vs. 1.13, P=0.07). There was no significant difference in the adenoma miss rates between the two groups (21.8% vs. 21.2%). Multivariate analysis showed that the use of 190-NBI (odds ratio (OR) 1.85; 95% confidence interval (CI) 1.10-3.12), withdrawal time (OR 1.29; CI 1.19-1.38), patient's age (OR 1.04; CI 1.01-1.06), and male gender (OR 2.38; CI 1.42-3.99) were associated with adenoma detection. CONCLUSIONS: 190-NBI colonoscopy was superior to the conventional HD-WL in detecting colorectal adenomas or polyps, but there was no significant difference in adenoma miss rates.

Survival following laparoscopic versus open resection for colorectal cancer.

BACKGROUND: This study aimed to compare the overall and disease specific survivals of patients who underwent laparoscopic and open resection of colorectal cancer in a high volume tertiary center. METHODS: Consecutive patients who underwent elective resection for colorectal cancer (open resection, n = 1,197; laparoscopic resection, n = 814) from January 2000 to December 2009 were included. The operative details, postoperative complications, postoperative outcomes, and survival data were collected prospectively. Comparison was made between patients who had laparoscopic and open surgery. RESULTS: The age, gender, medical morbidity, and American Society of Anesthesiologists status were similar in the two groups. Laparoscopic resection was associated with significantly less blood loss and a shorter hospital stay. The operating mortality and morbidity were significantly lower in the laparoscopic group. The qualities of the specimens in terms of the distal resection margin and the number of lymph nodes examined were not inferior in the laparoscopic group. With the median follow-up of 40.3 months, the 5-year overall survival (74.1% vs. 65.5%, p < 0.001) and disease specific survival (81.9% vs. 75.2%, p = 0.002) were significantly better in patients with non-disseminated disease in the laparoscopic group. The operative approach was an independent prognostic factor in the overall (risk ratio 1.36, 95% CI 1.093-1.700, p = 0.006) and disease specific (risk ratio 1.32, 95% CI 1.005-1.738, p = 0.048) survivals in multivariate analysis. CONCLUSION: Laparoscopic resection for colorectal cancer is associated with more favorable overall and disease specific survivals when compared with open resection in a high volume tertiary center.

Enhanced recovery program in laparoscopic colectomy for cancer.

INTRODUCTION: Both laparoscopic colectomy and application of enhanced recovery program (ERP) in open colectomy have been demonstrated to enable early recovery and to shorten hospital stay. This study evaluated the impact of ERP on results of laparoscopic colectomy and comparison was made with the outcomes of patients prior to the application of ERP. METHODS: An ERP was implemented in the authors' center in December 2006. Short-term outcomes of consecutive 84 patients who underwent laparoscopic colonic cancer resection 23 months before (control group) and 96 patients who were operated within 13 months; after application of ERP (ERP group) were compared. RESULTS: Between the ERP and control groups, there was no statistical difference in patient characteristics, pathology, operating time, blood loss, conversion rate or complications. Compared to the control group, patients in the ERP group had earlier passage of flatus [2 (range: 1-5) versus 2 (range: 1-4) days after operation respectively; p = 0.03)] and a lower incidence of prolonged post-operative ileus (6% versus 0 respectively; p = 0.02). There was no difference in the hospital stay between the two groups [4 (range: 2-34) days in control group and 4 (range: 2-23) days in ERP group; p = 0.4)]. The re-admission rate was also similar (7% in control group and 5% in ERP group; p = 0.59). CONCLUSIONS: In laparoscopic colectomy for cancer, application of ERP was associated with no increase in complication rate but significant improvement of gastrointestinal function. ERP further hastened patient recovery but resulted in no difference in hospital stay.

Impact of neoadjuvant treatment on total mesorectal excision for ultra-low rectal cancers.

