Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers.

BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.

The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program.

BACKGROUND: Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. METHODS: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months. RESULTS: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p < 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1-13, p = 0.03). CONCLUSIONS: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation.

BACKGROUND: Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation. METHODS: Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3-5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients ( NCT02072720 ). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation. RESULTS: Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2-3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction. CONCLUSIONS: Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.

Yield of Surveillance Colonoscopies 1 Year After Curative Surgical Colorectal Cancer Resections.

BACKGROUND & AIMS: Endoscopic surveillance after curative colorectal cancer (CRC) resection is routine. However, there is controversy whether the 1-year interval between preoperative and postoperative colonoscopy is justified owing to improved colonoscopy standards. We aimed to assess the yield of surveillance colonoscopies 1 year after CRC surgery. METHODS: We performed a retrospective cohort study of 572 patients (54.9% male; mean age, 66.2 ± 9.9 y), who underwent curative surgical resection of a first CRC from June 2013 through April 2016 in the Northwest region of The Netherlands. Patients were included if a complete clearing colonoscopy was performed before surgery and the interval between the preoperative and postoperative colonoscopy was 12 months (range, 6-20 mo), conforming to Dutch guidelines. The primary outcome of the study was the yield of CRC at the surveillance colonoscopy performed 1 year after curative resection. A secondary outcome was the yield of advanced neoplasia. RESULTS: After a mean surveillance interval of 13.7 months (±2.8 mo), 10 of 572 patients (1.7%; 95% CI, 0.7%-2.8%) received a diagnosis of CRC. Of these, 5 CRCs were apparently metachronous cancers (3 were stage III or IV) and 5 were recurrences at the anastomosis (1 was stage IV). In 11.4% of patients (95% CI, 8.9%-13.8%), advanced neoplasia was detected at the 1-year follow-up colonoscopy. Synchronous advanced neoplasia at baseline colonoscopy was a risk factor for detection of advanced neoplasia at the follow-up colonoscopy (odds ratio, 2.2; 95% CI, 1.3-3.8; P ≤ .01). CONCLUSIONS: Despite high colonoscopy quality, the yield of CRC at surveillance colonoscopy 1 year after CRC resection was 1.7%. These were metachronous CRCs and recurrences, often of advanced stage. The high yield justifies the recommendation of a 1-year surveillance interval after surgical CRC resection.

Long-Term Colon Stent Patency for Obstructing Colorectal Cancer Combined with Bevacizumab.

Self-expanding metal stents can be considered as initial treatment for malignant large bowel obstruction in the palliative setting. It is suggested that systemic anti-angiogenic therapy increases the risk of stent perforation. We report a 65-year-old woman with a metastatic, obstructing colon tumor who has been successfully treated with stent placement and chemoimmunotherapy consisting of capecitabine and bevacizumab for 8 years.

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial).

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.

Colonic stenting as bridge to surgery versus emergency surgery for management of acute left-sided malignant colonic obstruction: a multicenter randomized trial (Stent-in 2 study).

