Evidence for molecular subtyping in pancreatic ductal adenocarcinoma: a systematic review.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) patients exhibit varied responses to multimodal therapy. RNA gene sequencing has unravelled distinct tumour biology subtypes, forming the focus of this review exploring its impact on survival outcomes. METHODS: A systematic search across PubMed, Medline, Embase, and CINAHL databases targeted studies assessing long-term overall and disease-free survival in PDAC patients with molecular subtyping. RESULTS: Fifteen studies including 2731 patients were identified. Molecular subtyping was performed by RNA sequencing and Immunohistochemistry in 14 studies and by Mass Spectrometry in 1 study. Two main tumour subtypes were identified (classical and basal-like or squamous) with basal like associated with poorer outcomes. Further subtypes were identified in individual studies. Superior survival was seen with classical subtype in all other analyses that compared the classical and basal subtypes. High risk stromal subtypes were identified on further analysis of the stroma and were associated with a worse survival independent of the tumour subtype. CONCLUSION: Molecular subtyping of PDAC specimens can identify patients with high-risk tumour biology and poor survival outcomes. Routine subtyping is limited by the cost of RNA sequencing and the volume of raw data generated which has made its translation into routine clinical practice difficult.

Risk of Recurrence after Surgical Resection for Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasia (IPMN) with Patterns of Distribution and Treatment: An International, Multicentre, Observational Study.

OBJECTIVE: This international multicentre cohort study aims to identify recurrence patterns and treatment of first and second recurrence in a large cohort of patients after pancreatic resection for adenocarcinoma arising from IPMN. SUMMARY BACKGROUND DATA: Recurrence patterns and treatment of recurrence post resection of adenocarcinoma arising from IPMN are poorly explored. METHOD: Patients undergoing pancreatic resection for adenocarcinoma from IPMN between January 2010 to December 2020 at 18 pancreatic centres were identified. Survival analysis was performed by the Kaplan-Meier log rank test and multivariable logistic regression by Cox-Proportional Hazards modelling. Endpoints were recurrence (time-to, location, and pattern of recurrence) and survival (overall survival and adjusted for treatment provided). RESULTS: Four hundred and fifty-nine patients were included (median, 70 y; IQR, 64-76; male, 54 percent) with a median follow-up of 26.3 months (IQR, 13.0-48.1 mo). Recurrence occurred in 209 patients (45.5 percent; median time to recurrence, 32.8 months, early recurrence [within 1 y], 23.2 percent). Eighty-three (18.1 percent) patients experienced a local regional recurrence and 164 (35.7 percent) patients experienced distant recurrence. Adjuvant chemotherapy was not associated with reduction in recurrence (HR 1.09;P=0.669) One hundred and twenty patients with recurrence received further treatment. The median survival with and without additional treatment was 27.0 and 14.6 months (P<0.001), with no significant difference between treatment modalities. There was no significant difference in survival between location of recurrence (P=0.401). CONCLUSION: Recurrence after pancreatic resection for adenocarcinoma arising from IPMN is frequent with a quarter of patients recurring within 12 months. Treatment of recurrence is associated with improved overall survival and should be considered.

Intraoperative pancreas stump perfusion assessment during pancreaticoduodenectomy: A systematic scoping review.

BACKGROUND: Post-operative pancreatic fistula (POPF) is the primary cause of morbidity following pancreaticoduodenectomy. Rates of POPF have remained high despite well known risk factors. The theory that hypoperfusion of the pancreatic stump leads to anastomotic failure has recently gained interest. AIM: To define the published literature with regards to intraoperative pancreas perfusion assessment and its correlation with POPF. METHODS: A systematic search of available literature was performed in November 2022. Data extracted included study characteristics, method of assessment of pancreas stump perfusion, POPF and other post-pancreatic surgery specific complications. RESULTS: Five eligible studies comprised two prospective non-randomised studies and three case reports, total 156 patients. Four studies used indocyanine green fluorescence angiography to assess the pancreatic stump, with the remaining study assessing pancreas perfusion by visual inspection of arterial bleeding of the pancreatic stump. There was significant heterogeneity in the definition of POPF. Studies had a combined POPF rate of 12%; intraoperative perfusion assessment revealed hypoperfusion was present in 39% of patients who developed POPF. The rate of POPF was 11% in patients with no evidence of hypoperfusion and 13% in those with evidence of hypoperfusion, suggesting that not all hypoperfusion gives rise to POPF and further analysis is required to analyse if there is a clinically relevant cut off. Significant variance in practice was seen in the pancreatic stump management once hypoperfusion was identified. CONCLUSION: The current published evidence around pancreas perfusion during pancreaticoduodenectomy is of poor quality. It does not support a causative link between hypoperfusion and POPF. Further well-designed prospective studies are required to investigate this.

