Implementation of Best Practices in Pancreatic Cancer Care in the Netherlands: A Stepped-Wedge Randomized Clinical Trial.

Importance: Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. Objective: To improve the implementation of guideline-based best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. Design, setting, and participants: This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). Intervention: The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. Main Outcomes and Measures: The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] global health score). Results: Overall, 5887 patients with pancreatic cancer (median age, 72.0 [IQR, 64.0-79.0] years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio [OR], 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, -1.09, 95% CI, -3.05 to 0.94). Conclusions and Relevance: In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT03513705.

Digital single-operator cholangioscopy to guide selective cannulation of complex biliary strictures.

BACKGROUND: Selective cannulation and stenting of complex, tight, and/or angulated biliary strictures under endoscopic retrograde cholangiopancreaticography (ERCP) can be challenging. Digital single-operator cholangioscopy (SOC) may facilitate guidewire advancement through the stricture with endoscopic visual guidance. We aimed to describe a case series on clinical outcomes of this technique for selective cannulation, when used after failed conventional ERCP attempts. METHODS: Consecutive patients who underwent therapeutic digital SOC for selective cannulation of biliary strictures after failed conventional ERCP were retrospectively included. RESULTS: Ten patients with a malignant (n = 6) or benign (n = 4) biliary stricture were included. Digital SOC-assisted selective guidewire insertion and stent placement across the biliary stricture were technically successful in five (50%) patients. Bilirubin levels improved in all patients with technical success. One (10%) patient developed a post-ERCP pancreatitis. CONCLUSIONS: Technically successful cannulation of biliary strictures with digital SOC was achieved in half of patients in whom cannulation with conventional ERCP failed, sparing them more invasive interventions. Stricture opacification during the failed ERCP was seen in all technically successful SOCs.

Dysplastic Recurrence After Successful Treatment for Early Barrett's Neoplasia: Development and Validation of a Prediction Model.

BACKGROUND & AIMS: The combination of endoscopic resection and radiofrequency ablation is the treatment of choice for eradication of Barrett's esophagus (BE) with dysplasia and/or early cancer. Currently, there are no evidence-based recommendations on how to survey patients after successful treatment, and most patients undergo frequent follow-up endoscopies. We aimed to develop and externally validate a prediction model for visible dysplastic recurrence, which can be used to personalize surveillance after treatment. METHODS: We collected data from the Dutch Barrett Expert Center Registry, a nationwide registry that captures outcomes from all patients with BE undergoing endoscopic treatment in the Netherlands in a centralized care setting. We used predictors related to demographics, severity of reflux, histologic status at baseline, and treatment characteristics. We built a Fine and Gray survival model with least absolute shrinkage and selection operator penalization to predict the incidence of visible dysplastic recurrence after initial successful treatment. The model was validated externally in patients with BE treated in Switzerland and Belgium. RESULTS: A total of 1154 patients with complete BE eradication were included for model building. During a mean endoscopic follow-up of 4 years, 38 patients developed recurrent disease (1.0%/person-year). The following characteristics were independently associated with recurrence (strongest to weakest predictor): a new visible lesion during treatment phase, higher number of endoscopic resection treatments, male sex, increasing BE length, high-grade dysplasia or cancer at baseline, and younger age. External validation showed a C-statistic of 0.91 (95% confidence interval, 0.86-0.94) with good calibration. CONCLUSIONS: This is the first externally validated model to predict visible dysplastic recurrence after successful endoscopic eradication treatment of BE with dysplasia or early cancer. On external validation, our model has good discrimination and calibration. This model can help clinicians and patients to determine a personalized follow-up strategy.

Development and External Validation of a Model to Predict Complex Treatment After Radiofrequency Ablation for Barrett's Esophagus With Early Neoplasia.

