Toward a new paradigm of care: a surgical leaders' Delphi consensus on the organizational factors of the new pancreas units (E-AHPBA PUECOF study).

Pancreas units represent new organizational models of care that are now at the center of the European debate. The PUECOF study, endorsed by the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), aims to reach an expert consensus by enquiring surgical leaders about the Pancreas Units' most relevant organizational factors, with 30 surgical leaders from 14 countries participating in the Delphi survey. Results underline that surgeons believe in the need to organize multidisciplinary meetings, nurture team leadership, and create metrics. Clinical professionals and patients are considered the most relevant stakeholders, while the debate is open when considering different subjects like industry leaders and patient associations. Non-technical skills such as ethics, teamwork, professionalism, and leadership are highly considered, with mentoring, clinical cases, and training as the most appreciated facilitating factors. Surgeons show trust in functional leaders, key performance indicators, and the facilitating role played by nurse navigators and case managers. Pancreas units have a high potential to improve patients' outcomes. While the pancreas unit model of care will not change the technical content of pancreatic surgery, it may bring surgeons several benefits, including more cases, professional development, easier coordination, less stress, and opportunities to create fruitful connections with research institutions and industry leaders.

The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS).

OBJECTIVE: To develop and update evidence-based and consensus-based guidelines on laparoscopic and robotic pancreatic surgery. SUMMARY BACKGROUND DATA: Minimally invasive pancreatic surgery (MIPS), including laparoscopic and robotic surgery, is complex and technically demanding. Minimizing the risk for patients requires stringent, evidence-based guidelines. Since the International Miami Guidelines on MIPS in 2019, new developments and key publications have been reported, necessitating an update. METHODS: Evidence-based guidelines on 22 topics in 8 domains were proposed: terminology, indications, patients, procedures, surgical techniques and instrumentation, assessment tools, implementation and training, and artificial intelligence. The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS, September 2022) used the Scottish Intercollegiate Guidelines Network (SIGN) methodology to assess the evidence and develop guideline recommendations, the Delphi method to establish consensus on the recommendations among the Expert Committee, and the AGREE II-GRS tool for guideline quality assessment and external validation by a Validation Committee. RESULTS: Overall, 27 European experts, 6 international experts, 22 international Validation Committee members, 11 Jury Committee members, 18 Research Committee members, and 121 registered attendees of the 2-day meeting were involved in the development and validation of the guidelines. In total, 98 recommendations were developed, including 33 on laparoscopic, 34 on robotic, and 31 on general MIPS, covering 22 topics in 8 domains. Out of 98 recommendations, 97 reached at least 80% consensus among the experts and congress attendees, and all recommendations were externally validated by the Validation Committee. CONCLUSIONS: The EGUMIPS evidence-based guidelines on laparoscopic and robotic MIPS can be applied in current clinical practice to provide guidance to patients, surgeons, policy-makers, and medical societies.

Obesity, Sarcopenia and Myosteatosis: Impact on Clinical Outcomes in the Operative Management of Crohn's Disease.

