GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells.

GP-2250, a novel anticancer agent, severely limits the energy metabolism, as demonstrated by the inhibition of hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase and a decrease of ATP. Rescue experiments with supplementary pyruvate or oxaloacetate demonstrated that a TCA cycle deficit largely contributed to cytotoxicity. Activation of the energy-deficit sensor, AMP-dependent protein kinase, was associated with increased phosphorylation of acetyl-CoA carboxylase and Raptor, pointing to a possible deficit in the synthesis of fatty acids and proteins as essential cell components. Binding of p65 to DNA was dose-dependently reduced in nuclear lysates. A transcriptional deficit of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) was substantiated by the downregulation of cyclin D1 and of the anti-apoptotic Bcl2, in line with reduction in tumour cell proliferation and induction of apoptosis, respectively. The upregulation of p53 concomitant with an excess of ROS supported apoptosis. Thus, the anticancer activity of GP-2250 is a result of disruption of energy metabolism and inhibition of tumour promotion by NF-κB.

In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes.

Enhanced glycolysis (Warburg effect) driven by the BRAF oncogene, dysregulated GAPDH expression, and activation of the PI3K/AKT/mTOR signaling pathway may significantly contribute to the resistance-targeted therapy of BRAF-mutated melanomas. Therefore, we aimed to study for the first time the anti-tumor activity of the GAPDH inhibitor GP-2250 in BRAF-mutated melanoma cell lines and benign melanocytes. We employed three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4 and ATCC-PCS-200-013, respectively), which were exposed to different GP-2250 doses. GP-2250's effects on cell proliferation and viability were evaluated by means of the BrdU and MTT assays, respectively. The RealTime-Glo Annexin V Apoptosis and Necrosis Assay was performed for the evaluation of apoptosis and necrosis induction. RT-PCR and western blotting were implemented for the determination of AKT and STAT3 gene and protein expression analyses, respectively. The melanoma cell lines showed a dose-dependent response to GP-2250 during BrDU and MTT testing. The RealTime-Glo Annexin V assay revealed the heterogenous impact of GP-2250 on apoptosis as well as necrosis. With respect to the melanoma cell lines Ma-Mel-86a and SH-4, the responses and dosages were comparable to those used for the MTT viability assay. Using the same dose range of GP-2250 administered to melanoma cells, however, we observed neither the noteworthy apoptosis nor necrosis of GP-2250-treated benign melanocytes. The gene expression profiles in the melanoma cell lines for AKT and STAT3 were heterogenous, whereby AKT as well as STAT3 gene expression were most effectively downregulated using the highest GP-2250 doses. Immunoblotting revealed that there was a time-dependent decrease in protein expression at the highest GP-2250 dose used, whereas a time- as well as dose-dependent AKT decrease was predominantly observed in Ma-Mel-61a. The STAT3 protein expression of Ma-Mel-86a and SH-4 was reduced in a time-dependent pattern at lower and moderate doses. STAT3 expression in Ma-Me-61a was barely altered by GP-2250. In conclusion, GP-2250 has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. GP-2250 is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines. Since GP-2250 is a GAPDH inhibitor, the substance may be a promising combination therapy for tumors presenting the Warburg effect, such as melanoma.

Substance GP-2250 as a New Therapeutic Agent for Malignant Peritoneal Mesothelioma-A 3-D In Vitro Study.

Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis remains poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects. GP-2250 is a novel antineoplastic agent, currently under clinical investigation. This in vitro study aims to investigate effects of GP-2250 including combinations with CP and MMC on malignant mesothelioma. JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP, MMC and combination therapies of GP-2250 + CP/MMC. Microscopic effects were documented, and a flow-cytometric apoptosis/necrosis assay was performed. Synergistic and antagonistic effects were analyzed by computing the combination index by Chou-Talalay. GP-2250 showed an antiadhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cultured cells, inducing apoptosis and necrosis. Combination treatments of GP-2250 with MMC and CP led to significant reductions of the effective doses of CP/MMC. Synergistic and additive effects were observed. GP-2250 showed promising antineoplastic effects on malignant mesothelioma cells in vitro especially in combination with CP/MMC. This forms the basis for further in vivo and clinical investigations in order to broaden treatment options.

Long-term survival after pancreaticoduodenectomy in patients with ductal adenocarcinoma of the pancreatic head.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all malignant tumors due to unavailable screening methods, late diagnosis with a low proportion of resectable tumors and resistance to systemic treatment. Complete tumor resection remains the cornerstone of modern multimodal strategies aiming at long-term survival. This study was performed to investigate the overall rate of long-term survival (LTS) and its contributing factors. METHODS: This was a retrospective single-center analysis of consecutive patients undergoing pancreaticoduodenectomy (PD) for PDAC between 2007 and 2014 at the St. Josef Hospital, Ruhr University Bochum, Germany. Clinical and laboratory parameters were assessed and evaluated for prediction of LTS with Cox regression analysis. RESULTS: The overall rate of LTS after PD for PDAC was 20.4% (34/167). Median survival was 24 months regardless of adjuvant treatment. Carbohydrate antigen 19-9 levels, tumor grade, lymph vessel invasion, perineural invasion and reduced general condition were significantly associated with LTS in univariate analysis (P < 0.05). Serum levels of carbohydrate antigen 19-9, American Joint Committee on Cancer stage, tumor grade, abdominal pain, male, exocrine pancreatic insufficiency and duration of postoperative hospital stay were independent predictors of cancer survival in multivariable analysis. CONCLUSIONS: Cancer related characteristics are associated with LTS in multimodally treated patients after curative PDAC surgery.

