Prediction of Isolated Local Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Nationwide Study.

BACKGROUND: Distinguishing postoperative fibrosis from isolated local recurrence (ILR) after resection of pancreatic ductal adenocarcinoma (PDAC) is challenging. A prognostic model that helps to identify patients at risk of ILR can assist clinicians when evaluating patients' postoperative imaging. This nationwide study aimed to develop a clinically applicable prognostic model for ILR after PDAC resection. PATIENTS AND METHODS: An observational cohort study was performed, including all patients who underwent PDAC resection in the Netherlands (2014-2019; NCT04605237). On the basis of recurrence location (ILR, systemic, or both), multivariable cause-specific Cox-proportional hazard analysis was conducted to identify predictors for ILR and presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A predictive model was developed using Akaike's Information Criterion, and bootstrapped discrimination and calibration indices were assessed. RESULTS: Among 1194/1693 patients (71%) with recurrence, 252 patients (21%) developed ILR. Independent predictors for ILR were resectability status (borderline versus resectable, HR 1.42; 95% CI 1.03-1.96; P = 0.03, and locally advanced versus resectable, HR 1.11; 95% CI 0.68-1.82; P = 0.66), tumor location (head versus body/tail, HR 1.50; 95% CI 1.00-2.25; P = 0.05), vascular resection (HR 1.86; 95% CI 1.41-2.45; P < 0.001), perineural invasion (HR 1.47; 95% CI 1.01-2.13; P = 0.02), number of positive lymph nodes (HR 1.04; 95% CI 1.01-1.08; P = 0.02), and resection margin status (R1 < 1 mm versus R0 ≥ 1 mm, HR 1.64; 95% CI 1.25-2.14; P < 0.001). Moderate performance (concordance index 0.66) with adequate calibration (slope 0.99) was achieved. CONCLUSIONS: This nationwide study identified factors predictive of ILR after PDAC resection. Our prognostic model, available through www.pancreascalculator.com , can be utilized to identify patients with a higher a priori risk of developing ILR, providing important information in patient evaluation and prognostication.

Comparing practice and outcome of laparoscopic liver resection between high-volume expert centres and nationwide low-to-medium volume centres.

BACKGROUND: Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands. METHOD: An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups. RESULTS: A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004). CONCLUSION: High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.

The treatment and survival of elderly patients with locally advanced pancreatic cancer: A post-hoc analysis of a multicenter registry.

BACKGROUND: The treatment options for patients with locally advanced pancreatic cancer (LAPC) have improved in recent years and consequently survival has increased. It is unknown, however, if elderly patients benefit from these improvements in therapy. With the ongoing aging of the patient population and an increasing incidence of pancreatic cancer, this patient group becomes more relevant. This study aims to clarify the association between increasing age, treatment and overall survival in patients with LAPC. METHODS: Post-hoc analysis of a multicenter registry including consecutive patients with LAPC, who were registered in 14 centers of the Dutch Pancreatic Cancer Group (April 2015-December 2017). Patients were divided in three groups according to age (<65, 65-74 and ≥75 years). Primary outcome was overall survival stratified by primary treatment strategy. Multivariable regression analyses were performed to adjust for possible confounders. RESULTS: Overall, 422 patients with LAPC were included; 162 patients (38%) aged <65 years, 182 patients (43%) aged 65-74 and 78 patients (19%) aged ≥75 years. Chemotherapy was administered in 86%, 81% and 50% of the patients in the different age groups (p<0.01). Median overall survival was 12, 11 and 7 months for the different age groups (p<0.01).Patients treated with chemotherapy showed comparable median overall survival of 13, 14 and 10 months for the different age groups (p=0.11). When adjusted for confounders, age was not associated with overall survival. CONCLUSION: Elderly patients are less likely to be treated with chemotherapy, but when treated with chemotherapy, their survival is comparable to younger patients.

Patient-derived organoid models help define personalized management of gastrointestinal cancer.

BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models. METHODS: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. RESULTS: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. CONCLUSION: High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects.

Self-reported domain-specific and accelerometer-based physical activity and sedentary behaviour in relation to psychological distress among an urban Asian population.

