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.

Endoscopic management of subepithelial lesions including neuroendocrine neoplasms: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

1: ESGE recommends endoscopic ultrasonography (EUS) as the best tool to characterize subepithelial lesion (SEL) features (size, location, originating layer, echogenicity, shape), but EUS alone is not able to distinguish among all types of SEL.Strong recommendation, moderate quality evidence. 2: ESGE suggests providing tissue diagnosis for all SELs with features suggestive of gastrointestinal stromal tumor (GIST) if they are of size > 20 mm, or have high risk stigmata, or require surgical resection or oncological treatment.Weak recommendation, very low quality evidence. 3: ESGE recommends EUS-guided fine-needle biopsy (EUS-FNB) or mucosal incision-assisted biopsy (MIAB) equally for tissue diagnosis of SELs ≥ 20 mm in size.Strong recommendation, moderate quality evidence. 4: ESGE recommends against surveillance of asymptomatic gastrointestinal (GI) tract leiomyomas, lipomas, heterotopic pancreas, granular cell tumors, schwannomas, and glomus tumors, if the diagnosis is clear.Strong recommendation, moderate quality evidence. 5: ESGE suggests surveillance of asymptomatic esophageal and gastric SELs without definite diagnosis, with esophagogastroduodenoscopy (EGD) at 3-6 months, and then at 2-3-year intervals for lesions < 10 mm in size, and at 1-2-year intervals for lesions 10-20 mm in size. For asymptomatic SELs > 20 mm in size that are not resected, ESGE suggests surveillance with EGD plus EUS at 6 months and then at 6-12-month intervals.Weak recommendation, very low quality evidence. 6: ESGE recommends endoscopic resection for type 1 gastric neuroendocrine neoplasms (g-NENs) if they grow larger than 10 mm. The choice of resection technique should depend on size, depth of invasion, and location in the stomach.Strong recommendation, low quality evidence. 7: ESGE suggests considering removal of histologically proven gastric GISTs smaller than 20 mm as an alternative to surveillance. The decision to resect should be discussed in a multidisciplinary meeting. The choice of technique should depend on size, location, and local expertise.Weak recommendation, very low quality evidence. 8: ESGE suggests that, to avoid unnecessary follow-up, endoscopic resection is an option for gastric SELs smaller than 20 mm and of unknown histology after failure of attempts to obtain diagnosis.Weak recommendation, very low quality evidence. 9: ESGE recommends basing the surveillance strategy on the type and completeness of resection. After curative resection of benign SELs no follow-up is advised, except for type 1 gastric NEN for which surveillance at 1-2 years is advised.Strong recommendation, low quality evidence. 10: For lower or upper GI NEN with a positive or indeterminate margin at resection, ESGE recommends repeating endoscopy at 3-6 months and another attempt at endoscopic resection in the case of residual disease.Strong recommendation, low quality evidence.

Argon plasma coagulation for Barrett's esophagus with low-grade dysplasia: a randomized trial with long-term follow-up on the impact of power setting and proton pump inhibitor dose.

BACKGROUND: This study evaluated the impact of power setting and proton pump inhibitor (PPI) dose on efficacy and safety of argon plasma coagulation (APC) of Barrett's esophagus (BE) with low-grade dysplasia (LGD). METHODS : 71 patients were randomized to APC with power set at 90 W or 60 W followed by 120 mg or 40 mg omeprazole. The primary outcome was the rate of complete (endoscopic and histologic) ablation of BE at 6 weeks. Secondary outcomes included safety and long-term efficacy. RESULTS : Complete ablation rate in the 90 W/120 mg, 90 W/40 mg, and 60 W/120 mg groups was 78 % (18/23; 95 % confidence interval [CI] 61-95), 60 % (15/25; 95 %CI 41-79), 74 % (17/23; 95 %CI 56-92), respectively, at 6 weeks and 70 % (16/23; 95 %CI 51-88), 52 % (13/25; 95 %CI 32-72), and 65 % (15/23; 95 %CI 46-85) at 2 years post-treatment (differences not significant). Additional APC was required in 28 patients (23 residual and 5 recurrent BE). At median follow-up of 108 months, 66/71 patients (93 %; 95 %CI 87-99) maintained complete ablation. No high-grade dysplasia or adenocarcinoma developed. Overall, adverse events (97 % mild) did not differ significantly between groups. Chest pain/discomfort was more frequent in patients receiving 90 W vs. 60 W power (P < 0.001). One patient had esophageal perforation and two developed stenosis. CONCLUSIONS: APC power setting and PPI dose did not impact efficacy and safety of BE ablation. Complete ablation of BE with LGD was durable in > 90 % of patients, without any evidence of neoplasia progression in the long term.

