Impact of an enhanced anti-infection prophylaxis strategy for pancreatoduodenectomy: a single centre analysis.

INTRODUCTION : Surgical site infection (SSI) after pancreatoduodenectomy (PD) is a significant concern. Targeted antibiotic prophylaxis (pAP) has been tested to mitigate antibiotic resistance patterns, especially after preoperative bile duct stenting. The aim of this study was to investigate the effect of enhanced anti-infective prophylaxis (EAP) on the incidence of superficial and intraabdominal SSI. METHODS: All patients who underwent PD at a single centre between May 2018 and May 2021 were retrospectively analysed. A control cohort of patients who received pAP with intravenous cefuroxime and metronidazole and routine intraoperative abdominal lavage according to the surgeons' preferences. Since March 2020, pAP has been changed to piperacillin/tazobactam according to local resistance patterns and combined with routine intraoperative extended abdominal lavage (EIPL). Preoperative selective decontamination of the digestive tract (SDD) has been applied routinely since Jan 2019. RESULTS: In total, 163 patients were included. The standard (n = 100) and EAP (n = 63) groups did not significantly differ with regard to pertinent patient and operative characteristics. In the EAP group, the rates of SSI (14% vs. 37%, p = 0.002, total rate: 28%) and urinary tract infection (24% vs. 8%, p = 0.011, total rate 18%) were significantly lower. Other septic complications were not significantly different. In addition, the risk of developing gastrointestinal bleeding and delayed gastric emptying was significantly lower in the EAP group. Multivariate analysis showed that an age > 67 years was a significant risk factor for SSI. CONCLUSION: The results indicate that enhanced anti-infective prophylaxis may significantly decrease the incidence of SSI in patients after PD.

Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

Chemokines as Prognostic Factor in Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

Chemokines orchestrate many aspects of tumorigenic processes such as angiogenesis, apoptosis and metastatic spread, and related receptors are expressed on tumor cells as well as on inflammatory cells (e.g., tumor-infiltrating T cells, TILs) in the tumor microenvironment. Expressional changes of chemokines and their receptors in solid cancers are common and well known, especially in affecting colorectal cancer patient outcomes. Therefore, the aim of this current systematic review and meta-analysis was to classify chemokines as a prognostic biomarker in colorectal cancer patients. A systematic literature search was conducted in PubMed, CENTRAL and Web of Science. Information on the chemokine expression of 25 chemokines in colorectal cancer tissue and survival data of the patients were investigated. The hazard ratio of overall survival and disease-free survival with chemokine expression was examined. The risk of bias was analyzed using Quality in Prognosis Studies. Random effects meta-analysis was performed to determine the impact on overall respectively disease survival. For this purpose, the pooled hazard ratios (HR) and their 95% confidence intervals (CI) were used for calculation. Twenty-five chemokines were included, and the search revealed 5556 publications. A total of thirty-one publications were included in this systematic review and meta-analysis. Overexpression of chemokine receptor CXCR4 was associated with both a significantly reduced overall survival (HR = 2.70, 95%-CI: 1.57 to 4.66, p = 0.0003) as well as disease-free survival (HR = 2.68, 95%-CI: 1.41 to 5.08, p = 0.0026). All other chemokines showed either heterogeneous results or few studies were available. The overall risk of bias for CXCR4 was rated low. At the current level of evidence, this study demonstrates that CXCR4 overexpression in patients with colorectal cancer is associated with a significantly diminished overall as well as disease-free survival. Summed up, this systematic review and meta-analysis reveals CXCR4 as a promising prognostic biomarker. Nevertheless, more evidence is needed to evaluate CXCR4 and its antagonists serving as new therapeutic targets.

Preoperative anaemia in distal pancreatectomy: a propensity-score matched analysis.

