[Quality assurance and improvement in healthcare: instruments and perspectives]. / Qualität in der Gesundheitsversorgung sichern und weiterentwickeln: Maßnahmen und Perspektiven.

In the German statutory health insurance system, quality healthcare is an imperative - healthcare must correspond to current medical knowledge. The central decision-making body, the Federal Joint Committee (G-BA), uses directives to regulate quality standards and instruments to ensure compliance. The Institute for Quality Assurance and Transparency in Health Care (IQTIG) supports the G­BA in this task with independent scientific recommendations. A central task of the institute is the development of quality indicators based on billing data, patient records, and patient surveys.With regard to instruments for the improvement of quality, the IQTIG distinguishes between improvement instruments, instruments based on selection decisions, and instruments based on incentives for providers. Quality improvement requires quality management and intrinsic motivation on the part of the providers. However, due to perverse incentives, intrinsic motivation and thus quality improvement alone are not always sufficient and must be supplemented by extrinsic incentives and other instruments. In particular, instruments enabling quality-oriented physician and hospital choice have not yet been implemented in Germany. The quality information required to enable patients to make such choices does not yet exist and should be based on billing data and patient surveys. Further, such quality information should be presented as simply and understandably as possible on online comparison platforms.To ensure high-quality healthcare, the various instruments for improving quality must be coordinated with one another and aligned with a system of healthcare targets. Such a system of overarching healthcare targets allows the limited resources to be focused on those areas in which the need for action is greatest.

Current practice of stress ulcer prophylaxis in a surgical patient cohort in a German university hospital.

INTRODUCTION: Stress ulcer prophylaxis (SUP) has been a widespread practice both in intensive care units (ICU) and internal wards at the beginning of the twenty-first century. Clinical data suggests an important overuse of acid suppressive therapy (AST) for this indication. Data on current clinical practice of SUP in surgical patients in a non-ICU setting are spares. In the light of a growing number of reports on serious side effects of AST, this study evaluates the use of AST for SUP in a normal surgical ward in a German university hospital. METHODS: Between January 2016 and June 2016, SUP was analysed retrospectively in 1132 consecutive patients of the Department of Surgery of the Universitätsmedizin Greifswald. RESULTS: The patients managed with and without SUP were similar with respect to demographic data and treatment with anticoagulants, SSRI and glucocorticoids. Patients with SUP were treated more frequently by cyclooxygenase inhibiting drugs (NSAID, COX2-inhibitors), were more frequently treated in the intermediated care unit and had a longer hospital stay. Risk factors for the development of stress ulcers were similarly present in patient groups managed with and without SUP. About 85.7-99.6% of patients were given SUP without an adequate risk for stress ulcer development, depending on the method used for risk assessment. DISCUSSION: Still today, SUP is widely overused in non-ICU surgical patients. Information campaigns on risk factors for stress ulcer development and standard operating procedures for SUP are required to limit potential side effects and increased treatment costs.

[Routine Practice Data for Evaluating Intervention Effects: Part 2 of the Manual]. / Versorgungsnahe Daten zur Evaluation von Interventionseffekten: Teil 2 des Manuals.

The evaluation of intervention effects is an important domain of health services research. The ad hoc commission for the use of routine practice data of the German Network for Health Services Research (DNVF) therefore provides this second part of its manual focusing on the use of routine practice data for the evaluation of intervention effects. First, we discuss definition issues and the importance of contextual factors. Subsequently, general requirements for planning, data collection and analysis as well as concrete examples for the evaluation of intervention effects for the 3 fields of application regarding pharmacotherapy, nonpharmaceutical interventions as well as complex interventions are elaborated. We consider scenarios in which no information from randomized controlled trials (RCTs) comparing the two groups directly is yet available or in which RCTs are already available but an extension of the research question is required. In all examples either with or without randomization, the first and foremost question is always whether the data source is suitable for the specific research question. Most of the examples chosen are from oncology trials, because the necessary data are already available for Germany, at least in some form. Finally, the manual discusses possible challenges for future use of these data.

Influence of COVID-19 confinement measures on appendectomies in Germany-a claims data analysis of 9797 patients.