Mutational Mosaics of Cell-Free DNA from Pancreatic Cyst Fluids.

BACKGROUND: Pancreatic cyst fluids (PCFs) enriched in tumor-derived DNA are a potential source of new biomarkers. The study aimed to analyze germinal variants and mutational profiles of cell-free (cf)DNA shed into the cavity of pancreatic cysts. METHODS: The study cohort consisted of 71 patients who underwent endoscopic ultrasound fine-needle aspiration of PCF. Five malignant cysts, 19 intraductal papillary mucinous neoplasms (IPMNs), 11 mucinous cystic neoplasms (MCNs), eight serous cystic neoplasms (SCNs), and 28 pseudocysts were identified. The sequencing of 409 genes included in Comprehensive Cancer Panel was performed using Ion Proton System. The mutation rate of the KRAS and GNAS canonical loci was additionally determined using digital PCR. RESULTS: The number of mutations detected with NGS varied from 0 to 22 per gene, and genes with the most mutations were: TP53, KRAS, PIK3CA, GNAS, ADGRA2, and APC. The frequencies of the majority of mutations did not differ between non-malignant cystic neoplasms and pseudocysts. NGS detected KRAS mutations in malignant cysts (60%), IPMNs (32%), MCNs (64%), SCNs (13%), and pseudocysts (14%), with GNAS mutations in 20%, 26%, 27%, 13%, and 21% of samples, respectively. Digital PCR-based testing increased KRAS (68%) and GNAS (52%) mutations detection level in IPMNs, but not other cyst types. CONCLUSIONS: We demonstrate relatively high rates of somatic mutations of cancer-related genes, including KRAS and GNAS, in cfDNA isolated from PCFs irrespectively of the pancreatic cyst type. Further studies on molecular mechanisms of pancreatic cysts malignant transformation in relation to their mutational profiles are required.

Pancreatic cyst surveillance imposes low psychological burden.

BACKGROUND/OBJECTIVES: For the currently recommended pancreatic cyst surveillance to be feasible, participant adherence is a prerequisite. Our objective was to evaluate the psychological burden of pancreatic cyst surveillance from a participant's perspective. METHODS: The present participant survey is part of an international cohort study (PACYFIC study, www.pacyfic.net), which prospectively records the outcome of surveillance of asymptomatic pancreatic cysts. Participants are invited to complete questionnaires before and during cyst surveillance. RESULTS: 109 participants, 31 enrolled before and 78 during surveillance (median time since cyst diagnosis 16.5 (IQR 36) months), returned a total of 179 questionnaires. The majority indicated that surveillance reduces concerns of developing pancreatic cancer (82%), gives a sense of certainty (81%) and is a good method to detect cancer (91%). Participants already undergoing surveillance reported more negative aspects than those still to commence, like sleeping worse (30% vs 13%, P = 0.035), postponing plans (32% vs 13%, P = 0.031), and finding the follow-up burdensome (33% vs 13%, P = 0.044). Overall, the vast majority (94%) deemed advantages to outweigh disadvantages. Anxiety and depression scores were low (median Hospital Anxiety and Depression Scale 4 for anxiety (IQR 6), 2 for depression (IQR 5)). CONCLUSION: The psychological burden of pancreatic cyst surveillance is low. Therefore, participant adherence is expected to be high and annual surveillance seems feasible.

The impact of low- versus standard-volume bowel preparation on participation in primary screening colonoscopy: a randomized health services study.