BACKGROUND: Acute left-sided colonic obstruction is most often caused by malignancy and the surgical treatment is associated with a high mortality and morbidity rate. Moreover, these operated patients end up with a temporary or permanent stoma. Initial insertion of an enteral stent to decompress the obstructed colon, allowing for surgery to be performed electively, is gaining popularity. In uncontrolled studies stent placement before elective surgery has been suggested to decrease mortality, morbidity and number of colostomies. However stent perforation can lead to peritoneal tumor spill, changing a potentially curable disease in an incurable one. Therefore it is of paramount importance to compare the outcomes of colonic stenting followed by elective surgery with emergency surgery for the management of acute left-sided malignant colonic obstruction in a randomized multicenter fashion. METHODS/DESIGN: Patients with acute left-sided malignant colonic obstruction eligible for this study will be randomized to either emergency surgery (current standard treatment) or colonic stenting as bridge to elective surgery. Outcome measurements are effectiveness and costs of both strategies. Effectiveness will be evaluated in terms of quality of life, morbidity and mortality. Quality of life will be measured with standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-CR38, EQ-5D and EQ-VAS). Morbidity is defined as every event leading to hospital admission or prolonging hospital stay. Mortality will be analyzed as total mortality as well as procedure-related mortality. The total costs of treatment will be evaluated by counting volumes and calculating unit prices. Including 120 patients on a 1:1 basis will have 80% power to detect an effect size of 0.5 on the EORTC QLQ-C30 global health scale, using a two group t-test with a 0.05 two-sided significance level. Differences in quality of life and morbidity will be analyzed using mixed-models repeated measures analysis of variance. Mortality will be compared using Kaplan-Meier curves and log-rank statistics. DISCUSSION: The Stent-in 2 study is a randomized controlled multicenter trial that will provide evidence whether or not colonic stenting as bridge to surgery is to be performed in patients with acute left-sided colonic obstruction. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46462267.

Long-term results of endoscopic drainage of common bile duct strictures in chronic pancreatitis.

OBJECTIVES: Endoscopic stent therapy is an established treatment modality for postoperative biliary strictures. At present, biliary stenting is also widely applied in chronic pancreatitis (CP), but results regarding long-term outcome are scarce. METHODS: All CP patients who underwent endoscopic biliary drainage of a benign stricture in our hospital between 1987 and 2000 were included in this retrospective study. RESULTS: Fifty-eight CP patients underwent biliary stenting (median age, 54 years; 44 male). The procedure-related mortality rate was 2% and the complication rate 4%. Median follow-up was 45 months (range, 0-182 months). Endoscopic treatment was successful in 22 patients (38%). Concomitant acute pancreatitis was the only factor identified as predictive of a successful outcome by multivariate analyses. Subanalysis of these 12 patients revealed a success rate of 92%, as opposed to 24% in cases without acute inflammation. In this latter group, continued stenting beyond a 1-year period almost never resulted in additional stricture resolvement. If stricture resolution was accomplished, however, no recurrences were observed. CONCLUSIONS: For biliary strictures due to CP, without evidence of concomitant acute pancreatitis, the long-term success rate of endoscopic therapy is poor and only one out of four strictures is treated successfully. When a biliary stricture has not resolved after 1 year of endoscopic stenting, surgery should be considered.

A prospective randomized trial of Tannenbaum-type Teflon-coated stents versus polyethylene stents for distal malignant biliary obstruction.

OBJECTIVE: Stent clogging is a major limitation in the palliative treatment of malignant biliary obstruction. Preliminary studies suggested improved duration of patency of a Tannenbaum design stent with a stainless steel mesh and an inner Teflon coating (TTC). We compared the patency of a TTC stent with a conventional polyethylene (PE) stent in a prospective randomized trial. METHODS: Between February 1998 and September 1998 we included 60 patients with distal malignant bile duct obstruction. Diagnosis included carcinoma of the pancreas (n = 57) and ampullary cancer (n = 3). There were 29 men and 31 women with a median age of 77 years. Stent diameter (10 Fr) and length (11 cm) were similar but both stent design and material were different: a Tannenbaum design stent with a stainless steel mesh and an inner Teflon coating, and an Amsterdam-type PE stent. RESULTS: Sixty patients were evaluated; 30 in the TTC group and 30 in the PE group. Early complications occurred in two patients in each group. Stent dysfunction occurred in 18 of TTC stents and 12 of PE stents. Median stent patency was 102 days for TTC and 142 days for PE stents (P = 0.41). Median survival did not differ significantly for both treatment groups (TTC, 121 days; PE, 105 days). Stent migration, in all cases proximal into the common bile duct, occurred in four patients in the TTC group versus zero in the PE group (P = 0.038). CONCLUSIONS: This study did not confirm improved patency of Tannenbaum-type Teflon-coated stents. Proximal migration prompts for additional design modifications.