A novel cryoballoon ablation system for eradication of dysplastic Barrett's esophagus:a first-in-human feasibility study

BACKGROUND:  Endoscopic cryoablation for Barrett's esophagus (BE) might offer advantages over heat-based ablation. Focal cryoballoon ablation has been promising for short-segment BE, whereas the novel 90°-swipe cryoballoon ablation system (CbSAS90) ablates larger areas in a single step (90° over 3 cm). The system allows for dose adjustment. CbSAS90 has been feasible and safe in animal and pre-esophagectomy studies. This is the first clinical study to assess feasibility, safety, and efficacy of CbSAS90 for eradication of dysplastic BE. METHODS:  In this prospective study in dysplastic BE patients, dose finding started with semi-circumferential treatment at 0.8 mm/s (dose 1). The dose was escalated by reducing speed by 0.1 mm/s in six patients until BE surface regression was ≥ 80 % without complications ("effective dose"). The effective dose was subsequently confirmed with circumferential treatment in 12 new patients. Post-procedural pain (0 - 10) and dysphagia (0 - 4) were evaluated. Outcomes were feasibility, safety, and BE surface regression. RESULTS:  25 patients were included, with technically successful treatment in 92 % (95 %CI 73 % - 99 %). Median (95 %CI) BE surface regression was 78 % (50 % - 85 %) for dose 1 and 85 % (55 % - 95 %) for dose 2 (0.7 mm/s), which was defined as the effective dose. Circumferential treatment resulted in 93 % (88 % - 96 %) regression. Two of 12 patients with circumferential treatment developed strictures that required dilation. Median pain and dysphagia scores were low (0 - 3 and 0, respectively). CONCLUSIONS: CbSAS90 was feasible and effective for ablating larger BE areas. The optimal dose for circumferential treatment that balances safety and efficacy requires further evaluation

Optimization of ERCP Technique to Improve the Sensitivity of Biliary Brushing: A Systematic Review and Meta-analysis

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology is an important tool in the diagnosis of hepatobiliary malignancies. However, reported sensitivity of brush cytology is suboptimal and differs markedly per study. The aim of this study is to analyze the optimal technique of endobiliary brushing during ERCP. METHODS: A systematic review and meta-analysis according was performed using Pubmed, Embase and Cochrane library, and reported reported according to the PRISMA guidelines. The intervention reported should involve ERCP, performed by the endoscopist with a comparison of different brushing techniques. The primary outcome was sensitivity for malignancy. Studies published up to December 2022 were included. Percutaneous techniques and cytological or laboratory techniques for processing of material were excluded. Bias was assessed using the Quadas-2 tool. Pooled sensitivity rates and Forest plots were analyzed for the primary outcome. RESULTS: A total of 16 studies were included. Three studies reported on brushing before or after dilation of a biliary stricture. No improvement in sensitivity was found. Five studies reported on alternative brush designs. This did not lead to improved sensitivity. Seven studies reported on the aspiration and analysis of bile fluid, which resulted in a 16% increase in sensitivity (95% CI 4-29%). One study reported an increased in the number of brush passes to the stricture, providing an increase in sensitivity of 20%. Substantial heterogeneity between studies was found, both methodological and statistical. CONCLUSIONS: Increasing the number of brush-passes and sending bile fluid for cytology increases the sensitivity of biliary brushings during ERCP. Dilation before brushing or alternative brush designs did not increase sensitivity

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands A Nationwide Analysis

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection

DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms

Background & Aims: Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms. Methods: DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin. Results: After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample. Conclusions: Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting

Axial slicing versus bivalving in the pathological examination of pancreatoduodenectomy specimens (APOLLO): a multicentre randomized controlled trial

Background: In pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving. Methods: In four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0–100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate. Results: In total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar. Conclusion: This study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest

Efficacy of dose-escalated chemoradiation on complete tumour response in patients with locally advanced rectal cancer (RECTAL-BOOST); a phase 2 randomised controlled trial