BACKGROUND: The aim of this study was to evaluate the impact of low-volume vs. standard-volume bowel preparation on participation in screening colonoscopy, bowel preparation quality, and lesion detection rates. METHODS: This was a multicenter, randomized, health services study within the population-based primary colonoscopy screening program in Poland. Individuals aged 55 - 62 years were randomized in a 1:1 ratio to bowel preparation with a low-volume (0.3 L sodium picosulfate with magnesium citrate) or standard-volume (4 L polyethylene glycol) regimen and then invited to participate in screening colonoscopy. The primary outcome measure was the rate of participation in screening colonoscopy. Compliance with the assigned bowel preparation, bowel preparation quality, and lesion detection rates were also evaluated. RESULTS: A total of 13 621 individuals were randomized and 13 497 were analyzed (6752 in the low-volume group and 6745 in the standard-volume group). The participation rate (16.6 % vs. 15.5 %; P = 0.08) and compliance rate (93.3 % vs. 94.1 %; P = 0.39) did not differ significantly between the groups. In the low-volume group, fewer participants had adequate bowel preparation compared with the standard-volume group (whole colon 79.0 % vs. 86.4 %, P < 0.001; proximal colon 80.1 % vs. 87.3 %, P < 0.001). Detection rates of advanced adenoma (AADR) and advanced serrated polyps (ASPDR) were lower in the low-volume group than in the standard-volume group (AADR in the proximal colon 2.6 % vs. 4.3 %, P = 0.02; ASPDR in the whole colon 2.0 % vs. 3.3 %, P = 0.04; ASPDR in the proximal colon 1.0 % vs. 1.9 %, P = 0.048). CONCLUSION: When compared with a standard-volume bowel preparation with polyethylene glycol, low-volume bowel preparation with sodium picosulfate/magnesium citrate did not improve participation rate or lesion detection rates, and negatively affected bowel preparation quality.

Preoperative radiotherapy and local excision of rectal cancer: Long-term results of a randomised study.

BACKGROUND AND PURPOSE: It is uncertain whether local control is acceptable after preoperative radiotherapy and local excision (LE). An optimal preoperative dose/fractionation schedule has not yet been established. MATERIAL AND METHODS: In a phase III study, patients with cT1-2N0M0 or borderline cT2/T3N0M0 < 4 cm rectal adenocarcinomas were randomised to receive either 5 × 5 Gy plus 1 × 4 Gy boost or chemoradiation: 50.4 Gy in 28 fractions plus 3 × 1.8 Gy boost and 5-fluorouracil with leucovorin bolus. LE was performed 6-8 weeks later. Patients with ypT0-1R0 disease were observed. Completion total mesorectal excision (CTME) was recommended for poor responders, i.e. ypT1R1/ypT2-3. RESULTS: Of 61 randomised patients, 10 were excluded leaving 51 for analysis; 29 in the short-course group and 22 in the chemoradiation group. YpT0-1R0 was observed in 66% of patients in the short-course group and in 86% in the chemoradiation group, p = 0.11. CTME was performed only in 46% of patients with ypT1R1/ypT2-3. The median follow-up was 8.7 years. Local recurrence incidences and overall survival at 10 years were respectively for the short-course group vs. the chemoradiation group 35% vs. 5%, p = 0.036 and 47% vs. 86%, p = 0.009. In total, local recurrence at 10 years was 79% for ypT1R1/T2-3 without CTME. CONCLUSIONS: This trial suggests that in the LE setting, both local recurrence and survival are worse after short-course radiotherapy than after chemoradiation. Because of the risk of bias, a confirmatory study is desirable. Lack of CTME is associated with an unacceptably high local recurrence rate.

Mass Spectrometry-Based Comprehensive Analysis of Pancreatic Cyst Fluids.