BACKGROUND & AIMS: Endoscopic eradication therapy for Barrett's esophagus (BE)-related neoplasia is safe and leads to complete eradication in the majority of patients. However, a subgroup will experience a more complex treatment course with a risk for failure or disease progression. Early identification of these patients may improve patient counseling and treatment outcomes. We aimed to develop a prognostic model for a complex treatment course. METHODS: We collected data from a nationwide registry that captures outcomes for all patients undergoing endoscopic eradication therapy for early BE neoplasia. A complex treatment course was defined as neoplastic progression, treatment failure, or the need for endoscopic resection during the radiofrequency ablation treatment phase. We developed a prognostic model using logistic regression. We externally validated our model in an independent registry. RESULTS: A total of 1386 patients were included, of whom 78 (6%) had a complex treatment course. Our model identified patients with a BE length of 9 cm or longer with a visible lesion containing high-grade dysplasia/cancer, and patients with less than 50% squamous conversion after radiofrequency ablation were identified as high risk for a complex treatment. This applied to 8% of the study population and included 93% of all treatment failures and 76% of all patients with advanced neoplastic progression. The model appeared robust in multiple sensitivity analyses and performed well in external validation (area under the curve, 0.84). CONCLUSIONS: We developed a prognostic model that identified patients with a BE length of 9 cm or longer and high-grade dysplasia/esophageal adenocarcinoma and those with poor squamous regeneration as high risk for a complex treatment course. The good performance in external validation suggests that it may be used in clinical management (Netherlands Trial Register: NL7039).

Impact of expert center endoscopic assessment of confirmed low grade dysplasia in Barrett's esophagus diagnosed in community hospitals.

BACKGROUND : The optimal management for patients with low grade dysplasia (LGD) in Barrett's esophagus (BE) is unclear. According to the Dutch national guideline, all patients with LGD with histological confirmation of the diagnosis by an expert pathologist (i. e. "confirmed LGD"), are referred for a dedicated re-staging endoscopy at an expert center. We aimed to assess the diagnostic value of re-staging endoscopy by an expert endoscopist for patients with confirmed LGD. METHODS : This retrospective cohort study included all patients with flat BE diagnosed in a community hospital who had confirmed LGD and were referred to one of the nine Barrett Expert Centers (BECs) in the Netherlands. The primary outcome was the proportion of patients with prevalent high grade dysplasia (HGD) or cancer during re-staging in a BEC. RESULTS : Of the 248 patients with confirmed LGD, re-staging in the BEC revealed HGD or cancer in 23 % (57/248). In 79 % (45/57), HGD or cancer in a newly detected visible lesion was diagnosed. Of the remaining patients, re-staging in the BEC showed a second diagnosis of confirmed LGD in 68 % (168/248), while the remaining 9 % (23/248) had nondysplastic BE. CONCLUSION : One quarter of patients with apparent flat BE with confirmed LGD diagnosed in a community hospital had prevalent HGD or cancer after re-staging at an expert center. This endorses the advice to refer patients with confirmed LGD, including in the absence of visible lesions, to an expert center for re-staging endoscopy.

Incidence and outcomes of poor healing and poor squamous regeneration after radiofrequency ablation therapy for early Barrett's neoplasia.

BACKGROUND: Endoscopic eradication therapy with radiofrequency ablation (RFA) is effective in most patients with Barrett's esophagus (BE). However, some patients experience poor healing and/or poor squamous regeneration. We evaluated incidence and treatment outcomes of poor healing and poor squamous regeneration. METHODS: We included all patients treated with RFA for early BE neoplasia from a nationwide Dutch registry based on a joint treatment protocol. Poor healing (active inflammatory changes or visible ulcerations ≥ 3 months post-RFA), poor squamous regeneration (< 50 % squamous regeneration), and treatment success (complete eradication of BE [CE-BE]) were evaluated. RESULTS: 1386 patients (median BE C2M5) underwent RFA with baseline low grade dysplasia (27 %), high grade dysplasia (30 %), or early cancer (43 %). In 134 patients with poor healing (10 %), additional time and acid suppression resulted in complete esophageal healing, and 67/134 (50 %) had normal squamous regeneration with 97 % CE-BE. Overall, 74 patients had poor squamous regeneration (5 %). Compared with patients with normal regeneration, patients with poor squamous regeneration had a higher risk for treatment failure (64 % vs. 2 %, relative risk [RR] 27 [95 % confidence interval [CI] 18-40]) and progression to advanced disease (15 % vs. < 1 %, RR 30 [95 %CI 12-81]). Higher body mass index, longer BE segment, reflux esophagitis, and < 50 % squamous regeneration after baseline endoscopic resection were independently associated with poor squamous regeneration in multivariable logistic regression. CONCLUSIONS: In half of the patients with poor healing, additional time and acid suppression led to normal squamous regeneration and excellent treatment outcomes. In patients with poor squamous regeneration, however, the risk for treatment failure and progression to advanced disease was significantly increased.

Long-term outcomes after endoscopic treatment for Barrett's neoplasia with radiofrequency ablation ± endoscopic resection: results from the national Dutch database in a 10-year period.

