Using a CA19-9 Tumor Marker Gene Test to Assess Outcome After Pancreatic Cancer Surgery.

BACKGROUND: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. Individuals can be grouped into one of four functional FUT groups (FUT3-null, FUT-low, FUT-intermediate, FUT-high), each with its own CA19-9 reference range based on its predicted capacity to produce CA19-9. The authors hypothesized that a FUT variant-based CA19-9 tumor marker gene test could improve the prognostic performance of CA19-9. METHODS: Preoperative and pre-treatment CA19-9 levels were measured, and FUT variants were determined in 449 patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2010 and 2020, including 270 patients who underwent neoadjuvant therapy. Factors associated with recurrence-free and overall survival were determined in Cox proportional hazards models. RESULTS: Higher preoperative CA19-9 levels were associated with recurrence and mortality for patients in the higher-FUT groups (FUT-intermediate, FUT-high for mortality, with adjustment for other prognostic factors; hazard ratio [HR], 1.34 and 1.58, respectively; P < 0.001), but not for those in the lower-FUT groups (FUT3-null, FUT-low). As a tumor marker, CA19-9 levels of 100 U/ml or lower after neoadjuvant therapy and normalization of CA19-9 based on FUT group were more sensitive but less specific predictors of evidence for a major pathologic response to therapy (little/no residual tumor) and of early recurrence (within 6 months). CONCLUSION: Among patients undergoing pancreatic cancer resection, a CA19-9 tumor marker gene test modestly improved the prognostic performance of CA19-9.

Duodenal and pancreatic tissue microbiome profiles of PPI users and non-users.

Factors that influence the pancreas microbiome are not well understood. Regular proton pump inhibitor (PPI) use induces significant alterations in the gut microbiome, including an increase in the abundance of Streptococcus, and may be associated with pancreatic cancer risk. The aim of this study was to examine whether PPI use is associated with pancreatic and duodenal tissue microbiomes. We compared 16S rRNA microbiome profiles of normal pancreatic and duodenal tissue from 103 patients undergoing pancreatic surgery for non-malignant indications, including 34 patients on PPIs, accounting for factors including age, smoking, body mass index and the presence of main pancreatic duct dilation. Histologically normal tissue from the pancreatic head had higher alpha diversity and enrichment of Firmicutes by phylum-level analysis and Streptococcus species compared to normal pancreas body/tail tissues (16.8 % vs 8.8 %, P = .02, and 5.9 % vs 1.4 %, P = .03, respectively). Measures of beta diversity differed significantly between the pancreas and the duodenum, but in subjects with main pancreatic duct dilation, beta diversity of pancreatic head tissue was more similar to normal duodenal tissue than those without pancreatic duct dilation. Duodenal tissue of PPI users had significant enrichment of Firmicute phyla (34.7 % vs. 14.1 %, P = .01) and Streptococcus genera (19.5 % vs. 5.2 %, P = .01) compared to non-users; these differences were not evident in pancreas tissues. By multivariate analysis, PPI use was associated with alpha diversity in the duodenum, but not in the pancreas. However, some differences in pancreas tissue beta diversity were observed between PPI users and non-users. In summary, we find differences in the microbiome profiles of the pancreas head versus the pancreatic body/tail and we find PPI use is associated with alterations in duodenal and pancreatic tissue microbiome profiles.

Esophageal Lichen Planus: A Descriptive Multicenter Report.

GOALS: To better understand the characteristics, treatment approaches, and outcomes of patients with esophageal lichen planus (ELP). BACKGROUND: ELP is a rare, often unrecognized and misdiagnosed disorder. Data on this unique patient population are currently limited to small, single-center series. STUDY: A multicenter, retrospective descriptive study was conducted of adults diagnosed with ELP over a 5-year period, between January 1, 2015, and October 10, 2020, from 7 centers across the United States. RESULTS: Seventy-eight patients (average age 65 y, 86% female, 90% Caucasian) were included. Over half had at least 1 extraesophageal manifestation. Esophageal strictures (54%) and abnormal mucosa (50%) were frequent endoscopic findings, with the proximal esophagus the most common site of stricture. Approximately 20% had normal endoscopic findings. Topical steroids (64%) and/or proton pump inhibitors (74%) dominated management; endoscopic response favored steroids (43% vs. 29% respectively). Almost half of the patients required switching treatment modalities during the study period. Adjunctive therapies varied significantly between centers. CONCLUSIONS: Given its at times subtle clinical and endoscopic signs, a high index of suspicion and biopsy will improve ELP diagnosis, especially in those with extraesophageal manifestations. Effective therapies are lacking and vary significantly. Prospective investigations into optimal treatment regimens are necessary.

Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals.

BACKGROUND & AIMS: To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection. METHODS: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs. RESULTS: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range [IQR], 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7-57 mm), a median of 11 months (IQR, 8; range 3-17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525-19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812-0.976/mm). CONCLUSIONS: In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.

Transoral incisionless fundoplication for recurrent symptoms after laparoscopic fundoplication.

BACKGROUND: Revision of a failed laparoscopic fundoplication carries higher risk of complication and lower chance of success compared to the original surgery. Transoral incisionless fundoplication (TIF) may be an endoscopic alternative for select GERD patients without need of a moderate/large hiatal hernia repair. The aim of this study was to assess feasibility, efficacy, and safety of TIF 2.0 after failed laparoscopic Nissen or Toupet fundoplication (TIFFF). METHODS: This is a multicenter retrospective cohort study of patients who underwent TIFFF between September 2017 and December 2020 using TIF 2.0 technique (EsophyX Z/Z+) performed by gastroenterologists and surgeons. Patients were included if they had (1) recurrent GERD symptoms, (2) pathologic reflux based upon pH testing or Grade C/D esophagitis or Barrett's esophagus, and (3) hiatal hernia ≤ 2 cm. The primary outcome was improvement in GERD Health-Related Quality of Life (GERD-HRQL) post-TIFFF. The TIFFF cohort was also compared to a similar surgical re-operative cohort using propensity score matching. RESULTS: Twenty patients underwent TIFFF (median 4.1 years after prior fundoplication) and mean GERD-HRQL score improved from 24.3 ± 22.9 to 14.75 ± 21.6 (p = 0.014); mean Reflux Severity Index (RSI) score improved from 14.1 ± 14.6 to 9.1 ± 8.0 (p = 0.046) with 8/10 (80%) of patients with normal RSI (< 13) post-TIF. Esophagitis healed in 78% of patients. PPI use decreased from 85 to 55% with 8/20 (45%) patients off of PPI. Importantly, mean acid exposure time decreased from 12% ± 17.8 to 0.8% ± 1.1 (p = 0.028) with 9/9 (100%) of patients with normalized pH post-TIF. There were no statistically significant differences in clinical efficacy outcomes between TIFFF and surgical revision, but TIFFF had significantly fewer late adverse events. CONCLUSION: Endoscopic rescue with TIF is a safe and efficacious alternative to redo laparoscopic surgery in symptomatic patients with appropriate anatomy and objective evidence of persistent or recurrent reflux.

Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.

Alterations in the Duodenal Fluid Microbiome of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: The tumor microbiome of patients with pancreas ductal adenocarcinoma (PDAC) includes bacteria normally present in the upper gastrointestinal tract. If the predominant source of intratumoral bacteria in patients with PDAC is retrograde migration from the duodenum, duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC. METHODS: We performed a case-control study comparing bacterial and fungal (16S and 18S rRNA) profiles of secretin-stimulated duodenal fluid collections from 308 patients undergoing duodenal endoscopy including 134 normal pancreas control subjects, 98 patients with pancreatic cyst(s) and 74 patients with PDAC. RESULTS: Alterations in duodenal fluid microbiomes with diminished alpha diversity were significantly associated with age >70 and proton pump inhibitor use. Patients with PDAC had significantly decreased duodenal microbial alpha diversity compared with age-matched control subjects with normal pancreata and those with pancreatic cyst(s). There was evidence of enrichment of Bifidobacterium genera in the duodenal fluid of patients with PDAC compared with control subjects and those with pancreatic cyst(s). There were also enrichment of duodenal fluid Fusobacteria and Rothia bacteria among patients with PDAC with short-term survival. Duodenal fluid microbiome profiles were not significantly different between control subjects and patients with pancreatic cyst(s). CONCLUSION: Patients with PDAC have alterations in their duodenal fluid microbiome profiles compared with patients with pancreatic cysts and those with normal pancreata. ClinicalTrials.gov, Number: NCT02000089.

Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer.

BACKGROUND AND AIMS: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer. METHODS: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated. RESULTS: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%. CONCLUSION: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.

BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk. METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress. RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant. CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.