PURPOSE: COVID-19 pandemic had multiple influences on the social, industrial, and medical situation in all affected countries. Measures of obligatory medical confinement were suspensions of scheduled non-emergent surgical procedures and outpatients' clinics as well as overall access restrictions to hospitals and medical practices. The aim of this retrospective study was to assess if the obligatory confinement (lockdown) had an effect on the number of appendectomies (during and after the period of lockdown). METHODS: This retrospective study was based on anonymized nationwide administrative claims data of the German Local General Sickness Fund (AOK). Patients admitted for diseases of the appendix (ICD-10: K35-K38) or abdominal and pelvic pain (ICD-10: R10) who underwent an appendectomy (OPS: 5-470) were included. The study period included 6 weeks of German lockdown (16 March-26 April 2020) as well as 6 weeks before (03 February-15 March 2020) and after (27 April-07 June 2020). These periods were compared to the respective one in 2018 and 2019. RESULTS: The overall number of appendectomies was significantly reduced during the lockdown time in 2020 compared to that in 2018 and 2019. This decrease affects only appendectomies due to acute simple (ICD-10: K35.30, K35.8) and non-acute appendicitis (ICD-10: K36-K38, R10). Numbers for appendectomies in acute complex appendicitis remained unchanged. Female patients and in the age group 1-18 years showed the strongest decrease in number of cases. CONCLUSION: The lockdown in Germany resulted in a decreased number of appendectomies. This affected mainly appendectomies in simple acute and non-acute appendicitis, but not complicated acute appendicitis. The study gives no evidence that the confinement measures resulted in a deterioration of medical care for appendicitis.

Rates of Complications After Appendectomy in Children and Adolescents: Pediatric Surgical Compared to General Surgical Hospitals.

BACKGROUND: Appendectomies in children and adolescents are performed in Germany in pediatric surgical (PS) or general surgical hospitals (GS). The aim of this study is to evaluate whether the surgery in a PS or GS hospital has an influence on the postoperative course after appendectomy in children and adolescents. MATERIALS AND METHODS: Nationwide routine data from children and adolescents aged 1-17 y insured by the Local Health Insurance Fund who underwent appendectomy between 2014 and 2016 were analyzed (cohort study). Descriptive statistics were calculated both overall and in the two groups (PS and GS). Patients were additionally examined by age (1-5, 6-12, and 13-17 y), treatment (laparoscopic, open surgical, and conversion), and appendicitis type (nonacute: K36/K37/K38/R10, acute simple: K35.30/K35.8, and acute complex: K35.2/K35.31/K35.32). The influence of surgeon specialization on 90-d secondary surgery and 90-d general complications was assessed by multiple logistic regression. RESULTS: Altogether, 25,065 patients who underwent surgery in 83 PS and 906 GS hospitals were included. Logistic regression analysis revealed that PS was associated with a reduced risk of interventions in the 1-5- and 6-12-y age groups (odds ratio: 0.44, 0.62). Acute complex appendicitis, comorbidities, and open surgery significantly increased the risk for reintervention. PS was associated with an increased risk for complications in the 13-17-y age group (odds ratio: 1.66). CONCLUSIONS: PS and GS hospitals provided safe appendectomies in children and adolescents with low reintervention and complication rates. PS hospitals demonstrated advantages for patients in the 1-5- and 6-12-y age groups and GS hospitals for patients 13-17 y.

A Klebsiella pneumoniae ST307 outbreak clone from Germany demonstrates features of extensive drug resistance, hypermucoviscosity, and enhanced iron acquisition.