OBJECTIVE: Radiofrequency ablation (RFA)±endoscopic resection (ER) is the preferred treatment for early neoplasia in Barrett's oesophagus (BE). We aimed to report short-term and long-term outcomes for all 1384 patients treated in the Netherlands (NL) from 2008 to 2018, with uniform treatment and follow-up (FU) in a centralised setting. DESIGN: Endoscopic therapy for early BE neoplasia in NL is centralised in nine expert centres with specifically trained endoscopists and pathologists that adhere to a joint protocol. Prospectively collected data are registered in a uniform database. Patients with low/high-grade dysplasia or low-risk cancer, were treated by ER of visible lesions followed by trimonthly RFA sessions of any residual BE until complete eradication of BE (CE-BE). Patients with ER alone were not included. RESULTS: After ER (62% of cases; 43% low-risk cancers) and median 1 circumferential and 2 focal RFA (p25-p75 0-1; 1-2) per patient, CE-BE was achieved in 94% (1270/1348). Adverse events occurred in 21% (268/1386), most commonly oesophageal stenosis (15%), all were managed endoscopically. A total of 1154 patients with CE-BE were analysed for long-term outcomes. During median 43 months (22-69) and 4 endoscopies (1-5), 38 patients developed dysplastic recurrence (3%, annual recurrence risk 1%), all were detected as endoscopically visible abnormalities. Random biopsies from a normal appearing cardia showed intestinal metaplasia (IM) in 14% and neoplasia in 0%. A finding of IM in the cardia was reproduced during further FU in only 33%, none progressed to neoplasia. Frequent FU visits in the first year of FU were not associated with recurrence risk. CONCLUSION: In a setting of centralised care, RFA±ER is effective for eradication of Barrett's related neoplasia and has remarkably low rates of dysplastic recurrence. Our data support more lenient FU intervals, with emphasis on careful endoscopic inspection. Random biopsies from neosquamous epithelium and cardia are of questionable value. NETHERLANDS TRIAL REGISTER NUMBER: NL7039.

Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution.

The upper gastrointestinal tract, consisting of the esophagus, stomach, and duodenum, controls food transport, digestion, nutrient uptake, and hormone production. By single-cell analysis of healthy epithelia of these human organs, we molecularly define their distinct cell types. We identify a quiescent COL17A1high KRT15high stem/progenitor cell population in the most basal cell layer of the esophagus and detect substantial gene expression differences between identical cell types of the human and mouse stomach. Selective expression of BEST4, CFTR, guanylin, and uroguanylin identifies a rare duodenal cell type, referred to as BCHE cell, which likely mediates high-volume fluid secretion because of continual activation of the CFTR channel by guanylin/uroguanylin-mediated autocrine signaling. Serotonin-producing enterochromaffin cells in the antral stomach significantly differ in gene expression from duodenal enterochromaffin cells. We, furthermore, discover that the histamine-producing enterochromaffin-like cells in the oxyntic stomach express the luteinizing hormone, yet another member of the enteroendocrine hormone family.

International multicenter comprehensive analysis of adverse events associated with lumen-apposing metal stent placement for pancreatic fluid collection drainage.

BACKGROUND AND AIMS: High rates of technical and clinical success were reported for lumen-apposing metal stent (LAMS) placement for peripancreatic fluid collection (PFC) drainage. However, data on the adverse event (AE) rates are heterogeneous. The aim of this study was to evaluate the incidence, severity, management, and risk factors of AEs related to the use of LAMSs for drainage of PFCs in a large cohort of patients. METHODS: This is a multicenter, international, retrospective review from 15 centers of all patients who underwent placement of LAMSs for the management of PFCs. A nested case-control study was conducted in patients with (case) or without (control) AEs. RESULTS: Three hundred thirty-three procedures in 328 patients were performed (5 patients treated with 2 LAMSs). Technical success was achieved in 321 patients (97.9%). Three hundred four patients were finally included in the study (7 excluded for lost to follow-up information; 10 excluded for deaths unrelated to LAMSs). The rate of clinical success was 89.5%. Seventy-nine LAMS-related AEs occurred in 74 of 304 patients (24.3%), after a mean time of 25.3 days (median, 18 days; interquartile range, 6-30) classified as 20 (25.3%) mild, 54 (68.4%) moderate, or 5 (6.3%) severe. On multivariable analysis compared with control subjects, cases were more likely to have walled-off necrosis (WON) versus pancreatic pseudocysts (odds ratio, 2.18; 95% confidence interval, 1.09-4.46; P = .028), whereas cases were less likely to have undergone tract (balloon) dilation (yes vs no; odds ratio, .47; 95% confidence interval, .22-.93; P = .034). CONCLUSIONS: Data from this large international retrospective study confirm that the use of LAMSs for management of PFCs has excellent technical and good clinical success rates. The rate of AEs, however, is not negligible and should be carefully considered before using these stents for drainage of PFCs and in particular for WON. Further prospective studies are needed to confirm these findings. (Clinical trial registration number: NCT03544008.).

