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Abstract Background It has been suggested that the use of adjunctive hyperbaric oxygen therapy improves the healing of diabetic foot ulcers, and decreases the risk of lower extremity amputations. A limited number of studies have used a double blind approach to evaluate the efficacy of hyperbaric oxygen therapy in the treatment of diabetic ulcers. The primary aim of this study is to assess the efficacy of hyperbaric oxygen therapy plus standard wound care compared with standard wound care alone in preventing the need for major amputation in patients with diabetes mellitus and chronic ulcers of the lower limb. Methods/Design One hundred and eighteen (59 patients per arm) patients with non-healing diabetic ulcers of the lower limb, referred to the Judy Dan Research and Treatment Centre are being recruited if they are at least 18 years of age, have either Type 1 or 2 diabetes with a Wagner grading of foot lesions 2, 3 or 4 on lower limb not healing for at least 4 weeks. Patients receive hyperbaric oxygen therapy every day for 6 weeks during the treatment phase and are provided ongoing wound care and weekly assessments. Patients are required to return to the study centre every week for an additional 6 weeks of follow-up for wound evaluation and management. The primary outcome is freedom from having, or meeting the criteria for, a major amputation (below knee amputation, or metatarsal level) up to 12 weeks after randomization. The decision to amputate is made by a vascular surgeon. Other outcomes include wound healing, effectiveness, safety, healthcare resource utilization, quality of life, and cost-effectiveness. The study will run for a total of about 3 years. Discussion The results of this study will provide detailed information on the efficacy of hyperbaric oxygen therapy for the treatment of non-healing ulcers of the lower limb. This will be the first double-blind randomized controlled trial for this health technology which evaluates the efficacy of hyperbaric oxygen therapy in prevention of amputations in diabetic patients. Trial registration ClinicalTrials.gov Identifier: NCT00621608

Abstract Background A standard of prehospital care for patients presenting with ST-segment elevation myocardial infarction (STEMI) includes prehospital 12-lead and advance Emergency Department notification or prehospital bypass to percutaneous coronary intervention centres. Implementation of either care strategies is variable across communities and neither may exist in some communities. The main objective is to compare prehospital care strategies for time to treatment and survival outcomes as well as cost effectiveness. Methods/Design PREDICT is a multicentre, prospective population-based cohort study of all chest pain patients 18 years or older presenting within 30 mins to 6 hours of symptom onset and treated with nitroglycerin, transported by paramedics in a number of different urban and rural regions in Ontario. The primary objective of this study is to compare the proportion of study subjects who receive reperfusion within the target door-to-reperfusion times in subjects obtained after four prehospital strategies: 12-lead ECG and advance emergency department (ED) notification or 3-lead ECG monitoring and alert to dispatch prior to hospital arrival; either with or without the opportunity to bypass to a PCI centre. Discussion We anticipate four challenges to successful study implementation and have developed strategies for each: 1) diversity in the interpretation of the ethical and privacy issues across 47 research ethics boards/commiittees covering 71 hospitals, 2) remote oversight of data guardian abstraction, 3) timeliness of implementation, and 4) potential interference in the study by concurrent technological advances. Research ethics approvals from academic centres were obtained initially and submitted to non academic centre applications. Data guardians were trained by a single investigator and data entry is informed by a detailed data dictionary including variable definitions and abstraction instrucations and subjected to error and logic checks. Quality oversight provided by a single investigator. The window of the trial in each community has been confirmed with the basehospital medical director to correspond to the planned technological advances of the system of care. We hope this comparative analysis across treatment strategies for clinical outcomes and cost will provide sufficient evidence to implement the superior strategy across all communities and improve outcomes for all STEMI patients. Trial registration ClinicalTrials.gov: NCT00747656

Abstract Objectives To quantify the improvement in health outcomes in patients after total knee replacement (TKR). Methods This was a two-year non-randomized prospective observational study in knee osteoarthritis (OA) patients undergone TKR. Patients were interviewed one week before, six months after, and two years after surgery using a standardized questionnaire including the SF-36, the Oxford Knee Score (OKS), and the Knee Society Clinical Rating Scale (KSS). A generalized estimating equation (GEE) model was used to estimate the magnitudes of the changes with and without the adjustment of age, ethnicity, BMI, and years with OA. Results A total of 298 (at baseline), 176 (at six-months), and 111 (at two-years) eligible patients were included in the analyses. All the scores changed significantly over time, with the exception of SF-36 social functioning, vitality, and mental health. With the adjustment of covariates, the magnitude of changes in these scores was similar to those without the adjustment. Conclusions Both general and knee-specific physical functioning had been significantly improved after TKR, while other health domains have not been substantially improved after the surgery.

Abstract Objectives Intravenous immunoglobulin (IVIG) has demonstrated improvement in chronic inflammatory demyelinating polyneuropathy (CIDP) patients in placebo controlled trials. However, IVIG is also much more expensive than alternative treatments such as corticosteroids. The objective of the paper is to evaluate, from a Canadian perspective, the cost-effectiveness of IVIG compared to corticosteroid treatment of CIDP. Methods A markov model was used to evaluate the costs and QALYs for IVIG and corticosteroids over 5 years of treatment for CIDP. Patients initially responding to IVIG could remain a responder or relapse every 12 week model cycle. Non-responding IVIG patients were assumed to be switched to corticosteroids. Patients on corticosteroids were at risk of a number of adverse events (fracture, diabetes, glaucoma, cataract, serious infection) in each cycle. Results Over the 5 year time horizon, the model estimated the incremental costs and QALYs of IVIG treatment compared to corticosteroid treatment to be $124,065 and 0.177 respectively. The incremental cost per QALY gained of IVIG was estimated to be $687,287. The cost per QALY of IVIG was sensitive to the assumptions regarding frequency and dosing of maintenance IVIG. Conclusions Based on common willingness to pay thresholds, IVIG would not be perceived as a cost effective treatment for CIDP.

