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IMPORTANCE: The 1-year results of the SECURE trial, a randomized trial comparing a restrictive strategy vs usual care for select patients with symptomatic cholelithiasis for cholecystectomy, resulted in a significantly lower operation rate after restrictive strategy. However, a restrictive strategy did not result in more pain-free patients at 1 year. OBJECTIVE: To gauge pain level and determine the proportion of pain-free patients, operation rate, and biliary and surgical complications at the 5-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was a multicenter, parallel-arm, noninferiority, prospective study. Between February 2014 and April 2017, patients from 24 hospitals with symptomatic, uncomplicated cholelithiasis were included. Uncomplicated cholelithiasis was defined as gallstone disease without signs of complicated cholelithiasis, ie, biliary pancreatitis, cholangitis, common bile duct stones, or cholecystitis. Follow-up data for this analysis were collected by telephone from July 11, 2019, to September 23, 2023. INTERVENTIONS: Patients were randomized (1:1) to receive usual care or a restrictive strategy with stepwise selection for cholecystectomy. MAIN OUTCOMES AND MEASURES: The primary, noninferiority end point was proportion of patients who were pain free as evaluated by Izbicki pain score at the 5-year follow-up. A 5% noninferiority margin was chosen. The secondary end points included cholecystectomy rates, biliary and surgical complications, and patient satisfaction. RESULTS: Among 1067 patients, the median (IQR) age was 49.0 years (38.0-59.0 years); 786 (73.7%) were female, and 281 (26.3%) were male. At the 5-year follow-up, 228 of 363 patients (62.8%) were pain free in the usual care group, compared with 216 of 353 patients (61.2%) in restrictive strategy group (difference, 1.6%; 1-sided 95% lower confidence limit, −7.6%; noninferiority P = .18). After cholecystectomy, 187 of 294 patients (63.6%) in the usual care group and 160 of 254 patients (63.0%) in the restrictive strategy group were pain free, respectively (P = .88). The restrictive care strategy was associated with 387 of 529 cholecystectomies (73.2%) compared with 437 of 536 in the usual care group (81.5%; 8.3% difference; P = .001). No differences between groups were observed in biliary and surgical complications or in patient satisfaction. CONCLUSIONS AND RELEVANCE: In the long-term, a restrictive strategy results in a significant but small reduction in operation rate compared with usual care and is not associated with increased biliary and surgical complications. However, regardless of the strategy, only two-third of patients were pain free. Further criteria for selecting patients with uncomplicated cholelithiasis for cholecystectomy and rethinking laparoscopic cholecystectomy as treatment is needed to improve patient-reported outcomes. TRIAL REGISTRATION: CCMO Identifier: NTR4022

Substantial variability exists in what pathologists consider as pT4a in colorectal cancer when tumor cells are within 1 mm of the free peritoneal surface. This study aimed to determine if the measured sub-millimeter distance between tumor cells and the free peritoneal surface would offer an objective means of stratifying patients according to the risk of developing peritoneal metastases. Histological slides of patients included in the COLOPEC trial, with resectable primary c/pT4N0-2M0 colon cancer, were centrally reassessed. Specific tumor morphological variables were collected, including distance from tumor to free peritoneal surface, measured in micrometers (µm). The primary outcome, 3-year peritoneal metastasis rate, was compared between four groups of patients stratified for relation of tumor cells to the peritoneum: 1) Full peritoneal penetration with tumor cells on the peritoneal surface, 2) 0–99 µm distance to the peritoneum, 3) 100–999 µm to the peritoneum, and 4) ≥1000 µm to the peritoneum, by using Kaplan-Meier analysis. In total, 189 cases were included in the present analysis. Cases with full peritoneal penetration (n= 89), 0–99 µm distance to the peritoneal surface (n= 34), 100–999 µm distance (n= 33), and ≥1000 µm distance (n= 33), showed significantly different 3-year peritoneal metastases rates of 25% vs 29% vs 6% vs 12%, respectively (Log Rank, p= 0.044). N-category did not influence the risk of peritoneal metastases in patients with a tumor distance beyond 100 µm, while only the N2 category seemed to result in an additive risk in patients with a distance of 0–99 µm. The findings of this study suggest that the measured shortest distance between tumor cells and the free peritoneal surface is useful as an objective means of stratifying patients according to the risk of developing peritoneal metastases. This simple measurement is practical and may help in providing a precise definition of pT4a. Trial registration: NCT02231086 (Clinicaltrials.gov).