Is transoral incisionless fundoplication (TIF) an answer to post-peroral endoscopic myotomy gastroesophageal reflux? A multicenter retrospective study.

BACKGROUND: The use of peroral endoscopic myotomy (POEM) for achalasia has a high incidence of post-procedural gastroesophageal reflux (GER). Transoral incisionless fundoplication (TIF) may be an ideal endoscopic treatment. We report our experience with the use of post-POEM TIF. METHODS: In this multicenter retrospective study, post-POEM patients with GER who underwent TIF were included. The study end points were: (i) technical success; (ii) safety; (iii) effectiveness (changes in symptoms, scores, proton pump inhibitor [PPI] use, pH studies). RESULTS: 12 patients underwent TIF after POEM, nine of whom had daily symptoms, with 91.7% requiring twice daily (BID) PPIs. Technical success was achieved in all patients. Two adverse events occurred. There were significant decreases in the percentage of patients on BID PPIs (P = 0.03), frequency of daily symptoms (P = 0.03), Reflux Severity Index questionnaire, and GERD Health-related Quality of Life scores (P = 0.03 and P = 0.003; n = 6). pH studies performed in seven of the patients showed a significant reduction in the mean DeMeester score (P = 0.05) and mean percentage acid exposure time (P = 0.04). CONCLUSION: Our experience suggests that TIF may be effective and safe in treating GER after POEM. Larger prospective trials are needed.

COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals.

BACKGROUND: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. METHODS: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. RESULTS: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. CONCLUSIONS: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.

Guidelines on management of pancreatic cysts detected in high-risk individuals: An evaluation of the 2017 Fukuoka guidelines and the 2020 International Cancer of the Pancreas Screening (CAPS) consortium statements.

BACKGROUND: Objectives: Pancreatic cysts are frequently detected in high-risk individuals (HRI) undergoing surveillance for pancreatic cancer. The International Cancer of the Pancreas Screening (CAPS) Consortium developed consensus recommendations for surgical resection of pancreatic cysts in HRI that are similar to the Fukuoka guidelines used for the management of sporadic cysts. We compared the performance characteristics of CAPS criteria for pancreatic cyst management in HRI with the Fukuoka guidelines originally designed for the management of cysts in non-HRI. METHODS: Using prospectively collected data from CAPS studies, we determined for each patient with resected screen-detected cyst(s) whether Fukuoka guidelines or CAPS consensus statements would have recommended surgery. We compared sensitivity, specificity, PPV, NPV, and Receiver Operator Characteristics (ROC) curves of these guidelines at predicting the presence of high-grade dysplasia or invasive cancer in pancreatic cysts. RESULTS: 356/732 HRI had ≥ one pancreatic cyst detected; 24 had surgery for concerning cystic lesions. The sensitivity, specificity, PPV, and NPV for the Fukuoka criteria were 40%, 85%, 40%, and 85%, while those of the CAPS criteria were 60%, 85%, 50%, 89%, respectively. ROC curve analyses showed no significant difference between the Fukuoka and CAPS criteria. CONCLUSIONS: In HRI, the CAPS and Fukuoka criteria are moderately specific, but not sufficiently sensitive for detecting advanced neoplasia in cystic lesions. New approaches are needed to guide the surgical management of cystic lesions in HRI.

Initial multicenter experience with nitrous oxide cryoballoon for treatment of flat duodenal adenomas (with video).

BACKGROUND AND AIMS: EMR is the preferred endoscopic therapy for duodenal adenomas (DAs) but is associated with an overall adverse event rate of 26%. Cryotherapy using a Cryoballoon Focal Ablation System (CbFAS) can safely and effectively eradicate esophageal intestinal metaplasia. We report our first experience with cryoballoon ablation for treatment of flat DAs. METHODS: This was an American, multicenter, retrospective study involving 5 centers. DAs (Paris 0-IIa and 0-IIb) were treated with nitrous oxide for 5 to 12 seconds using CbFAS. Follow-up EGD was performed at 3 to 12 months. RESULTS: Seventeen DAs (mean size, 22.7 ± 14.3 mm; 12 tubular, 5 tubulovillous) from 13 patients (mean age, 66.5 ± 9.99 years; 61.5% males) were included in the study. Thirteen of 17 DAs (76.5%) had failed previous treatment, and 4 of 17 (23.5%) were treatment naÏve. All procedures were technically successful and achieved a >50% decrease in size after cryoballoon ablation There was no increase in size or progression of disease for any lesions. Overall, treatment was completed in 15 of 17 patients, and recurrence-free survival was achieved in 12 of 17 (71%) after a median follow-up of 15.5 months (interquartile range [IQR], 6.8-19.4). The median cryoablation time per polyp was 4 minutes (IQR, 1-7.5 minutes), and the median total procedure time was 25 minutes (IQR, 22-30.5 minutes). There were no intra- or postprocedural adverse events. CONCLUSIONS: Nitrous oxide cryoballoon ablation of nonpolypoid DAs is feasible, with promising safety and efficacy.

