Introduction

Fibrosis has been proposed as a main driver of progression from acute pancreatitis (AP) to chronic pancreatitis (CP)¹. Due to the anatomy, complexity and risk associated with direct sampling from pancreatic tissue, most of our knowledge on the fibrogenic process underlying CP comes from animal studies or human studies based on circulating markers of pancreatic injury or stress. Simultaneous measurement of fibrosis biomarkers in both pancreatic fluid collections and the systemic circulation can hypothetically provide new insight to the underlying fibro-inflammatory process, which was the aim of the present study.
Five fibrosis biomarkers thought to be involved in progression from AP to CP were evaluated. PRO-C3 is a type III collagen marker reflecting levels of the N-terminal pro-peptide released by A Disintegrin and matrix metalloproteinases (MMPs) during collagen maturation, thus a marker of collagen formation². PRO-C11, a fragment of N-terminal Type XI collagen, reflects the Type XI collagen formation³ and PRO-C19 which targets the C-terminus of collagen XIX reflects the Type XIX collagen formation⁴. During fibrogenesis the normally balanced collagen formation and degradation is disrupted and MMP’s induced fragments of extra cellular matrix (ECM) turnover such as C3M (from Type III collagen) and C4M (from Type IV collagen) are released to the bloodstream^5,6.

Aims & Methods

The study was carried out as prospective cohort study including patients undergoing either diagnostic or therapeutic drainage of pancreatic fluid collections in the period August 2019 to January 2022. The blood samples were obtained just prior to puncture of the pancreatic fluid collection. The pancreatic collection was localized with the use of endoscopic ultrasound, punctured with 19 G needle and fluid aspirated for later analysis before further intervention was performed. Twenty age- and sex matched healthy controls were included for blood samples only.

Results

Forty-three patients were included, 26 with walled-off necrosis and 17 with pseudocysts. The median age was 64 and 63 years. Serum levels of all five biomarkers of fibrosis, PRO-C3, C3M, PRO-C11, PRO-C19 and C4M, were significantly elevated in patients as compared to the healthy subjects, p<0.001 for all 5 biomarkers.
Levels of PRO-C3 were significantly higher in pancreatic fluid as compared to levels in serum, (median 280.6 vs. 20.8 ng/mL, p<0.001). On opposite, levels of C3M, PRO-C19 and C4M where significantly higher in serum as compared to pancreatic fluid (median 20.5 vs. 13.1 ng/mL, 64.9 vs. 14.3 ng/mL and 55.6 vs. 20.4 ng/mL, p=0.003, p<0.001, p<0.001, respectively). No difference between serum and pancreatic fluid levels was found for PRO-C11 (28.0 vs. 27.5 ng/mL, p=0.924).

Conclusion

All five fibrosis biomarkers demonstrated elevated serum levels in patients as compared to healthy subjects indicating increased fibrotic activity in patients with pancreatic fluid collections. PRO-C3 elicited higher levels in the pancreatic fluid indicating localized fibrotic activity, whereas serum levels of C3M, PRO-C11, PRO-C19 and C4M were significantly higher as compared to levels in pancreatic fluid, thus indicating increased systemic fibrosis.

References

1. Kurzepa J, et al. Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases. Hepatobiliary Pancreat Dis Int. 2014;13(6):570-579.
2. Nielsen MJ, et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res. 2013;5(3):303-315.
3. Nissen NI, et al. Noninvasive prognostic biomarker potential of quantifying the propeptides of Type XI collagen alpha-1 chain (PRO-C11) in patients with pancreatic ductal adenocarcinoma. Int J Cancer. 2021;149(1):228-238.
4. Thorlacius-Ussing J, et al. Serum type xix collagen is significantly elevated in non-small cell lung cancer: A preliminary study on biomarker potential. Cancers (Basel). 2020;12(6):1-14.
5. Barascuk N, et al. A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem. 2010;43(10-11):899-904.
6. Sand JM, et al. MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis - Validation of two novel biomarker assays. PLoS One. 2013;8(12):1-12.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary malignant liver cancer globally and ranks as the third leading cause of cancer-related mortality. Treatment with immune checkpoint inhibitors (most commonly atezolizumab in combination with bevacizumab) is the most effective first-line systemic therapy for patients with advanced HCC. Since it is a new method of treatment, there is little clinical data on the use of this combination of drugs in practice (outside of prospective studies). This study aims to present the clinical outcomes of patients with HCC who underwent immunotherapy at our center over the past three years.

Aims & Methods

In this retrospective observational study, we included patients treated with the atezolizumab and bevacizumab combination between March 2020 and September 2023. Demographic information, general physical assesments, disease etiology, disease staging, liver cirrhosis status, portal hypertension and laboratory values (aminotransferases and total bilirubin) were collected. Adverse events were analyzed according to the Common Terminology Criteria (CTCAE). Descriptive statistics and survival analysis were performed using Statistical Package for the Social Sciences (SPSS) version 22.

Results

53 HCC patients received atezolizumab and bevacizumab in studied time period, 8 (15.1%) females and 45 (84.9%) males. The median age at the initiation of immunotherapy was 68 years (range 41 – 84 years). Thirteen patients (24.5%) had esophageal varices prior to immunotherapy, with three (5.6%) requiring ligation. The majority of patients had liver cirrhosis A 27 (50.9%) according to Child Pugh criteria, a minority B (9.4%), and 21 patients (39.6%) were without cirrhosis. The primary causes of the disease were alcohol (51.6%), metabolic dysfunction-associated steatotic liver disease (MASLD) (16.1%), hepatitis C virus (12.9%), hepatitis B virus (6.5%), and hemochromatosis (3.2%). Stage C HCC, according to The Barcelona Clinic Liver Cancer, World Health Organization (WHO) performance status 0, and absence of macrovascular invasion and extrahepatic spread were predominant at treatment initiation. Grade I or II adverse events occurred in almost all patients (98.1%). Severe adverse events were present in 36 patients (67.9%). Due to severe side effects, 8 (15.1%) patients discontinued treatment, 2 (3.8%) died due to treatment related complications (encephalitis and bleeding from esophageal varices). Treatment was modified in 21 (39.6%) patients due to adverse events. The estimated median survival was 15.7 months.

Conclusion

The majority of patients with unresectable HCC, treated with a combination of atezolizumab and bevacizumab immunotherapy, experienced adverse events, primarily grades I-II. The immunotherapy combination proved to be more effective in patients with viral etiology of liver cirrhosis. The estimated median survival was 15.7 months. This combination of immunotherapy has been demonstrated to be a safe and effective treatment method. Currently, there is limited data regarding the utilization of this treatment in standard clinical practice and our data aligns reasonably well with the findings of the registration study.

References

1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021 Jan;73 Suppl 1(Suppl 1):4–13.
2. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681–93.
3. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894–905.
4. Lee YC, Huang WT, Lee MY, Tsao CJ, Feng YH. Bevacizumab and Atezolizumab for Unresectable Hepatocellular Carcinoma: Real-world Data in Taiwan-Tainan Medical Oncology Group H01 Trial. In Vivo. 2023;37(1):454–60.
5. Himmelsbach V, Pinter M, Scheiner B, Venerito M, Sinner F, Zimpel C, et al. Efficacy and Safety of Atezolizumab and Bevacizumab in the Real-World Treatment of Advanced Hepatocellular Carcinoma: Experience from Four Tertiary Centers. Cancers (Basel). 2022 Mar 28;14(7):1722.
6. de Castro T, Jochheim LS, Bathon M, Welland S, Scheiner B, Shmanko K, et al. Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience. Ther Adv Med Oncol. 2022;14:17588359221080298.

Introduction

Peri-pancreatic fluid collections (PFCs) are frequent complications of acute pancreatitis and their management, especially in the presence of necrosis, is often challenging. Invasive interventions are indicated in case of PFC infection or symptoms related to organ compression. Endoscopic ultrasound (EUS)-guided transluminal drainage rapidly developed over time and the introduction of new dedicated stents represented a game changer of PFC treatment. In particular Bi-Flanged Metal Stent (BFMS) and Lumen Apposing Metal Stent (LAMS), with their technical characteristics, facilitate to create a stable connection between the gastrointestinal wall and the target cavity, allowing the introduction of the endoscope through the stent for direct therapeutic intervention, reporting high rates of technical and clinical success. To date, only one retrospective study have compared Nagi and Hot-Axios for EUS-guided drainage of PFCs.

