A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

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 α3/α6 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.

From prehab to rehab: Nutritional support for people undergoing pancreatic cancer surgery.

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.

Nutritional assessment and management in acute pancreatitis: Ongoing lessons of the NCEPOD report.

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.

A fast-track surgery programme leads to timelier treatment and higher resection rates in pancreatic cancer.

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.

The assessment of pancreatic exocrine function in patients with inoperable pancreatic cancer: In need of a new gold-standard.

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.

The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

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.

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

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/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 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.

Mis-use of antibiotics in acute pancreatitis: Insights from the United Kingdom's National Confidential Enquiry into patient outcome and death (NCEPOD) survey of acute pancreatitis.

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.

Development of MR quantified pancreatic fat deposition as a cancer risk biomarker.

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.

Patterns of progression, treatment of progressive disease and post-progression survival in the New EPOC study.

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.

Antibiotic use in acute pancreatitis: Global overview of compliance with international guidelines.

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.

Antibiotic use in acute pancreatitis: An audit of current practice in a tertiary centre.

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.

The effect of hepatic steatosis on survival following resection of colorectal liver metastases in patients without preoperative chemotherapy.

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.

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

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/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 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/m2 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.

Combination of holographic imaging with robotic partial nephrectomy for renal hilar tumor treatment.

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.

A Multicenter, Randomized, Double-Blinded, Clinical Trial Comparing Cattell-Warren and Blumgart Anastomoses Following Partial Pancreatoduodenectomy: PANasta Trial.

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.

Pancreatic ductal adenocarcinoma cells employ integrin α6ß4 to form hemidesmosomes and regulate cell proliferation.

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 α6ß4 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 ß4 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 α6ß4-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.

Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue.

A clear understanding of oral drug absorption is an important aspect of the drug development process. The permeability of drug compounds across intact sections of small intestine from numerous species, including man, has often been investigated using modified Ussing chambers. The maintenance of viable, intact tissue is critical to the success of this technique. This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross-species Ussing chamber studies. Electrical parameters (potential difference, mV; short-circuit current, µA.cm(-2) ; resistance, Ω.cm(2) ) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10(-6) ) for a training-set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco-2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeability values generated in rat and human jejunum correlate well (R(2) = 0.86), however the relationship between permeability in human tissue and Caco-2 cells was comparatively weak (R(2) = 0.58). Relating permeability to known human fraction absorbed (hFabs) values results in a remarkably similar relationship to both rat and human jejunum Papp values. It can be concluded that human jejunum sourced from pancreatoduodenectomy is a suitable source of tissue for Ussing chamber permeability investigations. The relationship between permeability and hFabs is comparable to results reported using alternative test compounds.

Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial.

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.

The SPINK1 N34S variant is associated with acute pancreatitis.

OBJECTIVE: Acute pancreatitis (AP) is a disease whose pathogenesis remains largely obscure. Genetic research has focussed attention upon the role of the pancreatic protease/protease inhibitor system. The aim of this study was to investigate the prevalence of genetic variants of the trypsin inhibitor, SPINK1, in acute pancreatitis. METHODS: We genotyped 468 patients with AP and 1117 healthy controls for SPINK1 alterations by single-strand conformation polymorphism analysis and by melting curve analysis using fluorescence resonance energy transfer probes. RESULTS: The c.101A>G (p.N34S) variant was detected in 24/936 alleles of patients and in 18/2234 alleles of healthy controls (odds ratio=3.240; 95% confidence interval: 1.766-5.945; P<0.001). In the UK patients, the mean age of patients with N34S was 11.9 years younger compared with N34S negative patients (P=0.023), but this was not apparent in the German patients. Allele frequencies for the c.163C>T (p.P55S) variant did not differ between patients and controls. CONCLUSION: The SPINK1 N34S variant is associated with acute pancreatitis. This supports the importance of premature protease activation in the pathogenesis of AP and suggests that mutated SPINK1 may predispose certain individuals to develop this disease.