BACKGROUND: Preoperative anaemia is a prevalent morbidity predictor that adversely affects short- and long-term outcomes of patients undergoing surgery. This analysis aimed to investigate preoperative anaemia and its detrimental effects on patients after distal pancreatectomy. MATERIAL AND METHODS: The present study was a propensity-score match analysis of 286 consecutive patients undergoing distal pancreatectomy. Patients were screened for preoperative anaemia and classified according to WHO recommendations. The primary outcome measure was overall morbidity. The secondary endpoints were in-hospital mortality and rehospitalization. RESULTS: The preoperative anaemia rate before matching was 34.3% (98 patients), and after matching a total of 127 patients (non-anaemic 42 vs. anaemic 85) were included. Anaemic patients had significantly more postoperative major complications (54.1% vs. 23.8%; p < 0.01), a higher comprehensive complication index (26.2 vs. 4.3; p < 0.01), and higher in-hospital mortality rate (14.1% vs. 2.4%; p = 0.04). Multivariate regression analysis confirmed these findings and identified preoperative anaemia as a strong independent risk factor for postoperative major morbidity (OR 4.047; 95% CI: 1.587-10.320; p < 0.01). CONCLUSION: The current propensity-score matched analysis strongly considered preoperative anaemia as a risk factor for major complications following distal pancreatectomy. Therefore, an intense preoperative anaemia workup should be increasingly prioritised.

Shining a spotlight on sarcopenia and myosteatosis in liver disease and liver transplantation: Potentially modifiable risk factors with major clinical impact.

Muscle-wasting and disease-related malnutrition are highly prevalent in patients with chronic liver diseases (CLD) as well as in liver transplant (LT) candidates. Alterations of body composition (BC) such as sarcopenia, myosteatosis and sarcopenic obesity and associated clinical frailty were tied to inferior clinical outcomes including hospital admissions, length of stay, complications, mortality and healthcare costs in various patient cohorts and clinical scenarios. In contrast to other inherent detrimental individual characteristics often observed in these complex patients, such as comorbidities or genetic risk, alterations of the skeletal muscle and malnutrition are considered as potentially modifiable risk factors with a major clinical impact. Even so, there is only limited high-level evidence to show how these pathologies should be addressed in the clinical setting. This review discusses the current state-of-the-art on the role of BC assessment in clinical outcomes in the setting of CLD and LT focusing mainly on sarcopenia and myosteatosis. We focus on the disease-related pathophysiology of BC alterations. Based on these, we address potential therapeutic interventions including nutritional regimens, physical activity, hormone and targeted therapies. In addition to summarizing existing knowledge, this review highlights novel trends, and future perspectives and identifies persisting challenges in addressing BC pathologies in a holistic way, aiming to improve outcomes and quality of life of patients with CLD awaiting or undergoing LT.

Preoperative IL-8 levels as prognostic indicators of overall survival: an extended follow-up in a prospective cohort with colorectal liver metastases.

INTRODUCTION: CRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases. METHODS: Prospectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival. RESULTS: For disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil-lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors. CONCLUSION: This study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.

Clinical Research in Renal Transplantation: A Bibliometric Perspective on a Half-century of Innovation and Progress.

BACKGROUND: Groundbreaking biomedical research has transformed renal transplantation (RT) into a widespread clinical procedure that represents the mainstay of treatment for end-stage kidney failure today. Here, we aimed to provide a comprehensive bibliometric perspective on the last half-century of innovation in clinical RT. METHODS: The Web of Science Core Collection was used for a comprehensive screening yielding 123 303 research items during a 50-y period (January 1973-October 2022). The final data set of the 200 most-cited articles was selected on the basis of a citation-based strategy aiming to minimize bias. RESULTS: Studies on clinical and immunological outcomes (n = 63 and 48), registry-based epi research (n = 38), and randomized controlled trials (n = 35) dominated the data set. Lead US authors have signed 110 of 200 articles. The overall level of evidence was high, with 84% of level1 and -2 reports. Highest numbers of these articles were published in New England Journal of Medicine , Transplantation , and American Journal of Transplantation. Increasing trend was observed in the number of female authors in the postmillennial era (26% versus 7%). CONCLUSIONS: This study highlights important trends in RT research of the past half-century. This bibliometric perspective identifies the most intensively researched areas and shift of research interests over time; however, it also describes important imbalances in distribution of academic prolificacy based on topic, geographical aspects, and gender.

Integrating a microRNA signature as a liquid biopsy-based tool for the early diagnosis and prediction of potential therapeutic targets in pancreatic cancer.

