MicroRNAs as Bile-based biomarkers in pancreaticobiliary cancers (MIRABILE): a cohort study.

BACKGROUND: Biliary obstruction can be due to both malignant and benign pancreaticobiliary disease. Currently, there are no biomarkers that can accurately help make this distinction. MicroRNAs (miRNAs) are stable molecules in tissue and biofluids that are commonly deregulated in cancer. The MIRABILE study aimed to identify miRNAs in bile that can differentiate malignant from benign pancreaticobiliary disease. MATERIALS AND METHODS: There were 111 patients recruited prospectively at endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) for obstructive jaundice, and bile was aspirated for cell-free RNA (cfRNA) extraction and analysis. In a discovery cohort of 78 patients (27 with pancreatic ductal adenocarcinoma (PDAC), 14 cholangiocarcinoma (CCA), 37 benign disease), cfRNA was subjected to small-RNA sequencing. LASSO regression was used to define bile miRNA signatures, and NormFinder to identify endogenous controls. In a second cohort of 87 patients (34 PDAC, 14 CCA, 39 benign disease), RT-qPCR was used for validation. RESULTS: LASSO regression identified 14 differentially-expressed bile miRNAs of which 6 were selected for validation. When comparing malignant and benign pancreaticobiliary disease, bile miR-340 and miR-182 were validated and significantly differentially expressed (P<0.05 and P<0.001, respectively). This generated an AUC of 0.79 (95%CI 0.70-0.88, sensitivity 65%; specificity 82%) in predicting malignant disease. CONCLUSION: Bile collected during biliary drainage contains miRNAs able to differentiate benign from malignant pancreaticobiliary diseases in patients with obstructive jaundice. These bile miRNAs have the potential to increase diagnostic accuracy.

The microbial composition of pancreatic ductal adenocarcinoma: A systematic review of 16S rRNA gene sequencing.

BACKGROUND: Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), continues to pose a significant clinical and scientific challenge. The most significant finding of recent years is that PDAC tumours harbour their specific microbiome, which differs amongst tumour entities and is distinct from healthy tissue. This review aims to evaluate and summarise all PDAC studies that have used the next-generation technique, 16S rRNA gene amplicon sequencing within each bodily compartment. As well as establishing a causal relationship between PDAC and the microbiome. MATERIALS AND METHODS: This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive search strategy was designed, and 1727 studies were analysed. RESULTS: In total, 38 studies were selected for qualitative analysis and summarised significant PDAC bacterial signatures. Despite the growing amount of data provided, we are not able to state a universal 16S rRNA gene microbial signature that can be used for PDAC screening. This is most certainly due to the heterogeneity of the presentation of results, lack of available datasets and the intrinsic selection bias between studies. CONCLUSION: Several key studies have begun to shed light on causality and the influence the microbiome constituents and their produced metabolites could play in tumorigenesis and influencing outcomes. The challenge in this field is to shape the available microbial data into targetable signatures. Making sequenced data readily available is critical, coupled with the coordinated standardisation of data and the need for consensus guidelines in studies investigating the microbiome in PDAC.

Gastrointestinal Permeability After Bariatric Surgery: A Systematic Review.

Gastrointestinal permeability refers to the movement of substances across the gut wall. This is mediated by endotoxemia (bacterial products entering the systemic circulation), and is associated with metabolic disease. The effect of bariatric surgery on permeability remains uncertain; the associated dietary, metabolic and weight changes are suggested to influence, or trigger, altered permeability. The primary aim of this study is to synthesize evidence and analyze the effect of bariatric surgery on permeability. A systematic review was performed, searching MEDLINE, EMBASE, and Scopus until February 2023, using MESH terms "intestinal permeability", "bariatric", for studies reporting in vivo assessment of permeability. Three cohort studies and two case series were identified (n=96). Data was heterogeneous; methodology and controls preclude meta-analysis. Gastroduodenal permeability reduced post-sleeve gastrectomy (SG). Two studies showed an increase in small intestinal permeability after biliopancreatic diversion. Two studies revealed a decrease in post-Roux-en-Y gastric bypass. One study identified increased colonic permeability six months post-SG. Evidence regarding permeability change after bariatric surgery is conflicting, notably for the small intestine. Impaired colonic permeability post-SG raises concerns regarding colonic protein fermentation and harmful dietary sequelae. There are multiple interacting variables confounding gastrointestinal permeability change; procedure type, altered microbiota and metabolic response to surgery. Further understanding of this important aspect of obesity is required, both before and after bariatric surgery.

Impact of tertiary lymphoid structures on prognosis and therapeutic response in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known to have a heterogeneous desmoplastic tumour microenvironment (TME) with a large number of immunosuppressive cells. Recently, high B-cell infiltration in PDAC has received growing interest as a potential therapeutic target. METHODS: Our literature review summarises the characteristics of tumour-associated tertiary lymphoid structures (TLSs) and highlight the key studies exploring the clinical outcomes of TLSs in PDAC patients and the direct effect on the TME. RESULTS: The location, density and maturity stages of TLSs within tumours play a key role in determining the prognosis and is a new emerging target in cancer immunotherapy. DISCUSSION: TLS development is imperative to improve the prognosis of PDAC patients. In the future, studying the genetics and immune characteristics of tumour infiltrating B cells and TLSs may lead towards enhancing adaptive immunity in PDAC and designing personalised therapies.

What are the true benefits of robotic pancreaticoduodenectomy for patients with pancreatic cancer?

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, and multimodal treatment including high-quality surgery can improve survival outcomes. Pancreaticoduodenectomy (PD) has evolved with minimally invasive approaches including the implementation of robotic PD (RPD). In this special report, we review the literature whilst evaluating the 'true benefits' of RPD compared to open approach for the treatment of PDAC. AREAS COVERED: We have performed a mini-review of studies assessing PD approaches and compared intraoperative characteristics, perioperative outcomes, post-operative complications and oncological outcomes. EXPERT OPINION: RPD was associated with similar or longer operative times, and reduced intra-operative blood loss. Perioperative pain scores were significantly lower with shorter lengths of stay with the robotic approach. With regards to post-operative complications, post-operative pancreatic fistula rates were similar, with lower rates of clinically relevant fistulas after RPD. Oncological outcomes were comparable or superior in terms of margin status, lymph node harvest, time to chemotherapy and survival between RPD and OPD. In conclusion, RPD allows safe implementation of minimally invasive PD. The current literature shows that RPD is either equivalent, or superior in certain aspects to OPD. Once more centers gain sufficient experience, RPD is likely to demonstrate clear superiority over alternative approaches.

The Roles and Interactions of Porphyromonas gingivalis and Fusobacterium nucleatum in Oral and Gastrointestinal Carcinogenesis: A Narrative Review.

Epidemiological studies have spotlighted the intricate relationship between individual oral bacteria and tumor occurrence. Porphyromonas gingivalis and Fusobacteria nucleatum, which are known periodontal pathogens, have emerged as extensively studied participants with potential pathogenic abilities in carcinogenesis. However, the complex dynamics arising from interactions between these two pathogens were less addressed. This narrative review aims to summarize the current knowledge on the prevalence and mechanism implications of P. gingivalis and F. nucleatum in the carcinogenesis of oral squamous cell carcinoma (OSCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). In particular, it explores the clinical and experimental evidence on the interplay between P. gingivalis and F. nucleatum in affecting oral and gastrointestinal carcinogenesis. P. gingivalis and F. nucleatum, which are recognized as keystone or bridging bacteria, were identified in multiple clinical studies simultaneously. The prevalence of both bacteria species correlated with cancer development progression, emphasizing the potential impact of the collaboration. Regrettably, there was insufficient experimental evidence to demonstrate the synergistic function. We further propose a hypothesis to elucidate the underlying mechanisms, offering a promising avenue for future research in this dynamic and evolving field.

Bile Microbiome Signatures Associated with Pancreatic Ductal Adenocarcinoma Compared to Benign Disease: A UK Pilot Study.

Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3-V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.

Pancreatic Exocrine Insufficiency and the Gut Microbiome in Pancreatic Cancer: A Target for Future Diagnostic Tests and Therapies?

Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature review is to summarise the current evidence linking PEI with microbiome dysbiosis, assess how microbiome composition may be impacted by PERT treatment, and look towards possible future diagnostic and therapeutic targets in this area. Early evidence in the literature reveals that there are complex mechanisms by which pancreatic secretions modulate the gut microbiome, so when these are disturbed, as in PEI, gut microbiome dysbiosis occurs. PERT has been shown to return the gut microbiome towards normal, so called rebiosis, in animal studies. Gut microbiome dysbiosis has multiple downstream effects in pancreatic cancer such as modulation of the immune response and the response to chemotherapeutic agents. It therefore represents a possible future target for future therapies. In conclusion, it is likely that the gut microbiome of pancreatic cancer patients with PEI exhibits dysbiosis and that this may potentially be reversible with PERT. However, further human studies are required to determine if this is indeed the case.

The Role of the Multiparametric MRI LiverMultiScanTM in the Quantitative Assessment of the Liver and Its Predicted Clinical Applications in Patients Undergoing Major Hepatic Resection for Colorectal Liver Metastasis.

Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScanTM offers an attractive non-invasive assay of anatomy and histopathology in the pre-operative setting, especially in the context of CRLM. This narrative review examines the evidence for the LiverMultiScanTM in the assessment of hepatic fibrosis, steatosis/steatohepatitis, and potential applications for chemotherapy-associated hepatic changes. We postulate its future role and the hurdles it must surpass in order to be implemented in the pre-operative management of patients undergoing hepatic resection for colorectal liver metastasis. Such a role likely extends to other hepatic malignancies planned for resection.

Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines.

Cancer cell-derived extracellular vesicles activate hepatic stellate cells in colorectal cancer.

Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths worldwide, primarily due to the development of metastatic disease. The liver is the most frequently affected site. The metastatic cascade relies on a complex interaction between the immune system, tumor, and distant organs. Communication between the tumor and the metastatic site can be mediated by tumor-derived extracellular vesicles (EVs) and their cargo. The mechanisms underlying this process are starting to be understood through research that has rapidly expanded over the past 15 years. One crucial aspect is the remodeling of the microenvironment at the site of metastasis, which is essential for the formation of a premetastatic niche and the subsequent establishment of metastatic deposits. In the evaluated study, the authors use cellular experiments and a mouse model to investigate how tumour derived extracellular vesicles and their microRNA contents interact with hepatic stellate cells (HSCs). They demonstrate how this may lead to remodelling of the microenvironment and the formation of colorectal liver metastasis using their experimental model. In this mini review, we examine the current evidence surrounding tumour derived EVs and their effect on the tumour microenvironment to highlight potential areas for future research in CRC and other malignancies.

Graphene Sensor Arrays for Rapid and Accurate Detection of Pancreatic Cancer Exosomes in Patients' Blood Plasma Samples.

Biosensors based on graphene field effect transistors (GFETs) have the potential to enable the development of point-of-care diagnostic tools for early stage disease detection. However, issues with reproducibility and manufacturing yields of graphene sensors, but also with Debye screening and unwanted detection of nonspecific species, have prevented the wider clinical use of graphene technology. Here, we demonstrate that our wafer-scalable GFETs array platform enables meaningful clinical results. As a case study of high clinical relevance, we demonstrate an accurate and robust portable GFET array biosensor platform for the detection of pancreatic ductal adenocarcinoma (PDAC) in patients' plasma through specific exosomes (GPC-1 expression) within 45 min. In order to facilitate reproducible detection in blood plasma, we optimized the analytical performance of GFET biosensors via the application of an internal control channel and the development of an optimized test protocol. Based on samples from 18 PDAC patients and 8 healthy controls, the GFET biosensor arrays could accurately discriminate between the two groups while being able to detect early cancer stages including stages 1 and 2. Furthermore, we confirmed the higher expression of GPC-1 and found that the concentration in PDAC plasma was on average more than 1 order of magnitude higher than in healthy samples. We found that these characteristics of GPC-1 cancerous exosomes are responsible for an increase in the number of target exosomes on the surface of graphene, leading to an improved signal response of the GFET biosensors. This GFET biosensor platform holds great promise for the development of an accurate tool for the rapid diagnosis of pancreatic cancer.

A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.

Design of a Proficiency-Based Skills Training Curriculum for Our Newly Validated 3-Dimensional (3D) Laparoscopic Models, Using MISTELS.

Aim: There are presently no courses or training curricula for surgical simulation that include training with 3-Dimensional (3D) laparoscopic platforms. Our aim is to create an expert led design of a proficiency-based skills training curriculum for our newly validated 3D laparoscopic models, using MISTELS compensating speed for precision and accuracy. Method: In this study, 5 tasks were performed by 12 expert surgeons of different specializations on low-cost, portable models designed for 3D display. The competence level for each task was devised by using a target performance time (within the cutoff limit), maximum allowable error score and penalty error score, allowing real time instant scoring and feedback. The results were evaluated by MISTELS scoring system. Results: Out of the 12 experts, the top 3 with the shortest mean time with no errors would be chosen to design a proficiency curriculum. The final aim of developing such curriculum is to shorten learning curve and to improve technical skills of 3D laparoscopy. The curriculum provides a benchmark level for each task, indicating the cutoff and the target performance time, a list of the allowable errors and the number of repetitions. Conclusion: Our future plan is to investigate the cost and effectiveness of the curriculum and to reveal if practice and repetition will lead to mastering 3D skills among novices (medical students and junior doctors).

Eye-Tracking Technology in Surgical Training.

The aim of this review was to amalgamate literature on the use of eye tracking methodology as an adjunct to surgical training. The PRISMA Guidelines were used to undertake this systematic review. Our review studies has shown that recording a surgeon's eye movements; time to first fixation and gaze pattern through the use of eye tracking technology would be beneficial for surgical training.

Eye-tracking technology in medical education: A systematic review.

BACKGROUND: Eye-tracking technology is an established research tool within allied industries such as advertising, psychology and aerospace. This review aims to consolidate literature describing the evidence for use of eye-tracking as an adjunct to traditional teaching methods in medical education. METHODS: A systematic literature review was conducted in line with STORIES guidelines. A search of EMBASE, OVID MEDLINE, PsycINFO, TRIP database, and Science Direct was conducted until January 2017. Studies describing the use of eye-tracking in the training, assessment, and feedback of clinicians were included in the review. RESULTS: Thirty-three studies were included in the final qualitative synthesis. Three studies were based on the use of gaze training, three studies on the changes in gaze behavior during the learning curve, 17 studies on clinical assessment and six studies focused on the use of eye-tracking methodology as a feedback tool. The studies demonstrated feasibility and validity in the use of eye-tracking as a training and assessment method. CONCLUSIONS: Overall, eye-tracking methodology has contributed significantly to the training, assessment, and feedback practices used in the clinical setting. The technology provides reliable quantitative data, which can be interpreted to give an indication of clinical skill, provide training solutions and aid in feedback and reflection. This review provides a detailed summary of evidence relating to eye-tracking methodology and its uses as a training method, changes in visual gaze behavior during the learning curve, eye-tracking methodology for proficiency assessment and its uses as a feedback tool.

Financial Burden Secondary to Delay in Cholecystectomy Following Mild Biliary Pancreatitis.

AIM OF THE STUDY: The guidelines recommend that patients with mild gallstones pancreatitis should undergo a definitive management for gallstones during the same admission or within the next two weeks. The aim of this study was to estimate the financial cost resulting from a delay in surgical management following mild gallstones pancreatitis. This includes the costs of readmissions with biliary events and the subsequent investigations required during these admissions. MATERIALS AND METHODS: A retrospective analysis included patients with gallstone pancreatitis who were admitted to a district general hospital in the United Kingdom over one year. Patients with severe pancreatitis and those unfit for surgery were excluded. RESULTS: Forty patients were included in the study, 27 females (67%) and 13 males (33%). Mean age was 50.2 years. Twenty-two patients of the total presented with a single admission with gallstone pancreatitis prior to an elective surgery; however, 18 patients (45%) required recurrent admissions. The duration between the first admission and surgery ranged from 14 to 389 days (median of 99 days). Only one patient (2.5%) had cholecystectomy within two weeks of admission as per guidelines. Twenty-two ultrasound scans, four computed tomography scans, 15 magnetic resonance cholangiopancreatography, and two endoscopic retrograde cholangiopancreatography were the total of the extra-investigations required during readmissions. Estimated costs of extra admissions and extra investigations exceeded £33,000. CONCLUSIONS: The delay in cholecystectomy for patients admitted with mild gallstone pancreatitis and fit for surgery has resulted in high readmission rate with biliary events, and subsequently high extrax costs.

Non-healing gastro-duodenal ulcer: A rare presentation of primary abdominal tuberculosis.

INTRODUCTION: We present a case of primary gastrointestinal tuberculosis that has culminated in ulcer formation, in the absence of pulmonary involvement in an immunocompetent patient. PRESENTATION OF CASE: A 28-year-old Asian male presented to casualty with a 1-week history of epigastric cramping abdominal pain and several episodes of non-bilious vomiting. The patient deteriorated clinically, becoming more cachectic and given his unexplained weight loss, an oesophageal-gastro-duodenal endoscopic imaging confirmed a duodenal ulcer. The biopsy of the non-healing ulcer was the hallmark of the disease, revealing evidence of granulomatous inflammation consistent with tuberculosis bacilli. DISCUSSION: Gastrointestinal tuberculosis with ulceration is rare with respect to the oesophagus, stomach and duodenum. This case proves to be unique, as our patient had experienced primary isolated gastric tuberculosis in the absence of pulmonary tuberculosis in a healthy individual. Immunohistochemical staining, histopathology and radiological investigations have demonstrated their importance in confirming abdominal tuberculosis and the extent of bowel involvement. CONCLUSION: This case has illustrated the difficulties associated with a prompt diagnosis of an unusual case of primary duodenal tuberculosis from chronic peptic ulcer disease in an immunocompetent patient.