BACKGROUND: Antibiotic-resistant Klebsiella pneumoniae are a major cause of hospital- and community-acquired infections, including sepsis, liver abscess, and pneumonia, driven mainly by the emergence of successful high-risk clonal lineages. The K. pneumoniae sequence type (ST) 307 lineage has appeared in several different parts of the world after first being described in Europe in 2008. From June to October 2019, we recorded an outbreak of an extensively drug-resistant ST307 lineage in four medical facilities in north-eastern Germany. METHODS: Here, we investigated these isolates and those from subsequent cases in the same facilities. We performed whole-genome sequencing to study phylogenetics, microevolution, and plasmid transmission, as well as phenotypic experiments including growth curves, hypermucoviscosity, siderophore secretion, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance for an in-depth characterization of this outbreak clone. RESULTS: Phylogenetics suggest a homogenous phylogram with several sub-clades containing either isolates from only one patient or isolates originating from different patients, suggesting inter-patient transmission. We identified three large resistance plasmids, carrying either NDM-1, CTX-M-15, or OXA-48, which K. pneumoniae ST307 likely donated to other K. pneumoniae isolates of different STs and even other bacterial species (e.g., Enterobacter cloacae) within the clinical settings. Several chromosomally and plasmid-encoded, hypervirulence-associated virulence factors (e.g., yersiniabactin, metabolite transporter, aerobactin, and heavy metal resistance genes) were identified in addition. While growth, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance were comparable to several control strains, results from siderophore secretion and hypermucoviscosity experiments revealed superiority of the ST307 clone, similar to an archetypical, hypervirulent K. pneumoniae strain (hvKP1). CONCLUSIONS: The combination of extensive drug resistance and virulence, partly conferred through a "mosaic" plasmid carrying both antibiotic resistance and hypervirulence-associated features, demonstrates serious public health implications.

Gas Plasma-Conditioned Ringer's Lactate Enhances the Cytotoxic Activity of Cisplatin and Gemcitabine in Pancreatic Cancer In Vitro and In Ovo.

Pancreatic cancer is one of the most aggressive tumor entities. Diffuse metastatic infiltration of vessels and the peritoneum restricts curative surgery. Standard chemotherapy protocols include the cytostatic drug gemcitabine with limited efficacy at considerable toxicity. In search of a more effective and less toxic treatment modality, we tested in human pancreatic cancer cells (MiaPaca and PaTuS) a novel combination therapy consisting of cytostatic drugs (gemcitabine or cisplatin) and gas plasma-conditioned Ringer's lactate that acts via reactive oxygen species. A decrease in metabolic activity and viability, change in morphology, and cell cycle arrest was observed in vitro. The combination treatment was found to be additively toxic. The findings were validated utilizing an in ovo tumor model of solid pancreatic tumors growing on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM). The combination of the drugs (especially cisplatin) with the plasma-conditioned liquid significantly enhanced the anti-cancer effects, resulting in the induction of cell death, cell cycle arrest, and inhibition of cell growth with both of the cell lines tested. In conclusion, our novel combination approach may be a promising new avenue to increase the tolerability and efficacy of locally applied chemotherapeutic in diffuse metastatic peritoneal carcinomatosis of the pancreas.

Early removal of urinary drainage in patients receiving epidural analgesia after colorectal surgery within an ERAS protocol is feasible.

BACKGROUND: ERAS guidelines recommend early removal of urinary drainage after colorectal surgery to reduce the risk of catheter-associated urinary tract infections (CAUTI). Another recommendation is the postoperative use of epidural analgesia (EA). In many types of surgery, EA was shown to increase the risk of postoperative urinary retention (POUR). This study determines the impact of early urinary catheter removal on the incidence of POUR and CAUTI under EA after colorectal surgery. METHODS: Eligible patients were scheduled for colorectal surgery within the local ERAS protocol between April 2015 and September 2016. Urinary drainage was removed on the first postoperative day while EA was still in place (early removal group (ER)). The incidences of POUR and CAUTIs were recorded prospectively. Results were compared with a historical control (CG), which was operated between October 2013 and March 2015. RESULTS: POUR occurred significantly more often in the ER (ER 7.8%; CG 2.6%), while CAUTIs were significantly less frequent in the ER (13.8%) compared with the CG (30.4%). Patients who developed POUR were characterised by a significantly higher rate of abdominoperineal resections, by a higher frequency of rectal cancer, and a higher male-to-female ratio compared with patients who did not develop POUR. CONCLUSION: Early removal of urinary drainage after colorectal surgery while EA is still in place is feasible; it reduces the incidence of CAUTI but increases the risk of POUR. Thus, screening for POUR in patients with failure to void after six to 8 h is mandatory under these clinical conditions.

Risk Assessment of kINPen Plasma Treatment of Four Human Pancreatic Cancer Cell Lines with Respect to Metastasis.

Cold physical plasma has limited tumor growth in many preclinical models and is, therefore, suggested as a putative therapeutic option against cancer. Yet, studies investigating the cells' metastatic behavior following plasma treatment are scarce, although being of prime importance to evaluate the safety of this technology. Therefore, we investigated four human pancreatic cancer cell lines for their metastatic behavior in vitro and in chicken embryos (in ovo). Pancreatic cancer was chosen as it is particularly metastatic to the peritoneum and systemically, which is most predictive for outcome. In vitro, treatment with the kINPen plasma jet reduced pancreatic cancer cell activity and viability, along with unchanged or decreased motility. Additionally, the expression of adhesion markers relevant for metastasis was down-regulated, except for increased CD49d. Analysis of 3D tumor spheroid outgrowth showed a lack of plasma-spurred metastatic behavior. Finally, analysis of tumor tissue grown on chicken embryos validated the absence of an increase of metabolically active cells physically or chemically detached with plasma treatment. We conclude that plasma treatment is a safe and promising therapeutic option and that it does not promote metastatic behavior in pancreatic cancer cells in vitro and in ovo.

Over-the-Scope Clip Closure of Pancreatico-Colonic Fistula Secondary to Acute or Chronic Pancreatitis: A Case Series.

Introduction: Pancreatico-colonic fistula (PCF) is a rare adverse effect secondary to severe acute or chronic pancreatitis and potentially life-threatening because of abdominal sepsis. Over-the-scope clip (OTSC®) system is a recently developed endoscopic device and has been successfully used for bleeding and perforations of the gastrointestinal tract. We hereby report a series of patients with PCFs in whom OTSC was used. Materials and Methods: From January 2011 to December 2018, we retrospectively collected data on cases of PCFs with endoscopic treatment using the OTSC system. After conservative management, the endoscopic intervention was carried out on patients in deep sedation by single skilled operators. Results: A total of 9 patients were enrolled and patients were treated with 14/6 t-type OTSC. PCF occurred secondary to chronic (n = 5) and acute pancreatitis (n = 4). There were no adverse effects related to the endoscopic procedure itself. Further endoscopic evaluation was performed 8 weeks later and revealed a successful fistula closure in 4 patients with chronic pancreatitis (80%) and in 2 patients with acute pancreatitis (50%). An insufficient fistula closure was observed in 3 cases because of dislocation of the OTSC and an additional surgical procedure was required. Conclusion: The OTSC system seems to be safe and effective in short-term management of PCFs because of acute or chronic pancreatitis in addition to the already established nonsurgical therapy. However, the OTSC closure of PCFs in patients with acute pancreatitis seems to be associated with a higher failure rate. To sum up, more evidence and long-term studies are needed to determine the criteria for the use of OTSC in closure of PCFs owing to acute or chronic pancreatitis.

Laparoscopic-endoscopic Rendezvous Procedures for Upper Gastrointestinal Tumors Guided by Laser-supported Reverse Diaphanoscopy: A Modified Technique.

INTRODUCTION: Precisely locating benign upper gastrointestinal tumors during laparoscopic-endoscopic surgery remains difficult and inaccurate. We describe reverse laser-supported diaphanoscopy (RLSD) for locating gastrointestinal tumors during laparoscopic surgery and present prospective evaluation results of the first cases. MATERIALS AND METHODS: We studied 13 patients [women:men=7:6; mean age, 67 (range, 41 to 83) y] who underwent gastroscopic-laparoscopic rendezvous procedures during 2015 to 2018. Surgery duration, marking duration, and specimen resection size were recorded. The largest and smallest specimen resection margins were measured. RESULTS: After locating tumors using RLSD, patients underwent successful resections. Histopathologic examination confirmed 5 cases of gastrointestinal stromal tumor; 3, neuroendocrine tumors; 2, heterotopic pancreatic tissue; 1, leiomyoma; 1, adenoma; 1, hyperplastic polyp. We employed 4 to 6 marks, depending on tumor location and size. The average marking duration was 14 minute (1 to 21 min); the average surgery duration, 73 minute (37 to 143 min). The smallest resection median margin was 2.0 mm (1.0 to 5.0 mm); the largest, 7.0 mm (2.0 to 12.0 mm). CONCLUSIONS: RLSD precisely locates gastric benign tumors during laparoscopic-endoscopic rendezvous procedures.