Abstract Background Cost-utility analyses are commonly used in economic evaluations of interventions or conditions that have an impact on health-related quality of life. However, evaluating utilities in children presents several challenges since young children may not have the cognitive ability to complete measurement tasks and thus utility values must be estimated by proxy assessors. Another solution is to use utilities derived from an adult population. To better inform the future conduct of cost-utility analyses in paediatric populations, we reviewed the published literature reporting utilities among children and adults across selected conditions common to paediatric and adult populations. Methods An electronic search of Ovid MEDLINE, EMBASE, and the Cochrane Library up to November 2008 was conducted to identify studies presenting utility values derived from the Health Utilities Index (HUI) or EuroQoL-5Dimensions (EQ-5D) questionnaires or using time trade off (TTO) or standard gamble (SG) techniques in children and/or adult populations from randomized controlled trials, comparative or non-comparative observational studies, or cross-sectional studies. The search was targeted to four chronic diseases/conditions common to both children and adults and known to have a negative impact on health-related quality of life (HRQoL). Results After screening 951 citations identified from the literature search, 77 unique studies included in our review evaluated utilities in patients with asthma (n = 25), cancer (n = 23), diabetes mellitus (n = 11), skin diseases (n = 19) or chronic diseases (n = 2), with some studies evaluating multiple conditions. Utility values were estimated using HUI (n = 33), EQ-5D (n = 26), TTO (n = 12), and SG (n = 14), with some studies applying more than one technique to estimate utility values. 21% of studies evaluated utilities in children, of those the majority being in the area of oncology. No utility values for children were reported in skin diseases. Although few studies provided comparative information on utility values between children and adults, results seem to indicate that utilities may be similar in adolescents and young adults with asthma and acne. Differences in results were observed depending on methods and proxies. Conclusions This review highlights the need to conduct future research regarding measurement of utilities in children.

Background: There is an urgent need to identify and treat potentially modifiable factors that may improve quality of life and influence survival of people with pancreatic cancer. The present study aimed to assess nutritional status at diagnosis and in the early and later stages of postoperative recovery and to evaluate the feasibility of optimising nutritional status and symptoms in patients undergoing surgery, as part of a multidisciplinary prehabilitation intervention., Methods: Nutritional data collection and intervention took place at four time points: (1) baseline at diagnosis; (2) prior to surgery; (3) first postoperative review (within 6 weeks); and (4) at 6-12 months postoperatively. The 'Patient Generated Subjective Global Assessment' (PG-SGA) tool was used to undertake a detailed nutritional assessment and the modified 'Gastrointestinal Symptom Rating Scale' (GISRS) was completed for all patients. Handgrip strength was measured by dynamometry., Results: During the period between April 2016 and April 2018, 137 patients scheduled for pancreatic cancer surgery were included who had a baseline dietetic assessment and at least one further review. Baseline assessment demonstrated that malnutrition was highly prevalent, with 62.3% experiencing more than 5% and 29.2% experiencing more than 10% weight loss over the prior 6 months. With dietetic assessment and support for at least 14 days, these patients gained a mean 1.8% body weight during this period and a mean improved handgrip of 7.9%. Symptoms also improved, with absolute change in PG-SGA scores reduced by a mean of 6.19 and a 6.3 reduction of GISRS., Conclusions: Dietetic assessment and intervention for all patients undergoing pancreatic resection ensures timely identification of nutritional deficiencies and correction of avoidable causes of weight loss, such as pancreatic enzyme insufficiency., (© 2022 The British Dietetic Association Ltd.)