Pancreatic cyst fluids (PCFs) enriched in tumour-derived proteins are considered a potential source of new biomarkers. This study aimed to determine compositional and quantitative differences between the degradome and proteome of PCFs aspirated from different types of pancreatic cyst lesions (PCLs). 91 patients who underwent endoscopic ultrasound-fine needle aspiration under routine clinical diagnosis of PCLs were enrolled. Four cysts were malignant (CAs), and 87 were nonmalignant and consisted of 18 intraductal papillary mucinous neoplasms (IPMNs), 14 mucinous cystic neoplasms (MCNs), nine serous cystic neoplasms (SCNs), 29 pseudocysts (PCs), and 17 unclassified. Profiles of the <5 kDa fraction, the degradome, and the trypsin-digested proteome were analysed using an LTQ-Orbitrap Elite mass spectrometer coupled with a nanoACQUITY LC system. Qualitative analyses identified 796 and 366 proteins in degradome and proteome, respectively, and 689 (77%) and 285 (78%) of them were present in the Plasma Proteome Database. Gene Ontology analysis showed a significant overrepresentation of peptidases and peptidases inhibitors in both datasets. In the degradome fraction, quantitative values were obtained for 6996 peptides originating from 657 proteins. Of these, 2287 peptides were unique to a single type, and 515 peptides, derived from 126 proteins, were shared across cyst types. 32 peptides originating from 12 proteins had differential (adjusted p-value ≤0.05, FC ≥1.5) abundance in at least one of the five cysts types. In proteome, relative expression was measured for 330 proteins. Of them, 33 proteins had significantly (adjusted p-value ≤0.05, FC ≥1.5) altered abundance in at least one of the studied groups and 19 proteins appeared to be unique to a given cyst type. PCFs are dominated by blood proteins and proteolytic enzymes. Although differences in PCF peptide composition and abundance could aid classification of PCLs, the unpredictable inherent PCF proteolytic activity may limit the practical applications of PCF protein profiling.

Technical aspects of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Technical Guideline - March 2017.

For routine EUS-guided sampling of solid masses and lymph nodes (LNs) ESGE recommends 25G or 22G needles (high quality evidence, strong recommendation); fine needle aspiration (FNA) and fine needle biopsy (FNB) needles are equally recommended (high quality evidence, strong recommendation).When the primary aim of sampling is to obtain a core tissue specimen, ESGE suggests using 19G FNA or FNB needles or 22G FNB needles (low quality evidence, weak recommendation).ESGE recommends using 10-mL syringe suction for EUS-guided sampling of solid masses and LNs with 25G or 22G FNA needles (high quality evidence, strong recommendation) and other types of needles (low quality evidence, weak recommendation). ESGE suggests neutralizing residual negative pressure in the needle before withdrawing the needle from the target lesion (moderate quality evidence, weak recommendation).ESGE does not recommend for or against using the needle stylet for EUS-guided sampling of solid masses and LNs with FNA needles (high quality evidence, strong recommendation) and suggests using the needle stylet for EUS-guided sampling with FNB needles (low quality evidence, weak recommendation).ESGE suggests fanning the needle throughout the lesion when sampling solid masses and LNs (moderate quality evidence, weak recommendation).ESGE equally recommends EUS-guided sampling with or without on-site cytologic evaluation (moderate quality evidence, strong recommendation). When on-site cytologic evaluation is unavailable, ESGE suggests performance of three to four needle passes with an FNA needle or two to three passes with an FNB needle (low quality evidence, weak recommendation).For diagnostic sampling of pancreatic cystic lesions without a solid component, ESGE suggests emptying the cyst with a single pass of a 22G or 19G needle (low quality evidence, weak recommendation). For pancreatic cystic lesions with a solid component, ESGE suggests sampling of the solid component using the same technique as in the case of other solid lesions (low quality evidence, weak recommendation).ESGE does not recommend antibiotic prophylaxis for EUS-guided sampling of solid masses or LNs (low quality evidence, strong recommendation), and suggests antibiotic prophylaxis with fluoroquinolones or beta-lactam antibiotics for EUS-guided sampling of cystic lesions (low quality evidence, weak recommendation). ESGE suggests that evaluation of tissue obtained by EUS-guided sampling should include histologic preparations (e. g., cell blocks and/or formalin-fixed and paraffin-embedded tissue fragments) and should not be limited to smear cytology (low quality evidence, weak recommendation).

Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated January 2017.