Sarcopenia and Sarcopenic Obesity on Body Composition Analysis is a Significant Predictor of Mortality in Severe Acute Pancreatitis: A Longitudinal Observational Study.

BACKGROUND: The prevalence and impact of sarcopenia and sarcopenic obesity noted on body composition analysis in severe acute pancreatitis (SAP) is unknown. This study investigates the prevalence of sarcopenia at different timepoints and its effect on post-pancreatitis complications and mortality. METHODS: A prospective database of SAP admissions with organ failure at a single institution from 2015 to 2019 were analysed. Sarcopenia was determined by IMAGE J software on CT. Database was further queried for post-pancreatitis complications and mortality. RESULTS: 141 patients with a median age of 59 (range 18-88) and M:F ratio 1.52:1 of were analysed. Sarcopenia was present in 111/141 (79%) patients at admission, 78/79 (99%) at 3 months and 26/36 (72%) at 12 months. 67/111 patients with sarcopenia on admission had sarcopenic obesity. The mortality at 30 days, 3 months and 12 months was 16/141 (11%), 30/141 (21%) and 42/141 (30%) respectively. Mortality was significantly higher in sarcopenic patients at admission (35.14%) compared to the non-sarcopenic group (10%), P = 0.008). Mortality in the sarcopenic obesity group was significantly higher (45%) compared to the sarcopenic non-obese group (20%), P = 0.009) at admission. Multivariate logistic regression identified sarcopenic obesity (OR: 2.880), age (OR: 1.048) and number of organ failures (OR: 3.225) as significant predictors of mortality. CONCLUSIONS: Sarcopenia and Sarcopenic obesity are highly prevalent in SAP patients on admission and during follow up. Furthermore, sarcopenic obesity was shown to be a significant predictor of mortality at admission, suggesting that body composition analysis could be a potential predictive marker of mortality in SAP patients.

The development of new onset post-pancreatitis diabetes mellitus during hospitalisation is not associated with adverse outcomes.

BACKGROUND: Patients with acute pancreatitis (AP) are at increased risk of developing post pancreatitis diabetes mellitus (PPDM). The aim of this study was to explore the incidence, risk factors and sequelae of developing PPDM in a UK tertiary referral centre. METHODS: A prospectively collected single centre database was analysed. Patients were grouped according to whether they had DM or not. Patients with DM were further sub-grouped into pre-existing DM or PPDM. Outcomes measured included incidence of PPDM, mortality, ITU admission, overall length of stay (LOS) and local pancreatitis specific complications. RESULTS: 401 patients with AP between 2018 and 2021 were identified. Sixty-four (16%) of patients had pre-existing DM. Thirty-eight patients (11%) developed PPDM [mild (n = 4, 8.2%), moderate (n = 19, 10.1%), severe (n = 15, 15.2%), p = 0.326]. 71% required insulin therapy for the duration of follow-up or until death. The development of PPDM was strongly associated with the presence (p < 0.001) and extent of necrosis (p < 0.0001). On multi-variate analysis, the development of PPDM was not an independent predictor for increased LOS, ITU admission or overall mortality. CONCLUSIONS: The incidence of PPDM was 11%. There was a strong correlation with extent of necrosis and the development of PPDM. PPDM did not adversely affect morbidity or mortality.

Social deprivation does not impact on acute pancreatitis severity and mortality: a single-centre study.

