Introduction

Esophageal squamous cell carcinoma (ESCC) can be treated curatively with definitive chemoradiotherapy (CRT). However, local failure, characterized by residue just after CRT or recurrence after achieving complete response with CRT, occurs in 20-40% of patients who received this treatment. Salvage endoscopic therapy is one of the treatment options for cT1N0N0 local failure after CRT or radiotherapy (RT) for ESCC, but most reports on its outcomes are at single center.

Aims & Methods

This multicenter study aimed to clarify the short- and long-term outcomes of salvage endoscopic therapy (endoscopic resection [ER: EMR/ESD] and photodynamic therapy using Talaporfin Sodium [PDT]) for cT1N0M0 local failure after CRT/RT for ESCC, and to identify factors that influence the outcomes of salvage endoscopic therapy. Patients who underwent salvage endoscopic therapy (ER, PDT) for cT1N0M0 local failure after CRT/RT for ESCC at two institutions between December 2012 and August 2021 were retrospectively investigated. The patients were excluded if they were not followed up for more than three months after salvage therapy or had a history of salvage therapy. The selection of the procedure was primarily based on the depth of the tumor and the degree of submucosal fibrosis.

Results

A total of 168 patients were analyzed, of which 86 underwent ER (EMR/ESD = 15/71) and 82 underwent PDT. Among the patients, 140 were male, and the median age was 72 (range: 45-88) years. Lesion characteristics were as follows: The clinical T stage before CRT/RT; T1a/T1b/T2/T3/T4a/unknown = 5/78/24/48/9/4 cases. Local failure before salvage therapy; residual/local recurrent lesions = 107/61 cases. Clinical tumor depth before salvage therapy; EP-LPM/MM-SM1/SM2-SM3 = 54/35/79 cases. 53 of the 54 patients with a tumor depth of EP-LPM underwent ER, while 73 of the 79 patients with a tumor depth of SM2-SM3 underwent PDT. The local complete response rate in PDT was 62% (50/81 patients, 1 not evaluated), and the R0 resection rate in ER was 73% (63/84 patients, 2 not evaluated due to burn effect). One patient in the PDT group died from massive gastrointestinal bleeding due to esophageal-aortic fistula on the 69th day after PDT. The median observation period was 33.5 (2-109) months, and the three-year overall survival (OS), disease-specific survival, local recurrence-free survival (LRFS), and esophagectomy-free survival rates were 79% (95% confidence interval: 71-86%), 88% (80-93%), 54% (46-62%), and 76% (67-82%), respectively. Multivariate analysis revealed that age ≥75 years and residual lesion just after CRT were independent risk factors of OS (p = 0.039 and p = 0.024, respectively). Clinical tumor depth was not a significant risk factor for OS and LRFS. The clinical course after salvage treatment was as follows: 93 patients had no recurrence; 28 patients had lymph node and/or distant metastatic recurrence with/without local failure. Of the 53 patients with local failure (residual: 33, local recurrence: 20) after initial salvage endoscopic therapy, 46 underwent re-salvage therapy (ER: 11, PDT: 27, surgery: 8), and 24 of them are alive without the recurrence of ESCC, while 8 died from the primary disease.

Conclusion

Our results suggest that salvage endoscopic therapy including ER or PDT appears to be an effective treatment option for cT1N0M0 local failure after CRT/RT, regardless of clinical tumor depth, resulting in a certain number of patients achieving long-term survival without the primary disease and preserving their esophagus.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common neoplastic disease of the pancreas with a high mortality rate due to late diagnosis at an advanced stage for its asymptomatic progression. Chronic pancreatitis, one of the risk factors for the development of PDAC, complicates the diagnostic process as both conditions sometimes share overlapping clinical and pathological features. Identifying individuals at higher risk of developing the disease and detecting pancreatic cancer at an early, curable stage is critical to improving overall patient outcomes. This study investigates the potential of relative telomere length (RTL) in peripheral blood and microbiome composition as biomarkers for PDAC. These biomarkers could support a minimally invasive liquid biopsy approach for early diagnosis of PDAC, differentiation from chronic pancreatitis, and screening of high-risk individuals.

Aims & Methods

A total of 239 participants were enrolled in the study and were divided into four groups: patients with PDAC (n = 36), chronic pancreatitis (n = 60), type II diabetes mellitus (n = 91) and cancer-free individuals (n = 52). Peripheral blood samples were collected to estimate relative telomere length using the multiplex monochrome qPCR method. Stool samples from a subset comprising chronic pancreatitis patients (n = 13), PDAC patients (n = 12), and healthy controls (n = 7) were analysed using 16S rRNA sequencing for metataxonomic analysis of the gut microbiome.

Results

Microbiome analysis revealed dysbiosis in a subset of patients, with an overrepresentation of bacterial species such as Prevotella copri and Akkermansia muciniphila in chronic pancreatitis and PDAC patients. A trend towards reduced microbial diversity was observed in PDAC patients, with changes in bacterial composition already detectable in chronic pancreatitis patients. No significant differences were found in RTL between the PDAC and cancer-free patient groups, and the only risk factors associated with changes were age, gender and smoking.

Conclusion

The pilot findings suggest a general trend towards reduced microbial diversity in PDAC patients, with alterations in bacterial proportions already observed in individuals diagnosed with chronic pancreatitis. These data ptovide a basis for the development of non-invasive diagnostic strategies to improve early detection and clinical outcomes for patients with PDAC. However, relative telomere length has not been shown to be a reliable biomarker.

References

Wu H, Zou WB, Zhou DZ, Gu YT, Liao Z, Li ZS. Longer Leukocyte Telomere Length is Associated With an Increased Risk of Chronic Pancreatitis. Pancreas. 2017;46(8):e65-e66. doi:10.1097/MPA.0000000000000887
Riquelme E, Zhang Y, Zhang L, et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell. 2019;178(4):795-806.e12. doi:10.1016/j.cell.2019.07.008
Antwi SO, Petersen GM. Leukocyte Telomere Length and Pancreatic Cancer Risk: Updated Epidemiologic Review. Pancreas. 2018;47(3):265-271. doi:10.1097/MPA.0000000000000995
Campa D, Felici A, Corradi C, et al. Long or short? Telomere length and pancreatic cancer and its precursor lesions, a narrative review. Mutagenesis. 2025;40(1):39-47. doi:10.1093/mutage/gead034
Sexton RE, Uddin MH, Bannoura S, et al. Connecting the Human Microbiome and Pancreatic Cancer [published correction appears in Cancer Metastasis Rev. 2022 Jun;41(2):333. doi: 10.1007/s10555-022-10037-3.]. Cancer Metastasis Rev. 2022;41(2):317-331. doi:10.1007/s10555-022-10022-w

Introduction

Pancreatic fibrosis (PF) is a prominent histological feature of chronic pancreatitis and influences on vast majority of pancreatic disorders. So, PF early diagnosis gives a great opportunity to be a part of the strategy for preventing pancreatic diseases progression. It makes non-invasive PF assessment especially via biomarkers level measurement research perspective.

Aims & Methods

Aim was to evaluate the possibility of biomarkers levels measurement in PF grade assessment.
Methods. We measured interleukin-10 (IL-10) and interleukin-36 (IL-36), matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-9 (MMP-9), fibronectin (FN) and hyaluronic acid (HA) plasma levels from 165 patient who underwent surgery from April 2022 to February 2024 due to pancreatic tumors and advanced chronic pancreatitis. We included 69 (41.8%) male and 96 (58.2%) female patients, mean age was 57.91±13.5 (25-89). Serum levels of specified biomarkers were determined by enzyme immunoassay using commercial kits; data registration performed was carried out on a semi-automatic analyzer. PF morphological grade was assessed according to Klöppel & Maillet’s scoring system [1] and scaled into three grades: mild, moderate and severe PF.
This study was conducted within the healthcare research project “Assessment of pancreatic fibrosis as a prognostic factor for its diseases course” funded by Autonomous non-profit organization "Moscow Center for Innovative Technologies in Healthcare" administered by the Moscow Healthcare Department.

Results

Plasma FN (pFN) level was significantly (p=0.029) higher in patients with mild PF (pFN=110.7±72.7 μg/mL), than in patients with severe PF (pFN=74.9±32.8 μg/mL). The median pFN levels were significantly varied in groups with different grades of intralobular PF (p<0.05), but not in groups divided by perilobular PF grade (p>0.05). Moreover, pFN level significantly negatively correlated with PF integrative grade (Spearmen’s rho = -0.21, p=0.007). Regarding IL-10, IL36, MMP-1, MMP-9 and HA levels, there were no significant differences either in patients with different PF integrative grade, or in groups divided by perilobular and intralobular PF (p>0.05). We revealed no significant correlations between specified biomarkers levels and PF grade (p>0.05).

Conclusion

The FN serum level significantly decreased in patients with severe PF in contrast to patients with mild PF who had comparatively higher serum FN level. Oppositely, IL-10, IL36, MMP-1, MMP-9 and HA had shown no effect in PF grade assessment. It could be useful for noninvasive pancreatic fibrosis diagnosis and even for patients’ selection for advanced diagnostics.

References

1 Esposito I, Hruban RH, Verbeke C, et al. Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club. Pancreatology. 2020;20(4):586-593. doi:10.1016/j.pan.2020.04.009

Introduction

Our understanding of chronic pancreatitis (CP) etiology remains limited. Despite growing knowledge, it is believed that the known contributing factors to CP may still be underestimated. While most CP have a toxic etiology (TCP), a considerable proportion of CP is classified as idiopathic (ICP). It is plausible to speculate that some ICP cases may have a genetic basis that has not been tested or identified. Distinguishing between TCP, genetic CP (CGP) and ICP based solely on clinical features remains challenging and still the available evidence is still insufficient.

Aims & Methods

This study aimed at analyzing a prospective CP dataset to compare clinical features at diagnosis across etiologies, using principal component analysis (PCA)-based clustering to define distinct groups, with a focus on the idiopathic subtype.
We performed a retrospective analysis of a prospectively maintained database of CP patients seen in a single tertiary center (January 2019 until March 2025). We evaluated the differences in demographics, clinical characteristics, risk factors, and imaging features among patients categorized into six groups based on the TIGAR-O classification with a classical statistical analysis with Bonferroni correction for multiplicity. A PCA was performed to explore the data. To improve factor interpretability, an orthogonal rotation was applied, and the rotated factor pattern was obtained.

Results

A total of 282 patients with CP were included. Median age at diagnosis was 54 (IQR,42-64) years and 66.3% were female. TCP represented 47.2% of cases, ICP 18.8% (with early onset (<35 years) representing 15.1% of ICP cases), GCP 16.7%, autoimmune 5.7%, recurrent 6.4% and obstructive 5.3%. When comparing all etiology groups, patients with TCP were more frequently male (82%), heavy smokers (> 20 packs/year) (84.6%) and alcohol consumers (88%) than other etiologies and associated more with COPD with a statistically significant difference (p<0.0001). The family history of CP was more frequent in GCP (25.5%) compared to others. Incidental diagnosis and painless presentation were more frequent in ICP (49.1% and 62.3% respectively). Calcifications and a definite diagnosis were more frequent in the TCP and less frequent in the AIP compared to other groups (p<0.0001). After PCA analysis, five clusters were identified based on diagnostic characteristics. Focusing on the most common etiologies (TCP, ICP, GCP), a first cluster was linked with TCP and characterized by males aged 40-59, heavy smokers and drinkers, with cardiovascular and pulmonary comorbidities and jaundice among presenting signs. Another cluster was linked to late-onset ICP (>45 years), painless at diagnosis with no other symptoms or only pancreatic exocrine insufficiency (PEI). Finally, early-onset ICP (<45 years) clustered with younger patients and GCP, typically meeting minor Rosemont criteria EUS findings and lower severity according to the MANNHEIM classification.

Conclusion

Idiopathic CP behaves differently according to age of diagnosis. At the time of diagnosis, early-onset ICP clusters with genetic forms (probably due to still unknown genetic factors influencing the CP development) while late-onset ICP constitute a distinct, usually painless subgroup of patients that clusters separately from the most common TCP.

Introduction

The diagnosis of non-calcific chronic pancreatitis (CP) is challenging due to the limited accuracy of available diagnostic methods. Endoscopic ultrasound (EUS) is currently considered the most accurate method for the diagnosis of the disease, but age-related changes may affect this accuracy. In this setting, EUS-guided elastography may play a relevant role by quantifying the degree of pancreatic fibrosis, thus optimizing the diagnostic accuracy of the technique.

Aims & Methods

The aim of our study was to evaluate whether EUS-guided elastographic evaluation of the pancreas in patients with suspected CP is affected by patient age.
METHODS: Prospective comparative study of patients undergoing EUS-guided elastography for the evaluation of non-calcific CP. Procedures were performed with Fujifilm linear echoendoscopes attached to the Arietta 850 ultrasound system. The number of EUS criteria for CP according to the Rosemont classification was evaluated. The degree of pancreatic fibrosis was quantified by measuring the strain histogram (SH) and strain ratio (SR). For the evaluation of SH, an area of the pancreatic body was selected, and for the analysis of SR, the same area was selected (area A), and a soft extrapancreatic area was selected as a reference (B), with the quotient B/A being the result. Data are presented as mean ± standard deviation or median and range for quantitative variables and as percentages for categorical variables. Associations between categorical variables were tested using Fisher's exact test or chi-squared test, as appropriate. Quantitative variables were analyzed by ANOVA, and the correlation between SH and SR with Rosemont classification was analyzed by logistic regression. The Spearman test was used to assess the correlation between non-parametric variables.