Laparoscopic versus open gastrectomy for locally advanced gastric cancer: a systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: This meta-analysis sought to evaluate the potential benefits and harms of laparoscopic gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer versus open surgery. METHODS: A comprehensive search for randomized controlled studies that compared laparoscopic versus open gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer published until December 31, 2018, was conducted. Operative outcomes, early postoperative outcomes, and long-term results were analyzed using a random effects model. RESULTS: Five randomized controlled trials containing a collective total of 2157 patients were included. In comparison with open surgery, laparoscopic gastrectomy for locally advanced gastric cancer showed similar risks of short-term mortality and serious adverse events within 30 days after surgery. Regarding intraoperative outcomes, operative time was increased for the laparoscopic approach, whereas the estimated intraoperative blood loss tended to be less. However, the amount of evidence was low for most outcomes. In addition, the results for the length of hospital stay and time to first flatus did not show statistically significant differences. The number of harvested lymph nodes and compliance with D2 lymphadenectomy did not significantly differ between the two groups, indicating oncological equivalence of both approaches. However, long-term oncological results could not be evaluated due to a lack of relevant data in four of the trials. CONCLUSION: Laparoscopic gastrectomy with D2 lymphadenectomy can be performed with equivalent overall short-term morbidity and mortality versus the open approach for locally advanced gastric cancer. However, further well-designed randomized controlled trials are necessary to assess the possible advantages and risks of the laparoscopic approach as well as the long-term results.

Physical plasma-treated saline promotes an immunogenic phenotype in CT26 colon cancer cells in vitro and in vivo.

Metastatic colorectal cancer is the fourth most common cause of cancer death. Current options in palliation such as hyperthermic intraperitoneal chemotherapy (HIPEC) present severe side effects. Recent research efforts suggested the therapeutic use of oxidant-enriched liquid using cold physical plasma. To investigate a clinically accepted treatment regimen, we assessed the antitumor capacity of plasma-treated saline solution. In response to such liquid, CT26 murine colon cancer cells were readily oxidized and showed cell growth with subsequent apoptosis, cell cycle arrest, and upregulation of immunogenic cell death (ICD) markers in vitro. This was accompanied by marked morphological changes with re-arrangement of actin fibers and reduced motility. Induction of an epithelial-to-mesenchymal transition phenotype was not observed. Key results were confirmed in MC38 colon and PDA6606 pancreatic cancer cells. Compared to plasma-treated saline, hydrogen peroxide was inferiorly toxic in 3D tumor spheroids but of similar efficacy in 2D models. In vivo, plasma-treated saline decreased tumor burden in Balb/C mice. This was concomitant with elevated numbers of intratumoral macrophages and increased T cell activation following incubation with CT26 cells ex vivo. Being a potential adjuvant for HIPEC therapy, our results suggest oxidizing saline solutions to inactivate colon cancer cells while potentially stimulating antitumor immune responses.

Dysregulation of Mucosal Membrane Transporters and Drug-Metabolizing Enzymes in Ulcerative Colitis.

Intestinal transporters and metabolizing enzymes are the important factors of the intestinal absorption barrier. Because there is evidence that their expression and function may be affected during inflammatory conditions, we investigated gene expression, protein abundance, and regulation of relevant intestinal transporters and metabolizing enzymes in the intestinal mucosa of patients with ulcerative colitis (UC). Specimens from inflamed and noninflamed tissues of 10 patients with UC as well as colonic control tissues of 10 patients without inflammation were subjected to gene (9 enzymes, 15 transporters, 9 cytokines) and microRNA (N = 54) expression analysis. Protein abundance was quantified by liquid chromatography-tandem mass spectrometry-based targeted proteomics. Gene expression of several metabolizing enzymes (e.g., CYP2C9, UGT1A1) and transporters such as ABCB1 (ABCB1), ABCG2 (ABCG2), and monocarboxylate transporter 1 (MCT1, SLC16A1) were significantly decreased during inflammation and negatively correlated to microRNAs. On contrary, multidrug resistance-protein 4 (MRP4, ABCC4), organic anion-transporting polypeptide 2B1 (OATP2B1, SLCO2B1), and organic cation transporter-like 2 (ORCTL2, SLC22A18) were significantly elevated in inflamed tissue. However, at protein level, these findings could only be confirmed for MCT1. UC is associated with complex changes in the intestinal expression of enzymes, transporters, cytokines, and microRNAs, which may affect efficacy of anti-inflammatory drug therapy or the disease state itself.

Cold Physical Plasma Selectively Elicits Apoptosis in Murine Pancreatic Cancer Cells In Vitro and In Ovo.

BACKGROUND/AIM: Poor prognosis of pancreatic cancer has remained almost unchanged in recent years. Cold physical plasma was suggested as an innovative anticancer strategy, but its selective killing activity of malignant over non-malignant cells has only partially been explored. The present study aimed at exploring the effect of cold physical plasma on cellular viability. MATERIALS AND METHODS: Induction of cell death and apoptosis by cold physical plasma was investigated in murine PDA6606 pancreatic cancer cells and primary murine fibroblasts in vitro (2D and 3D cultures) and in ovo. RESULTS: Plasma increased apoptosis in PDA6606 to a significantly higher extent compared to fibroblasts. Antioxidants abrogated these effects, suggesting a prime role of reactive oxygen species in plasma-induced apoptosis. Plasma increased apoptosis of 3D PDA6606 multicellular spheres grown in vitro and in ovo, to significantly higher rates compared to that of fibroblasts, with minimum in ovo inflammation or necrosis observed by hematoxylin and eosin staining (H&E). CONCLUSION: These data support the future intra-operative application of cold physical plasma for the treatment of microscopic residual tumor tissue after surgical resection.

Efficiency of Emulsified Particle-Associated Polyhexamethylenbiguanid-Hydrochlorid (Polihexanide) for Peritoneal Lavage in a Murine Sepsis Model.

BACKGROUND: Peritoneal lavage is often used for peritonitis, however, the volume and type of lavage fluid varies. Saline or Ringer's solution are used most often and lavage is performed until the fluid is clear. However, at present there is no irrigation fluid for peritoneal lavage with residual antiseptic activity. Because the combination of aqueous polyhexamethylenbiguanid-hydrochlorid (PHMB) and egg phosphatidylcholine containing oil/water emulsions (Lipofundin® MCT 20%, B. Braun AG, Melsungen, Germany) protect mammalian cells without neutralizing the antiseptic effect of PHMB, it seemed promising to investigate such human cell protecting, yet antibacterial combination for peritoneal lavage in a murine sepsis model. METHODS: After induction of colon ascendens stent peritonitis (CASP) in mice, the foci were eradicated by re-laparotomy, followed by twofold lavage with 2 × 3 mL of the tested emulsion. The following lavage fluids were investigated blindly: 10% Lipofundin/0.05% PHMB, 100% Lipofundin, 0.05% PHMB, and 0.9% saline. After 24 hours the animals were euthanized and organs, blood, and lavage fluid were examined for cytokine levels (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-6, IL-10), liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [gamma-GT], glutamate dehydrogenase [GLDH]), creatinine, and bacterial density. RESULTS: Only the combination of Lipofundin/PHMB (n = 23) increased the survival rate. Compared with saline alone, PHMB alone decreased the survival rate. Twenty-four hours after induction of peritonitis, the lowest number of colony forming units (CFU) was observed after lavage with PHMB/Lipofundin in all examined organs, blood, and lavage fluid (p < 0.01). Alanine aminotransferase, AST, and creatinine levels were increased after lavage with PHMB compared with the other lavage fluids (p < 0.05). CONCLUSIONS: Peritoneal lavage using 0.05% aqueous PHMB alone resulted in no survival benefit in a CASP murine model. The increase of liver enzymes and creatinine seem to be a toxic side effect of PHMB. However, an emulsion of 0.05% PHMB/10% Lipofundin decreased cytotoxicity while maintaining antiseptic efficiency. The advantage for survival was explained by decrease of bacterial load in organs, blood, and lavage fluid. The results provide a new option for the treatment of peritonitis using peritoneal lavage with the combination of PHMB/Lipofundin.

