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Background: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable. Method: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan–Meier analysis. Results: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p =.01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR).3, p <.0001). Conclusions: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.

Background: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ~13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. Patients and Methods: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. Result(s): Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade >=3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade >=3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade >=3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months

Background: Unresectable LAPC has a poor prognosis. Current standard-of-care (SoC) is limited to chemotherapy or chemo-radiotherapy. Brachytherapy using a device containing beta-radiation-emitting Phosphorous-32 (P-32) microparticles is implanted directly into pancreatic tumours via endoscopic-ultrasound (EUS) guidance. We report a post-hoc analysis of resected vs. non-resected cohorts in PanCO, a single-arm, multi-centre, pilot study of P-32 microparticles with SoC chemotherapy in patients with unresectable LAPC. Method(s): Eligible patients with unresectable LAPC and ECOG 0/1 received either gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy. P-32 microparticles (OncoSilTM; OncoSil Medical) implantation was planned at weeks 4-5. P-32 activity was calculated from participants' tumour volume to deliver 100Gy absorbed dose. The primary endpoint was safety/tolerability graded using CTCAE v4.0. Response was assessed by independent central reader using RECIST 1.1 with 8-weekly CT scans and FDG-PET scans at baseline and week 12. Result(s): Fifty patients were enrolled (Intention-to-Treat); 42 participants were implanted with P-32 microparticles (Per Protocol [PP] population) at a median of 31 days. 40 participants received gemcitabine/nab-paclitaxel and 10 FOLFIRINOX (PP: 34/8, respectively). Median follow-up was 31.6 months. Ten participants (23.8% PP; 9 received gemcitabine/nab-paclitaxel, 1 FOLFIRINOX) underwent pancreaticoduodenectomy following repeat staging at a median of 5.8 months post-enrolment (4.4 months post-implant); 8 (80%) achieved R0 margins. Four further participants were sufficiently down-staged to be technically considered for surgical resection, but could not undergo surgery due to metastases, co-morbidities or patient choice. Baseline characteristics for resected and non-resected participants were similar for age (median 65 vs. 68 years), longest tumour diameter (median 4.5 vs. 4.5cm) and tumour volume (median 23.2 vs. 24.4cc), respectively. More

Background: This study: (i) assessed compliance with a consensus set of quality indicators (QIs) in pancreatic cancer (PC); and (ii) evaluated the association between compliance with these QIs and survival. Method(s): Four years of data were collected for patients diagnosed with PC. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A multivariable analysis tested the relationship between significant patient and hospital characteristics, patient cluster effects within hospitals and survival. Result(s): 1061 patients were eligible for this study. Significant association with improved survival were: (i) in the potentially resectable group having adjuvant chemotherapy administered following surgery or a reason documented (HR, 0.29; 95 CI, 0.19-0.46); (ii) in the locally advanced group included having chemotherapy +/- chemoradiation, or a reason documented for not undergoing treatment (HR, 0.38; 95 CI, 0.25-0.58); and (iii) in the metastatic disease group included having documented performance status at presentation (HR, 0.65; 95 CI, 0.47-0.89), being seen by an oncologist in the absence of treatment (HR, 0.48; 95 CI, 0.31-0.77), and disease management discussed at a multidisciplinary team meeting (HR, 0.79; 95 CI, 0.64-0.96). Conclusion(s): Capture of a concise data set has enabled quality of care to be assessed.Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc.

Over 95% of Pancreatic ductal adenocarcinomas (PDA) carry mutations in the oncogene KRas which has been proven to be a difficult drug target. P21-activated kinase 4 (PAK4), acts downstream of KRas, and is overexpressed in PDA contributing to its growth and chemoresistance, and thus becomes an attractive therapeutic target. We have developed a new PAK4 inhibitor, PAKib and tested its effect on pancreatic cancer (PC) cell growth in vitro and in a syngeneic mouse model of PC. PAKib suppressed PC cell growth by inducing cell death and cycle arrest. PAKib inhibited PC growth and enhanced the inhibition by gemcitabine of PC in cell culture and in PC mouse model. PAKib acted through multiple signaling pathways involved in cell cycle checkpoints, apoptosis, cell junction, and focal adhesion. These proof-of-concept studies demonstrated the anti-cancer effect of PAKib alone and in combination with gemcitabine and warrant a further clinical investigation.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for