Growth rate of small pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: results from an endoscopic ultrasound based cohort study.

Background and aims In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound (EUS) is used for identification and follow-up of pancreatic neuroendocrine tumors (PNETs). The role of EUS in surveillance of small ( < 20 mm) PNETs is unclear, mostly because the natural course of these lesions is largely unknown. We aimed to determine annual growth and incidence rate of small PNETs in patients with MEN1 using EUS-based surveillance. Patients and methods Linear array EUS procedures in patients with MEN1 between 2002 and 2015 were identified. Number, size, and location of PNETs were recorded. Annual growth of PNETs < 20 mm identified at the initial EUS ("prevalent" PNETs) and during follow-up ("incident" PNETs) was calculated using mixed model linear regression analysis. Results A total of 54 patients were identified and 38 patients were included. In all, 226 PNETs were identified (median size 5.0 mm, interquartile range 3.7 - 7.5) of which 124 (55 %) were prevalent and 102 (45 %) were incident PNETs. Annual incidence rate was 0.79 PNETs/year (95 % confidence interval [CI] 0.73 to 0.87). Overall growth rate was 0.10 mm/year (95 %CI 0.02 to 0.19; P = 0.01); PNETs < 10 mm (n = 198) did not grow (P = 0.23), whereas PNETs ≥ 10 mm (n = 28) grew 0.44 mm/year (95 %CI 0.10 to 0.78; P = 0.01). Prevalent PNETs grew 0.21 mm/year (95 %CI 0.10 - 0.32; P < 0.001), whereas incident PNETs did not grow (P = 0.26). Conclusions The annual growth rate of small, solid PNETs in patients with MEN1 is lower than previously thought. Surveillance intervals could probably be prolonged without compromising safety.

Challenges in oral drug delivery in patients with esophageal dysphagia.

INTRODUCTION: Esophageal dysphagia is a commonly reported symptom with various benign and malignant causes. Esophageal dysphagia can impede intake of oral medication, which often poses a major challenge for both patients and physicians. The best way to address this challenge depends of the cause of dysphagia. AREAS COVERED: The pathophysiology of esophageal dysphagia is discussed, diagnostic tools to determine its cause are reviewed and recent developments in the treatment of esophageal dysphagia are discussed. Alternative options to administer medication in dysphagia are discussed and the appropriateness of them reviewed. EXPERT OPINION: Two ways can be followed to allow medication intake in patients with esophageal dysphagia, i.e. altering medication or resolving dysphagia. The latter is generally preferred, since esophageal dysphagia rarely only impedes medication intake. Esophageal resection is possible in more advanced esophageal cancer stages due to advances in neo-adjuvant therapy. Due to recent improvements in intraluminal radiotherapy, it can be expected that this will be the primary treatment in a palliative setting. Temporary self-expandable metal stent placement is a promising new alternative for bougienage in difficult-to-treat benign strictures.

Long-term follow up in patients with gastroesophageal reflux disease with specific emphasis on reflux symptoms, use of anti-reflux medication and anti-reflux surgery outcome: a retrospective study.