INTRODUCTION: Pancreatic cancer is a highly aggressive cancer, and early diagnosis significantly improves patient prognosis due to the early implementation of curative-intent surgery. Our study aimed to implement machine-learning algorithms to aid in early pancreatic cancer diagnosis based on minimally invasive liquid biopsies. MATERIALS AND METHODS: The analysis data were derived from nine public pancreatic cancer miRNA datasets and two sequencing datasets from 26 pancreatic cancer patients treated in our medical center, featuring small RNAseq data for patient-matched tumor and non-tumor samples and serum. Upon batch-effect removal, systematic analyses for differences between paired tissue and serum samples were performed. The robust rank aggregation (RRA) algorithm was used to reveal feature markers that were co-expressed by both sample types. The repeatability and real-world significance of the enriched markers were then determined by validating their expression in our patients' serum. The top candidate markers were used to assess the accuracy of predicting pancreatic cancer through four machine learning methods. Notably, these markers were also applied for the identification of pancreatic cancer and pancreatitis. Finally, we explored the clinical prognostic value, candidate targets and predict possible regulatory cell biology mechanisms involved. RESULTS: Our multicenter analysis identified hsa-miR-1246, hsa-miR-205-5p, and hsa-miR-191-5p as promising candidate serum biomarkers to identify pancreatic cancer. In the test dataset, the accuracy values of the prediction model applied via four methods were 94.4%, 84.9%, 82.3%, and 83.3%, respectively. In the real-world study, the accuracy values of this miRNA signatures were 82.3%, 83.5%, 79.0%, and 82.2. Moreover, elevated levels of these miRNAs were significant indicators of advanced disease stage and allowed the discrimination of pancreatitis from pancreatic cancer with an accuracy rate of 91.5%. Elevated expression of hsa-miR-205-5p, a previously undescribed blood marker for pancreatic cancer, is associated with negative clinical outcomes in patients. CONCLUSION: A panel of three miRNAs was developed with satisfactory statistical and computational performance in real-world data. Circulating hsa-miRNA 205-5p serum levels serve as a minimally invasive, early detection tool for pancreatic cancer diagnosis and disease staging and might help monitor therapy success.

Serum immune checkpoint profiling identifies soluble CD40 as a biomarker for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to systemic treatment, including new immunotherapeutic approaches. Biomarkers are urgently needed for early disease detection, patient stratification for treatment, and response prediction. The role of soluble CD40 (sCD40) is unknown in PDAC. In this study, we performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum samples from patients with various stages of PDAC in a discovery study (n = 107) and analyzed sCD40 by ELISA in a validation study (n = 317). Youden's J statistic was used for diagnostic cut-off optimization. A Cox proportional hazards regression model was applied in an empiric approach for prognostic threshold optimization. Kaplan-Meier estimator and multivariable Cox regression analyses were used for survival analysis. sCD40 was significantly increased in the serum of patients with PDAC compared to healthy cohorts and patients with IPMN. In the validation cohort, the area under the receiver operating characteristic (ROC) c-statistic was 0.8, and combining sCD40 with CA19-9 yielded a c-statistic of 0.95. sCD40 levels were independent of the tumor stage. However, patients who received neoadjuvant chemotherapy had significantly lower sCD40 levels than those who underwent upfront surgery. Patients with a sCD40 level above the empirical threshold of 0.83 ng/ml had a significantly reduced overall survival with a hazard ratio of 1.4. This observation was pronounced in patients after neoadjuvant chemotherapy. Collectively, soluble CD40 may be considered as both a diagnostic and prognostic non-invasive biomarker in PDAC.

COMPASS: deCOMPressing stomA and two-Stage elective resection vs. emergency reSection in patients with left-sided obstructive colon cancer.