For pancreatic solid lesions, ESGE recommends performing endoscopic ultrasound (EUS)-guided sampling as first-line procedure when a pathological diagnosis is required. Alternatively, percutaneous sampling may be considered in metastatic disease.Strong recommendation, moderate quality evidence.In the case of negative or inconclusive results and a high degree of suspicion of malignant disease, ESGE suggests re-evaluating the pathology slides, repeating EUS-guided sampling, or surgery.Weak recommendation, low quality evidence.In patients with chronic pancreatitis associated with a pancreatic mass, EUS-guided sampling results that do not confirm cancer should be interpreted with caution.Strong recommendation, low quality evidence.For pancreatic cystic lesions (PCLs), ESGE recommends EUS-guided sampling for biochemical analyses plus cytopathological examination if a precise diagnosis may change patient management, except for lesions ≤ 10 mm in diameter with no high risk stigmata. If the volume of PCL aspirate is small, it is recommended that carcinoembryonic antigen (CEA) level determination be done as the first analysis.Strong recommendation, low quality evidence.For esophageal cancer, ESGE suggests performing EUS-guided sampling for the assessment of regional lymph nodes (LNs) in T1 (and, depending on local treatment policy, T2) adenocarcinoma and of lesions suspicious for metastasis such as distant LNs, left liver lobe lesions, and suspected peritoneal carcinomatosis.Weak recommendation, low quality evidence.For lymphadenopathy of unknown origin, ESGE recommends performing EUS-guided (or alternatively endobronchial ultrasound [EBUS]-guided) sampling if the pathological result is likely to affect patient management and no superficial lymphadenopathy is easily accessible.Strong recommendation, moderate quality evidence.In the case of solid liver masses suspicious for metastasis, ESGE suggests performing EUS-guided sampling if the pathological result is likely to affect patient management, and (i) the lesion is poorly accessible/not detected at percutaneous imaging, or (ii) a sample obtained via the percutaneous route repeatedly yielded an inconclusive result.Weak recommendation, low quality evidence.

Increased Rate of Adenoma Detection Associates With Reduced Risk of Colorectal Cancer and Death.

BACKGROUND & AIMS: The quality of endoscopists' colonoscopy performance is measured by adenoma detection rate (ADR). Although ADR is associated inversely with interval colorectal cancer and colorectal cancer death, the effects of an increasing ADR have not been shown. We investigated whether increasing ADRs from individual endoscopists is associated with reduced risks of interval colorectal cancer and subsequent death. METHODS: We performed a prospective cohort study of individuals who underwent a screening colonoscopy within the National Colorectal Cancer Screening Program in Poland, from January 1, 2004, through December 31, 2008. We collected data from 146,860 colonoscopies performed by 294 endoscopists, with each endoscopist having participated at least twice in annual editions of primary colonoscopy screening. We used annual feedback and quality benchmark indicators to improve colonoscopy performance. We used ADR quintiles in the whole data set to categorize the annual ADRs for each endoscopist. An increased ADR was defined as an increase by at least 1 quintile category, or the maintenance of the highest category in subsequent screening years. Multivariate frailty models were used to evaluate the effects of increased ADR on the risk of interval colorectal cancer and death. RESULTS: Throughout the enrollment period, 219 endoscopists (74.5%) increased their annual ADR category. During 895,916 person-years of follow-up evaluation through the National Cancer Registry, we identified 168 interval colorectal cancers and 44 interval cancer deaths. An increased ADR was associated with an adjusted hazard ratio for interval colorectal cancer of 0.63 (95% confidence interval [CI], 0.45-0.88; P = .006), and for cancer death of 0.50 (95% CI, 0.27-0.95; P = .035). Compared with no increase in ADR, reaching or maintaining the highest quintile ADR category (such as an ADR > 24.56%) decreased the adjusted hazard ratios for interval colorectal cancer to 0.27 (95% CI, 0.12-0.63; P = .003), and 0.18 (95% CI, 0.06-0.56; P = .003), respectively. CONCLUSIONS: In a prospective study of individuals who underwent screening colonoscopy within a National Colorectal Cancer Screening Program, we associated increased ADR with a reduced risk of interval colorectal cancer and death.