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.

Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma.

BACKGROUND: Distinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease. METHODS: Plasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma). RESULTS: Small RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC. CONCLUSIONS: This is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.

Introduction of day-case robotic liver surgery: a case series from a tertiary hepatobiliary and pancreatic centre.

BACKGROUND: Liver surgery is associated with a significant hospital stay regardless the type of liver resection. A large incision is essential for open liver surgery which is a major factor in the course of the patient's recovery. For patients with small parenchyma liver lesions requiring surgical resection, robotic surgery potentially offers the opportunity to transform the patient's post-operative course. A day-case robotic liver resection pathway was formulated and implemented at our institution when patients were planned for discharge within 24 h of admission for liver surgery. METHODS: Single surgeon case series of cases performed at a tertiary hepatobiliary and pancreatic centre between September 2022 and November 2023. The inclusion criteria were non-anatomical wedge resections, < 2 anatomical segmental resections, left lateral hepatectomy and minimally invasive surgery. RESULTS: This is the first series of robotic day-case minor liver resection in the United Kingdom. 20 patients were included in this case series. The mean operative time was 86.6 ± 30.9 min and mean console time was 58.6 ± 24.5 min. Thirteen patients (65%) were discharged within 24 h of surgery. The main cause of hospitalisation beyond 24 h was inadequate pain relief. There were no Clavien-Dindo grade III or above complications, no 30-day readmission and 90-day mortalities. CONCLUSION: This case series demonstrates that robotic day-case liver resection is safe and feasible. Robust follow-up pathways must be in place to allow for the safe implementation of this approach, to monitor for any complications and to allow intervention as required in a timely manner.

Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. METHODS: Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. RESULTS: Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. CONCLUSIONS: Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

A bile-based microRNA signature for differentiating malignant from benign pancreaticobiliary disease.

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68-0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66-0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67-0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67-0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70-0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement current approaches for diagnosing pancreaticobiliary cancers.

A Not-So-Sweet Syndrome: A Case Report of a Male Presenting With Acute Febrile Neutrophilic Dermatosis.

Physicians often encounter patients who present with a chief complaint of skin changes or lesions in both acute and primary care settings. Early initiation of appropriate treatment and pharmacotherapy in patients who present with rash is crucial to prevent decompensation, morbidity, and further downstream utilization of hospital resources. Acute febrile neutrophilic dermatosis, more commonly known as Sweet syndrome, is a rare and highly symptomatic inflammatory skin condition. Early recognition of Sweet syndrome is important as it requires specific treatment considerations and often can be a sign of an underlying pro-inflammatory condition, malignancy, or reaction to new medication that must be identified. This article discusses the presentation and management of a 50-year-old male who presented with a classic presentation of Sweet syndrome.

Robotic Distal Pancreatectomy Yields Superior Outcomes Compared to Laparoscopic Technique: A Single Surgeon Experience of 123 Consecutive Cases.

Technical limitations of laparoscopic distal pancreatectomy (LDP), in comparison to robotic distal pancreatectomy (RDP), may translate to high conversion rates and morbidity. LDP and RDP procedures performed between December 2008 and January 2023 in our tertiary referral hepatobiliary and pancreatic centres were analysed and compared with regard to short-term outcomes. A total of 62 consecutive LDP cases and 61 RDP cases were performed. There was more conversion to open surgeries in the laparoscopic group compared with the robotic group (21.0% vs. 1.6%, p = 0.001). The LDP group also had a higher rate of postoperative complications (43.5% vs. 23.0%, p = 0.005). However, there was no significant difference between the two groups in terms of major complication or pancreatic fistular after operations (p = 0.20 and p = 0.71, respectively). For planned spleen-preserving operations, the RDP group had a shorter mean operative time (147 min vs. 194 min, p = 0.015) and a reduced total length of hospital stay compared with the LDP group (4 days vs. 7 days, p = 0.0002). The failure rate for spleen preservation was 0% in RDP and 20% (n = 5/25) in the LDP group (p = 0.009). RDP offered a better method for splenic preservation with Kimura's technique compared with LDP to avoid the risk of splenic infarction and gastric varices related to ligation and division of splenic pedicles. RDP should be the standard operation for the resection of pancreatic tumours at the body and tail of the pancreas without involving the celiac axis or common hepatic artery.

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.

The influence of procedural volume on short-term outcomes for robotic pancreatoduodenectomy-a cohort study and a learning curve analysis.

BACKGROUND: An increasing number of robotic pancreatoduodenectomies (RPD) are reported, however, questions remain on the number of procedures needed for gaining technical proficiency in RPD. Therefore, we aimed to assess the influence of procedure volume on short-term RPD outcomes and assess the learning curve effect. METHODS: A retrospective review of consecutive RPD cases was undertaken. Non-adjusted cumulative sum (CUSUM) analysis was performed to identify the procedure volume threshold, following which before-threshold and after-threshold outcomes were compared. RESULTS: Since May 2017, 60 patients had undergone an RPD at our institution. The median operative time was 360 min (IQR 302.25-442 min). CUSUM analysis of operative time identified 21 cases as proficiency threshold, indicated by curve inflexion. Median operative time was significantly shorter after the threshold of 21 cases (470 vs 320 min, p < 0.001). No significant difference was found between before- and after-threshold groups in major Clavien-Dindo complications (23.8 vs 25.6%, p = 0.876). CONCLUSIONS: A decrease in operative time after 21 RPD cases suggests a threshold of technical proficiency potentially associated with an initial adjustment to new instrumentation, port placement and standardisation of operative step sequence. RPD can be safely performed by surgeons with prior laparoscopic surgery experience.