Does autologous fibrin sealant (vivostat©) reduce the incidence of postoperative pancreatic fistula after distal pancreatectomy? - a matched pairs analysis.

BACKGROUND: Postoperative pancreatic fistula (POPF) is the most common complication following distal pancreatectomy. This retrospective study investigated the effects of autologous fibrin sealant (Vivostat©) in reducing the incidence of POPF after distal pancreatectomy. METHODS: A matched pairs analysis was performed to compare the incidence of clinically relevant POPF of 41 patients who underwent a distal pancreatectomy with application of autologous fibrin sealant (Vivostat©) with a historical control group. RESULTS: Clinically relevant POPF were present in 11 patients in the study group (27%) and in 13 patients in the control group (32%, p = .639). No patient of the study group required emergency angiographic treatment for postoperative hemorrhage due to POPF, whereas three patients were identified in the control group (7%, p = .079). CONCLUSIONS: POPF cannot be prevented under treatment with autologous fibrin sealant (Vivostat©). We observed the tendency of a lower rate of postoperative pancreatic hemorrhage due to POPF. However, prospective randomized controlled studies are required.

Ultrasonic-assisted wound debridement: report from a closed panel meeting.

Mechanical debridement can be considered as an alternative to surgical debridement if surgery is not available, or is considered impractical or too high risk. One form of selective mechanical debridement is ultrasonic-assisted wound (UAW) debridement. As the published evidence on this is limited, a closed international expert meeting was held to review the existing evidence base on it, present preliminary findings of research currently in progress and discuss individual cases selected from the clinical experts' own practice. The panel also explored the potential barriers to the implementation of UAW debridement and how these might be addressed. It concluded there is sufficient evidence that UAW debridement is an effective method of cleansing and debriding almost all hard-to-heal wounds. Patients who are most likely to benefit from it are not medically stable, on anticoagulants, unable to visit a hospital for wound treatment, and/or have wounds with a poor vascular supply or are close to critical structures. The panel also observed that UAW debridement can be used to prepare the wound for negative pressure wound therapy (NPWT) or as an adjunctive to it. Given the potential to experience pain during the procedure, the panel considered that patients will benefit from topical analgesia. The panel noted that health professionals, patients and visitors must be protected from the aerosolisation associated with UAW, to reduce risk of cross-contamination.

Prognostic value and impact of cerebral metastases in pancreatic cancer.

Background: Pancreatic cancer is a fatal disease most often diagnosed at an advanced stage. Most patients already suffer from irresectable tumor or distant metastases being most commonly found in the liver or the lung. However, cerebral metastases occur extremely rare.Methods: We performed a retrospective analysis of our database to identify all patients diagnosed with pancreatic cancer and cerebral metastases who underwent surgical treatment in our department from January 2004 to November 2016.Results: Only 0.2% (4 of 2492) were diagnosed with cerebral metastases. Two patients had surgical resection of the cerebral metastases. One patient underwent palliative radiation therapy and the fourth patient received only palliative therapy. Mean interval between initial diagnosis and development of brain metastases was 8.5 months (range 1-20). Mean survival period after diagnosis of brain metastases was 4.75 months (range 1-10).Conclusions: Cerebral metastases of pancreatic cancer occur extremely rare. They are associated with an advanced tumor stage, commonly liver and lung metastases. All patients presenting with neurological symptoms, multifocal metastases, and significantly elevated CA 19-9 levels are suspicious of sustaining cerebral metastases and should undergo brain imaging.

Complications After Ostomy Surgery: Emergencies and Obese Patients are at Risk-Data from the Berlin OStomy Study (BOSS).

BACKGROUND: Complications are common after ostomy surgery. Data from the Berlin OStomy Study were evaluated to determine risk factors for complications. PATIENTS AND METHODS: Patients with a bowel ostomy were questioned using a questionnaire concerning patients' characteristics and history as well as the ostomy and its complications. The questionnaire also contained a nine-fielded abdominal sketch to determine the exact ostomy location. RESULTS: Over 42 months, 2647 patients completed the questionnaire. Obese patients and patients after emergency surgery were more prone to ostomy-related complications. This result was independent of the kind of ostomy (small bowel ostomy or colostomy) and of the abdominal location. The overall ostomy complication rate was 55.6%. CONCLUSION: Significantly more complications were recorded after emergency surgery and in obese patients than after elective surgery and in non-obese patients, respectively. There was no preferential abdominal location for avoiding general ostomy complications. The results emphasized the importance of preoperative ostomy site marking by qualified personnel such as ostomy nurses or surgeons to reduce complication rates by respecting individual abdominal configurations. With an increasing prevalence of obesity, ostomy surgery will become even more challenging in the future. A division of the abdominal wall into nine regions might be helpful and more precise for describing and examining ostomy-related complications in the future.

Use of a gelling fibre dressing in complex surgical or chronic wounds: a case series.

OBJECTIVE: To evaluate the safety and performance of a gelling fibre dressing, with respect to wound exudate management, maceration and periwound skin conditions. METHOD: Complex (non-healing) surgical or chronic wounds healing by secondary intention were treated with a gelling fibre dressing (Biosorb, Acelity) as part of a prospective, two-centre case series product evaluation study. