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.

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.

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.

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.

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.

Appendiceal adenocarcinoma with breast metastases.

Malignant lesions of the vermiform appendix make up a rare subset of colorectal cancer. While colorectal cancer frequently metastasises to the liver, lung, regional lymph nodes and peritoneum, metastasis to the breast is extremely rare. Here, we describe the case of an 84-year-old woman who had the incidental finding of appendiceal adenocarcinoma following emergency laparoscopic appendectomy. She declined further operative or adjuvant treatment for her disease. She represented 1 year later with metastatic appendiceal adenocarcinoma disease to her left breast. A simple mastectomy for symptomatic treatment was performed. In this report, we describe the first case of appendiceal adenocarcinoma metastases to the breast. Due to its rarity, there is a paucity of evidence related to the management of this condition. The limited evidence is reviewed and discussed.

A combined open and laparoscopic technique for the management of De Garengeot's hernia with acute appendicitis: A case report.

INTRODUCTION: De Garengeot's hernia is a rare type of femoral hernia which describes the vermiform appendix incarcerated within the hernia sac. In this case report we present our case and review the surgical approaches described in the literature. PRESENTATION OF CASE: We present the case of an 84-year-old female with a background of Parkinson's Disease who presented to the emergency department with a five day history of a right-sided groin lump with worsening pain, nausea and reduced appetite. Computed tomography of the abdomen and pelvis revealed an inflamed appendix herniating through the right femoral canal. She had a two staged surgical approach involving an open repair of her femoral hernia followed by laparoscopic appendicectomy. DISCUSSION: Due to its rarity, there is no standard surgical approach to the appendicectomy and femoral hernia repair. Multiple approaches have been described in the literature, however most reports describe a simultaneous femoral hernia repair and appendicectomy. If an additional abdominal incision is required to complete the appendicectomy safely, we advocate the consideration of a hybrid open-laparoscopic approach, particularly in patients such as this with a history of Parkinson's disease. CONCLUSION: Here we highlight the usefulness of combining an open low inguinal approach followed by a laparoscopic appendicectomy.

Learning curves in surgery: variables, analysis and applications.

Learning curves graphically represent the relationship between learning effort and learning outcome. Learning curves are increasingly used in research, the design of randomised controlled trials, the assessment of competency, healthcare education and training programme design. In this review we have outlined the principles behind plotting learning curves, described the common methods used to analyse learning curves, how to interpret learning curves, the multitude of learning models, their applications and potential pitfalls, and the importance of a mathematically rigorous approach to learning curve analytics.

An enhanced fresh cadaveric model for reconstructive microsurgery training.

BACKGROUND: Performing microsurgery requires a breadth and depth of experience that has arguably been reduced as result of diminishing operating exposure. Fresh frozen cadavers provide similar tissue handling to real-time operating; however, the bloodless condition restricts the realism of the simulation. We describe a model to enhance flap surgery simulation, in conjunction with qualitative assessment. METHODS: The fresh frozen cadaveric limbs used in this study were acquired by the University. A perfused fresh cadaveric model was created using a gelatin and dye mixture in a specific injection protocol in order to increase the visibility and realism of perforating vessels, as well as major vessels. A questionnaire was distributed amongst 50 trainees in order to assess benefit of the model. Specifically, confidence, operative skills, and transferable procedural-based learning were assessed. RESULTS: Training with this cadaveric model resulted in a statistically significant improvement in self-reported confidence (p < 0.005) and prepared trainees for unsupervised bench work (p < 0.005). Respondents felt that the injected model allowed easier identification of vessels and ultimately increased the similarity to real-time operating. Our analysis showed it cost £10.78 and took 30 min. CONCLUSIONS: Perfusion of cadaveric limbs is both cost- and time-effective, with significant improvement in training potential. The model is easily reproducible and could be a valuable resource in surgical training for several disciplines.Level of Evidence: Not ratable.