BACKGROUND: This study reviewed the impact of pre-operative chemoradiotherapy or post-operative chemotherapy and/or radiotherapy on total mesorectal excision (TME) for ultralow rectal cancers that required either low anterior resection with peranal coloanal anastomosis or abdomino-perineal resection (APR). We examined surgical complications, local recurrence and survival. METHODS: Of the 1270 patients who underwent radical resection for rectal cancer from 1994 till 2007, 180 with tumors within 4 cm with either peranal coloanal anastomosis or APR were analyzed. Patients were compared in groups that had surgery only (Group A), pre-operative chemoradiotherapy (Group B), and post-operative therapy (Group C). RESULTS: There were 115 males and the mean age was 65.43 years (range 30-89). APR was performed in 134 patients while 46 had a sphincter-preserving resection with peranal coloanal anastomosis. The mean follow-up period was 52.98 months (range: 0.57 to 178.9). There were 69, 58 and 53 patients in Groups A, B, and C, respectively. Nine patients in Group B could go on to have sphincter-saving rectal resection. The overall peri-operative complication rate was 43.4% in Group A vs. 29.3% in Group B vs. 39.6% in Group C, respectively. The local recurrence rate was significantly lower in Group B (8.6.9% vs. 21.7% in Group A vs. 33.9% in Group C) p < 0.05. The 5-year cancer-specific survival rates for Group A was 49.3%, Group B was 69.9% and Group C was 38.8% (p = 0.14). CONCLUSION: Pre-operative chemoradiation in low rectal cancer is not associated with a higher incidence of peri-operative complications and its benefits may include reduction local recurrence.

Impact of laparoscopic colorectal resection on surgical site infection.

OBJECTIVES: This study aimed to identify the risk factors of surgical site infection (SSI) in elective colorectal resection and the strategy for prevention of SSI in modern era of colorectal surgery. BACKGROUND: The practice of colorectal surgery has undergone remarkable evolution recently because of application of laparoscopic resection. This could affect SSI in colorectal patients. An updated investigation of SSI under current practice of colorectal surgery would provide valuable information. METHODS: This was a prospective study of SSI on 1011 patients, who had elective colorectal resection in a university teaching hospital, during January 2002 to December 2006. Standard definition and postoperation follow-up of SSI were adopted through collaboration between surgeons and wound surveillance program of Infection Control Unit. Risk factors of SSI were evaluated. Logistic regression was used to perform multivariate analysis and decide independent risk factors of SSI. RESULTS: The overall rate of incisional SSI and organ/space SSI was 4.8% and 1.7%, respectively. Rate of incisional SSI in open and laparoscopic colorectal resection was 5.7% and 2.7%, respectively. Anastomotic leakage was the only factor that predicted organ/space SSI (P < 0.01). Independent risk factors of incisional SSI included blood transfusion [P = 0.047; odds ratio (OR) = 2.43; 95% confidence interval (CI): 1.0-5.9], anastomotic leakage (P < 0.01; OR = 6.5; 95% CI: 2.3-18.6), and open colorectal resection (P = 0.037; OR = 2.36; 95% CI: 1.1-5.3). CONCLUSION: In current practice of colorectal surgery, operative factors are more important than patient factors for SSI. Good surgical technique to reduce anastomotic leakage and reduce blood transfusion has paramount importance in SSI prevention. Laparoscopic surgery was associated with reduction of rate of SSI by more than 50% when compared with open surgery and would have a strong impact on the prevention of surgical infection.

Laparoscopic bowel resection in the setting of metastatic colorectal cancer.