Background: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery., Methods: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m 2 on days 1, 8, and 15, and oral capecitabine 830 mg/m 2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , folinic acid given according to local practice, and fluorouracil 400 mg/m 2 bolus injection on days 1 and 15 followed by 2400 mg/m 2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m 2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete., Findings: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia., Interpretation: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma., Funding: Cancer Research UK., Competing Interests: Declaration of interests PG has grant funding from CRUK. DC has research grants received from MedImmune, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, and Roche all paid to the Royal Marsden NHS Foundation Trust, and participated on the scientific advisory board for OVIBIO (unpaid). CMH has research grants from CRUK, Royal College of Surgeons of England and Pancreatic cancer UK. JPN has research grants from CRUK, Stiftung Deutsche Krebshilfe, Bundesministerium für Bildung und Forschung, Heidelberger Stiftung Chirurgie, and Dietmar Hopp Stiftung. DP has grant funding from BMS, Nucana, Astra Zeneca, Sirtex, honoraria from Boston Scientific and Sirtex, and support for travel from Nucana. SM has grant funding from CRUK. JW has consulting fees from Lilly, Novartis and Eisai and honoraria from Lilly, Eisai, Roche, Bayer, Novartis, Ipsen, AstraZeneca, Sanofi-Genzyme. JWV has received personal fees from Agios, Astra Zeneca, Baxter, Genoscience Pharma, Hutchison Medipharma, Imaging Equipment Ltd–AAA, Incyte, Ipsen, Mundipharma EDO, Mylan, Nucana, QED, Servierm Sirtex, and Zymeworks, and grant funding and non-financial support from Nucana. CS has participated on advisory boards for Bayer, BMS, Eisai, MSD, Roche and Incyte., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Whether a Blumgart anastomosis (BA) is superior to Cattell-Warren anastomosis (CWA) in terms of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy., Importance: Complications driven by POPF following pancreatic cancer resection may hinder adjuvant therapy, shortening survival. BA may reduce complications compared to CWA, improving the use of adjuvant therapy and prolonging survival., Methods: A multicenter double-blind, controlled trial of patients undergoing resection for suspected pancreatic head cancer, randomized during surgery to a BA or CWA, stratified by pancreatic consistency and duct diameter. The primary end point was POPF, and secondary outcome measures were adjuvant therapy use, specified surgical complications, quality of life, and survival from the date of randomization. For a 10% POPF reduction, 416 patients were required, 208 per arm (two-sided α = 0·05; power = 80%)., Results: Z-score at planned interim analysis was 0.474 so recruitment was held to 238 patients; 236 patients were analyzed (112 BA and 124 CWA). No significant differences in POPF were observed between BA and CWA, odds ratio (95% confidence interval [CI]) 1·04 (0.58-1.88), P = 0.887, nor in serious adverse events. Adjuvant therapy was delivered to 98 (62%) of 159 eligible patients with any malignancy; statistically unrelated to arm or postoperative complications. Twelve-month overall survival, hazard ratio (95% CI), did not differ between anastomoses; BA 0.787 (0.713-0.868) and CWA 0.854 (0.792-0.921), P = 0.266, nor for the 58 patients with complications, median (IQR), 0.83 (0.74-0.91) compared to 101 patients without complications 0.82 (0.76-0.89) ( P = 0.977)., Conclusions: PANasta represents the most robust analysis of BA versus CWA to date., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: To evaluate the clinical value of the holographic imaging technology in combination with robotic-assisted partial nephrectomy (RAPN) for renal hilar tumor treatment., Patients and Methods: From Dec. 2018 to Dec. 2021, patients diagnosed with renal hilar tumor were included in this retrospective study. Before the surgery, the engineers established the holographic image models based on the enhanced CT data. The models were used in patient consultation, pre-surgery planning and surgery simulation. During the RAPN, the navigation was achieved by real-time overlapping of the holographic images on the robotic surgery endoscopic views. The navigation technique helped the surgeon to identify the important anatomic structures such as tumor, renal vein, renal artery, and pelvis., Results: There were total of eight patients with renal hilar tumor who underwent RAPN combined with holographic imaging technique. The mean age was 57.3 years, the median ASA score was 2. The mean tumor size was 42.4 mm and the median RENAL Nephrometry score was 9.5. The clinical stages were cT1a (37.5%) and cT1b (62.5%). All the procedures were performed uneventfully by one surgeon. The mean operative time was 144.3 min, and the mean warm ischemia time was 27.9 min. The mean estimated blood loss was 86.3 ml. There was no conversion to open surgery or radical nephrectomy. There were no Clavien-Dindo ≥ 3 perioperative complications., Conclusions: Using the holographic imaging technique, the pre-surgery planning, simulation of renal arterial clamp and excision of the tumor, and intraoperative navigation were feasible and helpful in facilitating RAPN., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to its aggressive progression, late detection and lack of druggable driver mutations, which often combine to result in unsuitability for surgical intervention. Together with activating mutations of the small GTPase KRas, which are found in over 90% of PDAC tumours, a contributory factor for PDAC tumour progression is formation of a rigid extracellular matrix (ECM) and associated desmoplasia. This response leads to aberrant integrin signalling, and accelerated proliferation and invasion. To identify the integrin adhesion systems that operate in PDAC, we analysed a range of pancreatic ductal epithelial cell models using 2D, 3D and organoid culture systems. Proteomic analysis of isolated integrin receptor complexes from human pancreatic ductal epithelial (HPDE) cells predominantly identified integrin α6β4 and hemidesmosome components, rather than classical focal adhesion components. Electron microscopy, together with immunofluorescence, confirmed the formation of hemidesmosomes by HPDE cells, both in 2D and 3D culture systems. Similar results were obtained for the human PDAC cell line, SUIT-2. Analysis of HPDE cell secreted proteins and cell-derived matrices (CDM) demonstrated that HPDE cells secrete a range of laminin subunits and form a hemidesmosome-specific, laminin 332-enriched ECM. Expression of mutant KRas (G12V) did not affect hemidesmosome composition or formation by HPDE cells. Cell-ECM contacts formed by mouse and human PDAC organoids were also assessed by electron microscopy. Organoids generated from both the PDAC KPC mouse model and human patient-derived PDAC tissue displayed features of acinar-ductal cell polarity, and hemidesmosomes were visible proximal to prominent basement membranes. Furthermore, electron microscopy identified hemidesmosomes in normal human pancreas. Depletion of integrin β4 reduced cell proliferation in both SUIT-2 and HPDE cells, reduced the number of SUIT-2 cells in S-phase, and induced G1 cell cycle arrest, suggesting a requirement for α6β4-mediated adhesion for cell cycle progression and growth. Taken together, these data suggest that laminin-binding adhesion mechanisms in general, and hemidesmosome-mediated adhesion in particular, may be under-appreciated in the context of PDAC. Proteomic data are available via ProteomeXchange with the identifiers PXD027803, PXD027823 and PXD027827., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Acute pancreatitis (AP) is a medical emergency that is common, poorly understood and carries a significant risk of death. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) undertook a comprehensive report into the current management of AP in the UK. The study aimed to provide a more detailed analysis of the findings related to nutritional assessment and support., Methods: The data presented here were analysed from the core dataset used in the NCEPOD study. Adult patients admitted between January and June 2014 with a coded diagnosis of AP were included. A clinical and organisational questionnaire was used to collect data and submitted case notes subjected to peer review. Nutritional data, including assessment and provision of support, were analysed., Results: One hundred and forty-seven out of 168 (87.5%) hospitals had a nutrition team in place. A screening nutritional assessment was performed in only 67.4% (368/546) of patients. Subsequent referral to a dietitian and nutrition team input occurred in 39% (201/521) and 25% (143/572) of patients, respectively. Supplemental nutrition was considered and used in 240/555 (43.2%) patients. Overall management of the patients' nutrition was considered adequate by the case reviewers in only 281/332 (85%) of cases and by the clinicians in 77% (421/555) of cases., Conclusions: Many patients do not receive adequate nutritional assessment and, in up to 23% of cases, nutritional intervention is not adequate. Pancreatic exocrine insufficiency is likely under recognised and undertreated. Nutritional strategies to support early intervention and to support clinicians outside of tertiary pancreatic centres are warranted., (© 2021 The British Dietetic Association.)

Background: The aim was to perform a propensity-matched comparison of patients with pancreatic cancer undergoing surgery, with and without biliary stenting and an intention to treat analysis of long-term survival between the two groups., Methods: This was an observational study of a cohort of consecutive patients presenting with obstructive jaundice and undergoing pancreatoduodenectomy for pancreatic and periampullary malignancies between November 2015 and May 2019., Results: In this study of 216 consecutive operable patients, 70 followed the fast-track pathway and 146 had pre-operative biliary drainage. All 70 patients in the FT group and 122 out of 146 in the PBD group proceeded to surgery (100% and 83.6% respectively, p = 0.001). Interval time from diagnostic CT scan to surgery and from MDT decision to treat to surgery was shorter in the FT group, (median 8 vs 43 days p < 0.001 and 3 vs 36 days p < 0.001 respectively) as was the overall time from diagnostic CT to adjuvant treatment (88 vs 121 days p < 0.001). Postoperative outcomes including complications, readmission and mortality rates were comparable in the two groups. There was no difference in survival., Conclusion: For a person with pancreatic cancer who is proceeding to surgery, the best approach is to avoid pre-operative biliary drainage., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α 3 /α 6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Pancreatic exocrine insufficiency is commonplace in patients with pancreatic cancer, adversely impacting on quality of life and survival. Whilst the management of exocrine insufficiency is well established, diagnosis remains challenging in clinical practice. A plethora of diagnostic tests exist. Nevertheless, a lack of consensus remains about the optimal diagnostic method, specifically in patients with pancreatic cancer. Research, to date, has primarily been undertaken in patients with chronic pancreatitis and cystic fibrosis. This manuscript will review the current literature and will examine the evidence around the diagnostic tests available for pancreatic exocrine insufficiency and whether any exists specifically for pancreatic cancer cohorts., Findings: Evidence to recommend an individual test for the diagnosis of pancreatic exocrine insufficiency in clinical practice is lacking. Direct testing (by direct sampling of pancreatic secretions) has the highest specificity and sensitivity but is no longer routinely deployed or feasible in practice. Indirect testing, such as faecal elastase, is less accurate with high false-positive rates, but is routinely available in clinical practice. The 13C-mixed triglyceride breath test and the gold-standard 72-h faecal fat test have high specificity for indirect tests, but are not routinely available and cumbersome to undertake. A combination approach including nutritional markers and faecal elastase has more recently been proposed., Conclusion: Further research is required to identify the most optimal and accurate diagnostic tool to diagnose pancreatic exocrine insufficiency in patients with pancreatic cancer in clinical practice., Competing Interests: Declaration of competing interest LC, AL, NB and DOR received education and travel support from Mylan. Authors do not have other conflict of interest related to this manuscript., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear., Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival., Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019., Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine., Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence., Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03)., Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection., Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