Results

The study included 284 patients with a mean age of 49.8 years (range 17-85), 142 males. Normal pancreas on EUS was described in 43 patients (15.1%), indeterminate changes for CP in 110 (38.7%), and suggestive findings for CP in 131 (46.1%) according to the Rosemont classification. A statistically significant positive correlation was found between age and the number of EUS criteria according to the Rosemont classification for CP, regardless of etiology (r=0.127, p=0.03), as well as in patients without risk factors (idiopathic CP) (r=0.383, p=0.008). However, no significant correlation was observed between age and EUS elastography (neither SR nor SH) in any of the patient groups.

Conclusion

The evaluation of pancreatic fibrosis by EUS-guided elastography is not influenced by the age of the patients and is therefore accurate for the evaluation of CP.

Disclosure

Julio Iglesias-Garcia, international advisor for Fujifilm, Boston-Scientific, Viatris
Yessica Dominguez-Novoa, international advisor for Fujifilm, Viatris
Jose Lariño-Noia, international advisor for Fujifilm, Boston Scientific, Viatris
J. Enrique Domínguez, international advisor for Boston Scientific, Viatris

Introduction

Pancreatic ductal adenocarcinoma carries a dismal prognosis because it is often diagnosed at an advanced stage, with five-year survival rates below 10%. High-grade pancreatic intraepithelial neoplasia (HG-PanIN) represents a stage 0 lesion confined to the ductal epithelium and marks an essential precursor to invasive cancer. Early detection of HG-PanIN makes curative treatment possible. Magnetic resonance cholangiopancreatography (MRCP) provides a noninvasive means of visualizing both ductal and parenchymal pancreatic changes, but its ability to distinguish HG-PanIN from low-grade PanIN (LG-PanIN) has not been fully characterized.

Aims & Methods

This study aimed to identify specific MRCP imaging features that differentiate HG-PanIN from LG-PanIN. To this end, we conducted a multicenter retrospective analysis of 57 surgically confirmed PanIN cases—41 HG-PanIN and 16 LG-PanIN—collected between January 2010 and October 2023 at four Japanese tertiary centers. Two experienced abdominal radiologists independently reviewed MRCP images for main pancreatic duct (MPD) stenosis morphology, the morphology of the transition zone between stenosis and dilation, upstream MPD dilation, perilesional branch pancreatic duct (BPD) dilation, perilesional cysts, and focal pancreatic parenchymal atrophy (PPA). Disagreements were resolved by consensus. Receiver operating characteristic analysis established optimal thresholds for graded variables, which were then converted into binary measures. We assessed interobserver agreement using Cohen’s weighted κ statistics and calculated sensitivity, specificity, and accuracy for each imaging feature.

Results

Perilesional BPD dilation demonstrated substantial agreement (κ = 0.64) and yielded sensitivity of 87.8 %, specificity of 62.5 %, and accuracy of 80.7 %, representing the highest diagnostic performance. MPD stenosis morphology also showed substantial agreement (κ = 0.67) with sensitivity of 48.8 %, specificity of 75.0 %, and accuracy of 56.1 %. Upstream MPD dilation exhibited substantial agreement (κ = 0.76) but produced sensitivity of 65.9 % and specificity of 31.3 %. Focal PPA achieved high sensitivity (85.4 %) despite only fair agreement (κ = 0.23). When BPD dilation was combined with PPA, specificity increased to 93.8 % and overall accuracy reached 77.2 %.

Conclusion

These results highlight perilesional BPD dilation on MRCP as a key noninvasive indicator of HG-PanIN. Integrating ductal and parenchymal imaging markers may refine early diagnostic strategies and guide timely surgical intervention in high-risk patients. Prospective validation in larger cohorts and the development of standardized MRCP protocols are warranted to enhance surveillance of pancreatic precursor lesions and improve patient outcomes.

Introduction

​Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths, with a five-year survival rate under 10% [1]. Its lethality stems from its aggressive progression and strong chemotherapy resistance, both closely linked to epithelial-mesenchymal transition (EMT). EMT enables epithelial cells to gain migratory mesenchymal traits and is regulated by transcription factors such as SNAIL, SLUG, ZEB1/2, and TWIST [2]. Among these, SNAIL plays a major role in metastasis [3], while ZEB1 is associated with poor prognosis [4]. EMT is tightly modulated by networks including ELAVL1, which encodes the RNA-binding protein HuR. HuR stabilizes mRNAs by binding AU-rich elements (AREs) in their 3′ untranslated regions (3′UTRs), promoting their expression [5].

Aims & Methods

This study aimed to identify post-transcriptional interactions between ELAVL1 and EMT-related genes and assess their prognostic value in PDAC. mRNA was extracted from cancerous and adjacent normal tissues (n=65), converted to cDNA, and analyzed by RT-PCR. BxPC-3, MiaPaCa-2, and Su.86.86 cell lines were cultured under standard conditions. Immunoprecipitation was performed on 1–2×10⁷ cells using a mouse monoclonal anti-HuR antibody, with IgG as control. qRT-PCR assessed mRNA enrichment. Binding sites were annotated using CISBP-RNA, considering only RNAdirect-confirmed 3′UTR motifs. Target 3′UTR sequences were retrieved from GENCODE V47. Statistical analysis was performed using GraphPad Prism, applying the Wilcoxon signed-rank test, Kruskal-Wallis test with Dunn’s correction, and Spearman correlation. Data were presented as median ± interquartile range, with p<0.05 considered significant.

Results

​Expression levels of EMT-related genes and ELAVL1 varied according to survival outcomes. In short-term survivors (1–12 months), SNAIL and SLUG were significantly upregulated (2.19- and 1.92-fold), while ZEB2 was downregulated (0.65-fold). Medium-term survivors (13–35 months) showed reduced ZEB1 (0.53), SNAIL (0.30), SLUG (0.35), and TWIST (0.68). Long-term survivors (36–125 months) had the lowest levels of ZEB1 (0.24), ZEB2 (0.50), SLUG (0.24), TWIST (0.35), and ELAVL1 (0.72). ELAVL1 showed strong positive correlations with ZEB1, SNAIL, and SLUG (r = 0.74–0.76), whereas overall survival was weakly negatively correlated with the expression of ZEB1, SNAIL, SLUG, and TWIST (r = -0.25 to -0.32). Although ZEB1, SNAIL, and TWIST did not show significant survival differences individually, low SLUG predicted better early survival (36 vs. 15 months, p = 0.0278). ELAVL1 expression was stratified as high and low. High ELAVL1 corresponded to a 71.65-fold increase in ZEB1, whereas high ZEB1 reduced ELAVL1 by 96.1%. High ELAVL1 also led to a 312.35-fold increase in SNAIL, while low ELAVL1 still supported elevated SNAIL expression (8.45-fold). High SNAIL expression reduced ELAVL1 by 90%, though simultaneous high expression of both resulted in a 3.71-fold ELAVL1 increase. High SLUG reduced ELAVL1 by 93%, whereas low SLUG led to a 198.11-fold increase. Binding site analysis revealed ELAVL1 targets within 3′UTRs: 34 in ZEB1, 1 in SNAIL, and 9 in SLUG.

Conclusion

ELAVL1 (HuR) likely plays a central role in regulating EMT in PDAC through stabilization of key transcription factor mRNAs. High levels of ELAVL1, SNAIL, SLUG, and ZEB1 were associated with worse outcomes, particularly in short-term survivors. Conversely, low expression of SLUG was linked to improved survival. The strong correlations and validated binding sites suggest ELAVL1 as a promising prognostic biomarker and potential therapeutic target in PDAC.

References

1. Nakaoka K, Ohno E, Kawabe N, Kuzuya T, Funasaka K, Nakagawa Y, et al. Current status of the diagnosis of early-stage pancreatic ductal adenocarcinoma. Diagnostics (Basel). 2023;13(2).
2. Kaşıkcı E, Aydemir E, Bayrak ÖF, Şahin F. Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells - role of Snail, Slug and Twist and small molecule inhibitors. Onco Targets Ther. 2020;13:5763-77.
3. Tang X, Sui X, Weng L, Liu Y. SNAIL1: Linking tumor metastasis to immune evasion. Front Immunol. 2021;12:724200.
4. Liu M, Zhang Y, Yang J, Zhan H, Zhou Z, Jiang Y, et al. Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer. Gastroenterology. 2021;160(5):1771-1783.e1.
5. Majumder M, Chakraborty P, Mohan S, Mehrotra S, Palanisamy V. HuR as a molecular target for cancer therapeutics and immune-related disorders. Adv Drug Deliv Rev. 2022;188(114442):114442.