Purpose Pathological complete tumour response following chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with favourable prognosis and allows organ-sparing treatment strategies. We aimed to investigate the effect of an external radiation boost to the tumour prior to chemoradiation on pathological or sustained clinical complete tumour response in LARC. Methods and materials This multicentre, non-blinded, phase 2, randomised controlled trial followed the trials within cohorts-design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can accept or refuse this), whereas patients in the control group are not notified about the randomisation. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of two radiotherapy centres were eligible. Patients were randomised to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathological complete response (pCR, i.e. ypT0N0) in patients with planned surgery at 12 weeks or, as surrogate for pCR, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCTXXXXXX. Results Between Sept 2014 and July 2018, 128 patients were randomised. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4-stage and a low rectal tumour (31.3% versus 17.2% and 56.3% versus 45.3% respectively), and more patients had a cN2-stage (59.4% versus 70.3% respectively). Rate of pathological or sustained clinical complete tumour response was similar between the groups: 23 of 64 (35.9%, 95%CI 24.3-48.9) in the intervention group versus 24 of 64 (37.5%, 95%CI 25.7-50.5) in the control group (OR=0.94 95%CI 0.46-1.92). Near-complete or complete tumour regression was more common in the intervention group: 34 of 49 (69.4%) versus 24 of 53 (45.3%) in the control group (OR=2.74, 95%CI 1.21-6.18). Grade >3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR=1.22 95%CI 0.35-4.22). Conclusion Dose escalation with an external radiotherapy boost to the tumour prior to neoadjuvant chemoradiation did not increase the pathological or sustained clinical complete tumour response rate in LARC

Optimizing histopathologic evaluation of EMR specimens of Barrett's esophagus–related neoplasia: a randomized study of 3 specimen handling methods

Background and Aims: Endoscopic resection is the cornerstone of treatment of Barrett's esophagus (BE)-related neoplasia. However, accurate histopathologic evaluation of endoscopic resection specimens can be challenging, and the preferred specimen handling method remains unknown. Therefore, the aim of our study was to compare 3 different specimen handling methods for assessment of all clinically relevant histopathologic parameters and time required for specimen handling. Methods: In this multicenter, randomized study EMR specimens of BE-related neoplasia with no suspicion of submucosal invasion during endoscopy were randomized to 3 specimen handling methods: pinning on paraffin using needles, direct fixation in formalin without prior tissue handling, and the cassette technique (small box for enclosing specimens). The histopathologic evaluation scores were assessed by 2 dedicated GI pathologists blinded to the handling method. Results: Of the 126 randomized EMR specimens, 45 were assigned to pinning on paraffin, 41 to direct fixation in formalin, and 40 to the cassette technique. The percentages of specimens with overall optimal histopathologic evaluation scores were similar for the pinning method (98%; 95% confidence interval [CI], 88.0-99.9) and for no handling (90%; 95% CI, 76.9-97.3) but were significantly lower (64%; 95% CI, 47.2-78.8) for the cassette technique (P < .001). Time required for specimen handling was shortest when no handling method was used (P < .001 vs pinning and cassette). Conclusions: Both pinning on paraffin and direct fixation in formalin resulted in optimal histopathologic evaluation scores in a high proportion of specimens, whereas the cassette technique performs significantly worse, and its use in clinical daily practice should be discouraged. Given the significantly shorter handling time, direct fixation in formalin appears to be the preferred method over pinning on paraffin. However, the latter needs to be confirmed in larger studies with inclusion of all EMR specimens. (Clinical trial registration number: ISRCTN50525266.

A novel cryoballoon ablation system for eradication of dysplastic Barrett's esophagus : a first-in-human feasibility study

BACKGROUND:  Endoscopic cryoablation for Barrett's esophagus (BE) might offer advantages over heat-based ablation. Focal cryoballoon ablation has been promising for short-segment BE, whereas the novel 90°-swipe cryoballoon ablation system (CbSAS90) ablates larger areas in a single step (90° over 3 cm). The system allows for dose adjustment. CbSAS90 has been feasible and safe in animal and pre-esophagectomy studies. This is the first clinical study to assess feasibility, safety, and efficacy of CbSAS90 for eradication of dysplastic BE. METHODS:  In this prospective study in dysplastic BE patients, dose finding started with semi-circumferential treatment at 0.8 mm/s (dose 1). The dose was escalated by reducing speed by 0.1 mm/s in six patients until BE surface regression was ≥ 80 % without complications ("effective dose"). The effective dose was subsequently confirmed with circumferential treatment in 12 new patients. Post-procedural pain (0 - 10) and dysphagia (0 - 4) were evaluated. Outcomes were feasibility, safety, and BE surface regression. RESULTS:  25 patients were included, with technically successful treatment in 92 % (95 %CI 73 % - 99 %). Median (95 %CI) BE surface regression was 78 % (50 % - 85 %) for dose 1 and 85 % (55 % - 95 %) for dose 2 (0.7 mm/s), which was defined as the effective dose. Circumferential treatment resulted in 93 % (88 % - 96 %) regression. Two of 12 patients with circumferential treatment developed strictures that required dilation. Median pain and dysphagia scores were low (0 - 3 and 0, respectively). CONCLUSIONS: CbSAS90 was feasible and effective for ablating larger BE areas. The optimal dose for circumferential treatment that balances safety and efficacy requires further evaluation

A novel cryoballoon ablation system for eradication of dysplastic Barrett's esophagus: A first-in-human feasibility study

Background â Endoscopic cryoablation for Barrett's esophagus (BE) might offer advantages over heat-based ablation. Focal cryoballoon ablation has been promising for short-segment BE, whereas the novel 90°-swipe cryoballoon ablation system (CbSAS 90) ablates larger areas in a single step (90° over 3âŠcm). The system allows for dose adjustment. CbSAS 90 has been feasible and safe in animal and pre-esophagectomy studies. This is the first clinical study to assess feasibility, safety, and efficacy of CbSAS 90 for eradication of dysplastic BE. Methods â In this prospective study in dysplastic BE patients, dose finding started with semi-circumferential treatment at 0.8âŠmm/s (dose 1). The dose was escalated by reducing speed by 0.1âŠmm/s in six patients until BE surface regression was ≥âŠ80âŠ% without complications (effective dose). The effective dose was subsequently confirmed with circumferential treatment in 12 new patients. Post-procedural pain (0âŠ-âŠ10) and dysphagia (0âŠ-âŠ4) were evaluated. Outcomes were feasibility, safety, and BE surface regression. Results â 25 patients were included, with technically successful treatment in 92âŠ% (95âŠ%CI 73âŠ%âŠ-âŠ99âŠ%). Median (95âŠ%CI) BE surface regression was 78âŠ% (50âŠ%âŠ-âŠ85âŠ%) for dose 1 and 85âŠ% (55âŠ%âŠ-âŠ95âŠ%) for dose 2 (0.7âŠmm/s), which was defined as the effective dose. Circumferential treatment resulted in 93âŠ% (88âŠ%âŠ-âŠ96âŠ%) regression. Two of 12 patients with circumferential treatment developed strictures that required dilation. Median pain and dysphagia scores were low (0âŠ-âŠ3 and 0, respectively). Conclusions CbSAS 90 was feasible and effective for ablating larger BE areas. The optimal dose for circumferential treatment that balances safety and efficacy requires further evaluation

Nationwide Impact of Centralization, Neoadjuvant Therapy, Minimally Invasive Surgery, and Standardized Pathology Reporting on R0 Resection and Overall Survival in Pancreatoduodenectomy for Pancreatic Cancer

Background: Surgeons aim for R0 resection in patients with pancreatic cancer to improve overall survival. However, it is unclear whether recent changes in pancreatic cancer care such as centralization, increased use of neoadjuvant therapy, minimally invasive surgery, and standardized pathology reporting have influenced R0 resections and whether R0 resection remains associated with overall survival. Methods: This nationwide retrospective cohort study included consecutive patients after pancreatoduodenectomy (PD) for pancreatic cancer from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database (2009–2019). R0 resection was defined as > 1 mm tumor clearance at the pancreatic, posterior, and vascular resection margins. Completeness of pathology reporting was scored on the basis of six elements: histological diagnosis, tumor origin, radicality, tumor size, extent of invasion, and lymph node examination. Results: Among 2955 patients after PD for pancreatic cancer, the R0 resection rate was 49%. The R0 resection rate decreased from 68 to 43% (2009–2019, P < 0.001). The extent of resections in high-volume hospitals, minimally invasive surgery, neoadjuvant therapy, and complete pathology reports all significantly increased over time. Only complete pathology reporting was independently associated with lower R0 rates (OR 0.76, 95% CI 0.69–0.83, P < 0.001). Higher hospital volume, neoadjuvant therapy, and minimally invasive surgery were not associated with R0. R0 resection remained independently associated with improved overall survival (HR 0.72, 95% CI 0.66–0.79, P < 0.001), as well as in the 214 patients after neoadjuvant treatment (HR 0.61, 95% CI 0.42–0.87, P = 0.007). Conclusions: The nationwide rate of R0 resections after PD for pancreatic cancer decreased over time, mostly related to more complete pathology reporting. R0 resection remained associated with overall survival