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Open research questions in Pancreatic and Hepatic Oncology Research

87 unresolved questions extracted from the limitations and future-work sections of 416 Pancreatic and Hepatic Oncology Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • However, diagnosing small branch-duct type IPMNs (BD-IPMNs) as the cause of RAP remains a clinical challenge, especially when standard imaging is inconclusive.

    Recurrent acute pancreatitis due to a subtle branch-duct type intraductal papillary mucinous neoplasm: A case report · 2026 · DOI

  • C_LIO_LIThe first-line priming strategy and early ECM normalisation used in this study may also be applicable to other combination therapy settings and warrants further investigation in ongoing clinical studies.

    Pulsed priming with the FAK inhibitor narmafotinib enhances both gemcitabine/Abraxane and FOLFIRINOX chemotherapy response in pancreatic cancer · 2026 · DOI

  • Abstract Background Superior mesenteric vein/portal vein (SMV/PV) resection is often required in borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) after neoadjuvant therapy (NAT), but its prognostic relevance and the role of histopathologic venous invasion remain unclear.

    Prognostic implications of superior mesenteric vein/portal vein resection and histologic venous invasion in BR/LA PDAC after neoadjuvant therapy · 2026 · DOI

  • 122394 Core Tip: Textbook outcome (TO) provides a multidimensional benchmark for pancreaticoduodenectomy, but standardized TO data from Türkiye are scarce.

    Preoperative C-reactive protein and textbook outcome following pancreaticoduodenectomy for pancreatic head adenocarcinoma · 2026 · DOI

  • Abstract Introduction: The optimal examined lymph node (ELN) count after resection for pancreatic body/tail ductal adenocarcinoma (PDAC) remains uncertain.

    Survival-anchored examined lymph node thresholds after resection for pancreatic body/tail ductal adenocarcinoma: a SEER-based cohort study with anatomical evidence synthesis · 2026 · DOI

  • A heterogenous population of secretory cells, including chemosensory tuft cells and hormone-expressing enteroendocrine cells (EECs), form during metaplasia and neoplastic progression in the pancreas, but the relevance of these populations as it relates to IPMN progression is not well characterized.

    Spatial analysis of Intraductal Papillary Mucinous Neoplasms reveals secretory cell-enriched neighborhoods · 2026 · DOI

  • Its association with immunotherapy efficacy suggests PPFIA1 warrants further investigation as a candidate biomarker and potential functional target for precision oncology.

    Unraveling the role of PPFIA1 in cancer: a comprehensive multi-omics analysis and functional validation from pan-cancer to pancreatic cancer · 2026 · DOI

  • This cellular diversity aligns with recent single-cell atlases of human pancreas but reveals immune landscapes in detail that have not been previously characterized. 27,28 Immune cell infiltration is a hallmark of pancreatitis; however, the specific immune populations and their functional states in pediatric CP have not been previously characterized.

    Single-nucleus transcriptomic analysis of pediatric pancreas reveals cellular heterogeneity and early neoplasia signatures during chronic pancreatitis · 2026 · DOI