Aims & Methods

The present study aimed to retrospectively evaluate the safety, technical and clinical success of the two different dedicated metal stents for EUS-guided drainage of PFC. Data from a large multicenter series of patients with PFCs treated with Hot-Axios and Nagi stents were retrieved among 30 italian centers during a 5-year period (January 2016–July 2020). Technical and clinical success, rate of adverse events were taken into account as outcome measures. To overcome biases owing to the different distribution of covariates among patients who were treated with the two kinds of stent, a 1-to-1 match was created using propensity score analysis.

Results

Out of 476 patients underwent EUS-guided drainage of PFC, 386 were treated with Hot-Axios and 90 with Nagi stent, with a median follow-up of 290 days (95% CI 244 to 361). After 1:1 propensity score matching two groups were compared, 84 subjects who experienced Hot-Axios and 84 Nagi stent, resulting well comparable in terms of several variables. Median age was 62 (49.5-73) years in the Hot-Axios group and 63 (50-74) years in the Nagi group (p=0.40), male patients were 70% and 61% in the two groups, respectively (p=0.59). WON represented 39% of cases in the Hot-Axios and 32% in the Nagi group (p=0.70); 52% and 61% of PFCs were located in the body of pancreas in the two groups respectively (p=0.62) with a median width of 92 mm (61-120) in the Hot-Axios and 88 mm (56-110) in the Nagi group (p=0.25).
The two stents did not differ in terms of adverse events (AE) rate (13% versus 15%, p=0.29).
Overall, 11 AEs were observed in the Hot-Axios group, of which 3 (3.5%) mild, 4 (4.7%) moderate, 3 (3.5%) severe and 1 (1.1%) fatal, whereas 13 AEs were registered in the Nagi group, of which 3 (3.5%), 5 (5.9%), 3 (3.5%), and 2 (2.3%) mild, moderate, severe and fatal, respectively (p=0.63). Most common AE was bleeding (5.9% in both groups). Collection recurrence was observed in 4 cases after Hot-Axios (4.7%) and 3 cases (3.5%) after Nagi stent (p=1.0).
Technical and clinical success in the two groups were respectively 92% versus 95% (p=0.36) and 91% versus 94% (p=0.64).

Conclusion

Although literature is not univocal on which type of stent offers the best outcome for EUS-guided PFC drainage, our study demonstrates that, among dedicated metal stents, Hot-Axios and Nagi stent have similar technical and clinical success rate with comparable safety profile, suggesting that the choice of one stent over another should be multifactorial, based on clinical and technical aspects and/or personal expertise, rather than just efficacy rate.

Disclosure

Chiara Coluccio is lecturer for Steris.
Andrea Anderloni is consultant for Boston Scientific, Olympus and Medtronic.
Carlo Fabbri is consultant for Boston Scientific and lecturer for Steris and Q3 Medical.
All the other authors have no conflict of interest to declare

Introduction

According to the European Society of Gastrointestinal Endoscopy guidelines, non-invasive treatments, such as endoscopic treatment (ET) and extracorporeal shock wave lithotripsy (ESWL), are available for treating pancreatic head stones. However, their efficacy for pancreatic tail stones (PTS) remains unclear.

Aims & Methods

The purpose of this study was to investigate the efficacy of ET and ESWL in the management of PTS. We conducted a single-center, retrospective study of 45 painful chronic pancreatitis patients with PTS and pancreatic body stones (PBS) who underwent non-invasive treatments between January 2008 to December 2021. The primary outcome was to determine the rates of pancreatic stone removal using ET and PTS. We also focused on and evaluated the “crab claw sign” specific to the pancreatography of caudal main pancreatic duct (MPD) stones. The secondary outcome was to identify procedural factors using logistic regression analysis.

Results

PTS (n=18) group had a significantly lower complete stone removal rate than PBS (n=27) group (22.2% versus 55.6%; P=0.03). ERCP revealed crab claw signs in 60% of cases (PTS, 77.8%; PBS, 48.1%; P=0.07), of which 48.1% could advance the guide wire into the peripheral MPD (PTS, 42.9%; PBS, 53.8%; P=0.7). Multivariate analysis revealed that PTS (OR, 0.23; 95% CI, 0.06–0.88; P=0.03), stone diameter (OR, 0.23; 95% CI, 0.06–0.88; P=0.03), number of ESWL total shots (OR, 0.06; 95% CI, 0.008–0.56; P=0.01), and crab claw sign (OR, 0.07; 95% CI, 0.01–0.28; P=0.0002) were significant factors associated with failure of stone removal.