Background: This study aimed to assess the impact of open or laparoscopic resection of primary colorectal cancer (CRC) on the development of metachronous colorectal peritoneal metastases (CPM) in a population-based cohort. Materials and methods: This was a retrospective, population-based study of CRC patients who underwent open or laparoscopic resection of the primary tumour in the Netherlands between January 1st and June 30th 2015. Patients with synchronous metastases were excluded. CPM were considered metachronous if diagnosed ≥ 90 days after resection of primary CRC. Multivariable cox regression analysis was performed to correct for tumour location, histology, differentiation, and stage, nodal stage, tumour perforation, primary surgery type, and unclear resection margins. Results: In total, 1516 CRC patients underwent open resection and 3236 CRC patients underwent laparoscopic resection, with a 3-year cumulative incidence of metachronous CPM of 7.3% and 3.7%, respectively (p< 0.001), after median follow-up of 42 months. Open surgical approach was significantly associated with the development of metachronous CPM: HR 1.4 [95%CI 1.1–1.8]. Other prognostic factors were mucinous adenocarcinoma histology (HR 1.6, 95%CI 1.0–2.5), T4 stage (HR 3.2, 95%CI 2.3–4.5), N1 stage (HR 2.9, 95%CI 2.1–4.0), and N2 stage (HR 4.2, 95%CI 2.9–6.1). Conclusions: Patients treated with open resection had a significantly higher risk to develop metachronous CPM than patients treated with laparoscopic resection. The mechanisms underlying this phenomenon remain unknown but might be related to differences in per-operative specimen handling, tumour spill, surgical trauma and pro-inflammatory response. This finding might imply the need for a personalized follow-up after primary resection of CRC.

IMPORTANCE: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). OBJECTIVE: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. INTERVENTIONS: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. MAIN OUTCOMES AND MEASURES: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). RESULTS: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. CONCLUSIONS AND RELEVANCE: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02758951

IMPORTANCE: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia. OBJECTIVE: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice. INTERVENTIONS: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy. MAIN OUTCOMES AND MEASURES: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks. RESULTS: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up. CONCLUSIONS AND RELEVANCE: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03205319

Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer.

International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10–41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy.

A significant proportion of gallbladder polyps are non-neoplastic, for which resection is not necessary. However, international guidelines advocate cholecystectomy for all polyps ≥ 1 cm. This study assessed a national cohort of histopathologically proven gallbladder polyps to distinguish neoplastic from non-neoplastic polyps. PALGA, the nationwide network and registry of histo- and cytopathology, was searched to identify all histopathologically proven gallbladder polyps between 2003 and 2013. All polyps and (focal) wall thickenings > 5 mm were included, and classified as neoplastic or non-neoplastic. Polyp subtype, size, distribution, presentation as wall thickening or protruding polyp, and presence of gallstones were assessed for neoplastic and non-neoplastic polyps. A decision tree to distinguish neoplastic and non-neoplastic polyps was made and diagnostic accuracy of 1 cm surgical threshold was calculated. A total of 2085 out of 220,612 cholecystectomies contained a polyp (0.9%). Of these polyps, 56.4% were neoplastic (40.1% premalignant, 59.9% malignant) and 43.6% non-neoplastic (41.5% cholesterol polyp, 37.0% adenomyomatosis, 21.5% other). Polyp size, distribution, and presence of gallstones were reported in 1059, 1739 and 1143 pathology reports, respectively. Neoplastic polyps differed from non-neoplastic polyps in size (18.1 mm vs 7.5 mm, p< 0.001), singularity (88.2% vs 68.2%, p< 0.001), wall thickening (29.1% vs 15.6%, p< 0.001), and presence of gallstones (50.1% vs 40.4%, p= 0.001). However, adenomyomatosis presented with similar characteristics as neoplastic polyps. Fifty percent of polyps were ≥ 1 cm surgical threshold (optimal surgical threshold based on ROC-curve); sensitivity for indicating neoplastic polyps was 68.1%, specificity was 70.2%, and positive and negative predictive values were 72.9% and 65.1%. The prevalence of gallbladder polyps on cholecystectomy is low and many of the polyps are non-neoplastic. Clinicopathological characteristics differ between neoplastic and non-neoplastic polyps in general, but these cannot properly indicate neoplasia. The 1 cm surgical threshold has moderate diagnostic accuracy and is insufficient to indicate surgery for neoplastic gallbladder polyps.

