Jorge D. Machicado

Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). Cytotoxic combination chemotherapy treatments are the mainstay of PDAC therapy, but patients rapidly develop chemoresistance, highlighting the need to elucidate how chemotherapy alters the TME and whether these changes drive chemoresistance. In this study, we examined matched pre- and posttreatment tissue specimens using single-cell RNA sequencing (scRNA-seq) and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAF) after treatment. These neural CAFs were enriched near sites of perineural invasion (PNI), coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrent lesions had the highest prevalence of neural CAFs versus primary tumors and untreated metastases. Neural CAFs showed elevated noncanonical WNT mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor–stroma cross-talk. Additionally, in vitro studies revealed enrichment of axonal guidance genes in patient-derived CAF lines upon exposure to chemotherapy or tumor cells. Altogether, these findings implicate fibroblast-derived axonal guidance genes in promoting PDAC invasion and point to a promising therapeutic target for this disease. Significance: Chemotherapy induces changes in the tumor microenvironment and induces fibroblasts with high expression of axonal-guidance genes that may drive tumor progression, uncovering a potential avenue for targeting pancreatic cancer.

Background: Advancements in endoscopic ultrasound-guided tissue acquisition (EUS-TA) for solid pancreatic masses have prompted updates in society guideline recommendations. However, the extent to which these recommendations have been adopted in clinical practice remains unclear. Thus, we sought to characterize current practice patterns and beliefs regarding EUS-TA for solid pancreatic masses in a large, international cohort of endosonographers. Methods: We developed and distributed an electronic survey to 1,281 endosonographers worldwide between September and November 2024. The survey aimed to evaluate EUS-TA practices across six domains: A) needle selection, B) sampling technique, C) method guiding the number of passes, D) specimen handling, E) quality indicator (QI) monitoring, and F) factors influencing decision-making. Results: The response rate was 30% ( n = 376). Most endosonographers often or always use fine needle biopsy (FNB) needles (90%) of 22-gauge (85%) and Franseen design (53%). The majority use a fanning technique (79%) and perform ≤ 10 actuations (60%). The number of FNB passes is mostly guided by visual on-site evaluation (60%). Advanced EUS imaging utilization was low (EUS elastography: 14%; contrast-enhanced EUS: 8%). Institutional QI monitoring was reported by 51% of endosonographers. Compared to other regions, endosonographers in North America are more likely to use rapid on-site evaluation, but less likely to use advanced EUS imaging modalities or have QI monitoring (all p < 0.001). Conclusion: There are significant global variations in EUS-TA practices for solid pancreatic masses. These survey data provide a benchmark to guide standardization, inform quality monitoring, and support evolving technologies to optimize diagnostic outcomes and patient care worldwide.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) provides inadequate pain relief in nearly half of patients with chronic pancreatitis (CP). With no reliable predictors for ERCP response, patient-reported outcome measures (PROMs) of nociplastic pain, which have demonstrated predictive value in other chronic pain conditions, are appealing but remain unexamined in CP. This study assessed whether PROMs of nociplastic pain are associated with analgesic response to ERCP in CP. Methods: Between October and November 2025, we conducted an electronic survey of patients with definite CP who had undergone technically successful pancreatic ERCP during 2019-2025. Treatment response was defined by a Patient Global Impression of Change rating of “very much improved” or “much improved”. Evaluated PROMs included: A) Michigan Body Map (MBM); B) Fibromyalgia Survey Questionnaire (FSQ); C) Generalized Sensory Sensitivity (GSS); and D) Central Sensitization Inventory (CSI). Results: Of 53 participants, 47% responded to ERCP. Using the MBM, the odds of treatment response to ERCP was lower in participants with greater number of painful body sites (OR=0.82; 95%CI 0.64-0.98; P =0.029) and regions (OR=0.73; 95%CI 0.49-0.99; P =0.06). Similarly, the odds of responding to ERCP was lower in those with higher FSQ (OR 0.85; 95%CI 0.73-0.97; P =0.05) and higher GSS (OR 0.79; 95%CI 0.61-0.99; P =0.05). Treatment response was not associated with the CSI. Conclusion: Simple PROMs such as a body map, FSQ, and GSS, can identify patients with CP who have less pain relief from ERCP. Prospective studies are needed to confirm the predictive value of these tools.

Primary sclerosing cholangitis (PSC) is a progressive fibroinflammatory disease characterized by multifocal biliary strictures, recurrent cholangitis, and a markedly increased lifetime risk of cholangiocarcinoma (CCA). Endoscopic retrograde cholangiopancreatography (ERCP) remains central to the diagnosis of CCA and management of PSC-related complications. This review synthesizes current evidence guiding the use of ERCP in patients with PSC, highlighting the importance of careful patient selection to mitigate adverse events. We review traditional ERCP techniques for the evaluation of dominant strictures such as brush cytology, fluorescence in situ hybridization (FISH), and biopsies, which exhibit limited sensitivity for detecting CCA in PSC. We also review the role of advanced endoscopic approaches including cholangioscopy, endoscopic ultrasound, and confocal endomicroscopy, alongside novel molecular diagnostics (next generation sequencing, DNA methylation markers), metabolomics, bile microbiome, and radiomics, which shown promise for risk stratification and CCA detection in PSC. Therapeutically, we review evidence supporting the use of balloon dilation as first line therapy for the management of PSC strictures and discuss settings where plastic stents might be beneficial. Furthermore, we review the endoscopic management of other PSC complications such as cholangitis, stones, acute cholecystitis, and post-transplant strictures. Finally, we provide best practice recommendations to minimize risk of complications, including use of peri-procedural antibiotic prophylaxis, technique modifications, and individualized sphincterotomy decisions. As innovative diagnostic and therapeutic strategies for PSC continue to evolve, rigorous multicenter, prospective studies are needed to assess efficacy, safety, and cost-effectiveness of these strategies prior to widespread adoption. Export