BACKGROUND AND AIMS: The incidence of acute pancreatitis (AP) is increasing in the UK. Patients with severe AP require a significant amount of resources to support them during their admission. The ability to predict which patients will develop multiorgan dysfunction remains poor leading to a delay in the identification of these patients and a window of opportunity for early intervention is missed. Social deprivation has been linked with increased mortality across surgical specialties. Its role in predicting mortality in patients with AP remains unclear but would allow high-risk patients to be identified early and to focus resources on high-risk populations. METHODS: A prospectively collected single-centre database was analysed. English Index of Multiple Deprivation (IMD) was calculated based on postcode. Patients were grouped according to their English IMD quintile. Outcomes measured included all-cause mortality, Intestive care unit (ITU) admission, overall length of stay (LOS) and local pancreatitis-specific complications. RESULTS: 398 patients with AP between 2018 and 2021 were identified. There were significantly more patients with AP in Q1 (IMD 1-2) compared with Q5 (IMD 9-10) (156 vs 38, p<0.001). Patients who were resident in the most deprived areas were significantly younger (52.4 in Q1 vs 65.2 in Q5, p<0.001), and more often smokers (39.1% in Q1 vs 23.7% in Q5, p=0.044) with IHD (95.0% vs 92.1% in Q5, p<0.001). In multivariate modelling, there was no significance difference in pancreatitis-related complications, number of ITU visits, number of organs supported and overall, LOS by IMD quintile. CONCLUSIONS: Although there was a significantly higher number of patients admitted to our unit with AP from the most socially deprived quintiles, there was no correlation between social economic deprivation and mortality following AP.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

The Macrophage Activation Marker Soluble CD163 is Associated With Early Allograft Dysfunction After Liver Transplantation.

BACKGROUND/OBJECTIVES: Soluble CD163 (sCD163), a macrophage activation marker, is upregulated in conditions of macrophage proliferation and activation. Elevated sCD163 levels have been associated with liver disease severity and progression. During liver transplantation, the implanted liver is exposed to ischaemia and reperfusion injury, resulting in an acute inflammatory response and macrophage activation. The relationship between sCD163 levels during liver transplantation and the development of early allograft dysfunction (EAD) has not been investigated. METHODS: We included 27 cirrhosis patients (age 55 [range 32-72] years, 23 men) on the waiting list for liver transplantation. Alcohol consumption and viral hepatitis were the most frequent causes for cirrhosis. Patients were characterised by standard biochemical analysis and based on clinical disease severity scores. Information about donor, graft and course of the liver transplantation was recorded. sCD163 levels were measured at the time of liver transplantation before surgery, 2 h after reperfusion, and then at 24 h after transplantation. RESULTS: We observed above-normal sCD163 levels at baseline (5.9 mg/L [4.7-8.8]). Two hours after reperfusion, sCD163 levels increased significantly from baseline (8.4 mg/L [7.4-10.9]; P < 0.01). Twenty-four hours after transplantation, sCD163 levels were significantly reduced compared with baseline (3.7 mg/L [2.9-5.5]; P < 0.01). However, in patients with EAD (n = 16), sCD163 levels were increased compared with patients without EAD (4.1 [3.2-7.4] vs. 3.1 [2.8-3.8] mg/L; P = 0.03). CONCLUSIONS: We observed elevated sCD163 levels in patients with EAD after liver transplantation, confirming macrophage activation to play a role in EAD. Thus, sCD163 may be used as an early marker for EAD after liver transplantation, but larger studies are warranted to validate these findings.

Urinary Neutrophil Gelatinase Associated Lipocalins (NGALs) predict acute kidney injury post liver transplant.

BACKGROUND: Acute Kidney Injury, a common complication of liver transplant, is associated with a significant increase in the risk of morbidity, mortality and graft loss. Current diagnostic criteria leaves a delay in diagnosis allowing further potential irreversible damage. Early biomarkers of renal injury are of clinical importance and Neutrophil Gelatinase Associated Lipocalins (NGALs) and Syndecan-1 were investigated. METHODS: AKI was defined according to the Acute Kidney Injury Network criteria. Urine and blood samples were collected pre-operatively, immediately post-op and 24 h post reperfusion to allow measurement of NGAL and Syndecan-1 levels. RESULTS: 13 of 27 patients developed an AKI. Patients who developed AKI had significantly higher peak transaminases. Urinary NGAL, plasma NGAL and Syndecan-1 levels were significantly elevated in all patients post reperfusion. Urinary NGAL levels immediately post-op were significantly higher in patients who developed an AKI than those that didn't [1319 ng/ml vs 46.56 ng/ml, p ≤ 0.001]. ROC curves were performed and urinary NGAL levels immediately post-op were an excellent biomarker for AKI with an area under the curve of 0.948 (0.847-1.00). CONCLUSIONS: Urinary NGAL levels measured immediately post-op accurately predict the development of AKI and their incorporation into clinical practise could allow early protocols to be developed to treat post transplant AKI.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) in predicting acute kidney injury following orthotopic liver transplantation: A systematic review.