Objective and Background: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies., Methods: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial., Results: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence., Conclusions: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Background: International guidelines for the management of acute pancreatitis state that antibiotics should only be used to treat infectious complications. Antibiotic prophylaxis is not recommended. The aim of this study was to analyse antibiotic use, and its appropriateness, from a national review of acute pancreatitis., Methods: Data were collected from The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) study into the management of acute pancreatitis. Adult patients admitted to hospitals in England and Wales between January and June 2014 with a coded diagnosis of acute pancreatitis were included. Clinical and organisational questionnaires were used to collect data and these submissions subjected to peer review. Antibiotic use, including indication and duration were analysed., Results: 439/712 (62%) patients received antibiotics, with 891 separate prescriptions and 23 clinical indications. A maximum of three courses of antibiotics were prescribed, with 41% (290/712) of patients receiving a second course and 24% (174/712) a third course. For the first antibiotic prescription, the most common indication was "unspecified" (85/439). The most common indication for the second course was sepsis (54/290), "unspecified" was the most common indication for the third course (50/174). In 72/374 (19.38%) the indication was deemed inappropriate by the clinicians and in 72/393 (18.3%) by case reviewers., Conclusions: Inappropriate use of antibiotics in acute pancreatitis is common. Healthcare providers should ensure that antimicrobial policies are in place as part of an antimicrobial stewardship process. This should include specific guidance on their use and these policies must be accessible, adherence audited and frequently reviewed., (Copyright © 2018. Published by Elsevier B.V.)

Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC., Aims and Methods: This narrative review aims to explore the potential role and timing for the use of IRE in patients with LAPC., Results: To date, there is limited and inconsistent level I and II evidence available in the literature regarding the use of IRE for the treatment of PDAC., Discussion: Although some of the preliminary experience of the use of IRE in patients with LAPC is encouraging, it should only be used after conventional evidence-based treatments and/or within the research context., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Excess body adiposity is associated with increased risk of pancreatic cancer, and in animal models excess intra-pancreatic fat is a driver of pancreatic carcinogenesis. Within a programme to evaluate pancreatic fat and PC risk in humans, we assessed whether MR-quantified pancreatic fat fraction (PFF) was 'fit for purpose' as an imaging biomarker., Methods: We determined PFF using MR spectroscopy (MRS) and MR chemical shift imaging (CS-MR), in two groups. In Group I, we determined accuracy of MR-derived PFF with histological digital fat quantification in 12 patients undergoing pancreatic resection. In a second study, we assessed reproducibility in 15 volunteers (Group IIa), and extended to 43 volunteers (Group IIa & IIb) to relate PFF with MR-derived hepatic fat fraction (HFF), body mass index (BMI), and waist circumference (WC) using linear regression models. We assessed intra- and inter-observer, and between imaging modality levels of agreement using Bland-Altman plots., Results: In Group I patients, we found strong levels of agreement between MRS and CS-MR derived PFF and digitally quantified fat on histology (rho: 0.781 and 0.672 respectively). In Group IIa, there was poor reproducibility in initial assessments. We refined our protocols to account for 3D dimensionality of the pancreas, and found substantially improved intra-observer agreements. In Group II, HFF and WC were significantly correlated with PFF (p values < 0.05)., Interpretation: Both CS-MR and MRS (after accounting for pancreatic 3D dimensionality) were 'fit for purpose' to determine PFF and might add information on cancer prediction independent from measures of general body adiposity., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: Over the last decade trauma services have undergone a reconfiguration in England and Wales. The objective is to describe the epidemiology, management and outcomes for liver trauma over this period and examine factors predicting survival., Methods: Patients sustaining hepatic trauma were identified using the Trauma Audit and Research Network database. Demographics, management and outcomes were assessed between January 2005 and December 2014 and analysed over five, 2-year study periods. Independent predictor variables for the outcome of liver trauma were analysed using multiple logistic regression., Results: 4368 Patients sustained hepatic trauma (with known outcome) between January 2005 and December 2014. Median age was 34 years (interquartile range 23-49). 81% were due to blunt and 19% to penetrating trauma. Road traffic collisions were the main mechanism of injury (58.2%). 241 patients (5.5%) underwent liver-specific surgery. The overall 30-day mortality rate was 16.4%. Improvements were seen in early consultant input, frequency and timing of computed tomography (CT) scanning, use of tranexamic acid and 30-day mortality over the five time periods. Being treated in a unit with an on-site HPB service increased the odds of survival (odds ratio 3.5, 95% confidence intervals 2.7-4.5)., Conclusions: Our study has shown that being treated in a unit with an on-site HPB service increased the odds of survival. Further evaluation of the benefits of trauma and HPB surgery centralisation is warranted.

Introduction: Advances in surgical technologies allowed safe laparoscopic pancreaticoduodenectomy (LPD). The aim of this study is to compare the oncologic outcomes of LPD to open pancreaticoduodenectomy (OPD) in terms of safety and recurrence rate., Materials and Methods: A cohort of 30 patients were matched for age, sex, American Society of Anaesthesiologists, tumor size, pancreatic duct diameter, and histopathologic diagnosis on a 1:1 basis (15 LPD, 15 OPD). Comparison between groups was performed on intention-to-treat basis. Survival following resection was compared using the Kaplan-Meier survival analysis., Results: The median operating time for LPD group was longer than for OPD group (470 vs. 310 min; P=0.184). However, estimated blood loss (300 vs. 620 mL; P=0.023), high dependency unit stay (2.0 vs. 6.0 d; P=0.013) and postoperative hospital stay (9.0 vs. 17.4 d; P=0.017) were significantly lower in the LPD group. There was no significant difference in postoperative rates of morbidity (40% vs. 67%; P=0.431) and mortality (0% vs. 6.7%; P=0.99). The surgical resection margins R0 status (87% vs. 73%; P=0.79) and the number of lymph nodes (18 vs. 20; P=0.99) in the resected specimens were comparable between the 2 groups. There was no significant difference in overall survival outcomes., Conclusions: In selected patients, the laparoscopic approach to pancreaticoduodenectomy in the hands of the experienced offers advantages over open surgery without compromising the oncologic resection.

