A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. METHODS AND FINDINGS: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. CONCLUSIONS: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.

Performance and Safety of EUS Ablation Techniques for Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis.

BACKGROUND: Pancreatic cystic lesions (PCL) represent an increasingly diagnosed condition with significant burden to patients' lives and medical resources. Endoscopic ultrasound (EUS) ablation techniques have been utilized to treat focal pancreatic lesions. This systematic review with meta-analysis aims to assess the efficacy of EUS ablation on PCL in terms of complete or partial response and safety. METHODS: A systematic search in Medline, Cochrane and Scopus databases was performed in April 2023 for studies assessing the performance of the various EUS ablation techniques. The primary outcome was complete cyst resolution, defined as cyst disappearance in follow-up imaging. Secondary outcomes included partial resolution (reduction in PCL size), and adverse events rate. A subgroup analysis was planned to evaluate the impact of the available ablation techniques (ethanol, ethanol/paclitaxel, radiofrequency ablation (RFA), and lauromacrogol) on the results. Meta-analyses using a random effects model were conducted and the results were reported as percentages with 95% confidence intervals (95%CI). RESULTS: Fifteen studies (840 patients) were eligible for analysis. Complete cyst resolution after EUS ablation was achieved in 44% of cases (95%CI: 31-57; 352/767; I2 = 93.7%), and the respective partial response rate was 30% (95%CI: 20-39; 206/767; I2 = 86.1%). Adverse events were recorded in 14% (95%CI: 8-20; 164/840; I2 = 87.2%) of cases, rated as mild in 10% (95%CI: 5-15; 128/840; I2 = 86.7%), and severe in 4% (95%CI: 3-5; 36/840; I2 = 0%). The subgroup analysis for the primary outcome revealed rates of 70% (95%CI: 64-76; I2 = 42.3%) for ethanol/paclitaxel, 44% (95%CI: 33-54; I2= 0%) for lauromacrogol, 32% (95%CI: 27-36; I2 = 88.4%) for ethanol, and 13% (95%CI: 4-22; I2 = 95.8%) for RFA. Considering adverse events, the ethanol-based subgroup rated the highest percentage (16%; 95%CI: 13-20; I2 = 91.0%). CONCLUSION: EUS ablation of pancreatic cysts provides acceptable rates of complete resolution and a low incidence of severe adverse events, with chemoablative agents yielding higher performance rates.

Serum biomarker-based early detection of pancreatic ductal adenocarcinomas with ensemble learning.

BACKGROUND: Earlier detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes, as it is mostly detected at advanced stages which are associated with poor survival. Developing non-invasive blood tests for early detection would be an important breakthrough. METHODS: The primary objective of the work presented here is to use a dataset that is prospectively collected, to quantify a set of cancer-associated proteins and construct multi-marker models with the capacity to predict PDAC years before diagnosis. The data used is part of a nested case-control study within the UK Collaborative Trial of Ovarian Cancer Screening and is comprised of 218 samples, collected from a total of 143 post-menopausal women who were diagnosed with pancreatic cancer within 70 months after sample collection, and 249 matched non-cancer controls. We develop a stacked ensemble modelling technique to achieve robustness in predictions and, therefore, improve performance in newly collected datasets. RESULTS: Here we show that with ensemble learning we can predict PDAC status with an AUC of 0.91 (95% CI 0.75-1.0), sensitivity of 92% (95% CI 0.54-1.0) at 90% specificity, up to 1 year prior to diagnosis, and at an AUC of 0.85 (95% CI 0.74-0.93) up to 2 years prior to diagnosis (sensitivity of 61%, 95% CI 0.17-0.83, at 90% specificity). CONCLUSIONS: The ensemble modelling strategy explored here outperforms considerably biomarker combinations cited in the literature. Further developments in the selection of classifiers balancing performance and heterogeneity should further enhance the predictive capacity of the method.

Pancreatic cancers are most frequently detected at an advanced stage. This limits treatment options and contributes to the dismal survival rates currently recorded. The development of new tests that could improve detection of early-stage disease is fundamental to improve outcomes. Here, we use advanced data analysis techniques to devise an early detection test for pancreatic cancer. We use data on markers in the blood from people enrolled on a screening trial. Our test correctly identifies as positive for pancreatic cancer 91% of the time up to 1 year prior to diagnosis, and 78% of the time up to 2 years prior to diagnosis. These results surpass previously reported tests and should encourage further evaluation of the test in different populations, to see whether it should be adopted in the clinic.

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies.

Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.

Biliary Strictures and Cholangiocarcinoma - Untangling a Diagnostic Conundrum.

Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.

Modelling Pancreatic Neuroendocrine Cancer: From Bench Side to Clinic.

Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise and patient outcomes, although variable, have been linked with 5-year survival rates as low as 40%. Improvement of diagnostic and treatment modalities strongly relies on disease models that reconstruct the disease ex vivo. A key constraint in pNET research, however, is the absence of human pNET models that accurately capture the original tumour phenotype. In attempts to more closely mimic the disease in its native environment, three-dimensional culture models as well as in vivo models, such as genetically engineered mouse models (GEMMs), have been developed. Despite adding significant contributions to our understanding of more complex biological processes associated with the development and progression of pNETs, factors such as ethical considerations and low rates of clinical translatability limit their use. Furthermore, a role for the site-specific extracellular matrix (ECM) in disease development and progression has become clear. Advances in tissue engineering have enabled the use of tissue constructs that are designed to establish disease ex vivo within a close to native ECM that can recapitulate tumour-associated tissue remodelling. Yet, such advanced models for studying pNETs remain underdeveloped. This review summarises the most clinically relevant disease models of pNETs currently used, as well as future directions for improved modelling of the disease.

Early detection of pancreatic cancer.

Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.

Does preoperative ischaemic conditioning with gastric vessel ligation reduce anastomotic leaks in oesophagectomy?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'does preoperative ischaemic conditioning with gastric vessel ligation prior to oesophagectomy reduce anastomotic leaks? Altogether more than 70 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Five papers represent level III evidence while the remainder two are considered level IV. None of the seven papers reports statistically significant P-values, although one non-randomized controlled cohort study approaches statistical significance at P = 0.07. Three of the level III papers suggest that preoperative ischaemic conditioning prior to oesophagectomy may be associated with a lower anastomotic leak severity; being managed endoscopically rather than with a surgical intervention, however, again, none reached statistical significance. Preoperative ischaemic conditioning prior to oesophagectomy may not be associated with an increase in blood loss or length of time at definitive operation, reported by one of the seven studies. One paper reports that the timing of preoperative ischaemic conditioning may be associated with a better anastomotic leak profile if carried out 2 weeks previously as opposed to 5 days ahead of definitive surgery, although not statistically significant. The most consistent method in the literature reported ligation or division of the left gastric artery reported in six of the seven papers. We, therefore, cannot conclude that preoperative ischaemic conditioning with gastric vessel ligation prior to oesophagectomy is associated with reduced anastomotic leaks.