  • The ongoing development of imaging technologies should improve the diagnosis and treatment of cystic neoplasms. One of the most intriguing advances is high-resolution micro-ultrasound, which offers higher spatial resolution than conventional EUS[110] Contrast-enhanced ultrasonic waves (CEUS) also make it possible to tell the difference between benign and malignant cystic lesions by providing real-time vascular imaging. By making tissue contrast better and being able to see small changes in cyst content[111] Spectral and dual-energy CT (DECT) are becoming more useful tools for better characterizing cystic lesions. Also, more advanced MRI techniques like MR elastography and diffusion-weighted imaging (DWI) are better at identifying lesions and figuring out who is at risk[38]. Artificial intelligence (AI) and machine learning (ML) transform medical imaging by automatically detecting and classifying cystic neoplasms[112]. AI-assisted radiomics can get quantitative information from imaging data that humans cannot see. This leads to higher diagnostic accuracy[113]. Deep learning models that have been trained on huge amounts of data have shown promise in predicting cancer in pancreatic cystic neoplasms. This can help doctors decide whether to monitor the tumors or perform surgery[114]. Using AI algorithms along with computer-aided diagnosis systems also helps radiologists interpret imaging results more accurately and consistently. Imaging developments open the path for customized treatment plans catered to the particular patient[115,116]. Through-the-needle microforceps biopsy during EUS is one of the imaging-guided liquid biopsy methods under development for better molecular profiling of cystic lesions[117]. Imaging biomarkers and genetic and proteomic analysis are likely to be used together in future studies to better group patients, which will improve treatment outcomes and cut down on procedures that are not needed. Theranostic imaging is also becoming more popular. This type of imaging can both diagnose and treat diseases. It is especially useful for guiding minimally invasive treatments for cystic neoplasms[118] Combining several imaging modalities is expected to improve the accuracy of cystic neoplasm evaluation. Hybrid imaging techniques like PET/MRI and PET/CT give us better information about anatomy and metabolism, which helps in identifying the difference between benign and malignant cysts. Furthermore, the project is projected to improve preoperative planning and procedure direction through 3D imaging reconstruction and virtual endoscopy, thus improving patient outcomes[119,120].

    Evaluation of cystic neoplasms using EUS, MRI, and CT scan and treatment strategy · 2026 · DOI

  • Second, because GS constituted the predominant neoadjuvant regimen in this cohort, the generalizability of the observed response dis- tribution and outcome estimates to other contemporary regimens, such as modified FOLFIRINOX or gemcitabine plus nab-paclitaxel, remains uncertain and warrants exter- nal validation. Future studies integrating baseline tumor volume, site- stratified analyses, and molecular biomarkers are warranted to delineate the intrinsic predictors of chemotherapy respon- siveness in PDAC. Although dis- crepant or ambiguous cases were resolved by consensus review by two pathologists, we did not formally quantify interobserver agreement such as kappa statistics; therefore, broader validation using standardized protocols and repro- ducibility metrics is warranted.

    Histological treatment response to neoadjuvant chemotherapy predicts the survival outcomes of patients with resectable pancreatic cancer: validation of the Japan Pancreas Society grading system · 2026 · DOI

  • Although our results suggest that complete excision of the mesopancreas is technically possible with a high R0 resection rate, the consistently high recurrence rates, particularly for distant metastases, raise questions concerning the long-term impact of this procedure on survival rates.

    Mesopancreas excision in pancreatic ductal adenocarcinoma: recurrence patterns — a single-arm descriptive study · 2026 · DOI

  • EUS should be considered in the evaluation of cysts of uncertain significance, in assessing the malignant risk of mucinous lesions, and when MRI is insufficient to define the clinical approach.

    Portuguese Pancreatic Club Perspective on Intraductal Papillary Mucinous Neoplasm Diagnosis, Characterization and Indications for Fine Needle Aspiration/Biopsy, Advanced Endoscopic Ultrasound Imaging Techniques and Role of Pancreatoscopy · 2026 · DOI

  • The TGF{beta} and JAK/STAT signaling networks are recognized regulators of tumor progression, immune modulation, and therapeutic resistance; however, their genomic architecture in clinically stratified PDAC populations remains poorly defined.

    Conversational Artificial Intelligence-Enabled Precision Oncology Reveals Context-Specific TGFβ and JAK/STAT Alterations in Pancreatic Cancer · 2026 · DOI

  • ABSTRACT Background There are no consensus guidelines for staging laparoscopy (SL) in pancreatic ductal adenocarcinoma (PDAC) and existing data largely reflect insured referral populations.

    The Role of Routine Staging Laparoscopy for Pancreatic Adenocarcinoma in Underserved Populations: A 14‐Year Experience at a Safety‐Net Hospital · 2026 · DOI

  • The types of blood supply to the spleen after WP and their incidence have not been previously described, nor has the significance of these types for locally advanced pancreatic head cancer (LAPHC) surgery been determined.