Conclusion

Our findings indicate that large PTS with crab claw signs resist ET/ESWL treatments. These findings contribute to determining whether PTS patients should initially undergo non-invasive therapy or surgical treatment.

References

Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated August 2018. Endoscopy 2019;51:179-193.

Clinical Case Summary

Background: Juvenile polyposis syndrome (JPS) is a rare inherited autosomal dominant disease predisposing to the development of hamartomatous polyps along the gastrointestinal (GI) tract. JPS patients face a significantly higher risk of colorectal cancer (CRC), which makes endoscopic screening mandatory. JPS phenotype in patients with SMAD4 gene mutation, probably due to the dysregulation in the transforming growth factor β (TGF-β)–mediated pathways, is featured by several extraintestinal manifestations, including cutaneous and congenital abnormalities (predominantly, cardiovascular).
Case presentation: Two male brothers, aged 24 and 28 respectively, with a family history of colorectal polyposis and CRC were admitted to our Department in November 2023. For both, the colonoscopy revealed multiple GI polyps, histologically compatible with hamartomatous lesions. Next Generation Sequencing (NGS) analysis was then requested.
In the following 8 weeks, the older brother experienced a cerebral stroke, and a patent foramen ovale (PFO) was detected as the cause of this acute cerebrovascular event determining a permanent neurological impairment. Considering this, a cardiological work-up aiming to assess the same cardiac defect was performed and PFO was finally diagnosed also in the younger brother, as well as a prompt percutaneous PFO closure was disposed for both to prevent further cardiovascular accidents.
Finally, NGS analysis identified a single nucleotide mutation in the locus of the SMAD4 gene (18q21.1) confirming the diagnosis of JPS and the reported events as crucial extra-GI JPS manifestations.
Conclusion: The reported association between SMAD-4 mutation-related JPS and cardiovascular disorders, potentially leading to acute cerebrovascular accidents, highlights the need for an appropriate preventive cardiological workup in young patients for which endoscopy reveals multiple GI tract polyps.

References

[1] Cichy W, Klincewicz B, Plawski A. Juvenile polyposis syndrome. Arch Med Sci. 2014 Jun 29;10(3):570-7. doi: 10.5114/aoms.2014.43750. Epub 2014 Jun 27. PMID: 25097590; PMCID: PMC4107262.
[2] Dal Buono A, Gaiani F, Poliani L, Laghi L. Juvenile polyposis syndrome: An overview. Best Pract Res Clin Gastroenterol. 2022 Jun-Aug;58-59:101799. doi: 10.1016/j.bpg.2022.101799. Epub 2022 Apr 4. PMID: 35988962.
[3] Harris RE, Russell RK. BMPR1A mutation-positive juvenile polyposis syndrome and atrial septal defect: coincidence or association? BMJ Case Rep. 2019 Jun 21;12(6):e229881. doi: 10.1136/bcr-2019-229881. PMID: 31229977; PMCID: PMC6605934.

Introduction

H. pylori infection can remain after several eradication attempts. The objective of this study was to evaluate the effectiveness of the sixth-line rescue treatment in Europe.

Aims & Methods

Systematic and prospective registry on the clinical management of H. pylori infection. All cases with six eradication attempts registered in AEG-REDCap up to December 2022 were evaluated. The modified intention-to-treat (mITT) and per-protocol (PP) effectiveness was analysed.

Results

Overall, 81 patients were included, mainly from Spain (44% of cases), Italy (26%) and the United Kingdom (17%). The mean age was 52 years, with 52% women and 1.2% of patients allergic to penicillin. Culture was performed in 26 cases (32%), of which: 13 (50%) had bacterial antibiotic resistance to clarithromycin, 12 (46%) to nitroimidazole, and 8 (31%) to quinolones. In addition, 8 (35%) patients had dual resistance (both to clarithromycin and metronidazole) and 7 (27%) triple resistance (also to levofloxacin). Twenty-two different therapeutic combinations were used, most of them prescribed for 14 days (57%) and with low doses (39%) of PPIs. The most frequent treatments were: quadruple bismuth-tetracycline-metronidazole prescribed as three-in-one single-capsule (17%), triple amoxicillin-rifabutin (15%), quadruple bismuth-furazolidone-amoxicillin (11%), triple amoxicillin-levofloxacin (7.4%), and classical quadruple bismuth-tetracycline-metronidazole (6.2%). The highest eradication rates (mITT) were achieved with the single-capsule (77%) and with the quadruple therapy with bismuth-furazolidone-amoxicillin (67%). Overall effectiveness was 53%, both by mITT and PP analyses. Additional information on effectiveness, tolerability, compliance, and prior therapies is shown in the table.