Objective: To assess use of imaging in patients admitted to UK hospitals with acute pancreatitis (AP)., Methods: 4,479 patients had a diagnosis AP in the first 6 months of 2014. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) selected patients with more severe AP for case review. Clinicians completed 712 questionnaires and case reviewers assessed 418 cases. The use of imaging in patients with AP is reported., Results: The common causes of AP were gallstones (46.5%) and alcohol excess (22%) with no cause identified in 17.5%. Imaging was needed to diagnose AP in 12%. 60.1% of patients had one or more CT scan. The timing of the CT scan(s) was appropriate in 90% of patients. The number of CTs was appropriate in all except 6.6% (equally split between too many and too few). AP collection intervention was radiological in 49/613 and surgical in 23/613. 69.8% had an ultrasound scan which diagnosed gallstones in 46.4% and bile duct dilatation in 12.9%. At least 21% had ultrasound scan inappropriately omitted. The National Confidential Enquiry into Patient Outcome and Death recommends gallstones are excluded in all patients with AP, including suspected alcohol-related AP. 29.8% underwent magnetic resonance cholangio--pancreatography diagnosing gallstones in 62.4%, bile duct dilatation in 25.4% and common bile duct stones in 14.4%. 20.6% had recurrent pancreatitis with gallstones accounting for a third. 17% with gallstone AP had a cholecystectomy within the guideline recommended time period., Conclusion: Imaging is rarely required for the diagnosis of AP. CT is used responsibly in AP management. Imaging should be used more to exclude gallstones, including in presumed alcohol related AP. Increased diagnostic efforts will not reduce recurrent biliary AP unless matched by earlier gallstone treatment. Advances in knowledge: Whilst CT is used responsibly in AP greater use of other diagnostic modalities is required to identify reversible causes, in particular gallstones, in order to prevent recurrent AP.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) is an independent organisation whose remit is to review the quality of medical and surgical care provided in the United Kingdom. We undertook a review into the care provided to patients treated for acute pancreatitis during a 6 month study period between 1st January and 30th June 2014. This included assessment of care at an organisational level, clinical level within hospitals and external peer review. From a random sample, 712 patients underwent hospital clinician review and 418 patients had external peer review. Overall, we found that there was room for improvement in care in over 50% of patients with acute pancreatitis. Case reviewers felt that efforts to prevent recurrent episodes due to gallstones and alcohol were inadequate as 21% of patients in the study had one or more previous episodes of acute pancreatitis. Aspects of general care where improvements could be made include better antibiotic stewardship; as 1/5 of patients were considered to have been given antibiotics unnecessarily. Overall management of the patients' nutrition was considered adequate by the case reviewers in only 85% of cases. The use of an early warning score was omitted in 31% of emergency department admissions. Recommendations include standardised early warning scoring systems to be used throughout the hospital and commenced in the emergency department. The development of better networking arrangements and regional pancreatitis units, with shared management guidelines, is also essential to improve the coordination of care., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer., Methods: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m 2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m 2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434., Findings: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group., Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma., Funding: Cancer Research UK., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Intravenous antibiotic prophylaxis is not recommended in acute pancreatitis. According to current international guidelines antibiotics together with further intervention should be considered in the setting of infected necrosis. Appropriate antibiotic therapy particularly avoiding over-prescription is important. This study examines antibiotic use in acute pancreatitis in a tertiary centre using the current IAP/APA guidelines for reference., Methods: Data were collected on a consecutive series of patients admitted with acute pancreatitis over a 12 month period. Data were dichotomized by patients admitted directly to the centre and tertiary transfers. Information was collected on clinical course with specific reference to antibiotic use, episode severity, intervention and outcome., Results: 111 consecutive episodes of acute pancreatitis constitute the reported population. 31 (28%) were tertiary transfers. Overall 65 (58.5%) patients received antibiotics. Significantly more tertiary transfer patients received antibiotics. Mean person-days of antibiotic use was 23.9 (sd 29.7) days in the overall study group but there was significantly more use in the tertiary transfer group as compared to patients having their index admission to the centre (40.9 sd 37.1 vs 10.2 sd 8.9; P < 0.005). Thirty four (44%) of patients with clinically mild acute pancreatitis received antibiotics., Conclusions: There is substantial use of antibiotics in acute pancreatitis, in particular in patients with severe disease. Over-use is seen in mild acute pancreatitis. Better consideration must be given to identification of prophylaxis or therapy as indication. In relation to repeated courses of antibiotics in severe disease there must be clear indications for use., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Aim: Surgery is the only modality of cure in patients diagnosed with neuroendocrine tumours (NETs). The aim of this study was to identify prognostic factors associated with disease relapse in patients with NETs treated by potentially-curative surgery., Methods: Sequential patients registered in The Christie European NET Society (ENETS) Centre of Excellence, with grade (G)1 or G2 NETs who had undergone curative surgery (February 2002-June 2014) were included. Investigated prognostic factors for relapse were: age, gender, TNM stage, tumour-localisation, functionality, genetic predisposition, presence of multiple NETs, second malignancy, grade (Ki-67-based), presence of vascular and/or perineural invasion, necrosis, surgical margin (R0/R1), Eastern Cooperative Oncology Group performance status and Adult Comorbidity Evaluation co-morbidity score., Results: One hundred and eighty-eight patients were identified [median age of 60 years (range 16-89)]. With a median follow-up of 2.6 years, 43 relapses occurred. The estimated median relapse-free survival (RFS) for the entire cohort was 8.0 years (95% confidence interval [CI] 5.9-10.0 years). In univariate analysis, primary NET location (p = 0.01), ENETS T-(HR-1.4; 95%-CI 1.0-2.0, p = 0.026), N-(HR-2.0, 95%-CI 1.1-3.9, p = 0.026) and M-stage (HR-2.6, 95%-CI 1.1-6.3, p = 0.052), grade (Ki-67%-based) (HR-2.5; 95%-CI 1.4-4.7; p = 0.003) and perineural invasion (HR-2.1; 95%-CI 1.1-3.9; p = 0.029) were prognostic for relapse. Factors remaining significant after multivariable analysis were tumour size (HR-1.67; 95%-CI 1.04-2.70; p = 0.03), nodal involvement (HR-2.61; 95%-CI 1.17-5.83; p = 0.013) and Ki-67 at the time of diagnosis (HR-1.93; 95%-CI 1.24-3.0; p = 0.002)., Conclusion: Size of tumour, lymph node involvement and Ki-67 were independent prognostic factors for relapse after potentially curative surgery in NET., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome., Methods: A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012., Results: The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent., Conclusions: Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Cryptococcal meningitis is uncommon in children, particularly in infants. A 2-day-old boy was admitted with signs suggestive of meningitis. Lumbar puncture confirmed meningitis and cryptococcal infection (cryptococcal antigen and Indian ink stain-positive). His mother was HIV-negative. This is thought to be the youngest case of cryptococcal meningitis to be reported. Cryptococcal infection should be considered in children of all ages with meningitis where there is possible immunodeficiency or failure to respond to initial treatment with antibiotics.