    Three Types of Collateral Arterial Supply to the Spleen After Spleen-Preserving Distal Pancreatectomies with Splenic Vessel Resection—How to Use This Knowledge for Organ(s) Preservation in Locally Advanced and Borderline Resectable Pancreatic Head Cancers Surgery—Hemodynamic, Surgical and Oncological Outcomes of 134 Spleen-Preserving Pancreatectomies · 2026 · DOI

  • BACKGROUND The rising detection of branch-duct intraductal papillary mucinous neoplasms (BD-IPMN) has led to updated surveillance guidelines, yet the true malignant transformation rate and the cost-effectiveness of these strategies remain uncertain.

    Optimizing branch-duct intraductal papillary mucinous neoplasms surveillance: Data-driven dimensional grouping for risk stratification and cost-effectiveness · 2026 · DOI

  • The mechanistic link between PPAP, clinically relevant POPF (CR-POPF), and mortality resulting from the inability to rescue patients after complications has not been fully elucidated.

    Interplay of Postpancreatectomy Acute Pancreatitis, Postoperative Pancreatic Fistula, and Mortality after Pancreatoduodenectomy: Insight from a Comprehensive Cohort Study of 1,594 Patients and Development of Predictive Nomograms · 2026 · DOI

  • This systematic review provides a comprehensive synthesis of the specific impact of the MDT approach for focal pancre- atic lesions, moving beyond survival to examine effects on diagnostics, treatment, compliance, and patient outcomes. However, our findings must be interpreted in light of several important limitations. The retrospective design and selection bias across studies limited the evidence qual- ity [51]. Furthermore, while the included studies were predominantly focused on PDAC, with only a minority specifically examining PCNs, the primary studies did not employ a uniform patient population or report outcomes in a manner that permitted formal subgroup analyses by lesion category. Given the substantial biological and clini- cal differences between PDAC and PCNs, this represents an important limitation of this review. Substantial heterogene- ity existed both in patient populations, ranging from exclu- sively PDAC cohorts to mixed or solely PCN cohorts, and in the MDT interventions evaluated (from case-based tumor boards to patient-facing clinics). This variation, together with the absence of standardized metrics for assessing MDT process quality, precluded a formal meta-analysis and complicated the attribution of observed effects to specific MDT components. Additionally, none of the pre–post study designs controlled for temporal improvements in imaging modalities or systemic therapies, which may have inflated the apparent benefit of MDT care. Finally, despite a broad search strategy, varied nomenclature for MDTs and poten- tial publication bias means some relevant studies may have been missed.

    Effectiveness of multidisciplinary team collaboration in focal pancreatic lesion management: a systematic review · 2026 · DOI

  • • Patient-facing MDC reduced time to first treatment and num- ber of pretreatment visits. • Improved care coordination and facilitated research enrollment. • Quality of care improved following establishment of a multi- disciplinary hepatopancreaticobiliary program. • Quality measurable via site-specific pancreatic quality indicator. • Mortality unchanged across volume periods; adjuvant therapy uses and Stage I/II resection improved, potentially contributing to long-term survivorship. • Institutional learning curve identified during transition from low- to high-volume center. • Multidisciplinary evaluation with radiologic review may improve surgical outcomes and therapeutic decision-making.

    Effectiveness of multidisciplinary team collaboration in focal pancreatic lesion management: a systematic review · 2026 · DOI