BACKGROUND: Obesity, sarcopenia, and myosteatosis in inflammatory bowel disease may confer negative outcomes, but their prevalence and impact among patients with Crohn's disease (CD) have not been systematically studied. The aim of this study was to assess nutritional status and body composition among patients undergoing resectional surgery for CD and determine impact on operative outcomes. METHODS: Consecutive patients with CD undergoing resection from 2000 to 2018 were studied. Total, subcutaneous, and visceral fat areas and lean tissue area (LTA) and intramuscular adipose tissue (IMAT) were determined preoperatively by computed tomography at L3 using SliceOmatic (Tomovision, Canada). Univariable and multivariable linear, logistic, and Cox proportional hazards regression were performed. RESULTS: One hundred twenty-four consecutive patients were studied (ileocolonic disease 53%, n = 62, biologic therapy 34.4% n = 43). Mean fat mass was 22.7 kg, with visceral obesity evident in 23.9% (n = 27). Increased fat stores were associated with reduced risk of emergency presentation but increased corticosteroid use (ß 9.09, standard error 3.49; P = .011). Mean LBM was 9.9 kg. Sarcopenia and myosteatosis were associated with impaired baseline nutritional markers. Myosteatosis markers IMAT (P = .002) and muscle attenuation (P = .0003) were associated with increased grade of complication. On multivariable analysis, IMAT was independently associated with increased postoperative morbidity (odds ratio [OR], 1.08; 95% confidence interval (CI), 1.01-1.16; P = .037) and comprehensive complications index (P = .029). Measures of adiposity were not associated with overall morbidity; however, increased visceral fat area independently predicted venous thromboembolism (OR, 1.02; 95% CI, 1.00-1.05; P = .028), and TFA was associated with increased wound infection (OR, 1.00; 95% CI, 1.00-1.01; P = .042) on multivariable analysis. CONCLUSION: Myosteatosis is associated with nutritional impairment and predicts increased overall postoperative morbidity following resection for CD. Despite its association with specific increased postoperative risks, increased adiposity does not increase overall morbidity, reflecting preservation of nutritional status and relatively more quiescent disease phenotype. Impaired muscle mass and function represent an appealing target for patient optimization to improve outcomes in the surgical management of CD.

Myosteatosis was predictive of postoperative morbidity following surgery for Crohn's Disease. Increased adiposity does not increase overall morbidity, reflecting a more quiescent disease phenotype. Obesity, myosteatosis, and sarcopenia represent appealing targets for patient optimization to improve outcomes surgical outcomes in Crohn's Disease.

Development of a clinical score to estimate pancreatitis-related hospital admissions in patients with a new diagnosis of chronic pancreatitis: the trinity score.

BACKGROUND: The clinical course of chronic pancreatitis is unpredictable and there is no globally accepted score to predict the disease course. We developed a clinical score to estimate pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis. METHODS: We conducted a retrospective cohort study using two clinical chronic pancreatitis databases held in tertiary referral centres in Dublin, Ireland, and in Tarragona, Spain. Individuals diagnosed with chronic pancreatitis between 2007 and 2014 were eligible for inclusion. Candidate predictors included aetiology, body mass index, exocrine dysfunction, smoking and alcohol history. We used multivariable logistic regression to develop the model. RESULTS: We analysed data from 154 patients with newly diagnosed chronic pancreatitis. Of these, 105 patients (68%) had at least one hospital admission for pancreatitis-related reasons in the 6 years following diagnosis. Aetiology of chronic pancreatitis, body mass index, use of pain medications and gender were found to be predictive of more pancreatic-related hospital admissions. These predictors were used to develop a clinical score which showed acceptable discrimination (area under the ROC curve = 0.70). DISCUSSION: We developed a clinical score based on easily accessible clinical parameters to predict pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis.

Significantly Lower Physical Activity Participation in Individuals with Chronic Pancreatitis Compared to Controls: An Exploratory Study of Objectively Assessed Physical Activity Levels.

INTRODUCTION: The beneficial effects of exercise and physical activity (PA) have been demonstrated in many chronic inflammatory diseases. Knowledge on PA levels is unknown in the chronic pancreatitis population, and there are currently no specific PA recommendations for this condition. METHODS: PA was measured objectively over a 7-day period in 17 individuals with chronic pancreatitis using an accelerometer (ActiGraph) and in 15 controls, matched for age, sex, and body mass index. RESULTS: Participants with chronic pancreatitis spent a significantly lower amount of time in moderate, light, and moderate/vigorous activity compared to the healthy control group. Mean time in light activity in the chronic pancreatitis group was 825.4 ± 972 (standard deviation [SD]) compared to 1,500 ± 958 (SD) in the healthy control group. Moderate activity mean minutes were 61.6 ± 85 in the chronic pancreatitis group compared to 161.4 ± 131.2 in the healthy control group. Moderate/vigorous mean minutes were 62.1 ± 86 (SD) in the chronic pancreatitis group compared to 164.3 ± 132 (SD) in the healthy control group. There was no significant difference found between the groups for either vigorous activity or time spent sedentary. CONCLUSION: This exploratory study offers early objective evidence that activity levels in the chronic pancreatic group are not meeting current international recommendations. Further investigation of this chronic illness population is strongly recommended.

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.

BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS. METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression. RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS. CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies.

Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 µg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Measurement of Body Composition in Pancreatic Cancer: A Systematic Review, Meta-Analysis, and Recommendations for Future Study Design.

BACKGROUND/OBJECTIVES: Sarcopenia in pancreatic cancer may increase the risk of chemotherapy-related toxicity and post-operative morbidity. This systematic review and meta-analysis aimed to quantify the prevalence of sarcopenia in early stage pancreatic cancer. METHODS: Relevant studies were identified using Ovid Medline and Elsevier Embase. Pooled estimates of prevalence rates (percentages) and corresponding 95% confidence interval (CI) were computed using a random-effects model to allow for heterogeneity between studies. RESULTS: The majority of the 33 studies (n = 5,593 patients) included in this meta-analysis utilized computed tomography (CT)-derived measures for body composition assessment in patients undergoing pancreatic resection. Reported prevalence of sarcopenia varied between 14 and 74%, and the pooled prevalence was 39% (95% CI: 38-40%) Heterogeneity was considerable, however, (I2 = 93%) and did not improve significantly when controlling for assessment method, and use of pre-defined cut-offs for sarcopenia, limiting potential to evaluate the true impact of sarcopenia. CONCLUSION: The ready availability of sequential CT offers a valuable opportunity for body composition assessment, but the quality of assessment and interpretation must improve before the impact of body composition on treatment-related outcomes and survival can be assessed. We suggest recommendations for the assessment of body composition for the design of future studies.

Physical activity for chronic pancreatitis: a systematic review.

BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. Sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength and is commonly associated with chronic pancreatitis. Regular physical activity and adequate functional fitness have been found to ameliorate the risk and effects of sarcopenia in other chronic diseases. The objective of this systematic review was to collate all the published evidence which has examined any type of physical activity as an intervention in the chronic pancreatitis patient population. METHODS: This systematic review was conducted in accordance with the PRISMA guidelines. The search strategy was designed by the medical librarian (DM) for Embase and then modified for the other search platforms. Two of the researchers (BM) and (AM) then performed the literature search using the databases Embase, Medline, CINAHL, and Web of Science. RESULTS: An electronic identified a total of 571 references imported to Covidence as 420 when the duplicates (151) were removed. 420 titles were screened and 390 were removed as not relevant from their titles. 30 full text papers were selected and from these, only one full text paper was deemed suitable for inclusion. CONCLUSIONS: There is currently insufficient evidence to advise physical activity in the chronic pancreatitis population. However, given the evidence to support physical activity in many other chronic diseases this review highlights the need for urgent investigation of physical activity as an intervention on this specific patient population.

Near infrared indocyanine green fluorescent cholangiography versus intraoperative cholangiography to improve safety in laparoscopic cholecystectomy for gallstone disease-a systematic review protocol.