INTRODUCTION: Some patients with chronic pancreatitis (CP) experience nociplastic pain due to central nervous system dysregulation, yet its recognition is limited by the lack of bedside tools. Self-reported body maps are used to assess pain widespreadedness and to differentiate pain mechanisms in chronic pain patients, but their utility in CP is unclear. This study aimed to determine whether pain widespreadedness, measured through a body map, is associated with features of nociplastic pain in CP. METHODS: We conducted a cross-sectional analysis of adults with definite CP enrolled in a single-center longitudinal cohort. Pain widespreadedness was assessed using the Michigan Body Map and categorized by the number of painful regions (0–7) and by the presence of localized vs widespread (≥3 regions) pain. Clinical features of nociplastic pain were measured using validated psychometric and pain surveys. Group comparisons were performed with multivariable regression models adjusted for demographics, comorbidities, and CP characteristics. RESULTS: Among 110 participants (mean age 54 years, 52% male), 93% reported abdominal pain. Of those with abdominal pain, 64% had widespread pain. Increasing the number of painful regions and widespread pain (vs localized) were independently associated with higher pain severity, pain interference, and neuropathic pain scores, as well as more fatigue, impaired physical functioning, greater chronic overlapping pain conditions, and poorer physical and mental health. DISCUSSION: Two-thirds of patients with CP had widespread pain assessed using a body map. This subgroup had more severe symptoms and features of nociplastic pain. This simple tool may facilitate targeted, mechanism-based pain management in CP.

Objectives: Treatment options for abdominal pain from chronic pancreatitis (CP) are limited. Transcutaneous electrical acustimulation (TEA) is a noninvasive, self-administered, needleless acupuncture modality, with proven analgesic effects in several gastrointestinal conditions. This study aimed to assess the feasibility and acceptability of TEA in patients with painful CP, and to explore its analgesic effects. Methods: This was a single-center, single-arm, open-label, feasibility trial. The study involved 3 periods: run-in (2 wk), treatment (4 wk with TEA), and follow-up (4 wk without TEA). TEA was self-administered at home over 2 daily treatment sessions of 30 minutes each. Subjects completed daily pain diaries, weekly brief pain inventory (BPI), a treatment acceptability scale at trial completion, and other assessments at the end of each of the 3 periods. Feasibility of recruitment and data collection, acceptability of the intervention, and preliminary health effects were measured. Results: Of 178 approached subjects, 12 with painful CP were recruited (6.7% recruitment rate). After excluding 2 subjects in the run-in period and 1 subject who withdrew before TEA initiation, 9 underwent TEA treatment. Completion rate of the electronic questionnaires was 76.5%. TEA was rated as an acceptable intervention for pain, with only 11% (1/9) who dropped out from treatment sessions. Compared with baseline, there was improvement of pain severity at the end of treatment and follow-up periods. Conclusions: We found that TEA was feasible and acceptable for the treatment of painful CP. These results lay the groundwork for larger trials evaluating the efficacy of TEA in painful CP.

Background: Intraductal papillary mucinous neoplasms with low‐grade dysplasia (IPMNs w/LGD) and benign cysts, including serous cystadenomas (SCAs), are common pancreatic cystic lesions (PCLs) that are better managed conservatively. The burden of patients who undergo surgical resection for these cysts is unknown. Our study aims to estimate the global prevalence of surgical resections for IPMNs w/LGD and benign cysts, as well as the pre‐operative misclassification rate among all resected PCLs. Methods: We searched the literature through September 2023 to identify full‐text articles that reported the surgical histopathology of resected PCLs. A proportional meta‐analysis was performed using a random‐effects model, with prevalence estimates reported as pooled proportions. Subgroup analysis and meta‐regression were performed based on use of endoscopic ultrasound (EUS), years of enrollment, and geographic location. Results: Sixteen studies ( n = 5830) were identified. Among all surgically resected PCLs, 24% were IPMNs w/LGD (95% CI: 18%–32%), 16% were SCAs (95% CI 13%–19%), 4% were other benign cysts (95% CI: 3%–6%), and 24% were pre‐operatively misclassified (95% CI: 16%–34%). Of the resected IPMNs, 62% had LGD (95% CI: 51%–71%). An increasing use of pre‐operative EUS is associated with a lower prevalence of resected SCAs ( p < 0.05) but has not impacted the rate of resections for IPMNs w/LGD. The pre‐operative misclassification of PCLs has significantly decreased over time ( p < 0.01), although not significantly influenced by increasing EUS utilization or geographic location. Conclusion: One quarter of PCLs are pre‐operatively misclassified and ∼44% are surgically resected for benign cysts or IPMNs w/LGD. Implementation of advanced diagnostic tools might improve pre‐operative classification and reduce overtreatment of PCLs.