  • This Review systematically elucidates that KRAS mutations in PDAC not only drive autonomous tumor cell proliferation but also orchestrate a profoundly immunosuppressive “cold” TME. This is achieved through multiple, interconnected mechanisms, including induction of immune cell dysfunction and exhaustion, recruitment of immunosuppressive populations such as MDSCs, establishment of a dense fibrotic stromal barrier, and metabolic reprogramming centered on enhanced glycolysis. Collectively, these processes constitute the fundamental basis for the intrinsic resistance of PDAC to immunotherapy. In response to the repeated failure of ICI monotherapy, the current ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT ARTICLE IN PRESS research paradigm has shifted toward multimodal combination strategies. This Review summarizes the major therapeutic avenues under active investigation: combinations of immunotherapy with radiotherapy or chemotherapy leverage the “in situ vaccine” effect of radiotherapy and the immunomodulatory properties of cytotoxic agents to promote immune activation; combinations of immunotherapy with targeted therapies—including direct KRAS G12C/G12D inhibitors, PARP inhibitors, MEK inhibitors, and FAK inhibitors—aim to disrupt oncogenic signaling or cooperative pathways while simultaneously alleviating immune suppression; emerging immunotherapeutic modalities such as CAR-T cell therapy, oncolytic viruses, and CD40 agonists seek to directly activate or reprogram antitumor immune responses; and innovative local drug-delivery systems—including injectable hydrogels, stimuli-responsive nanoparticles, and oral spore-based carriers—provide critical technological support for achieving high intratumoral drug concentrations with prolonged retention and minimal systemic toxicity. Accumulating preclinical and clinical evidence indicates that rational combination strategies capable of systematically remodeling the TME are central to reversing immune tolerance and restoring effective antitumor immunity in PDAC. Future perspectives: Future breakthroughs are likely to arise from a paradigm shift from “broad combination” approaches to “precision synergy.” A primary objective will be the development of predictive biomarker systems through the integration of ctDNA dynamics, spatial transcriptomics, proteomics, and other multi-omics technologies, enabling accurate identification of patient subgroups most likely to benefit from specific combination strategies. Such biomarker-driven stratification will be essential for implementing truly personalized immunotherapy. Building on this foundation, therapeutic strategies must evolve toward “dynamic precision intervention,” involving the development of agents or combinatorial regimens that simultaneously target KRAS signaling, stromal barriers, and metabolic reprogramming.

    Current advances in immunotherapy for KRAS-Mutant pancreatic cancer · 2026 · DOI

  • Although limited by the nature of a single case report, this case’s findings underscore the potential value of incorporating molecular characteristics alongside conventional clinicopathological factors in future prognostic research and personalized treatment strategies in PDAC.

    Early Metastatic Relapse in Resected Stage IB KRAS G12D Pancreatic Ductal Adenocarcinoma: Limitations of Anatomical Staging · 2026 · DOI

  • This highlights a major limitation of relying solely on CA 19-9 kinetics as a surrogate marker of therapeutic response in aggressive PDAC and emphasizes the importance of early reassessment when new symptoms arise despite apparent biochemical improvement.

    Early Metastatic Relapse in Resected Stage IB KRAS G12D Pancreatic Ductal Adenocarcinoma: Limitations of Anatomical Staging · 2026 · DOI

  • Pancreatic cancer has well-established precursor lesions, which, if identified and man- aged early on leads to surgery for pancreatic conditions with potentially better oncological prognosis. The increased use of cross-sectional imaging means more patients may be diag- nosed with early lesions such as IPMNs that have adverse radiological features but are not Cancers 2025, 17, 2602 18 of 20 yet invasive cancer. Similarly NETs although relatively rare, may be detected earlier when they are small neoplasms. For this group of patients with better prognosis lesions, quality of life after pancreatic surgery will become an increasingly important issue. Likewise, im- provements in perioperative outcomes such as declining early mortality, means that there are more patients for whom quality of survivorship rather than mere survivorship matters. Increasing use of neoadjuvant approaches to PDAC may change the profile of patients having surgery for invasive cancer in two ways: (1) Downstaging tumours pre-operatively may allow more patients to have surgery with curative intent and mean that more patients complete systemic treatment as well as surgery, which leads to longer survival. (2) Patients with aggressive lesions may progress while undergoing neoadjuvant treatment and this group may be spared high impact surgery that would have been futile, although the final outcome is palliative. PDAC is associated with poor prognosis, which is often attributed to the multifactorial nature by which it evolves. It is difficult to treat successfully with systemic therapy as it often develops resistance to treatments due to frequent mutations and demonstrates genetic heterogeneity within the same primary tumour. Treatments that have been successful in targeting single genes in other types of cancer such as EGFR in lung cancer or B-RAF in melanoma, are not effective in pancreatic cancer for this reason [40]. Standardised measures of quality of life after pancreatic surgery such as EORTC QLQ Pan 26 [3] and PEI Q [23]. The PEI Q can be used to identify areas of care that warrant further research. Improvements in type 3c Diabetes management and its monitoring can potentially improve quality of life in this patient group, potentially making total pancreatectomy, where indicated, a feasible option for more patients. Early involvement of diabetic specialist teams for patients who have undergone pancreatic resection is also important. Increased recognition of the importance of PERT can lead to better outcomes where this has been neglected historically. Involvement of multidisciplinary teams including dieticians and credentialled clinical nurse specialists may reap benefits. Involvement of palliative care physicians to assist with symptom control where appropriate is likely to be advantageous. There is a role for early referral of patients to supportive or palliative care due to the high burden of symptoms and poor prognosis. Interventions such as coeliac plexus neurolysis should be considered early when appropriate. The impact of delayed gastric emptying and other digestive disturbances after pancreaticoduodenectomy has tended to be under-recognised and resolving this issue remains a challenge. Further research into this problem, its solutions and its impact may be important for improving quality of life for pancreatectomy survivors.