BACKGROUND: Understanding the financial implications associated with the complications post-distal pancreatectomy (DP) may be beneficial for the future optimisation of postoperative care pathways and improved cost-efficiency. The primary outcome of this retrospective study was the characterisation of the additional cost associated with postoperative complications following DP. The secondary outcome was the estimation of the prevalence, type and severity of complications post-DP and the determination of which complications were associated with higher costs. METHODS: Postoperative complications were retrospectively examined for 62 adult patients undergoing distal pancreatectomy at an Australian university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo (CVD) classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology and was reported in US dollars at 2021 rates. Regression modelling was used to investigate the relationships among selected perioperative variables, complications and costs. RESULTS: 45 patients (72.6%) experienced one or more postoperative complications. The median (IQR) hospital cost in US dollars was 31.6% greater in patients who experienced complications compared to those who experienced no complications ($40,717.8 [27,358.0-59,834.3] vs. $30,946.9 [23,910.8-46,828.1]). Costs for patients with four or more complications were 43.5% higher than for those with three or fewer complications (p = 0.015). Compared to patients with no complications, the median hospital costs increased by 17.1% in patients with minor complications (CVD grade I/II) and by 252% in patients who developed major complication (i.e., CVD grade III/IV) complications. CONCLUSION: Postoperative complications are a key target for cost-containment strategies. Our findings demonstrate a high prevalence of postoperative complications following distal pancreatectomy with numbe

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Background: This study: (i) assessed compliance with a consensus set of quality indicators (QIs) in pancreatic cancer (PC); and (ii) evaluated the association between compliance with these QIs and survival. Method(s): Four years of data were collected for patients diagnosed with PC. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A multivariable analysis tested the relationship between significant patient and hospital characteristics, patient cluster effects within hospitals and survival. Result(s): 1061 patients were eligible for this study. Significant association with improved survival were: (i) in the potentially resectable group having adjuvant chemotherapy administered following surgery or a reason documented (HR, 0.29; 95 CI, 0.19-0.46); (ii) in the locally advanced group included having chemotherapy +/- chemoradiation, or a reason documented for not undergoing treatment (HR, 0.38; 95 CI, 0.25-0.58); and (iii) in the metastatic disease group included having documented performance status at presentation (HR, 0.65; 95 CI, 0.47-0.89), being seen by an oncologist in the absence of treatment (HR, 0.48; 95 CI, 0.31-0.77), and disease management discussed at a multidisciplinary team meeting (HR, 0.79; 95 CI, 0.64-0.96). Conclusion(s): Capture of a concise data set has enabled quality of care to be assessed.Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc.

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a significant cause of morbidity in patients undergoing distal pancreatectomy (DP). The use of polyethylene glycol (PEG) and recombinant human albumin sealant gel applied to the transected pancreatic margin in DP may reduce POPF rates and was assessed. METHODS: A retrospective single centre cohort study of patient undergoing DP at an Australian high volume tertiary institution between January 2015 and January 2021. Rates of POPF in patients undergoing stapled pancreatic transection with PEG sealant were compared to other methods. RESULTS: A total of 54 cases were identified for analysis, with 16 undergoing stapled DP combined with staple line application of PEG (PEG group). Most patients in the control group had stapled DP 92% (35 of 38), with 47% (18 of 38) combined with a reinforcing buttress, with or without the use other glue types. Overall, 28 of 54 (52%) developed a POPF, with a significantly lower rate in the PEG group (3 of 16 vs. 25 of 38 in the Control group; p = 0.003). Clinically significant Grade B/C POPF was lower in the PEG group (0 of 16 vs. 9 of 28 in the Control group; p = 0.045), and patients in the PEG group had a shorter median (range) length of hospital stay (6 [4-14] days vs. 10 [6-41] days p = 0.04). CONCLUSION: Stapled DP with the application of PEG and recombinant human albumin sealant to the transection line appears to be associated with a lower rate of clinically significant POPF.

BACKGROUND: The Victorian Pancreas Cancer summit 2017 analysed state-wide data on management of Victorians with pancreas cancer between 2011 and 2015 to identify variations in care and outcomes. Pancreas cancer remains a formidable disease but systemic therapies are increasingly effective. Surgery remains essential but insufficient alone for cure. Understanding patterns of care and identifying variations in treatment is critical to improving outcomes. METHOD(S): This population-based study analysed data collected prospectively by Department of Health and Human services (Victorian state government). Data were extracted from Victorian Cancer Registry (covering all Victorian cancer diagnoses), Victorian Admitted-Episodes Dataset (all inpatient data), Victorian Radiotherapy Minimum Dataset and Victorian Death Index providing demographics, tumour and treatment characteristics, age-standardized incidence, overall and median survival. RESULT(S): Of 3962 Victorian patients with any form of pancreatic malignancy, 82% were ductal adenocarcinoma (PDAC), of whom 67% had metastases at diagnosis. One-year overall survival for PDAC was 30% (60% non-metastatic, 15% if metastatic). Median survival with metastases increased from 2.7 to 3.9 months, and from 13.3 to 15.9 months for non-metastatic PDAC between 2011 and 2015. Thirty-one percent of non-metastatic patients underwent pancreatectomy. About 1.5% were treated with neoadjuvant chemotherapy/chemoradiation. Of patients undergoing intended curative resection, 77% proceeded to adjuvant therapy. Fifty-one percent of metastatic PDAC patients never received anti-tumour therapy. CONCLUSION(S): Nearly one-fourth of surgically treated patients never received systemic therapy. More than two-thirds of non-metastatic patients never proceeded to surgery. Further consideration of neoadjuvant therapy should be given to borderline resectable patients. Most patients with PDAC still die soon after diagnosis, but median survival is increasing.Copy