Introduction: Practice guidelines for the management of acute pancreatitis make recommendations in relation to antibiotic prophylaxis and treatment in acute pancreatitis. However, it is difficult to ascertain whether this information translates into clinical practice. The aim of this study is to obtain a global overview assessing reports from across the world of the use of antibiotic use in acute pancreatitis., Methods: A computerised literature search was performed from January 1992 to September 2015. Studies were either national physician surveys or national database reports on antibiotic prophylaxis in acute pancreatitis. Using these criteria, 10 studies were identified which comprise the final study population., Results: Eight studies report on the questionnaire responses of 2397 physicians. The range of response rate was 38-96%. A separate study reported on outcome of a national insurance database outcomes in 7193 patients. The lowest incidence of use of antibiotic prophylaxis was 41% and the highest 88%., Conclusion: This study provides a unique global perspective on antibiotic use in acute pancreatitis and indicates that the use of antibiotics, both as prophylaxis and as treatment in this disease is widespread., (Copyright © 2016 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Background: Failure of the pancreatic remnant anastomosis to heal following pancreato-duodenectomy is a major cause of significant and life-threatening complications, notably a post-operative pancreatic fistula. Recently, non-randomized trials have shown superiority of a most intuitive anastomosis (Blumgart technique), which involves both a duct-to-mucosa and a full-thickness pancreatic "U" stitch, in effect a mattress stitch, over a standard duct-mucosa technique (Cattell-Warren). The aim of this study is to examine if these findings remain within a randomized setting., Methods/design: The PANasta trial is a randomized, double-blinded multi-center study, whose primary aim is to assess whether a Blumgart pancreatic anastomosis (trial intervention) is superior to a Cattell-Warren pancreatic anastomosis (control intervention), in terms of pancreatic fistula rates. Patients with suspected malignancy of the pancreatic head, in whom a pancreato-duodenectomy is recommended, would be recruited from several UK specialist regional centers. The hypothesis to be tested is that a Blumgart anastomosis will reduce fistula rate from 20 to 10 %. Subjects will be stratified by research site, pancreatic consistency and diameter of pancreatic duct; giving a sample size of 253 per group. The primary outcome measure is fistula rate at the pancreatico-jejunostomy. Secondary outcome measures are: entry into adjuvant therapy, mortality, surgical complications, non-surgical complications, hospital stay, cancer-specific quality of life and health economic assessments. Enrolled patients will undergo pancreatic resection and be randomized immediately prior to pancreatic reconstruction. The operation note will only record "anastomosis constructed as per PANasta trial randomization," thus the other members of the trial team and patient are blinded. An inbuilt internal pilot study will assess the ability to randomize patients, while the construction of an operative manual and review of operative photographs will maintain standardization of techniques., Discussion: The PANasta trial will be the first multi-center randomized controlled trial (RCT) comparing two types of duct-to-mucosa pancreatic anastomosis with surgical quality assurance., Trial Registration: ISRCTN52263879 . Date of registration 15 January 2015.

Introduction: Although the laparoscopic approach to distal pancreatectomy for benign and malignant diseases is largely replacing open surgery in some centers, well-designed studies comparing these approaches are limited. We present a case-matched study that compares the outcomes of laparoscopic distal pancreatectomy (LDP) to open distal pancreatectomy (ODP)., Methods: Of 112 patients (51 female) who underwent surgery between January 2002 and December 2011, 44 patients were matched on a 1:1 basis (22 LDP, 22 ODP) according to age, sex, and tumor size. Outcomes were compared on an intention-to-treat basis. Data shown represent median where appropriate., Results: The laparoscopic and open groups were comparable for age (57 vs. 59.9 y, P=0.980), sex distribution (P=1.000), tumor size (3 vs. 4 cm, P=0.904), and the frequency of benign versus malignant disease (P=0.920). LDP was associated with significantly lower blood loss (100 vs. 500 mL, P=0.001), higher spleen preservation rate (45% vs. 18%, P=0.029), as well as shorter high dependency unit stay (1 vs. 5 d, P=0.001) and postoperative hospital stay (5 vs. 14 d, P=0.017). There was no significant difference in operating time (245 vs. 240 min, P=0.602) and postoperative morbidity (13.6% vs. 27.2%, P=0.431). In patients with malignant disease, there were no differences in R0 resection margin status (90% vs. 85.7%, P=0.88), the numbers of lymph nodes retrieved (12.7 vs. 14.1, P=0.82), the 1- and 2-year survival rates (89% vs. 81%, P=0.54 and 74.2% vs. 71.5%, P=0.63, respectively), and the mean duration of survival (45 vs. 31 mo, P=0.157)., Conclusions: The laparoscopic approach to distal pancreatectomy offers advantages over open surgery in terms of reductions in operative trauma and duration of postoperative recovery without compromising the oncologic resection.