    Psychological intervention and health education effects on quality of life in patients after pancreatic cancer surgery: A meta-analysis · 2026 · DOI

  • Third, the present study showed the presence of POU2F3‑positive tuft cells expressing H‑PGDS in IPMN; however, the function of PGD2 production in IPMN and the differences between H‑PGDS‑positive and H‑PGDS‑negative tuft cells remain unclear.

    Presence of tuft cells expressing haematopoietic prostaglandin D synthase in intraductal papillary mucinous neoplasms of the pancreas · 2026 · DOI

  • This study has several limitations that should be acknowledged. First, the sample size was small (n = 5), reflecting the pilot feasibility design. As such, the study was not powered to detect subtle biological effects or inter- individual variability in cfDNA kinetics. Second, the study employed a single-arm design without a control condition, which limits causal inference regarding the effect of Sonazoid® on cfDNA levels and leaves open the possibility of sampling-related variation. Future studies should incorporate an appropriate comparator design, such as a crossover, repeated-visit ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT within-patient control, or mock/placebo control, to more rigorously evaluate whether Sonazoid® alters circulating cfDNA kinetics. Third, blood sampling was limited to a 60-minute post-administration window; therefore, delayed effects of Kupffer cell engagement on cfDNA clearance may not have been captured. Fourth, an additional limitation is that plasma-based cfDNA concentrations (e.g., ng/mL plasma) could not be accurately calculated in this study. Because the total blood volume obtained at each sampling time point varied across samples due to practical constraints during serial sampling, the actual volume of plasma recovered after centrifugation also varied. As the recovered plasma volume for each individual sample was not recorded in a manner that allowed reliable retrospective conversion, the reported cfDNA values reflect concentrations measured in the purified eluate rather than standardized plasma-based concentrations. This limits direct comparison with other cfDNA studies. Future studies should prospectively standardize and record exact sample and plasma volumes to enable reporting in plasma-based units. Fifth, total cfDNA was quantified using a fluorometric assay, which does not distinguish tumor-derived ctDNA from non-tumor-derived cfDNA and does not provide information on mutation profiles, methylation patterns, or fragmentomic features. Because Sonazoid® may influence clearance in a size-dependent manner, assessment of cfDNA fragment length profiles may be particularly relevant in future studies, especially given the growing biological and clinical interest in cfDNA fragmentomics. ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT Finally, direct assessment of Kupffer cell uptake or downstream clearance pathways after perflubutane administration was not performed, precluding mechanistic conclusions regarding hepatic modulation of cfDNA dynamics. Despite these limitations, the present study provides transparent feasibility data that may inform the design of future studies incorporating ctDNA-focused endpoints, extended sampling windows, and appropriate control conditions.

    Feasibility of serial cfDNA measurement after perflubutane microbubble (Sonazoid®) administration in patients with pancreatic ductal adenocarcinoma: a first-in-human pilot study · 2026 · DOI

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