Background: Unresectable LAPC has a poor prognosis. Current standard-of-care (SoC) is limited to chemotherapy or chemo-radiotherapy. Phosphorus-32 (P-32) microparticles comprise a brachytherapy device that implants a predetermined dose of beta radiation-emitting P-32 into pancreatic tumors via endoscopic ultrasound (EUS) guidance. Here, we report updated results of the pilot PanCO study of P-32 microparticles combined with SoC chemotherapy in patients with unresectable LAPC. Method(s): Eligible patients could receive either gemcitabine + nab-paclitaxel (GNP; 28-day cycles) or FOLFIRINOX (14-day cycles) chemotherapy. P-32 microparticles (OncoSilTM; OncoSil Medical) implantation was planned at weeks 4-5. P-32 activity was calculated from patients' tumor volume (TV) to deliver 100 Gy absorbed dose, with implantation assessment by EUS and Bremsstrahlung SPECT/CT imaging. The primary endpoint was safety and tolerability, graded using CTCAE v4.0. Response was assessed using RECIST 1.1 with 8-weekly CT scans and FDG-PET scans at baseline and week 12. Result(s): A total of 50 patients were enrolled (Intention-to-Treat [ITT] population), of which 42 were implanted with the device (Per Protocol [PP] population); 40 patients received GNP and 10 FOLFIRINOX (PP: 34/8, respectively). Median age was 65 years; 28 (56%) male; all 50 were ECOG PS 0/1. Median longest target lesion diameter was 4.5 cm (range 2.6-7.1). Median follow-up was 16.1 months. In the PP/safety population, a median of 5 GNP cycles (range, 1-14) and 6 FOLFIRINOX cycles (range, 3-13) were administered. A total of 988 adverse events (AEs) were reported (PP population); 148 were grade >=3 involving 81% of patients. The most common AEs of grade >=3 were hematological (50% patients) and gastrointestinal (GI) disorders (38%). Of these, 330 AEs (33%) occurred pre-implantation (35 grade >=3) vs 658 (67%) AEs post-implantation (113 grade >=3); median follow-up: 1 vs 15.1 months, respectively. AE incidence overall and by k

In this retrospective observational study performed in a high-volume hepatobiliary-pancreatic unit, we evaluated the effect of a surgery-specific goal-directed therapy (GDT) physiologic algorithm on complications and length of hospital stay. We compared patients who underwent pancreaticoduodenectomy with either a standardised Enhanced Recovery After Surgery program (usual care group), or a standardised Enhanced Recovery After Surgery program in combination with a surgery-specific cardiac output-guided algorithm (GDT group). We included 145 consecutive patients: 47 in the GDT group and 98 in the usual care group. Multivariable associations between GDT and lengths of stay and complications were investigated using negative binomial regression. Postoperative complications were common and occurred at similar frequencies amongst the GDT and usual care groups: 64% versus 68% respectively, P=0.71; odds ratio 0.82; (95% confidence interval 0.39-1.70). There were fewer cardiorespiratory complications in the GDT group. Median (interquartile range) length of hospital stay was ten days (8.0-14.0) in the GDT group compared to 13 days (8.8-21.3) in the usual care group, P=0.01. Median (interquartile range) total intraoperative fluid was 3,000 ml (2,050-4,175) in the GDT group compared to 4,500 ml (3,275-5,325) in the usual care group, P <0.0001; but by day one, the median (interquartile range) fluid balance was similar (1,198 ml [700-1,729] in the GDT group versus 977 ml [419-2,044] in the usual care group, P=0.96). Use of vasoactive medications was higher in the GDT group. In our patients undergoing pancreaticoduodenectomy, GDT was associated with restrictive intraoperative fluid intervention, fewer cardiorespiratory complications and a shorter hospital length of stay compared to usual care. However, we could not exclude an influence of surgical caseload, which we have previously found to be an important variable. We also could not relate the increased hospital length of stay to