Maternal rumen and milk microbiota shape the establishment of early-life rumen microbiota in grazing yak calves.

Early-life gut microbial colonization and development exert a profound impact on the health and metabolism of the host throughout the life span. The transmission of microbes from the mother to the offspring affects the succession and establishment of the early-life rumen microbiome in newborns, but the contributions of different maternal sites to the rumen microbial establishment remain unclear. In the present study, samples from different dam sites (namely, oral, rumen fluid, milk, and teat skin) and rumen fluid of yak calves were collected at 6 time points between d 7 and 180 postpartum to determine the contributions of the different maternal sites to the establishment of the bacterial and archaeal communities in the rumen during early life. Our analysis demonstrated that the dam's microbial communities clustered according to the sites, and the calves' rumen microbiota resembled that of the dam consistently regardless of fluctuations at d 7 and 14. The dam's rumen microbiota was the major source of the calves' rumen bacteria (7.9%) and archaea (49.7%) compared with the other sites, whereas the potential sources of the calf rumen microbiota from other sites varied according to the age. The contribution of dam's rumen bacteria increased with age from 0.36% at d 7 to 14.8% at d 180, whereas the contribution of the milk microbiota showed the opposite trend, with its contribution reduced from 2.7% at d 7 to 0.2% at d 180. Maternal oral archaea were the main sources of the calves' rumen archaea at d 14 (50.4%), but maternal rumen archaea became the main source gradually and reached 66.2% at d 180. These findings demonstrated the potential microbial transfer from the dam to the offspring that could influence the rumen microbiota colonization and establishment in yak calves raised under grazing regimens, providing the basis for future microbiota manipulation strategies during their early life.

The Atlantic divide: contrasting surgical robotics training in the USA, UK and Ireland.

The uptake of robotic surgery is rapidly increasing worldwide across surgical specialties. However, there is currently a much higher use of robotic surgery in the United States of America (USA) compared to the United Kingdom (UK) and Ireland. Reduced exposure to robotic surgery in training may lead to longer learning curves and worse patient outcomes. We aimed to identify whether any difference exists in exposure to robotic surgery during general surgical training between trainees in the USA, UK and Ireland. Over a 15-week period from September 2021, a survey was distributed through the professional networks of the research team. Participants were USA, UK or Irish trainees who were part of a formal general surgical training curriculum. 116 survey responses were received. US trainees (n = 34) had all had robotic simulator experience, compared to only 37.93% of UK (n = 58) and 75.00% of Irish (n = 24) trainees (p < 0.00001). 91.18% of US trainees had performed 15 or more cases as the console surgeon, compared to only 3.44% of UK and 16.67% of Irish trainees (p < 0.00001). Fifty UK trainees (86.21%) and 22 Irish trainees (91.67%) compared to 12 US trainees (35.29%) do not think they have had adequate robotics training (p < 0.00001). Surgical trainees in the USA have had significantly more exposure to training in robotic surgery than their UK and Irish counterparts.

The Cancer Hub Approach for Upper Gastrointestinal Surgery During COVID-19 Pandemic: Outcomes from a UK Cancer Centre.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused unprecedented disruption to global healthcare delivery. In England, the majority of elective surgery was postponed or cancelled to increase intensive care capacity. Our unit instituted the 'RM Partners Cancer Hub' at the Royal Marsden Hospital in London, to deliver ongoing cancer surgery in a 'COVID-lite' setting. This article describes the operational set-up and outcomes for upper gastrointestinal (UGI) cancer resections performed during this period. METHODS: From April 2020 to April 2021, the Royal Marsden Hospital formed the RM Partners Cancer Hub. This approach was designed to coordinate resources and provide as much oncological treatment as feasible for patients across the RM Partners West London Cancer Alliance. A UGI surgical case prioritisation strategy, along with strict infection control pathways and pre-operative screening protocols, was adopted. RESULTS: A total of 231 patients underwent surgery for confirmed or suspected UGI cancer during the RM Partners Cancer Hub, with 213 completed resections and combined 90-day mortality rate of 3.5%. Good short-term survival outcomes were demonstrated with 2-year disease free survival (DFS) and overall survival (OS) for oesophageal (70.8% and 72.9%), gastric (66.7% and 83.3%) and pancreatic cancer resections (68.0% and 88.0%). One patient who developed perioperative COVID-19 during the RM Partners Cancer Hub operation made a full recovery with no lasting clinical sequelae. CONCLUSION: Our experience demonstrates that the RM Partners Cancer Hub approach is a safe strategy for continuing upper gastrointestinal (GI) resectional surgery during future periods of healthcare service disruption.