BACKGROUND: The interpretation of previous studies on the association of physical activity and sedentary behaviour with psychological health is limited by the use of mostly self-reported physical activity and sedentary behaviour, and a focus on Western populations. We aimed to explore the association of self-reported and devise-based measures of physical activity and sedentary behaviour domains on psychological distress in an urban multi-ethnic Asian population. METHODS: From a population-based cross-sectional study of adults aged 18-79 years, data were used from an overall sample (n = 2653) with complete self-reported total physical activity/sedentary behaviour and domain-specific physical activity data, and a subsample (n = 703) with self-reported domain-specific sedentary behaviour and accelerometry data. Physical activity and sedentary behaviour data were collected using the Global Physical Activity Questionnaire (GPAQ), a domain-specific sedentary behaviour questionnaire and accelerometers. The Kessler Screening Scale (K6) and General Health Questionnaire (GHQ-12) were used to assess psychological distress. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals, adjusted for socio-demographic and lifestyle characteristics. RESULTS: The sample comprised 45.0% men (median age = 45.0 years). The prevalence of psychological distress based on the K6 and GHQ-12 was 8.4% and 21.7%, respectively. In the adjusted model, higher levels of self-reported moderate-to-vigorous physical activity (MVPA) were associated with significantly higher odds for K6 (OR = 1.47 [1.03-2.10]; p-trend = 0.03) but not GHQ-12 (OR = 0.97 [0.77-1.23]; p-trend = 0.79), when comparing the highest with the lowest tertile. Accelerometry-assessed MVPA was not significantly associated with K6 (p-trend = 0.50) nor GHQ-12 (p-trend = 0.74). The highest tertile of leisure-time physical activity, but not work- or transport-domain activity, was associated with less psychological distress using K6 (OR = 0.65 [0.43-0.97]; p-trend = 0.02) and GHQ-12 (OR = 0.72 [0.55-0.93]; p-trend = 0.01). Self-reported sedentary behaviour was not associated with K6 (p-trend = 0.90) and GHQ-12 (p-trend = 0.33). The highest tertile of accelerometry-assessed sedentary behaviour was associated with significantly higher odds for K6 (OR = 1.93 [1.00-3.75]; p-trend = 0.04), but not GHQ-12 (OR = 1.34 [0.86-2.08]; p-trend = 0.18). CONCLUSIONS: Higher levels of leisure-time physical activity and lower levels of accelerometer-based sedentary behaviour were associated with lower psychological distress. This study underscores the importance of assessing accelerometer-based and domain-specific activity in relation to mental health, instead of solely focusing on total volume of activity.

The association of the dietary approach to stop hypertension (DASH) diet with blood pressure, glucose and lipid profiles in Malaysian and Philippines populations.

BACKGROUND AND AIM: Despite a growing body of evidence from Western populations on the health benefits of Dietary Approaches to Stop Hypertension (DASH) diets, their applicability in South East Asian settings is not clear. We examined cross-sectional associations between DASH diet and cardio-metabolic risk factors among 1837 Malaysian and 2898 Philippines participants in a multi-national cohort. METHODS AND RESULTS: Blood pressures, fasting lipid profile and fasting glucose were measured, and DASH score was computed based on a 22-item food frequency questionnaire. Older individuals, women, those not consuming alcohol and those undertaking regular physical activity were more likely to have higher DASH scores. In the Malaysian cohort, while total DASH score was not significantly associated with cardio-metabolic risk factors after adjusting for confounders, significant associations were observed for intake of green vegetable [0.011, standard error (SE): 0.004], and red and processed meat (-0.009, SE: 0.004) with total cholesterol. In the Philippines cohort, a 5-unit increase in total DASH score was significantly and inversely associated with systolic blood pressure (-1.41, SE: 0.40), diastolic blood pressure (-1.09, SE: 0.28), total cholesterol (-0.015, SE: 0.005), low-density lipoprotein cholesterol (-0.025, SE: 0.008), and triglyceride (-0.034, SE: 0.012) after adjusting for socio-demographic and lifestyle groups. Intake of milk and dairy products, red and processed meat, and sugared drinks were found to significantly associated with most risk factors. CONCLUSIONS: Differential associations of DASH diet and dietary components with cardio-metabolic risk factors by country suggest the need for country-specific tailoring of dietary interventions to improve cardio-metabolic risk profiles.

Randomized clinical trial of open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery after surgery programme (ORANGE II study).

BACKGROUND: Laparoscopic left lateral sectionectomy (LLLS) has been associated with shorter hospital stay and reduced overall morbidity compared with open left lateral sectionectomy (OLLS). Strong evidence has not, however, been provided. METHODS: In this multicentre double-blind RCT, patients (aged 18-80 years with a BMI of 18-35 kg/m2 and ASA fitness grade of III or below) requiring left lateral sectionectomy (LLS) were assigned randomly to OLLS or LLLS within an enhanced recovery after surgery (ERAS) programme. All randomized patients, ward physicians and nurses were blinded to the procedure undertaken. A parallel prospective registry (open non-randomized (ONR) versus laparoscopic non-randomized (LNR)) was used to monitor patients who were not enrolled for randomization because of doctor or patient preference. The primary endpoint was time to functional recovery. Secondary endpoints were length of hospital stay (LOS), readmission rate, overall morbidity, composite endpoint of liver surgery-specific morbidity, mortality, and reasons for delay in discharge after functional recovery. RESULTS: Between January 2010 and July 2014, patients were recruited at ten centres. Of these, 24 patients were randomized at eight centres, and 67 patients from eight centres were included in the prospective registry. Owing to slow accrual, the trial was stopped on the advice of an independent Data and Safety Monitoring Board in the Netherlands. No significant difference in median (i.q.r.) time to functional recovery was observed between laparoscopic and open surgery in the randomized or non-randomized groups: 3 (3-5) days for OLLS versus 3 (3-3) days for LLLS; and 3 (3-3) days for ONR versus 3 (3-4) days for LNR. There were no significant differences with regard to LOS, morbidity, reoperation, readmission and mortality rates. CONCLUSION: This RCT comparing open and laparoscopic LLS in an ERAS setting was not able to reach a conclusion on time to functional recovery, because it was stopped prematurely owing to slow accrual. Registration number: NCT00874224 ( https://www.clinicaltrials.gov).

Effect of Age on Liver Function in Patients Undergoing Partial Hepatectomy.

BACKGROUND: Postresectional liver failure is the most frequent cause of fatal outcome following liver surgery. Diminished preoperative liver function in the elderly might contribute to this. Therefore, the aim of the present study was to evaluate preoperative liver function in patients <60 or >70 years of age scheduled for liver resection. METHODS: All consecutive patients aged <60 or >70 years who are about to undergo elective liver surgery between 2011 and 2013 and underwent the methacetin breath liver function test (LiMAx) preoperatively were included. Histologic assessment of the resected liver gave insight into background liver disease. Correlation between age and liver function was calculated with Pearson's test. RESULTS: Fifty-nine patients were included, 31 were aged <60 and 28 were aged >70 years. General patient characteristics and liver function LiMAx values (340 (137-594) vs. 349 (191-530) µg/kg/h, p = 0.699) were not significantly different between patients aged <60 and >70 years. Moreover, no correlation between age and preoperative liver function LiMAx values was found (R = 0.04, p = 0.810). CONCLUSION: Liver function did not seem to differ between younger and older patients.

Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases.

BACKGROUND: The impact of postoperative complications on long-term outcomes after surgery for colorectal liver metastases (CRLM) remains controversial. During the last decade, advances in surgical as well as non-surgical treatment have increased resectability and altered outcomes. We sought to determine the influence of postoperative morbidity on disease-free (DFS) and overall survival (OS). METHODS: All patients undergoing liver resection for CRLM for the first time between 2000 and 2011 were retrospectively identified from a prospective database. Postoperative morbidity was classified according to Dindo-Clavien grade. A Dindo-Clavien grade ≥ 3a was considered a major complication. Primary outcomes were DFS and OS depending on the presence or absence of postoperative morbidity. RESULTS: Of the 266 included patients, 97 patients (37 %) developed postoperative complications, of whom 61 (23 %) had major complications. Median DFS and OS (5-year) were 17 and 53 months (42 %). The occurrence of postoperative morbidity did not significantly shorten OS (p = 0.130) and DFS (p = 0.101). However, major morbidity reduced DFS significantly (p < 0.05). CONCLUSION: In the present study, the occurrence of major postoperative complications was associated with diminished DFS. However, the effect of (major) complications on OS did not reach statistical significance.

Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population.

AIMS: The relation between selenium status and risk of Type 2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes. METHODS: We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50 years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20 years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted. RESULTS: At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) µg/l. During 20 years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio 1.06; 95% CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized ß -0.08; 95% CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of ß-cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account. CONCLUSIONS: Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals.

Is current perioperative practice in hepatic surgery based on enhanced recovery after surgery (ERAS) principles?

BACKGROUND: The worldwide introduction of multimodal enhanced recovery programs has also changed perioperative care in patients who undergo liver resection. This study was performed to assess current perioperative practice in liver surgery in 11 European HPB centers and compare it to enhanced recovery after surgery (ERAS) principles. METHODS: In each unit, 15 consecutive patients (N = 165) who underwent hepatectomy between 2010 and 2012 were retrospectively analyzed. Compliance was classified as "full," "partial," or "poor" whenever ≥ 80, ≥ 50, or <50 % of the 22 ERAS protocol core items were met. The primary study end point was overall compliance with the ERAS core program per unit and per perioperative phase. RESULTS: Most patients were operated on for malignancy (91 %) and 56 % were minor hepatectomies. The median number of implemented ERAS core items was 9 (range = 7-12) across all centers. Compliance was partial in the preoperative (median 2 of 3 items, range = 1-3) and perioperative phases (median 5 of 10 items, range: 4-7). Median postoperative compliance was poor (median 2 of 9 items, range = 0-4). A statistically significant difference was observed between median length of stay and median time to recovery (7 vs. 5 days, P < 0.001). CONCLUSION: Perioperative care among centers that perform liver resections varied substantially. In current HPB surgical practice, some elements of the ERAS program, e.g., preoperative counselling and minimal fasting, have already been implemented. Elements in the perioperative phase (avoidance of drains and nasogastric tube) and postoperative phase (early resumption of oral intake, early mobilization, and use of recovery criteria) should be further optimized.

Systematic review and meta-analysis of enhanced recovery after pancreatic surgery with particular emphasis on pancreaticoduodenectomies.

BACKGROUND: In the past decade, Enhanced Recovery after Surgery (ERAS) protocols have been implemented in several fields of surgery. With these protocols, a faster recovery and shorter hospital stay can be accomplished without an increase in morbidity or mortality. The purpose of this study was to review systematically the evidence for implementation of an ERAS protocol in pancreatic resections, with particular emphasis on pancreaticoduodenectomies (PDs). METHODS: A systematic search was performed in Medline, Embase, Pubmed, CINAHL, and the Cochrane library for papers describing an ERAS program in adult patients undergoing elective pancreatic surgery published between January 1966 and December 2012. The primary outcome measure was postoperative length of stay. Secondary outcome measures were time to recovery of normal function, overall postoperative complication rates, readmissions, and mortality. Subsequently, a meta-analysis of outcome measures focusing on PD was conducted. This systematic review and meta-analysis was performed according to the PRISMA statement. RESULTS: The literature search produced 248 potentially relevant papers. Of these, eight papers met the predefined inclusion criteria: five case-control studies, two retrospective studies, and one prospective study, describing a total of 1,558 patients. Only three of the studies reported data on discharge criteria and assessed time to recovery and return to normal function. Implementation of an ERAS protocol led in four of five comparative studies to a significant decrease in length of stay (reduction of 2-6 days in different studies). Meta-analysis of four studies focusing on PDs showed that there was a significant difference in complication rates in favor of the ERAS group (absolute risk difference 8.2 %, 95 % confidence interval (CI) 2.0-14.4, p = 0.008). Introduction of an ERAS protocol did not result in an increase in mortality or readmissions. Delayed gastric emptying and incidence of pancreatic fistula did not differ significantly between groups. All studies reporting on hospital costs showed a decrease after implementation of ERAS. CONCLUSIONS: This systematic review suggests that using an ERAS protocol in pancreatic resections may help to shorten hospital length of stay without compromising morbidity and mortality. This seemed to apply to distal pancreatectomy, total pancreatectomy, and PD. Meta-analysis was performed for those studies focusing on PD and showed that there were no differences in readmission or mortality. Morbidity rates were significantly lower for patients managed according ERAS principles.

Can body fat distribution, adiponectin levels and inflammation explain differences in insulin resistance between ethnic Chinese, Malays and Asian Indians?

OBJECTIVE: Diabetes in Asia constitutes approximately half of the global burden. Although insulin resistance and incidence of type 2 diabetes differ substantially between ethnic groups within Asia, the reasons for these differences are poorly understood. We evaluated to what extent body fatness, adiponectin levels and inflammation mediate the relationship between ethnicity and insulin resistance in an Asian setting. DESIGN: Cross-sectional population-based study. SUBJECTS: In total, 4136 adult Chinese, Malays and Asian Indians residing in Singapore. MEASUREMENTS: Insulin resistance was assessed using homeostasis model assessment (HOMA-IR) and systemic inflammation by C-reactive protein (CRP). Data were analyzed using path analysis. RESULTS: HOMA-IR was highest in Asian Indians, intermediate in Malays and lowest in Chinese (P<0.001). The difference in HOMA-IR between Malays and Chinese disappeared after adjusting for body mass index (BMI). For the comparison of Asian Indians with Chinese, the association between ethnicity and HOMA-IR was mediated by BMI (men: 32.9%; women: 48.5%), BMI-adjusted waist circumference (men: 6.1%; women: 3.5%), and CRP (men: 5.1%; women: 5.6%), and unidentified factors (men: 47.2%; women: 26.5%). Part of the mediating effects of body fatness was indirect through effects of body fatness on CRP and adiponectin concentrations. CONCLUSION: Mediators of ethnic differences in insulin resistance differed markedly depending on the ethnic groups compared. General adiposity explained the difference in insulin resistance between Chinese and Malays, whereas abdominal fat distribution, inflammation and unexplained factors contributed to excess insulin resistance in Asian Indians as compared with Chinese and Malays. These findings suggest that interventions targeting excess weight gain can reduce ethnic disparities in insulin resistance among Asian Indians, Chinese and Malays.

Development of a composite endpoint for randomized controlled trials in liver surgery.

BACKGROUND: The feasibility of randomized controlled trials (RCTs) in liver surgery using a single-component clinical endpoint is low as such endpoints require large sample sizes owing to their low incidence. A liver surgery-specific composite endpoint (CEP) could solve this problem. The aim of this study was to develop a liver surgery-specific CEP with well-defined components. METHODS: Components of a liver surgery-specific CEP were selected based on a systematic literature search and consensus among 28 international hepatopancreatobiliary (HPB) surgeons. As an example, two prospective cohorts of patients who had undergone liver surgery in high-volume HPB centres were used to assess the event rate and effect of implementing a liver surgery-specific CEP. RESULTS: Components selected for the liver surgery-specific CEP were ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality, all with a Clavien-Dindo grade of at least 3 and occurring within 90 days after initial surgery. The incidence of this liver surgery-specific CEP was 19.2 per cent in one cohort and 10.7 per cent in the other. These rates led to an approximately twofold reduction in the theoretical sample size required for an adequately powered RCT in liver surgery using the CEP as primary endpoint. CONCLUSION: The proposed liver surgery-specific CEP consists of ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality. It has a considerably higher event rate than any of its components. Its use as the primary endpoint will increase the feasibility and comparability of RCTs in liver surgery.

Microscopic resection margin status in pancreatic ductal adenocarcinoma - A nationwide analysis.

INTRODUCTION: First, this study aimed to assess the prognostic value of different definitions for resection margin status on disease-free survival (DFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC). Second, preoperative predictors of direct margin involvement were identified. MATERIALS AND METHODS: This nationwide observational cohort study included all patients who underwent upfront PDAC resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit. Patients were subdivided into three groups: R0 (≥1 mm margin clearance), R1 (<1 mm margin clearance) or R1 (direct margin involvement). Survival was compared using multivariable Cox regression analysis. Logistic regression with baseline variables was performed to identify preoperative predictors of R1 (direct). RESULTS: 595 patients with a median OS of 18 months (IQR 10-32 months) months were analysed. R0 (≥1 mm) was achieved in 277 patients (47%), R1 (<1 mm) in 146 patients (24%) and R1 (direct) in 172 patients (29%). R1 (direct) was associated with a worse OS, as compared with both R0 (≥1 mm) (hazard ratio (HR) 1.35 [95% and confidence interval (CI) 1.08-1.70); P < 0.01) and R1 (<1 mm) (HR 1.29 [95%CI 1.01-1.67]; P < 0.05). No OS difference was found between R0 (≥1 mm) and R1 (<1 mm) (HR 1.05 [95% CI 0.82-1.34]; P = 0.71). Preoperative predictors associated with an increased risk of R1 (direct) included age, male sex, performance score 2-4, and venous or arterial tumour involvement. CONCLUSION: Resection margin clearance of <1 mm, but without direct margin involvement, does not affect survival, as compared with a margin clearance of ≥1 mm. Given that any vascular tumour involvement on preoperative imaging was associated with an increased risk of R1 (direct) resection with upfront surgery, neoadjuvant therapy might be considered in these patients.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Randomized clinical trial of laxatives and oral nutritional supplements within an enhanced recovery after surgery protocol following liver resection.