Impedance planimetry values for predicting clinical response following peroral endoscopic myotomy.

BACKGROUND: There is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM). METHODS: A multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development. RESULTS: Of the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62. CONCLUSION: Percent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity.

Endoscopic ultrasound-directed transgastric ERCP (EDGE): a retrospective multicenter study.

BACKGROUND: Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (ERCP; EDGE) is an alternative to enteroscopy- and laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass anatomy. Although short-term results are promising, the long-term outcomes are not known. The aims of this study were: (1) to determine the rates of long-term adverse events after EDGE, with a focus on rates of persistent gastrogastric or jejunogastric fistula; (2) to identify predictors of persistent fistula; (3) to assess the outcomes of endoscopic closure when persistent fistula is encountered. METHODS: This was a multicenter retrospective study involving 13 centers between February 2015 and March 2019. Adverse events were defined according to the ASGE lexicon. Persistent fistula was defined as an upper gastrointestinal series or esophagogastroduodenoscopy showing evidence of fistula. RESULTS: 178 patients (mean age 58 years, 79 % women) underwent EDGE. Technical success was achieved in 98 % of cases (175/178), with a mean procedure time of 92 minutes. Periprocedural adverse events occurred in 28 patients (15.7 %; mild 10.1 %, moderate 3.4 %, severe 2.2 %). The four severe adverse events were managed laparoscopically. Persistent fistula was diagnosed in 10 % of those sent for objective testing (9/90). Following identification of a fistula, 5 /9 patients underwent endoscopic closure procedures, which were successful in all cases. CONCLUSIONS: The EDGE procedure is associated with high clinical success rates and an acceptable risk profile. Persistent fistulas after lumen-apposing stent removal are uncommon, but objective testing is recommended to identify their presence. When persistent fistulas are identified, endoscopic treatment is warranted, and should be successful in closing the fistula.

Gene Variants That Affect Levels of Circulating Tumor Markers Increase Identification of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) in blood are used as markers to determine the response of patients with cancer to therapy, but are not used to identify patients with pancreatic cancer. METHODS: We obtained blood samples from 504 patients undergoing pancreatic surveillance from 2002 through 2018 who did not develop pancreatic cancer and measured levels of the tumor markers CA19-9, CEA, CA-125, and thrombospondin-2. Single-nucleotide polymorphisms (SNPs) in FUT3, FUT2, ABO, and GAL3ST2 that have been associated with levels of tumor markers were used to establish SNP-defined ranges for each tumor marker. We also tested the association between additional SNPs (in FUT6, MUC16, B3GNT3, FAM3B, and THBS2) with levels of tumor markers. To calculate the diagnostic specificity of each SNP-defined range, we assigned the patients under surveillance into training and validation sets. After determining the SNP-defined ranges, we determined the sensitivity of SNP-adjusted tests for the tumor markers, measuring levels in blood samples from 245 patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC) from 2010 through 2017. RESULTS: A level of CA19-9 that identified patients with PDAC with 99% specificity had 52.7% sensitivity. When we set the cut-off levels of CA19-9 based on each SNP, the test for CA19-9 identified patients with PDAC with 60.8% sensitivity and 98.8% specificity. Among patients with FUT3 alleles that encode a functional protein, levels of CA19-9 greater than the SNP-determined cut-off values identified 66.4% of patients with PDAC, with 99.3% specificity. In the validation set, levels of CEA varied among patients with vs without SNP in FUT2, by blood group, and among smokers vs nonsmokers; levels of CA-125 varied among patients with vs without the SNP in GAL3ST2. The use of the SNPs to define the ranges of CEA and CA-125 did not significantly increase the diagnostic accuracy of the assays for these proteins. Combining data on levels of CA19-9 and CEA, CA19-9 and CA-125, or CA19-9 and thrombospondin-2 increased the sensitivity of detection of PDAC, but slightly reduced specificity. CONCLUSIONS: Including information on SNPs associated with levels of CA19-9, CEA, and CA-125 can improve the diagnostic accuracy of assays for these tumor markers in the identification of patients with PDAC. Clinicaltrials.gov no: NCT02000089.