Background and Aim Pancreatic cancer (PC) carries a poor prognosis and is often detected at later stages. Screening programs for moderate‐ and high‐risk people are still under debate. We present the results from a prospective study on endoscopic ultrasound (EUS) as a one‐off screening tool for pancreatic cancer screening. Methods Asymptomatic patients with moderate‐ or high‐risk of PC were invited to participate. Moderate risk consisted of one first‐degree and at least one second‐degree relative with PC and no PC‐associated genetic mutations. High risk consisted of >1 first‐degree relatives with PC or PC‐associated mutations (i.e. BRCA2, Lynch Syndrome, Familial Atypical Multiple Mole Melanoma Syndrome, STK11, or PALB2). All included patients had genetic counseling and a screening EUS done. Primary outcome was the detection of PC on EUS. Secondary outcomes assessed the evolution of psychological symptoms based on the Impact of Events Scale (IES) and Personal Consequences Questionnaire (PCQ) before and after the screening took place. Results A total of 122 patients had a screening EUS performed between 2013 and 2019; 60 were male, 55.8 years was the mean age, 78 were at high risk for PC, and 25 had PC‐associated mutations. No pancreatic cancers were identified at the one‐off EUS screening. Overall, patients' IES/PCQ scores did not change after screening and feedback of no malignancy, with the exception of females (less concerned about PC after screening EUS). Conclusions EUS did not detect any PCs in either a moderate‐ or high‐risk population as a one‐off screening method. The EUS procedure and genetic counseling improved psychological symptoms for the female subset of this population.

The anti-cancer effects of cannabinoids including CBD (Cannabidiol) and THC ((-)-trans-∆9-tetrahydrocannabinol) have been reported in the case of pancreatic cancer (PC). The connection of these cannabinoids to KRas oncogenes that mutate in more than 90% of PC, and their effects on PD-L1, a key target of immune checkpoint blockade, have not been thoroughly investigated. Using cell lines and mouse models of PC, the effects of CBD and THC on cancer growth, the interaction between PC cells and a stromal cell, namely pancreatic stellate cells (PSCs), and the mechanism(s) involved were determined by cell-based assays and mouse study in vivo. CBD and THC inhibited the proliferation of PC, PSC, and PSC-stimulated PC cells. They also suppressed pancreatic tumour growth in mice. Furthermore, CBD and/or THC reduced the expression of PD-L1 by either PC or PSC cells. Knockout of p-21 activated kinase 1 (PAK1, activated by KRas) in PC and PSC cells and, in mice, dramatically decreased or blocked these inhibitory effects of CBD and/or THC. These results indicated that CBD and THC exerted their inhibitions on PC and PSC via a p-21 activated kinase 1 (PAK1)-dependent pathway, suggesting that CBD and THC suppress Kras activated pathway by targeting PAK1. The inhibition by CBD and THC of PD-L1 expression will enhance the immune checkpoint blockade of PC.

Recent studies reveal substantial species and regional differences in enteroendocrine cell (EEC) populations, including differences in patterns of hormone coexpression, which limit extrapolation between animal models and human. In this study, jejunal samples, with no histologically identifiable pathology, from patients undergoing Whipple's procedure were investigated for the presence of gastrointestinal hormones using double- and triple-labelling immunohistochemistry and high-resolution confocal microscopy. Ten hormones (5-HT, CCK, secretin, proglucagon-derived peptides, PYY, GIP, somatostatin, neurotensin, ghrelin and motilin) were localised in EEC of the human jejunum. If only single staining is considered, the most numerous EEC were those containing 5-HT, CCK, ghrelin, GIP, motilin, secretin and proglucagon-derived peptides. All hormones had some degree of colocalisation with other hormones. This included a population of EEC in which GIP, CCK and proglucagon-derived peptides are costored, and four 5-HT cell populations, 5-HT/GIP, 5-HT/ghrelin, 5-HT/PYY, and 5-HT/secretin cell groups, and a high degree of overlap between motilin and ghrelin. The presence of 5-HT in many secretin cells is consistent across species, whereas lack of 5-HT and CCK colocalisation distinguishes human from mouse. It seems likely that the different subclasses of 5-HT cells subserve different roles. At a subcellular level, we examined the vesicular localisation of secretin and 5-HT, and found these to be separately stored. We conclude that hormone-containing cells in the human jejunum do not comply with a one-cell, one-hormone classification and that colocalisations of hormones are likely to define subtypes of EEC that have different roles.