Benign liver cysts are common and are often detected incidentally. Most patients do not require intervention. Occasionally, large dominant or multifocal small cysts cause symptoms as a result of rapid growth, secondary infection, intra-cystic bleeding or compression of adjacent organs. To compare presenting symptoms and outcomes of a consecutive series of patients with benign liver cysts treated either conservatively or by surgical intervention. Long-term quality of life (QoL) was also assessed. Retrospective analysis of prospectively collected data was conducted. Long-term general and disease-specific quality of life was also documented. Ninety-five patients were included in the study (46 treated operatively, 49 treated conservatively). 80% were female, and the mean age of the cohort was 58 years. Those who had surgical intervention were older (62 vs 55 years, p= 0.004), were more likely to have shortness of breath at presentation (11 vs 5%, p= 0.018) and had larger cysts (12 vs 4 cm, p< 0.001) compared with those offered conservative treatment. Laparoscopic stapled excision was the most common operative procedure (70%) and the overall complication rate was 20%. At a median follow-up of 64 months, 17% (8/46) of the surgically treated patients had radiological evidence of cyst recurrence but only 9% (4/46) were symptomatic. At median follow-up of 71 months, 37% (14/38) of conservatively treated patients had unchanged or new symptoms compared to the first presentation. Furthermore, 10% (4/38) of this group had additional radiological or surgical intervention for persistent symptoms during the follow-up period. Overall, there was no difference in long-term QoL between the two groups. Surgical intervention for selected patients with symptomatic benign liver cysts results in low long-term recurrence rates and excellent patient-reported outcomes and quality of life. Laparoscopic-stapled excision can be done safely and reliably in carefully selected patients.

The aim of this pilot study was to investigate whether acute rejection after liver transplantation is associated with known single-nucleotide polymorphisms (SNPs) in the CD86- and CTLA-4 genes of liver-transplant donors and recipients. Single nucleotide polymorphisms were determined in 135 liver transplant recipients and in 73 donors. Acute rejection was not associated with CD86 + 1057 G/A genotype distributions in donors and in recipients. In univariate analysis recipient CTLA-4 –318 G/T and + 49 A/G genotype distributions were both weakly associated with acute rejection. Multivariate analysis revealed that the CTLA-4 + 49 SNP, but not the –318 SNP, was independently of other risk factors associated with acute rejection. Only one out of 13 CTLA-4 + 49 G-homozygotes (8%) experienced acute rejection(s) compared with 40% of A/A or A/G recipients. The CTLA-4 + 49 A/G SNP, which results in an amino acid substitution in the signal peptide of the protein, did not, however, affect intracellular expression or trafficking of CTLA-4 in T cells, nor soluble serum CTLA-4 concentrations of the liver transplant recipients. In conclusion, this pilot study suggests that liver transplant recipients homozygous for CTLA-4 + 49 G have a reduced risk of acute rejection.

IMPORTANCE: There is currently no consensus on the indication for cholecystectomy in patients with uncomplicated gallstone disease. OBJECTIVE: To report on the development and validation of a multivariable prediction model to better select patients for surgery. DESIGN, SETTING, AND PARTICIPANTS: This study evaluates data from 2 multicenter prospective trials (the previously published Scrutinizing (In)efficient Use of Cholecystectomy: A Randomized Trial Concerning Variation in Practice [SECURE] and the Standardized Work-up for Symptomatic Cholecystolithiasis [Success] trial) collected from the outpatient clinics of 25 Dutch hospitals between April 2014 and June 2019 and including 1561 patients with symptomatic uncomplicated cholelithiasis, defined as gallstone disease without signs of complicated cholelithiasis (ie, biliary pancreatitis, cholangitis, common bile duct stones or cholecystitis). Data were analyzed from January 2020 to June 2020. EXPOSURES: Patient characteristics, comorbidity, surgical outcomes, pain, and symptoms measured at baseline and at 6 months’ follow-up. MAIN OUTCOMES AND MEASURES: A multivariable regression model to predict a pain-free state or a clinically relevant reduction in pain after surgery. Model performance was evaluated using calibration and discrimination. RESULTS: A total of 1561 patients were included (494 patients in 7 hospitals in the development cohort and 1067 patients in 24 hospitals in the validation cohort; 6 hospitals included patients in both cohorts). In the development cohort, 395 patients (80.0%) underwent cholecystectomy. After surgery, 225 patients (57.0%) reported that they were pain free and 295 (74.7%) reported a clinically relevant reduction in pain. A multivariable prediction model showed that increased age, no history of abdominal surgery, increased visual analog scale pain score at baseline, pain radiation to the back, pain reduction with simple analgesics, nausea, and no heartburn were independent predictors of clinically relevant pain reduction after cholecystectomy. After internal validation, good discrimination was found (C statistic, 0.80; 95% CI, 0.74-0.84) between patients with and without clinically relevant pain reduction. The model had very good overall calibration and minimal underestimation of the probability. External validation indicated a good discrimination between patients with and without clinically relevant pain reduction (C statistic, 0.74; 95% CI, 0.70-0.78) and fair calibration with some overestimation of probability by the model. CONCLUSIONS AND RELEVANCE: The model validated in this study may help predict the probability of pain reduction after cholecystectomy and thus aid surgeons in deciding whether patients with uncomplicated cholelithiasis will benefit from cholecystectomy.