Background: High intra-hepatic fat (IHF) content is associated with insulin resistance, visceral adiposity, and increased morbidity and mortality following liver resection. However, in clinical practice, IHF is assessed indirectly by pre-operative imaging [for example, chemical-shift magnetic resonance (CS-MR)]. We used the opportunity in patients undergoing liver resection to quantify IHF by digital histology (D-IHF) and relate this to CT-derived anthropometrics, insulin-related serum biomarkers, and IHF estimated by CS-MR., Methods: A reproducible method for quantification of D-IHF using 7 histology slides (inter- and intra-rater concordance: 0.97 and 0.98) was developed. In 35 patients undergoing resection for colorectal cancer metastases, we measured: CT-derived subcutaneous and visceral adipose tissue volumes, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting serum adiponectin, leptin and fetuin-A. We estimated relative IHF using CS-MR and developed prediction models for IHF using a factor-clustered approach., Results: The multivariate linear regression models showed that D-IHF was best predicted by HOMA-IR (Beta coefficient(per doubling): 2.410, 95% CI: 1.093, 5.313) and adiponectin (β(per doubling): 0.197, 95% CI: 0.058, 0.667), but not by anthropometrics. MR-derived IHF correlated with D-IHF (rho: 0.626; p = 0.0001), but levels of agreement deviated in upper range values (CS-MR over-estimated IHF: regression versus zero, p = 0.009); this could be adjusted for by a correction factor (CF: 0.7816)., Conclusions: Our findings show IHF is associated with measures of insulin resistance, but not measures of visceral adiposity. CS-MR over-estimated IHF in the upper range. Larger studies are indicated to test whether a correction of imaging-derived IHF estimates is valid., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Pancreatoduodenal (PD) injury is an uncommon but serious complication of blunt and penetrating trauma, associated with high mortality. The aim of this study was to assess the incidence, mechanisms of injury, initial operation rates and outcome of patients who sustained PD trauma in the UK from a large trauma registry, over the period 1989-2013., Methods: The Trauma Audit and Research Network database was searched for details of any patient with blunt or penetrating trauma to the pancreas, duodenum or both., Results: Of 356,534 trauma cases, 1,155 (0.32%) sustained PD trauma. The median patient age was 27 years for blunt trauma and 27.5 years for penetrating trauma. The male-to-female ratio was 2.5:1. Blunt trauma was the most common type of injury seen, with a ratio of blunt-to-penetrating PD injury ratio of 3.6:1. Road traffic collision was the most common mechanism of injury, accounting for 673 cases (58.3%). The median injury severity score (ISS) was 25 (IQR: 14-35) for blunt trauma and 14 (IQR: 9-18) for penetrating trauma. The mortality rate for blunt PD trauma was 17.6%; it was 12.2% for penetrating PD trauma. Variables predicting mortality after pancreatic trauma were increasing age, ISS, haemodynamic compromise and not having undergone an operation., Conclusions: Isolated pancreatic injuries are uncommon; most coexist with other injuries. In the UK, a high proportion of cases are due to blunt trauma, which differs from US and South African series. Mortality is high in the UK but comparison with other surgical series is difficult because of selection bias in their datasets.

Objectives: Nutritional deficiencies and immune dysfunction in cancer patients may contribute to postoperative septic morbidity. This trial compared the effects of perioperative enteral immunonutrition (EIN) versus standard enteral nutrition (SEN) on systemic and mucosal immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer., Methods: Thirty-seven patients were randomized (EIN, n = 17; SEN, n = 20) to receive feed for 14 days preoperatively and 7 days postoperatively. Mediators of systemic immunity (interleukin 1α, tumor necrosis factor α, lymphocytes subsets, and complement components) and of mucosal immunity in duodenal biopsies, nutritional markers and parameters were evaluated., Results: The groups were comparable for demographics, the concentrations of mediators of systemic and mucosal immunity at time of recruitment, and for the duration and amount of feed received. Preoperative EIN rather than SEN was associated with significant reductions in plasma tumor necrosis factor α and total hemolytic complement. Enteral immunonutrition-fed patients had significantly higher total lymphocyte count on the third postoperative day and significantly greater rise in CD4/CD8 ratio from day 3 to day 7 postoperatively compared with SEN-fed patients., Conclusions: The perioperative administration of EIN rather than SEN is associated with a favorable modulation of the inflammatory response and enhancement of systemic immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer.

Background: Cystgastrostomy is the commonest method of internal drainage of pancreatic pseudocysts (PPs). While large and persistent retrogastric pancreatic pseudocysts are amenable to laparoscopic cystgastrostomy, the potential benefits of this minimally invasive laparoscopic approach over open surgery remain to be demonstrated. The aim of this study was to compare the outcomes of the laparoscopic and open approaches for cystgastrostomy., Methods: Patients who underwent laparoscopic cystgastrostomy (LCG) were matched on a 3:1 basis to those who underwent open cystgastrostomy (OCG) according to age, sex distribution, and size of pseudocyst. The outcomes of the two approaches were compared on an intention-to-treat basis. Data shown represent medians., Results: A total of 54 patients underwent cystgastrostomy (35 LCG, 19 OCG) between 1997 and 2011. The final case matched cohort consisted of 40 patients (12 female and 28 male) of which 30 underwent LCG (two converted to open surgery) and 10 underwent OCG. The laparoscopic and open groups were comparable for age (55 vs. 59 years, P = 0.80), sex distribution, and size of pseudocyst (10 vs. 13 cm, P = 0.51). The laparoscopic approach had a significantly shorter operating time (62 vs. 95 min, P = 0.035) and carried a significantly lower risk of postoperative morbidity (10% vs. 60%, P = 0.024) and shorter postoperative hospital stay (6.2 vs. 11 days, P = 0.038). There was one operative death after OCG (10%)., Conclusion: The laparoscopic approach to cystgastrostomy for large and persistent retrogastric pancreatic pseudocysts is associated with a shorter operating time, smoother and more rapid recovery, and a shorter hospital stay compared with open surgery. The laparoscopic approach should be considered the preferable approach where expertise is available., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Excess adiposity is a risk factor for incidence of several gastrointestinal cancers, but it is unclear how these epidemiological observations translate into clinical practice., Methods: Critical appraisals and updated analyses of published systematic reviews were undertaken to quantify cancer risk associations better and to assess the impact of weight-reducing strategies (surgical and non-surgical) on cancer prevention., Results and Conclusion: A large volume of evidence demonstrates that body mass index (BMI), as an approximation for general adiposity, is a risk factor for the development of oesophageal adenocarcinoma, and colorectal, hepatocellular, gallbladder and pancreatic cancers. A smaller volume of evidence demonstrates that indices of increased central adiposity (such as waist circumference) are associated with increased risk of oesophageal adenocarcinoma and colorectal cancer, but these indices are not necessarily better predictors of risk compared with BMI. Several biological mechanisms may explain these associations but each hypothesis has several caveats and weaknesses. There are few data that convincingly demonstrate significant reductions in risk of gastrointestinal cancers following weight-reducing strategies. In turn, there are many methodological pitfalls in this literature, which prevent conclusive interpretation. The lack of robust intermediary obesity-related biomarkers is an additional unresolved challenge for prevention trials. Novel underpinning mechanisms (for example, local ectopic fat) and more accurate methods to measure these intermediaries are sought and explored as the most optimistic research strategies for the future., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: We previously reported that the presence of steatosis did not adversely influence survival in patients undergoing resection for colorectal liver metastases (CLM) without pre-operative chemotherapy. Here, this hypothesis is tested in patients undergoing resection for CLM following pre-operative chemotherapy., Methods: We assessed the effects of background liver pathology, categorized as 'normal', 'steatosis' and 'other', on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) in LiverMetSurvey patients. Survival analyses included log-rank tests and multivariate Cox models, incorporating well-established prognosticators. In secondary analyses, re-populating the model with non-chemotherapy patients, the effect modification of chemotherapy on the impact of steatosis on survival was tested., Results: Of 4329 patients undergoing first-time liver resection following pre-operative chemotherapy, histologies were normal in 1913 (44%), steatosis in 1675 (39%), and other abnormal pathologies in 741 (17%). For normal, steatosis and other, 90-day mortalities were 2.1%, 2.3%, and 3.5% (P = 0.103). For the three histo-pathological groups, 5-year OS rates were 39%, 42%, and 36% (Plogrank = 0.363); 5-year CSS rates were 43%, 45% and 41% (Plogrank = 0.496), respectively. The associations of steatosis with OS and CSS were materially unchanged in the multivariate models. Chemotherapy did not interact with the effect of steatosis on survival., Conclusion: The findings of equivalent survivals challenge the common perception that steatosis in CLM patients after pre-operative chemotherapy is associated with increased peri-operative mortality and poorer long-term survival., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, with as yet undetermined incidence and prevalence in the general population. Our understanding of it continues to evolve. In the last few years, 2 separate subtypes have been identified: type 1 AIP has been recognised as the pancreatic manifestation of a multiorgan disease, named immunoglobulin G4 (IgG4)-related disease while type 2 AIP is a pancreas specific disorder not associated with IgG4. International criteria for the diagnosis of AIP have been defined: the HISORt criteria from the Mayo clinic, the Japan consensus criteria and, most recently, the international association of pancreatology "International Consensus Diagnostic Criteria". Despite this, in clinical practice it can still be very difficult to confirm the diagnosis and differentiate AIP from a pancreatic cancer. There are no large studies into the long-term prognosis and management of relapses of AIP, and there is even less information at present regarding the Type 2 AIP subtype. Further studies are necessary to clarify the pathogenesis, treatment and long-term outcomes of this disease. Critically for clinicians, making the correct diagnosis and differentiating the disease from pancreatic cancer is of the utmost importance and the greatest challenge.