BACKGROUND: Acute kidney injury (AKI) is common after orthotopic liver transplantation (OLT) usually occurring early post-transplant. Multiple causes include graft preservation injury, blood loss, hypotension but also severity of recipient liver disease. Early intervention in AKI has both short and long term patient benefits. Unfortunately there are no current clinical biomarkers of early AKI. AIM: To assess the value of NGAL in predicting AKI following OLT. METHODS: Ovid MEDLINE and EMBASE were searched between the years of 2000 and 2017 for studies using keywords: Neutrophil Gelatinase Associated Lipocalin or NGAL variants combined with synonyms for liver transplantation. RESULTS: 96 studies were identified. 11 studies including 563 patients were considered suitable for analysis. Both urinary (uNGAL) and plasma NGAL (pNGAL) measurement were found to predict AKI after liver transplantation. Optimal reported area under the receiver-operator characteristics curve (AUROC) values of 0.5-0.83 and 0.54-0.86 respectively. CONCLUSIONS: NGAL is a good predictor of early AKI post OLT although there is considerable variation in the published results. Further studies with prospectively defined cut-off values, standardized definitions of AKI and rigorous data reporting should be conducted to establish its clinical usefulness and limitations.

Anaemia in patients with chronic liver disease and its association with morbidity and mortality following liver transplantation.

Pre-operative anaemia and the need for intra-operative transfusion have been associated with increased morbidity and mortality following cardiac and major non-cardiac surgery. Anaemia is highly prevalent in patients with severe chronic liver disease. Whether this correlates with an altered morbidity and mortality following liver transplant has not been established. METHODS: Prospectively collected data was analysed for the period 1998-2012. Donor and recipient characteristics, blood profiles and complications were recorded. Graft and patient survival was calculated. All patients were followed up for 1 year or until death. Pre-operative haemoglobin levels were correlated with patient demographics and outcome using a binary logistic regression analysis. RESULTS: Pre-operative anaemia, according to WHO criteria, occurred in 73% of patients. Anaemia was more common with advanced liver disease (higher MELD score). As MELD score increased, Haemoglobin levels dropped. Anaemic patients were more commonly transfused (p < 0.001), spent longer ventilated (7 day vs 5 days, p = 0.005) and required longer ITU stays (8 days vs 6 days, p = 0.015). Pre-operative anaemia did not correlate with patient morbidity or mortality. CONCLUSIONS: Reduced haemoglobin levels reflect the severity of chronic liver disease but are not an independent risk factor for a poor outcome following liver transplantation.

Determining the outcomes of post-mastectomy radiation therapy delivered to the definitive implant in patients undergoing one- and two-stage implant-based breast reconstruction: A systematic review and meta-analysis.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) is known to increase the complication rate and implant loss in implant-based breast reconstruction. The purpose of this study was to systematically review the literature regarding the outcome of PMRT delivered to the permanent/definitive implant. METHODS: Systematic review and meta-analysis of studies involving immediate implant-based reconstruction and PMRT when delivered to the permanent implant. RESULTS: Seven studies included 2921 patients (520 PMRT, 2401 control). PMRT was associated with significant increase in capsular contracture (7 studies, 2529 patients, 494 PMRT, 2035 control, OR 10.21, 95% CI 3.74 to 27.89, p < 0.00001). In addition, PMRT was associated with a significant increase in revisional surgery (7 studies, 2921 patients, 520 PMRT, 2401 control, OR 2.18, 95% CI 1.33 to 3.57, p = 0.002) and reconstructive failure (6 studies, 2814 patients, 496 PMRT, 2318 control, OR 2.52, 95% CI 1.48 to 4.29, p+0.0007). Moreover, it was associated with a significant reduction in patient satisfaction (4 studies, 468 patients, 138 PMRT, 294 control, OR 0.29, 95% CI 0.15 to 0.57, p = 0.0003) and cosmetic outcome (4 studies, 1317 patients, 238 PMRT, 1009 control, OR 28, 95% CI. 0.11 to 0.67, p = 0.005). CONCLUSIONS: This meta-analysis demonstrates that within the first 5 years, post implant-based reconstruction for those patients who receive PMRT, the rates of adverse events are increased, and there is a significant reduction in patient satisfaction and cosmetic outcome.