BACKGROUND: Colorectal cancer stands as a prevalent cause of cancer-related mortality, necessitating effective treatment strategies. Acute colonic obstruction occurs in approximately 20% of patients and represents a surgical emergency with substantial morbidity and mortality. The optimal approach for managing left-sided colon cancer with acute colonic obstruction remains debatable, with no consensus on whether emergency resection or bridge-to-surgery, involving initial decompressing stoma and subsequent elective resection after recovery, should be employed. Current studies show a decrease in morbidity and short-term mortality for the bridge-to-surgery approach, yet it remains unclear if the long-term oncological outcome is equivalent to emergency resection. METHODS: This prospective, randomized, multicenter trial aims to investigate the management of obstructive left-sided colon cancer in a comprehensive manner. The study will be conducted across 26 university hospitals and 40 academic hospitals in Germany. A total of 468 patients will be enrolled, providing a cohort of 420 evaluable patients, with an equal distribution of 210 patients in each treatment arm. Patients with left-sided colon cancer, defined as cancer between the left splenic flexure and > 12 cm ab ano and obstruction confirmed by X-ray or CT scan, are eligible. Randomization will be performed in a 1:1 ratio, assigning patients either to the oncological emergency resection group or the bridge-to-surgery group, wherein patients will undergo diverting stoma and subsequent elective oncological resection after recovery. The primary endpoint of this trial will be 120-day mortality, allowing for consideration of the time interval between diverting stoma and resection. DISCUSSION: The findings derived from this trial possess the potential to reshape the current clinical approach of emergency resection for obstructive left-sided colon cancer by favoring the bridge-to-surgery practice, provided that a reduction in morbidity can be achieved without compromising the oncological long-term outcome. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) under the identifier DRKS00031827. Registered on May 15, 2023. PROTOCOL: 28.04.2023, protocol version 2.0F.

Interleukin-8 is superior to CRP for the prediction of severe complications in a prospective cohort of patients undergoing major liver resection.

INTRODUCTION: Early detection of severe complications may reduce morbidity and mortality in patients undergoing hepatic resection. Therefore, we prospectively evaluated a panel of inflammatory blood markers for their value in predicting postoperative complications in patients undergoing liver surgery. METHODS: A total of 139 patients undergoing liver resections (45 wedge resections, 49 minor resections, and 45 major resections) were prospectively enrolled between August 2017 and December 2018. Leukocytes, CRP, neutrophil-lymphocyte ratio (NLR), thrombocyte-lymphocyte ratio (TLR), bilirubin, INR, and interleukin-6 and -8 (IL-6 and IL-8) were measured in blood drawn preoperatively and on postoperative days 1, 4, and 7. IL-6 and IL-8 were measured using standardized immunoassays approved for in vitro diagnostic use in Germany. ROC curve analysis was used to determine predictive values for the occurrence of severe postoperative complications (CDC ≥ 3). RESULTS: For wedge and minor resections, leukocyte counts at day 7 (AUC 0.80 and 0.82, respectively), IL-6 at day 7 (AUC 0.74 and 0.73, respectively), and CRP change (∆CRP) at day 7 (AUC 0.72 and 0.71, respectively) were significant predictors of severe postoperative complications. IL-8 failed in patients undergoing wedge resections, but was a significant predictor of severe complications after minor resections on day 7 (AUC 0.79), had the best predictive value in all patients on days 1, 4, and 7 (AUC 0.72, 0.72, and 0.80, respectively), and was the only marker with a significant predictive value in patients undergoing major liver resections (AUC on day 1: 0.70, day 4: 0.86, and day 7: 0.92). No other marker, especially not CRP, was predictive of severe complications after major liver surgery. CONCLUSION: IL-8 is superior to CRP in predicting severe complications in patients undergoing major hepatic resection and should be evaluated as a biomarker for patients undergoing major liver surgery. This is the first paper demonstrating a feasible implementation of IL-8 analysis in a clinical setting.

The role of local expression of hormone receptors in the genesis of idiopathic tracheal stenosis.

Background: Tracheal stenosis in adults is usually the result of mechanical injuries either from direct trauma, tracheotomy or intubation. Idiopathic stenosis in the cricotracheal section is a rare condition and occurs almost exclusively in females. Therefore, an influence of the female sexual hormones estrogen and progesterone has been assumed previously. Methods: Tracheal specimens of 27 patients who received tracheal resection for either idiopathic tracheal stenosis (ITS) (n=11) or posttraumatic tracheal stenosis (PTTS) (n=16) between 2008 and 2019 in our surgical department were included and retrospectively analyzed. Immunohistochemical staining of tracheal specimens concerning the hormone receptor status of progesterone and estrogen was performed. Results: While post-tracheotomy stenosis occurred in males (n=6) as well as in females (n=10), none of the patients with idiopathic stenosis were males. All of the idiopathic stenosis (n=11; 100%) showed a strong expression of the estrogen receptors (ERs) in the fibroblasts and expression of progesterone receptors (PRs) in fibroblasts in 8 of 11 (72.7%). In the post-tracheotomy patients, only 3/16 (18.8%) showed slight staining of PRs and 6/16 (37.5%) of ERs. Of those, only one male patient presented with expression of ERs and PRs and another male patient presented with isolated PRs. Oral intake of hormone compounds was seen in 11/27 (40.7%) patients: 7/11 (63.6%) in the ITS group and 4/16 (25%) in the PTTS (noteworthy that the PTTS group included 6 male patients). Conclusions: Although the number of patients is small, our results show that the expression of female sexual hormone receptors in the fibroblasts of the trachea is a persistent finding in ITS. Surgery provided good results with a favorable long-term outcome without recurrence of stenosis for ITS and PTTS. Further investigation with a special focus on hormones is needed to assist in the prevention of this rare disease.