BACKGROUND: Various treatment modalities are currently being used in patients with gastroesophageal reflux disease (GERD); however, long-term outcome is not clear. The aim is to evaluate long-term results of GERD treatments with regard to reflux symptoms, use of anti-reflux medication and anti-reflux surgery outcome. METHODS: Patients who had undergone 24-h pH monitoring for reflux symptoms between January 2002 and March 2012 were invited to fill out the Reflux Disease Questionnaire (RDQ) and a general questionnaire. Patients with and without anti-reflux surgery were compared using multiple linear and logistic regression models. RESULTS: In total, 1027 of 2190 included patients (47%) returned the questionnaires. After exclusion due to predefined criteria, 477 patients were analyzed. Median total RDQ score was 18 points (10.2% symptom-free) in the conservative group (n = 304) and 10 points (31.2% symptom-free) in the surgical group (n = 173) after a mean follow up of 5.1 years. Daily proton pomp inhibitor (PPI) use was higher in the conservative group than in the surgical group (80.9% vs. 51.4%, p = 0.000). Linear regression analysis showed an association between RDQ scores and anti-reflux surgery (ß = -5.477, p = 0.001) and male gender (ß = -4.306, p = 0.006). Logistic regression analyses showed that daily PPI use was lower in patients who underwent anti-reflux surgery (odds ratio [OR] = 0.24, p = 0.000), while it increased with age (OR = 1.03, p = 0.000). CONCLUSIONS: There is still a high prevalence of typical reflux symptoms and daily PPI use in GERD patients after >5 years of follow up. Male patients and patients who had undergone anti-reflux surgery were more often asymptomatic. Daily PPI use was lower after anti-reflux surgery, while it increased with age.

The incidence and natural course of occult inguinal hernias during TAPP repair: repair is beneficial.

BACKGROUND: One of the proposed advantages of laparoscopic inguinal hernia repair is complimentary inspection of the contralateral side and possible detection of occult hernias. Incidence of occult contralateral hernias is as high as 50 %. The natural course of such occult defects is unknown and therefore operative rationale is lacking. This study was designed to analyze the incidence of occult contralateral inguinal hernias and its natural course. METHODS: A total of 1,681 patients were diagnosed preoperatively with unilateral inguinal hernia. None of these patients had complaints of the contralateral side preoperatively. All patients underwent laparoscopic inguinal hernia transabdominal preperitoneal (TAPP) repair. Operative details were analyzed retrospectively. Patients with occult contralateral defects were identified and tracked. Patients with an evident occult hernia received immediate repair. Patients with a smaller beginning or incipient hernia were followed. RESULTS: In 218 (13 %) patients, an occult hernia was found at the contralateral side during preoperative exploration. In 129 (8 %) patients, an occult true hernia was found. In 89 (5 %) patients, an occult incipient hernia was found. An incipient hernia was defined as a beginning hernia. All patients with an incipient hernia were followed. The mean follow-up was 112 (range 16-218) months. Twenty-eight (32 %) patients were lost to follow-up. In the 61 remaining patients, 13 (21 %) occult incipient hernias became symptomatic requiring repair. The mean time between primary repair and development of a symptomatic hernia on the contralateral side was 88 (range 24-210) months. CONCLUSIONS: This study shows that the incidence of occult contralateral hernias is 13 % during TAPP repair of unilateral diagnosed inguinal hernias. In 5 % of the cases, the occult hernia consisted of a beginning hernia. Eventually, one of five will become symptomatic and require repair. These outcomes support immediate repair of occult defects, no matter its size.

Esophageal motility and impedance characteristics in patients with Barrett's esophagus before and after radiofrequency ablation.

INTRODUCTION: Radiofrequency ablation (RFA) is a valuable treatment option in Barrett's esophagus resulting in eradication of dysplasia and conversion of all Barrett's epithelium into normal squamous epithelium. In Barrett's esophagus, esophageal impedance monitoring is hampered by low baseline impedance values. Whether these low baselines are caused by an intrinsically low impedance of cylindrical epithelium or by the excessive reflux itself is hitherto unknown. Data on esophageal motility after RFA are scarce. Our aim was to examine the effect of RFA on esophageal motility and esophageal baseline impedance in patients with Barrett's esophagus. METHODS: In 10 patients, conventional esophageal manometry and 24-h pH-impedance measurements were performed before and after RFA. The number and type of reflux episodes were assessed and baseline impedance values were measured in all recording segments. In another five patients, high-resolution manometry was performed before and after RFA. RESULTS: Complete regression of all Barrett's epithelium was achieved in all 15 patients after 3 ± 1 RFA sessions. Overall, no significant motility changes were found after RFA. Patients had excessive acid exposure times before and after RFA [25 (17-42) and 16 (9-24)%, respectively]. Baseline esophageal impedance values were low, with the lowest values in the distal recording segments. RFA increased baseline impedance in all recording segments in the upright position; in the supine position, the effect just failed to reach statistically significant levels. CONCLUSION: RFA did not alter esophageal motility significantly. Low esophageal baseline impedance levels in patients with Barrett's esophagus reflect, at least in part, intrinsic impedance properties of cylindrical epithelium, as baselines increased after conversion into neosquamous epithelium.