Treatment experience with a novel 30-mm hydrostatic balloon in esophageal dysmotility: a multicenter retrospective analysis.

BACKGROUND AND AIMS: The newest addition in the management of achalasia and esophagogastric junction outflow obstruction (EGJOO) is a 30-mm hydrostatic balloon dilator that uses impedance planimetry technology. It allows for the measurement of the diameter and cross-sectional area to determine effective dilation. We aimed to (1) determine the clinical success (defined as a decrease in Eckardt score to ≤3) in the treatment of esophageal motility disorders and (2) report the safety (rate/severity of adverse events). METHODS: This retrospective multicenter study involved 4 centers. Patients with esophageal motility disorders who underwent hydrostatic balloon dilation between January 2015 and October 2018 were included. RESULTS: Fifty-one patients (mean age, 54.1 years; women, 49%) underwent hydrostatic dilation for achalasia (n = 37) or EGJOO (n = 14) during the study period. Forty-seven patients had a median baseline Eckardt score of 5 (range, 3-8; achalasia, n = 35, 6 [range, 3-8]; EGJOO, n = 12, 4 [range, 3.25-6.5]). Clinical success was achieved in 60% of cases (achalasia vs EGJOO: 68.4% vs 33.3%, P = .18). Dilation resulted in a significant decrease in the median Eckardt score from 5 (range, 3-8) to 1.5 (range, 1-4.75; P < .001). Patients with achalasia had a decrease in Eckardt score from 6 (range, 3-8) to 1 (range, 1-4; P < .001), whereas those with EGJOO experienced no significant change. One patient had mild postprocedure chest pain. CONCLUSIONS: The hydrostatic balloon dilator is a new tool in our armamentarium to treat esophageal motility disorders. This is the first multicenter study showing the device to be safe and moderately efficacious.

Safety and efficacy of the use of lumen-apposing metal stents in the management of postoperative fluid collections: a large, international, multicenter study.

BACKGROUND: Multiple studies have examined the use of lumen-apposing metal stents (LAMSs) for the drainage of peripancreatic fluid collections. Data on the use of LAMSs for postoperative fluid collections (POFCs) are scarce. POFCs may lead to severe complications without appropriate treatment. We aimed to study the outcomes (technical success, clinical success, rate/severity of adverse events, length of stay, recurrence) of the use of LAMSs for the drainage of POFCs. METHODS: This international, multicenter, retrospective study involved 19 centers between January 2012 and October 2017. The primary outcome was clinical success. Secondary outcomes included technical success and rate/severity of adverse events using the ASGE lexicon. RESULTS: A total of 62 patients were included during the study period. The most common etiology of the POFCs was distal pancreatectomy (46.8 %). The mean (standard deviation) diameter was 84.5 mm (30.7 mm). The most common indication for drainage was infection (48.4 %) and transgastric drainage was the most common approach (82.3 %). Technical success was achieved in 60/62 patients (96.8 %) and clinical success in 57/62 patients (91.9 %) during a median (interquartile range) follow-up of 231 days (90 - 300 days). Percutaneous drainage was needed in 8.1 % of patients. Adverse events occurred intraoperatively in 1/62 patients (1.6 %) and postoperatively in 7/62 (11.3 %). There was no procedure-related mortality. CONCLUSION: This is the largest study on the use of LAMSs for POFCs. It suggests good clinical efficacy and safety of this approach. The use of LAMSs in the management of POFCs is a feasible alternative to percutaneous and surgical drainage.

Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.

PURPOSE: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance. MATERIALS AND METHODS: Using a training/validation study design, FUT2/FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay. RESULTS: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2. CONCLUSION: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.

PURPOSE: Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers. MATERIALS AND METHODS: Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed. RESULTS: Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2, ATM, BRCA1, CDKN2A, MSH2/MLH1, and PALB2; the remaining 11% involved other cancer susceptibility genes such as BRIP1, BAP1, and MSH6. Almost all pathogenic variant carriers had a family history of cancer. CONCLUSION: Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.