BACKGROUND: This study aimed to review the outcomes of laparoscopic colorectal resection for patients with stage IV colorectal cancer. METHODS: From the prospectively collected database for patients who underwent surgery for colorectal cancer in our institution, those with stage IV colorectal cancer who underwent elective resection of tumor during the period from January 2000 to June 2006 were included. The outcomes of those with laparoscopic resection were reviewed and comparison was made between patients with laparoscopic and open resection. RESULTS: A total of 200 patients (127 men) with median age of 69 years (range: 25-91 years) were included, and 77 underwent laparoscopic resection. Conversion was required in ten patients (13.0%) and all except one conversion were due to fixed or bulky tumors. There was no operative mortality in the laparoscopic group. The complication rate was 14% and the median postoperative hospital stay was 7 days. When patients with laparoscopic resection were compared with those with open operations, there was no difference in age, gender, comorbidity, or tumor size between the two groups. However, the complication rate was significantly lower in those with laparoscopic resection (14% versus 32%, P = 0.007) and the median hospital stay was significantly shorter (7 days versus 8 days, P = 0.005). The operative mortalities and the survivals were similar in the two groups. CONCLUSIONS: Colorectal resection can be performed safely in patients with stage IV colorectal cancer. The operative outcomes in terms of complication rate and hospital stay compare favorably with patients with open resection.

Colorectal resection after stent insertion for obstructing cancer: comparison between open and laparoscopic approaches.

AIM: To evaluate surgical outcomes after stent insertion for obstructing colorectal malignancy and to compare between laparoscopic and open approach. METHODS: Surgical resection was performed after stent insertion for malignant colorectal obstruction in 36 patients with a median age of 73 years. Eighteen patients were treated with open resection, whereas 18 underwent a laparoscopic resection. The outcomes were evaluated and comparison was made between patients with laparoscopic and open resection. RESULTS: The mean interval between stent insertion and surgery was 11 days. One patient died within 30 days (2.8%). The overall incidence of postoperative morbidity was 22% and reoperation was required in 3 patients (8.8%). The median postoperative hospital stay was 8.5 days for the open surgery group and 5.5 days for the laparoscopic group (P = 0.004). The postoperative morbidity rates for the open and laparoscopic groups were 33.3% and 11.1%, respectively (P = 0.228). In those patients with nonmetastatic disease, with the median follow-up of 20 months, the 5-year survival rate was 49.5%. CONCLUSIONS: Our experience showed that after successful endoscopic stent insertion for malignant colorectal obstruction, elective surgical resection could be performed safely. The combined endoscopic and laparoscopic procedure provides a less invasive alternative to the multistage open operations and is feasible for patients with obstructing colon cancer.

Multimodality minimally invasive autopsy--a feasible and accurate approach to post-mortem examination.

BACKGROUND: Autopsy examination has been the bedrock of western medicine. With the decline in the autopsy rate secondary to the negative psychological impact to the deceased's relatives, the benefits of autopsy have been undermined. Minimally invasive autopsy has been introduced but has not been widely adopted as an alternative to the 'traditional' open approach. This technique not only provides information on the cause of death abut also minimizes the disfigurement induced to the deceased. Our study aims to explore the feasibility and evaluate the accuracy of this technique. METHODS: A series of coroner cases ordered for autopsy were examined by a group including an experienced forensic pathologist and two experienced laparoscopic surgeons using thoracoscopic, laparoscopic, endoluminal or endovascular approaches. The procedure was video-recorded and the provisional diagnoses and causes of death were made based on the findings. These findings were subsequently correlated with the full autopsy examination. A few limited clinical post-mortem examinations were also performed with consent from relatives. RESULTS: A total of 22 cases of minimally invasive autopsies were performed from November 2007 to March 2008. The median duration of the procedures was 78.3+/-20.7 min. Thoracoscopies and laparoscopies were performed in 18 patients while additional arterioscopic examination with endoscope was performed in two patients with suspected aortic diseases. Four consented limited clinical autopsies were also performed: two of them involved thoracoscopic biopsies of lung tissues, one was a para-mortem upper endoscopy for the investigation of pathology of the stomach and the other one was laparoscopy for a patient, who died of unexplained acidosis. Comparison with full autopsies showed that the accuracy of the diagnosis was 94.4%, the sensitivity was 90%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 88.9%. CONCLUSION: Minimally invasive autopsy is a feasible approach, yielding accurate findings when compared with conventional autopsies. The former can be a valuable tool for obtaining more valuable information in situations when the next-of-kin of the deceased does not consent to a conventional autopsy.