John Moir

Systematic review of irreversible electroporation in the treatment of advanced pancreatic cancer

BACKGROUND Irreversible electroporation (IRE) is a novel procedure to combat pancreatic cancer, whereby high voltage pulses are delivered, resulting in cell death. This represents an ideal alternative to other thermal treatment modalities, as there is no overriding heat effect, therefore reducing the risk of injury to vessels and ducts. METHODS Multiple databases were searched to January 2014. Primary outcome measures were survival and associated morbidity. 41 articles were initially identified; of these 4 studies met the inclusion criteria, yielding 74 patients in total. RESULTS 94.5% of patients had locally advanced tumours, the remainder had metastatic disease. Treated tumour size ranged from 1 to 7 cm. IRE approach included open (70.3%), laparoscopic (2.7%) and percutaneous (27%; ultrasound-guided 30%, CT-guided 70%) Morbidity ranged from 0 to 33%; due to the high number of simultaneous procedures performed (resection/bypass) it was difficult to ascertain IRE-related complications. However no significant bleeding occurred when IRE-alone was performed. Survival statistics suggest a prognostic benefit. Reported survival included: 6 month survival of 40% (n = 5) and 70% (n = 14); PFS and OS 14 and 20 months respectively (n = 54). Results of most interest showed a significant survival benefit in matched IRE vs non-IRE groups (PFS 14 vs 6 mths; p = 0.01, OS 20 vs 11 mths; p = 0.03). CONCLUSION Initial evidence suggests IRE incurs a prognostic benefit with minimal morbidity. More high quality research is required to determine the role IRE may play in the multi-modal management of pancreatic cancers.

The role of pancreatic stellate cells in pancreatic cancer

BACKGROUND The prognosis of pancreatic cancer remains desperately poor, with little progress made over the past 30 years despite the development of new combination chemotherapy regimens. Stromal activity is especially prominent in the tissue surrounding pancreatic tumours, and has a profound influence in dictating tumour development and dissemination. Pancreatic stellate cells (PaSCs) have a key role in this tumour microenvironment, and have been the subject of much research in the past decade. This review examines the relationship between PaSCs and cancer cells. METHODS A comprehensive literature search was performed of multiple databases up to March 2014, including Medline, Pubmed and Google Scholar. RESULTS A complex bidirectional interplay exists between PaSCs and cancer cells, resulting in a perpetuating loop of increased activity and an overriding pro-tumorigenic effect. This involves a number of signalling pathways that also impacts on other stromal components and vasculature, contributing to chemoresistance. The Reverse Warburg Effect is also introduced as a novel concept in tumour stroma. CONCLUSION This review highlights the pancreatic tumour microenvironment, and in particular PaSCs, as an ideal target for therapeutics. There are a number of cellular processes involving PaSCs which could hold the key to more effectively treating pancreatic cancer. The feasibility of targeting these pathways warrant further in depth investigation, with the aim of reducing the aggressiveness of pancreatic cancer and improving chemodelivery.

Arrested development and the great escape - The role of cellular senescence in pancreatic cancer

The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes.

Endourological Management of Urolithiasis in Donor Kidneys prior to Renal Transplant.

Background. We present our centres successful endourological methodology of ex vivo ureteroscopy (EVFUS) in the management of these kidneys prior to renal transplantation. Patient and Methods. A retrospective analysis was performed of all living donors (n = 157) identified to have asymptomatic incidental renal calculi from January 2004 until December 2008. The incidence of asymptomatic renal calculi was 3.2% (n = 5). Donors were subdivided into 2 groups depending on whether theydonated the kidney with the renal calculus (Group 1) versus the opposite calculus-free kidney (Group 2). Results. All donors in Group 1 underwent a left laparoscopic donor nephrectomy. The calculi were extracted in all 3 cases using a 7.5 Fr flexible ureteroscope either prior to transplant (n = 2) or on revascularization (n = 1). There were no urological complications in either group. At a mean followup at 64 months there was no recurrent calculi formation in the recipient in Group 1. However, 1 recipient formed a calculus in group 2 at a follow up of 72 months. Conclusions. Renal calculi can be successfully retrieved during living-related transplantation at the time of transplant itself using EVUS. This is technically feasible and is associated with no compromise in ureteral integrity or renal allograft function.

The novel use of a biodegradable stent placed by percutaneous transhepatic cholangiography for the treatment of a hepaticojejunostomy biliary leak following an extended left hepatectomy and pancreaticoduodenectomy.

A 61-year-old man presented with jaundice, and subsequently underwent an extended left hepatectomy and pancreaticoduodenectomy for a cholangiocarcinoma invading the head of the pancreas. The patient developed sepsis due to a biliary leak at the hepaticojejunostomy. We describe the original use of a biodegradable stent, deployed via percutaneous transhepatic cholangiography into the Roux limb, resulting in good drainage and resolution of sepsis. The chief benefit of this procedure is the lack of need for subsequent removal as well as purported reduced biofilm accumulation. We believe this to be the first reported case of this type and the literature surrounding the subject is also discussed.

Selective internal radiation therapy for liver malignancies

Selective internal radiation therapy (SIRT) is a non‐ablative technique for the treatment of liver primaries and metastases, with the intention of reducing tumour bulk. This study aimed to determine optimal patient selection, and elucidate its role as a downsizing modality.