BACKGROUND: The Victorian Pancreas Cancer summit 2017 analysed state-wide data on management of Victorians with pancreas cancer between 2011 and 2015 to identify variations in care and outcomes. Pancreas cancer remains a formidable disease but systemic therapies are increasingly effective. Surgery remains essential but insufficient alone for cure. Understanding patterns of care and identifying variations in treatment is critical to improving outcomes. METHODS: This population-based study analysed data collected prospectively by Department of Health and Human services (Victorian state government). Data were extracted from Victorian Cancer Registry (covering all Victorian cancer diagnoses), Victorian Admitted-Episodes Dataset (all inpatient data), Victorian Radiotherapy Minimum Dataset and Victorian Death Index providing demographics, tumour and treatment characteristics, age-standardized incidence, overall and median survival. RESULTS: Of 3962 Victorian patients with any form of pancreatic malignancy, 82% were ductal adenocarcinoma (PDAC), of whom 67% had metastases at diagnosis. One-year overall survival for PDAC was 30% (60% non-metastatic, 15% if metastatic). Median survival with metastases increased from 2.7 to 3.9 months, and from 13.3 to 15.9 months for non-metastatic PDAC between 2011 and 2015. Thirty-one percent of non-metastatic patients underwent pancreatectomy. About 1.5% were treated with neoadjuvant chemotherapy/chemoradiation. Of patients undergoing intended curative resection, 77% proceeded to adjuvant therapy. Fifty-one percent of metastatic PDAC patients never received anti-tumour therapy. CONCLUSIONS: Nearly one-fourth of surgically treated patients never received systemic therapy. More than two-thirds of non-metastatic patients never proceeded to surgery. Further consideration of neoadjuvant therapy should be given to borderline resectable patients. Most patients with PDAC still die soon after diagnosis, but median survival is increasing.

BACKGROUND: Acute cholecystitis (AC) is a surgical condition that is usually managed by emergency surgery. The presence of common bile duct stones (CBDS) in this setting mandates definitive treatment to avoid complications such as cholangitis. The incidence of CBDS in the setting of AC is poorly defined. METHODS: A systematic English literature search was conducted in PubMed, MEDLINE and Embase to determine the incidence of CBDS in patients presenting with AC. Outlier studies identified by funnel plot analysis were excluded and the incidence of CBDS was identified. The mean CBD diameter and liver function test values of patients with AC and CBDS were calculated. RESULTS: Data were extracted from 19 studies representing a total 4057 patients with AC. Routine biliary imaging was not performed in all studies. The pooled incidence of CBDS was 13.7% (95% confidence interval 11.8-15.9). The incidence of unsuspected retained CBDS was 1.1%. Histologically confirmed cases of AC had a similar rate of CBDS compared to those diagnosed clinically. The mean CBD diameter of patients with AC and CBDS was 7.2 mm compared to 5.8 mm without. Liver function test values in the presence of CBDS were more likely to be deranged, with gamma-glutamyltransferase the most sensitive and specific marker for CBDS in the setting of AC. CONCLUSION: CBDS is present in a significant proportion of patients presenting with AC. Routine biliary imaging is advised in all patients presenting with AC where possible.

BACKGROUND: Postoperative complications after major gastrointestinal surgery are a major contributor to hospital costs. Thus, reducing postoperative complications is a key target for cost-containment strategies. We aimed to evaluate the relationship between postoperative complications and hospital costs following small bowel resection. METHODS: Postoperative complications were recorded for 284 adult patients undergoing major small bowel resection surgery between January 2013 and June 2018. Complications were defined and graded according to the Clavien-Dindo classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology; it was reported in US dollars at 2019 rates. Regression modeling was used to investigate the relationships among a priori selected perioperative variables, complications, and costs. FINDINGS: The overall complication prevalence was 81.6% (95% CI: 85.7-77.5). Most complications (69%) were minor, but 22.9% of patients developed a severe complication (Clavien-Dindo grades III or IV). The unadjusted median total hospital cost for patients with any complication was 70% higher than patients without complications (median [IQR] USD 19,659.64 [13,545.81-35,407.14] vs. 11,551.88 [8,849.46-15,329.87], P < 0.001). The development of 1, 2, 3, and ≥ 4 complications increased hospital costs by 11%, 41%, 50%, and 195%, respectively. Similarly, more severe complications incurred higher hospital costs (P < 0.001). After adjustments were made (for the Charlson Comorbidity Index, anemia, surgical urgency and technique, intraoperative fluid administration, blood transfusion, and hospital readmissions), a greater number and increased severity of complications were associated with a higher adjusted median hospital cost. Patients who experienced complications had an adjusted additional median cost of USD 4,187.10 (95% CI: 1,264.89-7,109.31, P = 0.005) compared to those without complications. CONCLUSIONS: Postoperative c

Background: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Material(s) and Method(s): Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Result(s): Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. Conclusion(s): ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment int

Background: Best practise care optimises survival and quality of life in patients with pancreatic cancer (PC), but there is evidence of variability in management and suboptimal care for some patients. Monitoring practise is necessary to underpin improvement initiatives. We aimed to develop a core set of quality indicators that measure quality of care across the disease trajectory. Method(s): A modified, three-round Delphi survey was performed among experts with wide experience in PC care across three states in Australia. A total of 107 potential quality indicators were identified from the literature and divided into five areas: diagnosis and staging, surgery, other treatment, patient management and outcomes. A further six indicators were added by the panel, increasing potential quality indicators to 113. Rated on a scale of 1-9, indicators with high median importance and feasibility (score 7-9) and low disagreement (<1) were considered in the candidate set. Result(s): From 113 potential quality indicators, 34 indicators met the inclusion criteria and 27 (7 diagnosis and staging, 5 surgical, 4 other treatment, 5 patient management, 6 outcome) were included in the final set. Conclusion(s): The developed indicator set can be applied as a tool for internal quality improvement, comparative quality reporting, public reporting and research in PC care.Copyright © 2018