RAB27B expression in pancreatic cancer is predictive of poor survival but good response to chemotherapy.

BACKGROUND: Pancreatic cancer is the 4th leading cause of cancer-related death with poor survival even after curative resection. RAB27A and RAB27B are key players in the exosome pathway where they play important roles in exosome secretion. Evidence suggests that RAB27A and RAB27B expression not only leads to tumor proliferation and invasion, but also plays an important role in antigen transfer necessary for anticancer immunity. OBJECTIVE: In this study, we analyze the expression of RAB27A and RAB27B in patients after pancreatic cancer surgery with or without adjuvant chemotherapy and its influence on overall survival. METHODS: We analyzed a total of 167 patients with pancreatic cancer for their RAB27A and RAB27B expression. We dichotomized the patients along the median and compared survival in patients with high and low RAB27A and RAB27B expression with or without adjuvant chemotherapy treatment. RESULTS: We found a significant improvement in overall survival in patients with a negative resection margin (p= 0.037) and in patients who received adjuvant chemotherapy (p= 0.039). The survival benefit after chemotherapy was dependent on RAB27B expression status: only the subgroup of patients with high RAB27B expression benefited from adjuvant chemotherapy (p= 0.006), but not the subgroup with low RAB27B expression (p= 0.59). Patients with high RAB27B expression who did not receive adjuvant chemotherapy showed a trend towards worse survival compared to the other subgroups. This difference was abolished after treatment with adjuvant chemotherapy. CONCLUSION: These results suggest that RAB27B expression in pancreatic cancer might identify a subgroup of patients with poor survival who might respond well to adjuvant chemotherapy. If resectable, these patients could be considered for neoadjuvant chemotherapy to minimize the risk of not receiving adjuvant chemotherapy. Further prospective studies are needed to confirm these findings.

Fast and label-free intraoperative discrimination of malignant pancreatic tissue by attenuated total reflection infrared spectroscopy.

Significance: Pancreatic surgery is a highly demanding and routinely applied procedure for the treatment of several pancreatic lesions. The outcome of patients with malignant entities crucially depends on the margin resection status of the tumor. Frozen section analysis for intraoperative evaluation of tissue is still time consuming and laborious. Aim: We describe the application of fiber-based attenuated total reflection infrared (ATR IR) spectroscopy for label-free discrimination of normal pancreatic, tumorous, and pancreatitis tissue. A pilot study for the intraoperative application was performed. Approach: The method was applied for unprocessed freshly resected tissue samples of 58 patients, and a classification model for differentiating between the distinct tissue classes was established. Results: The developed three-class classification model for tissue spectra allows for the delineation of tumors from normal and pancreatitis tissues using a probability score for class assignment. Subsequently, the method was translated into intraoperative application. Fiber optic ATR IR spectra were obtained from freshly resected pancreatic tissue directly in the operating room. Conclusion: Our study shows the possibility of applying fiber-based ATR IR spectroscopy in combination with a supervised classification model for rapid pancreatic tissue identification with a high potential for transfer into intraoperative surgical diagnostics.

Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment.

Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.

Interrupted versus continuous suture technique for biliary-enteric anastomosis: randomized clinical trial.