Aims: The aims of this study were to compare the diagnostic performance of CT scan, MR liver, PET-CT and intra-operative ultrasound (IOUS) for the detection of liver metastases against the histopathological findings, and to compare PET-CT with CT for the detection of distant disease in metastatic colorectal cancer patients eligible for surgical treatment., Methods: A prospective study was performed that measured concordance between the number and stage of metastatic lesions identified with various preoperative imaging modalities and histology of patients undergoing surgical treatment for CRLM., Results: Compared with histopathology, concordance for the number of metastatic liver lesions was moderate for CT scan (K = 0.477, 95% CI: 0.28-0.66), moderate for MR scan (K = 0.574, 95% CI: 0.39-0.75), good for FDG PET-CT (K = 0.703, 95% CI: 0.52-0.87) and very good for IOUS (K = 0.904, 95% CI: 0.81-0.99). Additional CRLM were identified intraoperatively in six patients (9.1%) with IOUS and in 7.5% of the cases surgical strategy was changed according to the new intraoperative findings. The diagnosis of intra abdominal lymph node metastatic disease was made with PET-CT only in nine patients (13.6%), Discussion: Our study supports the recent recommendations of the Oncosurg Multidisciplinary International Consensus regarding the importance of high quality CT and MR in the staging of CRLM but provides further evidence for the added value of PET-CT, especially in detecting extrahepatic intra-abdominal metastatic disease that may be amenable to potentially curative resection. Despite these advances in preoperative staging, there still remains a role for IOUS in detecting additional metastases at the time of surgery., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Excess adiposity is an established risk factor for incident colorectal cancer (CRC) but whether this association extrapolates to poorer survival is unclear. We undertook a systematic review to examine relationships between measures of adiposity and survival in patients with CRC. For distinction, we included pre-diagnosis exposure and CRC-related mortality. We performed dose-response meta-analyses and assessed study quality using eight domains of bias. Six study categories were identified based on (i) timing of adiposity measurement relative to survival analysis time zero and (ii) clinical setting. Several types of adiposity measurements were reported; body mass index (BMI) was the commonest. For pre-diagnosis cohorts, baseline BMI negatively impacted on CRC-related mortality in men only (risk estimate per 5 kg m(-2)  = 1.19, 95% confidence intervals: 1.14-1.25). The other groups were pre-diagnosis BMI but diagnosis as time zero; population-based cohorts; treatment cohorts; observational analyses within adjuvant chemotherapy trials; patients with metastatic CRC - each had several biases (e.g. treatment selection, reverse causality) and sources of confounding (e.g. chemotherapy 'capping'). Overall, there was insufficient evidence for a strong link between adiposity and survival. These findings demonstrate an important principle: an established link between an exposure (here, adiposity) and increased cancer incidence does not necessarily extrapolate into an inferior post-treatment outcome., (© 2014 The Authors. obesity reviews © 2014 International Association for the Study of Obesity.)

Background: Hepatic steatosis, a common condition associated with insulin resistance and excess body weight, is reported to be associated with an increased risk for perioperative mortality in patients undergoing resection of colorectal liver metastases (CLM), but its impact upon longterm survival is less well documented., Methods: The effects of background liver pathology, categorized as 'normal', 'with steatosis' and 'other', on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) were assessed in patients undergoing resection for CLM according to data maintained in the LiverMetSurvey database. As preoperative chemotherapy may confound the effects of steatosis, patients who had been given preoperative chemotherapy were excluded. Survival analyses included log-rank tests for comparisons, and multivariate Cox models, including well-established prognosticators., Results: Of 5853 patients who underwent first-time liver resection without preoperative chemotherapy, 1793 (30.6%) had background steatosis. Rates of 90-day perioperative mortality in patients with normal, steatosis and other pathologies were 2.8%, 2.1% and 4.9%, respectively. Steatosis was associated with improved 5-year OS (47.4% versus 43.0%; log rank, P = 0.0017) and CSS (56.1% versus 50.3%; P = 0.002) compared with normal background liver. After adjustments, the survival advantage associated with steatosis remained (hazard ratio = 0.806, 95% confidence interval 0.717-0.905 for CSS)., Discussion: The paradoxical survival advantage observed in patients with steatosis undergoing liver resection for CLM generates a hypothesis that peri-diagnosis of excess body adiposity has a survival protective effect that warrants further research., (© 2012 International Hepato-Pancreato-Biliary Association.)