Background: While adjuvant therapy provides a survival benefit for patients (pts) with early-stage pancreatic cancer there are currently no biomarkers that define pts that are more or less likely to benefit from such treatment. This prospective study investigated the use of circulating tumour DNA (ctDNA) as a marker of residual disease, where detection could predict recurrence. Method(s): Patients newly diagnosed with operable pancreatic adenocarcinoma were enrolled. PCR-based-SafeSeqS assays were used to identify mutations at codons 12, 13 and 61 of KRAS in the primary tumor and to detect ctDNA in plasma samples. Patient management was as per standard of care, blinded to ctDNA data. Result(s): From January 2015 to June 2017, 42 pts with matched plasma samples, collected pre- and post-operatively, and tumor tissue available were evaluated. The median time between surgery and post-op blood collection was 6.3 (range:4-8) weeks. RAS mutations were identified in 38 (90.5%) tumor samples. ctDNA was detected in 23/37 (62.2%) pre-op and 13/35 (37.1%) post-op plasma samples. In multivariate analysis including stage, and resection margin, ctDNA status was the only statistically significant variable. Pre-op ctDNA detection was associated with worse median recurrence free survival (RFS), 10.3 months versus not reached, (Hazard Ratio (HR),3.4; 95% confidence interval (CI), 1.5- 7.6; P = 0.005) and 5.4 months versus 17.1 months, (HR, 5.4; 95% CI, 4.7-37.3; P < 0.0001) post-operatively. Similarly, the presence of ctDNA was associated with worse median overall survival (OS), 13.8 months versus not reached pre-operatively, (HR,3.4; 95% CI 1.1 to 8.3; P = 0.04) and 10.6 months versus not reached (HR,4.5; 95% CI 2.4-28.6; P = 0.001) post-operatively. Notably, recurrence occurred in 13 of 13 pts with detectable post-op ctDNA, despite more than half receiving standard adjuvant chemotherapy. Conclusion(s): ctDNA analysis is a promising prognostic marker in early-stage pancreatic cancer

Background: LAPC is associated with a poor prognosis. Current standard treatment is limited to chemotherapy or chemoradiotherapy. P-32 Microparticles is a brachytherapy device that implants a predetermined dose of P-32 into pancreatic tumours via endoscopic ultrasound (EUS) guidance. This reports the initial results of a pilot study in combination with chemotherapy. Method(s): Eligible patients were permitted to receive either GNP or FOLFIRINOX. P-32 was implanted at week 4 or 5. The dose of P-32 was calculated from tumour volume to deliver an absorbed dose of 100 Gy. Diffusion pattern of the P-32 suspension was assessed by EUS and bremsstrahlung SPECT/CT imaging. Safety data was graded using CTCAE v4.0 criteria. Response was assessed according to RECIST 1.1 with CT scans every 8 weeks and FDG-PET scans at baseline and week 12. Result(s): 50 patients were enrolled (Intent-to-Treat population (ITT)) of which 42 were implanted with the device (Per Protocol population (PP)). 10 received FOLFIRINOX and 40 GNP. Median age was 65, 28 were male and all had a PS 0/1. 1070 adverse events (ITT) were reported; 153 (80% of patients) were >= Grade 3. The most common AEs of >= Grade 3 were haematological (39, 46%) and gastrointestinal disorders (30, 34%). No serious device-or radiation-related toxicities have been reported. PP Local Disease Control Rate at Week 16 was 90%; 95% CI: 77-97% and at Week 24 was 71%; 95% CI: 55-84%. Overall Response Rate (ORR) was 31%; 95% CI: 18-47%. Median change in tumour volume from Baseline to Week 16 and to Week 24 was-38% (range +89% to-90%) and-27.5% (range +139% to-79%). Ten (24%) patients underwent surgical resection following repeat staging. Eight patients had R0 margin. Conclusion(s): The use of EUS-guided implantation of P-32 is feasible, with an acceptable safety profile in combination with first-line chemotherapy for LAPC patients. Encouraging OR and DCR are observed. Further follow-up to inform results of local progression free survival