BACKGROUND: Routine laxatives may expedite gastrointestinal recovery and early tolerance of food within an enhanced recovery after surgery (ERAS) programme. Combined with carbohydrate loading and oral nutritional supplements (ONS), it may further enhance recovery of gastrointestinal function and promote earlier overall recovery. METHODS: Seventy-four patients undergoing liver resection were randomized in a two-by-two factorial design to receive either postoperative magnesium hydroxide as a laxative, preoperative carbohydrate loading and postoperative ONS, their combination or a control group. Patients were managed within an ERAS programme of care. The primary outcome measure was time to first passage of stool. Secondary outcome measures were gastric emptying, postoperative oral calorie intake, time to functional recovery and length of hospital stay. RESULTS: Sixty-eight patients completed the trial. The laxative group had a significantly reduced time to passage of stool: median (interquartile range) 4 (3-5) versus 5 (4-6) days (P = 0.034). The ONS group showed a trend towards a shorter time to passage of stool (P = 0.076) but there was no evidence of interaction in patients randomized to the combination regimen. Median length of hospital stay was 6 (4-7) days. There were no differences in secondary outcomes between groups. CONCLUSION: Within an ERAS protocol for patients undergoing liver resection, routine postoperative laxatives result in an earlier first passage of stool but the overall rate of recovery is unaltered.

Vitamin D deficiency and myocardial structure and function in older men and women: the Hoorn study.

BACKGROUND: Vitamin D deficiency is frequently observed in heart failure patients and it has been shown that vitamin D exerts various effects on the heart that may be relevant for the pathogenesis of myocardial diseases. AIMS: We aimed to elucidate the largely unknown association of 25-hydroxyvitamin D [25(OH)D] serum levels with echocardiographic measures of left ventricular (LV) structure and function. MATERIAL/SUBJECTS AND METHODS: We measured 25(OH)D serum levels and performed standardized LV echocardiograms in 614 persons from a population-based cohort of older men and women. Echocardiographic data were used to calculate LV mass and geometry and for classification of systolic and diastolic dysfunction. To consider the seasonal variations of 25(OH)D levels we categorized our study participants according to season-specific 25(OH)D quartiles. RESULTS: LV systolic function, mass and geometry were not significantly associated with 25(OH)D serum levels. In binary logistic regression analyses, the prevalence of LV diastolic dysfunction was significantly higher in the first season-specific 25(OH)D quartile when compared to the fourth quartile [odds ratio 2.32 (95% CI: 1.42-3.80); p=0.001] but significance was lost after adjustments for age [odds ratio 1.51 (0.89-2.57); p=0.123] and established risk factors for heart failure [odds ratio 1.47 (0.84-2.59); p=0.178]. CONCLUSIONS: Serum levels of 25(OH)D are not significantly associated with LV structure and function but a non-significant trend towards increased risk of diastolic dysfunction in persons with vitamin D deficiency warrants further studies.

Care after pancreatic resection according to an algorithm for early detection and minimally invasive management of pancreatic fistula versus current practice (PORSCH-trial): design and rationale of a nationwide stepped-wedge cluster-randomized trial.

BACKGROUND: Pancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences such as postoperative bleeding, organ failure and death. The objective of this study is to investigate whether implementation of an algorithm for early detection and minimally invasive management of pancreatic fistula may improve outcomes after pancreatic resection. METHODS: This is a nationwide stepped-wedge, cluster-randomized, superiority trial, designed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. During a period of 22 months, all Dutch centers performing pancreatic surgery will cross over in a randomized order from current practice to best practice according to the algorithm. This evidence-based and consensus-based algorithm will provide daily multilevel advice on the management of patients after pancreatic resection (i.e. indication for abdominal imaging, antibiotic treatment, percutaneous drainage and removal of abdominal drains). The algorithm is designed to aid early detection and minimally invasive step-up management of postoperative pancreatic fistula. Outcomes of current practice will be compared with outcomes after implementation of the algorithm. The primary outcome is a composite of major complications (i.e. post-pancreatectomy bleeding, new-onset organ failure and death) and will be measured in a sample size of at least 1600 patients undergoing pancreatic resection. Secondary endpoints include the individual components of the primary endpoint and other clinical outcomes, healthcare resource utilization and costs analysis. Follow up will be up to 90 days after pancreatic resection. DISCUSSION: It is hypothesized that a structured nationwide implementation of a dedicated algorithm for early detection and minimally invasive step-up management of postoperative pancreatic fistula will reduce the risk of major complications and death after pancreatic resection, as compared to current practice. TRIAL REGISTRATION: Netherlands Trial Register: NL 6671. Registered on 16 December 2017.