BACKGROUND: Laparoscopic cholecystectomy has become the standard surgical approach in the treatment of cholelithiasis. Diverse surgical techniques and different imaging modalities have been described to evaluate the biliary anatomy and prevent or early detect bile duct injuries. X-ray intraoperative cholangiography (IOC) and near infrared indocyanine green fluorescent cholangiography (NIR-ICG) are safe and feasible techniques to assess biliary anatomy. The aim of this systematic review will be to evaluate if NIR-ICG can visualize extrahepatic biliary anatomy more efficiently and safer than IOC in minimally invasive cholecystectomy for gallstone disease. METHODS: Literature search will be performed via MEDLINE (PubMed), Embase, Scopus, the Cochrane Central Register of Controlled Trials, and Web of Science Core Collection from 2009 to present. All randomized controlled clinical trials and prospective non-randomized controlled trials which report on comparison of NIR-ICG versus IOC will be included. All patients over 18 years old who require elective or urgent minimally invasive cholecystectomy (undergoing NIR-ICG during this procedure) due to gallstone disease both acute and chronic will be included. Since BDI has a low incidence, the primary outcome will be the ability to visualize extrahepatic biliary anatomy and the time to obtain relevant images of these structures. Two researchers will individually screen the identified records, according to a list of inclusion and exclusion criteria. Bias of the studies will be evaluated with the Newcastle-Ottawa score for non-randomized studies and with The Cochrane Risk of Bias Tool for randomized controlled trials. Quality of evidence for all outcomes will be determined with the GRADE system. The data will be registered in a predesigned database. If selected studies are sufficiently homogeneous, we will perform a meta-analysis of reported results. In the event of a substantial heterogeneity, a narrative synthesis will be provided. Subgroup analysis will be used to investigate possible sources of heterogeneity. DISCUSSION: Understanding the benefits of this technique is critical to ensuring policymakers can make informed decisions as to where preventive efforts should be focused regarding specific imaging techniques. If ICG is proven to be faster and non-invasive, its routine use could be encouraged. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020177991 .

Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula.

BACKGROUND: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. RESULTS: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P = .45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P = .37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P = .05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P < .001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P = .020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P = .604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P = .693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. CONCLUSION: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.

Triple combination of BET plus PI3K and NF-κB inhibitors exhibit synergistic activity in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extraterminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while upregulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from peripheral blood mononuclear cells (PBMCs) of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multiagent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients and expands the potential treatments for this recalcitrant malignancy.

Pre-operative radiomics model for prognostication in resectable pancreatic adenocarcinoma with external validation.

OBJECTIVES: In resectable pancreatic ductal adenocarcinoma (PDAC), few pre-operative prognostic biomarkers are available. Radiomics has demonstrated potential but lacks external validation. We aimed to develop and externally validate a pre-operative clinical-radiomic prognostic model. METHODS: Retrospective international, multi-center study in resectable PDAC. The training cohort included 352 patients (pre-operative CTs from five Canadian hospitals). Cox models incorporated (a) pre-operative clinical variables (clinical), (b) clinical plus CT-radiomics, and (c) post-operative TNM model, which served as the reference. Outcomes were overall (OS)/disease-free survival (DFS). Models were assessed in the validation cohort from Ireland (n = 215, CTs from 34 hospitals), using C-statistic, calibration, and decision curve analyses. RESULTS: The radiomic signature was predictive of OS/DFS in the validation cohort, with adjusted hazard ratios (HR) 2.87 (95% CI: 1.40-5.87, p < 0.001)/5.28 (95% CI 2.35-11.86, p < 0.001), respectively, along with age 1.02 (1.01-1.04, p = 0.01)/1.02 (1.00-1.04, p = 0.03). In the validation cohort, median OS was 22.9/37 months (p = 0.0092) and DFS 14.2/29.8 (p = 0.0023) for high-/low-risk groups and calibration was moderate (mean absolute errors 7%/13% for OS at 3/5 years). The clinical-radiomic model discrimination (C = 0.545, 95%: 0.543-0.546) was higher than the clinical model alone (C = 0.497, 95% CI 0.496-0.499, p < 0.001) or TNM (C = 0.525, 95% CI: 0.524-0.526, p < 0.001). Despite superior net benefit compared to the clinical model, the clinical-radiomic model was not clinically useful for most threshold probabilities. CONCLUSION: A multi-institutional pre-operative clinical-radiomic model for resectable PDAC prognostication demonstrated superior net benefit compared to a clinical model but limited clinical utility at external validation. This reflects inherent limitations of radiomics for PDAC prognostication, when deployed in real-world settings. KEY POINTS: • At external validation, a pre-operative clinical-radiomics prognostic model for pancreatic ductal adenocarcinoma (PDAC) outperformed pre-operative clinical variables alone or pathological TNM staging. • Discrimination and clinical utility of the clinical-radiomic model for treatment decisions remained low, likely due to heterogeneity of CT acquisition parameters. • Despite small improvements, prognosis in PDAC using state-of-the-art radiomics methodology remains challenging, mostly owing to its low discriminative ability. Future research should focus on standardization of CT protocols and acquisition parameters.