BACKGROUND: Biliary-enteric anastomosis (BEA) can be performed using continuous or interrupted suture techniques, but high-quality evidence regarding superiority of either technique is lacking. The aim of this study was to compare the suture techniques for patients undergoing BEA by evaluating the suture time as well as short- and long-term biliary complications. METHODS: In this single-centre randomized clinical trial, patients scheduled for elective open procedure with a BEA between 21 January 2016 and 20 September 2017 were randomly allocated in a 1:1 ratio to have the BEA performed with continuous suture (CSG) or interrupted suture technique (ISG). The primary outcome was the time required to complete the anastomosis. Secondary outcomes were BEA-associated postoperative complications with and without operative revision of the BEA, including bile leakage, cholestasis, and cholangitis, as well as morbidity and mortality up to day 30 after the intervention and survival. RESULTS: Altogether, 82 patients were randomized of which 80 patients received the allocated intervention (39 in ISG and 41 in CSG). Suture time was longer in the ISG compared with the CSG (median (interquartile range), 22.4 (15.0-28.0) min versus 12.0 (10.0-17.0) min, OR 1.26, 95 per cent c.i. 1.13 to 1.40; unit of increase of 1 min; P < 0.001). Short-term and long-term biliary complications were similar between groups. The incidence of bile leakage (6 (14.6 per cent) versus 4 (10.3 per cent), P = 0.738) was comparable between groups. No anastomotic stenosis occurred in either group. CONCLUSION: Continuous suture of BEA is equally safe, but faster compared with interrupted suture. REGISTRATION NUMBER: NCT02658643 (http://www.clinicaltrials.gov).

Plasma extracellular vesicle messenger RNA profiling identifies prognostic EV signature for non-invasive risk stratification for survival prediction of patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6-8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery. METHODS: Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan-Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR. RESULTS: Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis. CONCLUSION: This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.

Tumour catabolism independent of malnutrition and inflammation in upper GI cancer patients revealed by longitudinal metabolomics.

BACKGROUND: The detrimental impact of malnutrition and cachexia in cancer patients subjected to surgical resection is well established. However, how systemic and local metabolic alterations in cancer patients impact the serum metabolite signature, thereby leading to cancer-specific differences, is poorly defined. In order to implement metabolomics as a potential tool in clinical diagnostics and disease follow-up, targeted metabolite profiling based on quantitative measurements is essential. We hypothesized that the quantitative metabolic profile assessed by 1 H nuclear magnetic resonance (NMR) spectroscopy can be used to identify cancer-induced catabolism and potentially distinguish between specific tumour entities. Importantly, to prove tumour dependency and assess metabolic normalization, we additionally analysed the metabolome of patients' sera longitudinally post-surgery in order to assess metabolic normalization. METHODS: Forty two metabolites in sera of patients with tumour entities known to cause malnutrition and cachexia, namely, upper gastrointestinal cancer and pancreatic cancer, as well as sera of healthy controls, were quantified by 1 H NMR spectroscopy. RESULTS: Comparing serum metabolites of patients with gastrointestinal cancer with healthy controls and pancreatic cancer patients, we identified at least 15 significantly changed metabolites in each comparison. Principal component and pathway analysis tools showed a catabolic signature in preoperative upper gastrointestinal cancer patients. The most specifically upregulated metabolite group in gastrointestinal cancer patients was ketone bodies (3-hydroxybutyrate, P < 0.0001; acetoacetate, P < 0.0001; acetone, P < 0.0001; false discovery rate [FDR] adjusted). Increased glycerol levels (P < 0.0001), increased concentration of the ketogenic amino acid lysine (P = 0.03) and a significant correlation of 3-hydroxybutyrate levels with branched-chained amino acids (leucine, P = 0.02; isoleucine, P = 0.04 [FDR adjusted]) suggested that ketone body synthesis was driven by lipolysis and amino acid breakdown. Interestingly, the catabolic signature was independent of the body mass index, clinically assessed malnutrition using the nutritional risk screening score, and systemic inflammation assessed by CRP and leukocyte count. Longitudinal measurements and principal component analyses revealed a quick normalization of key metabolic alterations seven days post-surgery, including ketosis. CONCLUSIONS: Together, the quantitative metabolic profile obtained by 1 H NMR spectroscopy identified a tumour-induced catabolic signature specific to upper gastrointestinal cancer patients and enabled monitoring restoration of metabolic homeostasis after surgery. This approach was critical to identify the obtained metabolic profile as an upper gastrointestinal cancer-specific signature independent of malnutrition and inflammation.

Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer.

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%-40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODSWe performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTSIn human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSIONNeoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDINGThis work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.