Cold Physical Plasma-Treated Buffered Saline Solution as Effective Agent Against Pancreatic Cancer Cells.

BACKGROUND: Cold physical plasma has been suggested as a new anticancer tool recently. However, direct use of plasma is limited to visible tumors and in some clinical situations, is not feasible. This includes repetitive treatment of peritoneal metastases, which commonly occur in advanced gastrointestinal cancer and in pancreatic cancer in particular. In case of diffuse intraperitoneal metastatic spread, Hyperthermic Intraperitoneal Intraoperative Chemotherapy (HIPEC) is used as a therapeutic approach. Plasma-treated solutions may combine non-toxic characteristics with the anticancer effects of HIPEC. Previous work has provided evidence for an anticancer efficacy of plasma-treated cell culture medium but the clinical relevance of such an approach is low due to its complex formulation and lack of medical accreditation. OBJECTIVE: Plasma-treated Phosphate-Buffered Saline (PBS), which closely resembles medically certified solutions, was investigated for its cytotoxic effect on 2D monolayer murine pancreatic cancer cells in vitro. METHODS: Toxicity studies of primary murine fibroblasts, PDA6606 murine pancreatic cancer cells, and COLO 357 human pancreatic cancer cells exposed to plasma-treated PBS were performed. RESULTS: Plasma-treated PBS significantly decreased cancer cell metabolisms and proliferation whereas plasma-treated Dulbecco's Modified Eagle Medium had no effect. Moreover, tumor cell growth attenuation was significantly higher when compared to syngeneic primary murine fibroblasts. Both results were confirmed in a human pancreatic cancer cell line. Finally, plasma-treated PBS also decreased the size of pancreatic tumors in a three-dimensional manner, and induction of apoptosis was found to be responsible for all anticancer effects identified. CONCLUSION: Plasma-treated PBS inhibited cell growth in 2D and 3D models of cancer. These results may help facilitate the development of new plasma-derived anticancer agent with clinical relevance in the future.

Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis.

OBJECTIVE: Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. DESIGN: For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. CONCLUSIONS: In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.

Partial pancreatoduodenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicentre, randomised, controlled, double-blind ChroPac trial.

BACKGROUND: There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. METHODS: This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. FINDINGS: Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference -2·3, 95% CI -6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. INTERPRETATION: No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. FUNDING: German Research Foundation (DFG).

Non-thermal plasma-treated solution demonstrates antitumor activity against pancreatic cancer cells in vitro and in vivo.

Pancreatic cancer is associated with a high mortality rate. In advanced stage, patients often experience peritoneal carcinomatosis. Using a syngeneic murine pancreatic cancer cell tumor model, the effect of non-thermal plasma (NTP) on peritoneal metastatic lesions was studied. NTP generates reactive species of several kinds which have been proven to be of relevance in cancer. In vitro, exposure to both plasma and plasma-treated solution significantly decreased cell viability and proliferation of 6606PDA cancer cells, whereas mouse fibroblasts were less affected. Repeated intraperitoneal treatment of NTP-conditioned medium decreased tumor growth in vivo as determined by magnetic resonance imaging, leading to reduced tumor mass and improved median survival (61 vs 52 days; p < 0.024). Tumor nodes treated by NTP-conditioned medium demonstrated large areas of apoptosis with strongly inhibited cell proliferation. Contemporaneously, no systemic effects were found. Apoptosis was neither present in the liver nor in the gut. Also, the concentration of different cytokines in splenocytes or blood plasma as well as the distribution of various hematological parameters remained unchanged following treatment with NTP-conditioned medium. These results suggest an anticancer role of NTP-treated solutions with little to no systemic side effects being present, making NTP-treated solutions a potential complementary therapeutic option for advanced tumors.