Dietary intake in patients with chronic pancreatitis: A systematic review and meta-analysis.

BACKGROUND: A progressive reduction in the secretion of pancreatic enzymes in patients with chronic pancreatitis (CP) results in malabsorption and ultimate malnutrition. However, the pathogenesis of malnutrition is multifactorial and other factors such as chronic inflammation, alcohol excess and poor dietary intake all contribute. Patients may restrict their dietary intake due to poor appetite or to avoid gastrointestinal symptoms and abdominal pain. Whilst up to half of patients with chronic pancreatitis are reportedly malnourished, the dietary intake of patients with CP is relatively understudied and has not been systematically reviewed to date. AIM: To perform a systematic review and meta-analysis of the dietary intakes of patients with CP compared to healthy controls, and to compare the dietary intake of patients with alcohol-related CP and non-alcohol-related CP. METHODS: A systematic literature search was performed using EMBASE, MEDLINE, and Cochrane review on studies published between 1946 and August 30th, 2019. Adult subjects with a diagnosis of CP who had undergone dietary assessment were included in the systematic review (qualitative analysis). Studies on patients with other pancreatic diseases or who had undergone pancreatic surgery were not included. Studies comparing the dietary intake of patients with CP to that of healthy controls were included in the meta-analysis (quantitative analysis). Meta-analysis was performed using Review Manager 5.3. Newcastle Ottawa Scale (NOS) was used to assess quality of studies. RESULTS: Of 6715 studies retrieved in the search, 23 were eligible for qualitative analysis while 12 were eligible for quantitative analysis. In the meta-analysis, the total energy (calorie) intake of patients with CP was similar to that of healthy controls [mean difference (MD): 171.3; 95% confidence interval (CI): -226.01, 568.5; P = 0.4], however patients with CP consumed significantly fewer non-alcohol calories than controls [MD: -694.1; 95%CI: -1256.1, (-132.1); P = 0.02]. CP patients consumed more protein, but carbohydrate and fat intakes did not differ significantly. Those with alcohol-related CP consumed more mean (standard deviation) calories than CP patients with a non-alcohol aetiology [2642 (1090) kcal and 1372 (394) kcal, respectively, P = 0.046], as well as more protein, fat, but not carbohydrate. CONCLUSION: Although patients with CP had similar calorie intake to controls, studies that analysed the contribution of alcohol to energy intake showed that patients with CP consumed fewer non-alcohol calories than healthy controls. A high calorie intake, made up to a large degree by alcohol, may in part contribute to poor nutritional status in CP.

Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies.

BACKGROUND: Full application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8+ lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3-5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen. METHODS: Eleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012). RESULTS: Impressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8+ T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56bright and CD56dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease. CONCLUSIONS: IL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy. TRIAL REGISTRATION NUMBERS: NCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.

Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration.

Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons-so called 'incidentalomas'. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current 'omics'-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.

If in Doubt Don't Act Out! Exploring Behaviours in Clinical Decision Making by General Surgeons Towards Surgical Procedures.