Purpose The Upper Gastrointestinal Cancer Registry (UGICR) was developed to monitor and improve the quality of care provided to patients with upper gastrointestinal cancers in Australia. Participants It supports four cancer modules: Pancreatic, oesophagogastric, biliary and primary liver cancer. The pancreatic cancer (PC) module was the first module to be implemented, with others being established in a staged approach. Individuals are recruited to the registry if they are aged 18 years or older, have received care for their cancer at a participating public/private hospital or private clinic in Australia and do not opt out of participation. Findings to date The UGICR is governed by a multidisciplinary steering committee that provides clinical governance and oversees clinical working parties. The role of the working parties is to develop quality indicators based on best practice for each registry module, develop the minimum datasets and provide guidance in analysing and reporting of results. Data are captured from existing data sources (population-based cancer incidence registries, pathology databases and hospital-coded data) and manually from clinical records. Data collectors directly enter information into a secure web-based Research Electronic Data Capture (REDCap) data collection platform. The PC module began with a pilot phase, and subsequently, we used a formal modified Delphi consensus process to establish a core set of quality indicators for PC. The second module developed was the oesophagogastric cancer (OGC) module. Results of the 1 year pilot phases for PC and OGC modules are included in this cohort profile. Future plans The UGICR will provide regular reports of risk-adjusted, benchmarked performance on a range of quality indicators that will highlight variations in care and clinical outcomes at a health service level. The registry has also been developed with the view to collect patient-reported outcomes (PROs), which will further add to our understanding

Purpose The Upper Gastrointestinal Cancer Registry (UGICR) was developed to monitor and improve the quality of care provided to patients with upper gastrointestinal cancers in Australia. Participants It supports four cancer modules: Pancreatic, oesophagogastric, biliary and primary liver cancer. The pancreatic cancer (PC) module was the first module to be implemented, with others being established in a staged approach. Individuals are recruited to the registry if they are aged 18 years or older, have received care for their cancer at a participating public/private hospital or private clinic in Australia and do not opt out of participation. Findings to date The UGICR is governed by a multidisciplinary steering committee that provides clinical governance and oversees clinical working parties. The role of the working parties is to develop quality indicators based on best practice for each registry module, develop the minimum datasets and provide guidance in analysing and reporting of results. Data are captured from existing data sources (population-based cancer incidence registries, pathology databases and hospital-coded data) and manually from clinical records. Data collectors directly enter information into a secure web-based Research Electronic Data Capture (REDCap) data collection platform. The PC module began with a pilot phase, and subsequently, we used a formal modified Delphi consensus process to establish a core set of quality indicators for PC. The second module developed was the oesophagogastric cancer (OGC) module. Results of the 1 year pilot phases for PC and OGC modules are included in this cohort profile. Future plans The UGICR will provide regular reports of risk-adjusted, benchmarked performance on a range of quality indicators that will highlight variations in care and clinical outcomes at a health service level. The registry has also been developed with the view to collect patient-reported outcomes (PROs), which will further add to our understanding

© 2018 Background: Best practise care optimises survival and quality of life in patients with pancreatic cancer (PC), but there is evidence of variability in management and suboptimal care for some patients. Monitoring practise is necessary to underpin improvement initiatives. We aimed to develop a core set of quality indicators that measure quality of care across the disease trajectory. Methods: A modified, three-round Delphi survey was performed among experts with wide experience in PC care across three states in Australia. A total of 107 potential quality indicators were identified from the literature and divided into five areas: diagnosis and staging, surgery, other treatment, patient management and outcomes. A further six indicators were added by the panel, increasing potential quality indicators to 113. Rated on a scale of 1–9, indicators with high median importance and feasibility (score 7–9) and low disagreement (<1) were considered in the candidate set. Results: From 113 potential quality indicators, 34 indicators met the inclusion criteria and 27 (7 diagnosis and staging, 5 surgical, 4 other treatment, 5 patient management, 6 outcome) were included in the final set. Conclusions: The developed indicator set can be applied as a tool for internal quality improvement, comparative quality reporting, public reporting and research in PC care.

BACKGROUND: Limited data exists concerning the health economics of liver resection, with even less information on the costs emerging from complications, despite this remaining an important target from a health economic perspective. Our objective was to describe the financial burden of complications following liver resection. METHODS: We conducted a systematic search and included studies reporting resource use of in-hospital complications during the index liver resection admission. All indications for liver resection were considered. All techniques were considered. Data was collected using a data extraction table and a narrative synthesis was performed. RESULTS: We identified 12 eligible articles. There was considerable heterogeneity in study designs, patient populations and outcome definitions. We found weak evidence of increased costs associated with major liver resection compared to minor resections. We found robust evidence supporting the increasing economic burden arising from complications after liver resection. Acceptable evidence for increased cost due to the presence and grade of complication was found. Strong evidence concerning the association of length of stay with costs was demonstrated. CONCLUSIONS: The presence and grade of complications increase hospital cost across diverse settings. The costing methodology should be transparent and complication grading systems should be consistent in future studies.