Conclusion

Sixth-line eradication treatments in Europe obtain suboptimal eradication rates. The only therapies that reach acceptable outcomes are the bismuth quadruple therapies with either tetracycline-metronidazole (single-capsule) or with furazolidone-amoxicillin.

Disclosure

Olga P. Nyssen received research funding from Mayoly and Allergan.
Javier P. Gisbert served as speaker, consultant, and advisory member for or received research funding from Mayoly, Allergan, Diasorin, Gebro Pharma, and Richen.

Introduction

Acute pancreatitis (AP) is a common cause of acute hospital admissions, with the potential for severe acute complications, progression to chronic pancreatitis and recurrent episodes. A first presentation leads to investigations to identify a cause, including serum blood tests and transabdominal ultrasound. Following these investigations, a significant minority of patients have no clear cause for pancreatitis. Endoscopic ultrasonography (EUS) can identify aetiologies of AP, and direct intervention to reduce recurrence. The goal of this study was to determine the diagnostic yield of EUS and the impact of subsequent biliary intervention on recurrence of AP.

Aims & Methods

This was a retrospective service evaluation of EUS referrals to a regional referral centre in the UK from January 2015 to December 2019. Demographics, symptoms, liver blood tests, non-invasive imaging, EUS records and outcomes were reviewed. A EUS was labelled as diagnostic if findings were identified which explained the cause for pancreatitis that had not been explained with other investigations. Symptom resolution was defined as no further episodes of acute pancreatitis or abdominal pain requiring investigation, imaging, or presentation to secondary care during the follow-up period. Statistical significance for the difference between proportions was calculated using chi-squared tests.­­­­­­­­­­

Results

Ninety-seven patients were included in the study. The median age of the cohort was 58 (range 18-88) years. 55 (57%) patients were male. 22/97 (23%) patients had previously had a cholecystectomy. 41/97 (42%) had abnormal liver blood tests at the time of referral. Three patients had no non-invasive imaging. 27/97 (28%) had one of either transabdominal ultrasound, MRCP or CT, 63/97 (65%) had two tests and 4/97 (4%) had all three. 5 (5%) patients previously had a non-diagnostic EUS.
72/97 (74%) EUS were diagnostic. Findings included gallstones (n=15), gallbladder microlithiasis/sludge (n=51), bile duct stones (n=13), bile duct microlithiasis/sludge (n=11), chronic pancreatitis (n=7) and a pancreatic mass (n=1) which was later diagnosed as a pancreatic adenocarcinoma.
65 patients had a biliary aetiology for their pancreatitis which was amenable to treatment. Of these, 12 had subsequent ERCP, 7 had ERCP and cholecystectomy, 33 had a cholecystectomy and 13 were treated conservatively. Recurrent pancreatitis occurred in 12/52 (23%) patients who had treatment for a biliary aetiology of their pancreatitis compared with 8/13 (75%; p<0.01) of patients who were managed conservatively despite a biliary aetiology for pancreatitis, 8/32 (25%; p=0.84) of patients with a diagnostic EUS with a finding not amenable to treatment or a non-diagnostic EUS experienced further episodes. One patient died from complications related to acute pancreatitis and was not included in this analysis. Median duration of follow-up was 51 months (range 32-80 months).

Conclusion

In our cohort of patients referred for EUS for unexplained acute pancreatitis, EUS had a high diagnostic yield. A lower proportion of patients had a biliary aetiology for their pancreatitis that was amenable to intervention with either ERCP, cholecystectomy or both procedures; these patients experienced fewer episodes of recurrent acute pancreatitis than those managed conservatively. This supports the use of EUS in patients with acute pancreatitis with no cause identified with non-invasive imaging.