Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.

INTRODUCTION: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. METHODS: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. RESULTS: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. CONCLUSION: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.

The in situ near-total pancreatectomy (LIVOCADO procedure) for end-staged chronic pancreatitis.

PURPOSE: Total pancreatectomy for severe pain in end-stage chronic pancreatitis may be the only option, but with vascular involvement, this is usually too high risk and/or technically not feasible. The purpose of the study was to present the clinical outcomes of a novel procedure in severe chronic pancreatitis complicated by uncontrollable pain and vascular involvement. METHODS: We describe an in situ near-total pancreatectomy that avoids peripancreatic vascular dissection (Livocado procedure) and report on surgical and clinical outcomes. RESULTS: The Livocado procedure was carried out on 18 (3.9%) of 465 patients undergoing surgery for chronic pancreatitis. There were 13 men and 5 women with a median (IQR) age of 48.5 (42.4-57) years and weight of 60.7 (58.0-75.0) kg. All had severe pain and vascular involvement; 17 had pancreatic parenchymal calcification; the median (IQR) oral morphine equivalent dose requirement was 86 (33-195) mg/day. The median (IQR) maximal pain scores were 9 (9-10); the average pain score was 6 (IQR 4-7). There was no peri-operative or 90-day mortality. At a median (IQR) follow-up of 32.5 (21-45.75) months, both maximal and average pain scores were significantly improved post-operatively, and at 12 months, two-thirds of patients were completely pain free. Six (33%) patients had employment pre-operatively versus 13 (72%) post-operatively (p = 0.01). CONCLUSIONS: The Livocado procedure was safe and carried out successfully in patients with chronic pancreatitis with vascular involvement where other procedures would be contraindicated. Perioperative outcomes, post-operative pain scores, and employment rehabilitation were comparable with other procedures carried out in patients without vascular involvement.

The diagnostic value of Rosemont and Japanese diagnostic criteria for 'indeterminate', 'suggestive', 'possible' and 'early' chronic pancreatitis.

BACKGROUND: Longitudinal data are lacking to support consensus criteria for diagnosing early chronic pancreatitis. METHODS: Retrospective single centre study of the initial evidence for chronic pancreatitis (CP), with reassessment after follow-up (January 2003-November 2016). RESULTS: 807 patients were previously diagnosed with chronic pancreatitis. This diagnosis was rejected in 118 patients: 52 had another pathology altogether, the remaining 66 patients formed the study population. 38 patients with 'normal' imaging were reclassified as chronic abdominal pain syndrome (CAPS), and 28 patients had minimal change features of CP on EUS (MCEUS) but never progressed. Strict application of the Japanese diagnostic criteria would diagnose only two patients with early CP and eleven as possible CP. Patients were more likely to have MCEUS if the EUS was performed within 12 months of an attack of acute pancreatitis. 40 patients with MCEUS were identified, including an additional 12 who progressed to definite CP after a median of 30 (18.75-36.5) months. Those continuing to consume excess alcohol and/or continued smoking were significantly more likely to progress. Those who progressed were more likely to develop pancreatic exocrine insufficiency, require pancreatic surgery and had higher mortality. CONCLUSION: There needs to be more stringent application of the systems used for diagnosing chronic pancreatitis with revision of the current terminology 'indeterminate', 'suggestive', 'possible', and 'early' chronic pancreatitis. All patients with MCEUS features of CP require ongoing clinical follow up of at least 30 months and all patients with these features should be strongly counselled regarding smoking cessation and abstinence from alcohol.

Aurora B suppresses microtubule dynamics and limits central spindle size by locally activating KIF4A.

Anaphase central spindle formation is controlled by the microtubule-stabilizing factor PRC1 and the kinesin KIF4A. We show that an MKlp2-dependent pool of Aurora B at the central spindle, rather than global Aurora B activity, regulates KIF4A accumulation at the central spindle. KIF4A phosphorylation by Aurora B stimulates the maximal microtubule-dependent ATPase activity of KIF4A and promotes its interaction with PRC1. In the presence of phosphorylated KIF4A, microtubules grew more slowly and showed long pauses in growth, resulting in the generation of shorter PRC1-stabilized microtubule overlaps in vitro. Cells expressing only mutant forms of KIF4A lacking the Aurora B phosphorylation site overextended the anaphase central spindle, demonstrating that this regulation is crucial for microtubule length control in vivo. Aurora B therefore ensures that suppression of microtubule dynamic instability by KIF4A is restricted to a specific subset of microtubules and thereby contributes to central spindle size control in anaphase.

Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage owing to dysregulated Aurora-A.

Mutations in the PPP6C catalytic subunit of protein phosphatase 6 (PP6) are drivers for the development of melanoma. Here, we analyse a panel of melanoma-associated mutations in PPP6C and find that these generally compromise assembly of the PP6 holoenzyme and catalytic activity towards a model substrate. Detailed analysis of one mutant, PPP6C-H114Y, in both primary melanoma and engineered cell lines reveals it is destabilized and undergoes increased proteasome-mediated turnover. Global analysis of phosphatase substrates by mass spectrometry identifies the oncogenic kinase Aurora-A as the major PP6 substrate that is dysregulated under these conditions. Accordingly, cells lacking PPP6C or carrying the PPP6C-H114Y allele have elevated Aurora-A kinase activity and display chromosome instability with associated Aurora-A-dependent micronucleation. Chromosomes mis-segregated to these micronuclei are preferentially stained by the DNA damage marker γ-H2AX, suggesting that loss of PPP6C promotes both chromosome instability and DNA damage. These findings support the view that formation of micronuclei rather than chromosome instability alone explains how loss of PPP6C, and more generally mitotic spindle and centrosome defects, can act as drivers for genome instability in melanoma and other cancers.

Spinal Epidural Abscess Presenting with Paraplegia Following Delayed Presentation of Traumatic Esophageal Perforation without Spinal Fracture: Lessons to be Learnt.

We describe a case of esophageal perforation following blunt chest trauma with delayed presentation as paraplegia secondary to spinal epidural abscess formation. The case highlights the importance of the awareness of the possibility of esophageal injury in patients following road traffic collisions.