Role of anti-stromal polypharmacy in increasing survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma

AIM To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects. RESULTS No survival benefit was observed with respect to ACEI/ARB (n = 41), aspirin or statins on individual drug analysis (n = 39). However, the entire CCB group (n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio (HR) of 0.475 (CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group (n = 15) compared with the group taking neither drug (n = 98); 1414 d vs 601 d (P = 0.029, log-rank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332 (CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination. CONCLUSION Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.

Extended Case Series Investigating Vascular Remodelling following Whole Pancreas Transplantation

Introduction Vascular remodelling describes the process of luminal narrowing through both physiological and pathological processes. Transplant vasculopathy, with associated remodelling, has typically been attributed to the inflammatory effect of graft rejection, however a number of other non-immunological mechanisms may be at play. This study examined the incidence, potential aetiology and clinical impact of vascular remodelling following combined kidney and pancreas transplantation. Materials and Methods After a protocol change in 2012 CT angiography became routine for pancreas transplants in the early (<5 days) and late (< 6 months) post-transplant period. This study examined changes in axial/coronal diameters of the conduit, external iliac artery (EIA), internal iliac artery (IIA), superior mesenteric artery (SMA), splenic artery (SA) and renal arteries. Measurements were made by experienced radiologists. Results and Discussion 24 transplants were performed (20 SPK, 3 PAK, 1 PTA) over a 40 month period. All patients received standard immunosuppression of tacrolimus, MMF +/- prednisolone. Significant uniform luminal narrowing was observed in all vessels except the renal arteries. This observation occurred regardless of the development of de novo DSAs. 4 patients were diagnosed with acute pancreatic graft rejection that resolved with steroids. Imaging demonstrated arterial branch thrombosis in 9 patients. All patients were insulin independent with functioning grafts at a median follow up of 24 months (range 7-51). Conclusion Luminal narrowing occurs in pancreatic graft vasculature, with sparing of the renal vessels, and this does not appear to impact on morbidity or short term graft function. Our data suggests mechanisms associated with atherosclerosis, host-donor response or rejection seem unlikely, although an association with a “low grade” chronic rejection causing transplant vasculopathy is plausible. Alternatively this may be due to physiological compensatory change due to altered haemodynamics. Further long-term studies may determine the true clinical impact and need for anti-angiogenic therapeutic intervention. Figure. No caption available.

Incidence of De-Novo Donor Specific Anti-Human Leucocyte Antigen (HLA) Antibodies (DSA) in Simultaneous Pancreas Kidney (SPK) Transplant Patients: A comparison between alemtuzumab and basiliximab based immunosuppression regimes

Introduction De-novo Donor Specific Human Leucocyte Antigen (HLA) Antibodies (DSA) are detrimental to organ transplants. Few studies have explored the incidence of DSA’s and subsequent outcomes after SPK transplant, and none have compared different immunosuppression regimes. The aim of this study was to compare two different immunosuppression regimes (Alemtuzumab versus Basiliximab) with regard to the development of DSA and their long-term outcomes. Materials and Methods We introduced Alemtuzumab for all our SPK recipients from March 2008 onwards along with a Tacrolimus and MMF (from day 7) for maintenance. Prior to this, we used Basiliximab along with our standard immunosuppression regime of a CNI, MMF and steroids. We performed a retrospective analysis of all our SPK transplant patients between 2003 – June 2016. DSA were measured as early (within 2 years) and late (>2 years post-transplantation). HLA antibody testing was performed as per clinical need using a Luminex 200 flow cytometer (Luminex, Inc., Austin, TX). Samples were initially screened for the presence or absence of HLA antibodies using Labscreen mixed HLA antibody screening kits (One Lambda Inc., Canoga Park, CA, USA). For all positive and reactive results, HLA antibody specificities were determined using a combination of Lifecodes ID (Immucor USA) and Labscreen single antigen kits (One Lambda Inc.). Data was analysed using Microsoft Excel 2011 and SPSS 23. Chi-square test was used to compare the groups. Results and Discussion A total of 83 SPK transplants were performed Alemtuzumab (n=53) and Basiliximab (n=30). For early DSA, 20 patients were tested in the Basiliximab group; none developed DSA. In contrast, 34% patients (14 out of 41 tested) in the Alemtuzumab group developed early DSA (p=0.009). Of those 14 patients, 3 (21%) lost their kidney grafts, 6 (43%) lost their pancreas and 3 (21%) eventually died. For late DSA, 18 patients were tested in the Basiliximab group and 3 (17%) were found to be positive. 2/3 patients suffered pancreas graft loss, 1 lost the kidney graft and 1 died as a complication of post-transplant lymphoproliferative disorder. In the Alemtuzumab group, 12 (41%) out of 29 tested developed DSA (p=0.077). Out of those 12 patients, 4 (33%) kidneys and 5 (42%) pancreas were lost and 3 (25%) deaths were recorded. 11 patients (92%) out of the 12 who were positive for late DSA, had early DSA as well. Conclusion Patients on an Alemtuzumab based regime had a significantly higher incidence of early DSA in comparison to a Basiliximab based regime in those patients that were tested. A higher proportion continued to develop late DSA in the Alemtuzumab group. The presence of DSA was associated with very high rates of both pancreas and kidney graft loss.

NARCA: A novel prognostic scoring system using neutrophil-albumin ratio and Ca19-9 to predict overall survival in palliative pancreatic cancer: TINGLE et al.

Several serum based‐markers and ratios have been investigated for their prognostic value in pancreatic ductal adenocarcinoma (PDAC). This cohort study aimed to combine these into a novel prognostic scoring system.