The aim of the study was to determine the financial burden of complications and examine the cost differentials between complicated and uncomplicated hospital stays, including the differences in cost due to extent of resection and operative technique.Liver resection carries a high financial cost. Despite improvements in perioperative care, postoperative morbidity remains high. The contribution of postoperative complications to the cost of liver resection is poorly quantified, and there is little data to help guide cost containment strategies.Complications for 317 consecutive adult patients undergoing liver resection were recorded using the Clavien-Dindo classification. Patients were stratified based on the grade of their worst complication to assess the contribution of morbidity to resource use of specific cost centers. Costs were calculated using an activity-based costing methodology.Complications dramatically increased median hospital cost ($22,954 vs $15,593, P < .001). Major resection cost over $10,000 more than minor resection and carried greater morbidity (82% vs 59%, P < .001). Similarly, open resection cost more than laparoscopic resection ($21,548 vs $15,235, P < .001) and carried higher rates of complications (72% vs 41.5%, P < .001). Hospital cost increased with increasing incidence and severity of complications. Complications increased costs across all cost centers. Minor complications (Clavien-Dindo Grade I and II) were shown to significantly increase costs compared with uncomplicated patients.Liver resection continues to carry a high incidence of complications, and these result in a substantial financial burden. Hospital cost and length of stay increase with greater severity and number of complications. Our findings provide an in-depth analysis by stratifying total costs by cost centers, therefore guiding future economic studies and strategies aimed at cost containment for liver resection.

BACKGROUND: Right hepatectomy is a complex procedure that carries inherent risks of perioperative morbidity. To evaluate outcome differences between a low central venous pressure fluid intervention strategy and a goal directed fluid therapy (GDFT) cardiac output algorithm we performed a retrospective observational study. We hypothesized that a GDFT protocol would result in less intraoperative fluid administration, reduced complications and a shorter length of hospital stay. METHODS: Patients undergoing hepatectomy using an established enhanced recovery after surgery (ERAS) programme between 2010 and 2017 were extracted from a prospectively managed electronic hospital database. Inclusion criteria included adult patients, undergoing open right (segments V-VIII) or extended right (segments IV-VIII) hepatectomy. PRIMARY OUTCOME: amount of intraoperative fluid administration used between the two groups. SECONDARY OUTCOMES: type and amount of vasoactive medications used, the development of predefined postoperative complications, hospital length of stay, and 30-day mortality. Complications were defined by the European Perioperative Clinical Outcome definitions and graded according to Clavien-Dindo classification. The association between GDFT and the amount of fluid and vasoactive medication used was investigated using logistic and linear regression models. RESULTS: Fifty-eight consecutive patients were identified. 26 patients received GDFT and 32 received Usual care. There were no significant differences in baseline patient characteristics. Less intraoperative fluid was used in the GDFT group: median (IQR) 2000 ml (1175 to 2700) vs. 2750 ml (2000 to 4000) in the Usual care group; p = 0.03. There were no significant differences in the use of vasoactive medications. Postoperative complications were similar: 9 patients (35%) in the GDFT group vs. 18 patients (56%) in the Usual care group; p = 0.10, OR: 0.41; (95%CI: 0.14 to 1.20). Median (IQR) length of stay for patients in t

BACKGROUND: The effect a restrictive goal directed therapy (GDT) fluid protocol combined with an enhanced recovery after surgery (ERAS) programme on hospital stay for patients undergoing major liver resection is unknown. METHODS: We conducted a multicentre randomized controlled pilot trial evaluating whether a patient-specific, surgery-specific intraoperative restrictive fluid optimization algorithm would improve duration of hospital stay and reduce perioperative fluid related complications. RESULTS: Forty-eight participants were enrolled. The median (IQR) length of hospital stay was 7.0 days (7.0:8.0) days in the restrictive fluid optimization algorithm group (Restrict group) vs. 8.0 days (6.0:10.0) in the conventional care group (Conventional group) (Incidence rate ratio 0.85; 95% Confidence Interval 0.71:1.1; p = 0.17). No statistically significant difference in expected number of complications per patient between groups was identified (IRR 0.85; 95%CI: 0.45-1.60; p = 0.60). Patients in the Restrict group had lower intraoperative fluid balances: 808 mL (571:1565) vs. 1345 mL (900:1983) (p = 0.04) and received a lower volume of fluid per kg/hour intraoperatively: 4.3 mL/kg/hr (2.6:5.8) vs. 6.0 mL/kg/hr (4.2:7.6); p = 0.03. No significant differences in the proportion of patients who received vasoactive drugs intraoperatively (p = 0.56) was observed. CONCLUSION: In high-volume hepatobiliary surgical units, the addition of a fluid restrictive intraoperative cardiac output-guided algorithm, combined with a standard ERAS protocol did not significantly reduce length of hospital stay or fluid related complications. Our findings are hypothesis-generating and a larger confirmatory study may be justified.