An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation.

Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field.

Remote ischaemic preconditioning in orthotopic liver transplantation (RIPCOLT trial): a pilot randomized controlled feasibility study.

BACKGROUND: Ischaemia Reperfusion (IR) injury is a major cause of morbidity, mortality and graft loss following Orthotopic Liver Transplantation (OLT). Utilising marginal grafts, which are more susceptible to IR injury, makes this a key research goal. Remote Ischaemic Preconditioning (RIPC) has been shown to ameliorate hepatic IR injury in experimental models. Whether RIPC can reduce IR injury in human liver transplant recipients is unknown. METHODS: Forty patients undergoing liver transplantation were randomized to RIPC or a sham. RIPC was induced through three 5 min cycles of alternate ischaemia and reperfusion of the left leg prior to surgery. Data on clinical outcomes was collected prospectively. Per-operative cytokine levels were measured. RESULTS: Fourty five of 51 patients approached (88%) were willing to enroll in the study. Five patients were excluded and 40 randomized, of which 20 underwent RIPC which was successfully completed in all patients. There were no complications following RIPC. Median day 3 AST levels were slightly higher in the RIPC group (221 IU vs 149 IU, p = 1.00). CONCLUSIONS: RIPC is acceptable and safe in liver transplant recipients. This study has not demonstrated evidence of a reduction in short-term measures of IR injury. Longer follow up will be required and consideration of an altered protocol.

Effect of Remote Ischaemic Preconditioning on Liver Injury in Patients Undergoing Major Hepatectomy for Colorectal Liver Metastasis: A Pilot Randomised Controlled Feasibility Trial.

BACKGROUND: Liver resection produces excellent long-term survival for patients with colorectal liver metastases but is associated with significant morbidity and mortality from ischaemia reperfusion injury (IRI). Remote ischaemic preconditioning (RIPC) can reduce the effect of IRI. This pilot randomised controlled trial evaluated RIPC in patients undergoing major hepatectomy at the Royal Free Hospital, London. METHODS: Sixteen patients were randomised to RIPC or sham control. RIPC was induced through three 10-min cycles of alternate ischaemia and reperfusion to the leg. At baseline and immediately post-resection, transaminases and indocyanine green (ICG) clearance were measured. FINDINGS: The RIPC group had lower ALT and AST levels immediately post-resection (ALT: 43% lower 497 ± 165 vs 889 ± 170 IU/L; p = 0.019 AST: 54% lower 408 ± 166 vs 836 ± 167 IU/L; p = 0.001) and at 24 h (ALT: 41% lower 412 ± 144 vs 698 ± 137 IU/L; p = 0.026 AST: 50% lower 316 ± 116 vs 668 ± 115 IU/L; p = 0.02). ICG clearance was reduced in controls versus RIPC immediately after resection (ICG-PDR: 11.1 ± 1.1 vs 16.5 ± 1.4%/min; p = 0.035). CONCLUSIONS: This pilot study shows that RIPC has potential to reduce liver injury following hepatectomy justifying a prospective RCT powered to demonstrate clinical benefits.

Eomeshi NK Cells in Human Liver Are Long-Lived and Do Not Recirculate but Can Be Replenished from the Circulation.

Human liver contains an Eomeshi population of NK cells that is not present in the blood. In this study, we show that these cells are characterized by a molecular signature that mediates their retention in the liver. By examining liver transplants where donors and recipients are HLA mismatched, we distinguish between donor liver-derived and recipient-derived leukocytes to show that Eomeslo NK cells circulate freely whereas Eomeshi NK cells are unable to leave the liver. Furthermore, Eomeshi NK cells are retained in the liver for up to 13 y. Therefore, Eomeshi NK cells are long-lived liver-resident cells. We go on to show that Eomeshi NK cells can be recruited from the circulation during adult life and that circulating Eomeslo NK cells are able to upregulate Eomes and molecules mediating liver retention under cytokine conditions similar to those in the liver. This suggests that circulating NK cells are a precursor of their liver-resident counterparts.