BACKGROUND: Clinical decision-making (CDM) plays an integral role to surgeons work and has ramifications for patient outcomes and experience. The factors influencing a surgeons decision-making and the utility of cognitive decisional short cuts used in CDM known as 'heuristics' remains unknown. The aim of this paper is to explore how general surgeons make decisions in high-stake biliary tract clinical scenarios. METHODS: This was a cross sectional survey comprising of two sections-a 'demographics section' and a 'clinical vignettes section'. Participants were recruited by an email distributed by the Royal College of Surgeons in Ireland. Non-parametric testing examined relationships and content analysis was applied for clinical reasoning. RESULTS: 73 participants or 37.6% of the overall population completed the survey. 71.4% of these were male. Most (50%) were higher trainees with moderate levels of overall reflective practice in decision-making. A majority of participants chose conservatively in high-stake biliary tract clinical cases with disease factors (43.5%) weighted highest, followed by personal factors (41.1%) and patient factors (15.4%) in clinical reasoning. The presence of a 'hook' associated with commonly used heuristics did not significantly change decision-making behaviour. CONCLUSION: In high-stake scenarios, surgeons make conservative clinical decisions, predominantly dominated by disease and personal justifications. The utility of heuristics in lower-stake scenarios should be explored regarding clinical decision-making rationale and outcomes. Practitioners should consider use of patient factors in high-stake decisions to enable shared decision-making when appropriate which can reduce post-decisional regret and support the vision of patient-centred care.

A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland.

BACKGROUND: Individual genetic architecture is considered central to susceptibility and progression of disease in chronic pancreatitis. The study aimed to evaluate the presence of common pancreatic gene mutations in a defined cohort of idiopathic and alcohol-induced chronic pancreatitis patients in Ireland. METHODS: The study comprised patients with idiopathic and alcohol-induced chronic pancreatitis and historic controls. Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, cationic trypsinogen (PRSS1) gene and serine protease inhibitor kazal type-1 (SPINK1) gene, were assessed by Taqman© genotyping assay. RESULTS: Of n = 126 patients and n = 167 controls, mutations were detected in 23 (20%) and in 10 (6%) respectively (P < 0.001). The majority of mutations found were in the SPINK1 gene variant N34S (13%) which increased disease risk almost six-fold (OR 5.9). Neither CFTR severe mutation (F508del) (P = 0.649) nor mild variant (R117H) (P = 0.327) were over-represented amongst patients compared to control subjects. PRSS1 variants were not detected in either patient or control subjects. CONCLUSION: There was a significant prevalence of chronic pancreatitis-associated gene mutations in this well-phenotyped cohort. In patients with alcohol-related or idiopathic chronic pancreatitis, the possibility of genetic mutations in the SPINK 1 gene should be considered as a contributing aetiology factor.

Enhanced efficacy of JAK1 inhibitor with mTORC1/C2 targeting in smoldering/chronic adult T cell leukemia.

Adult T-cell leukemia (ATL) is an aggressive T-cell lymphoproliferative malignancy of regulatory T lymphocytes (Tregs), caused by human T-cell lymphotropic virus 1 (HTLV-1). Interleukin 2 receptor alpha (IL-2Rα) is expressed in the leukemic cells of smoldering/chronic ATL patients, leading to constitutive activation of the JAK/STAT pathway and spontaneous proliferation. The PI3K/AKT/mTOR pathway also plays a critical role in ATL cell survival and proliferation. We previously performed a high-throughput screen that demonstrated additive/synergistic activity of Ruxolitinib, a JAK1/2 inhibitor, with AZD8055, an mTORC1/C2 inhibitor. However, effects of unintended JAK2 inhibition with Ruxolitinib limits it therapeutic potential for ATL patients, which lead us to evaluate a JAK1-specific inhibitor. Here, we demonstrated that Upadacitinib, a JAK-1 inhibitor, inhibited the proliferation of cytokine-dependent ATL cell lines and the expression of p-STAT5. Combinations of Upadacitinib with either AZD8055 or Sapanisertib, mTORC1/C2 inhibitors, showed anti-proliferative effects against cytokine-dependent ATL cell lines and synergistic effect with reducing tumor growth in NSG mice bearing IL-2 transgenic tumors. Importantly, the combination of these two agents inhibited ex vivo spontaneous proliferation of ATL cells from patients with smoldering/chronic ATL. Combined targeting of JAK/STAT and PI3K/AKT/mTOR pathways represents a promising therapeutic intervention for patients with smoldering/chronic ATL.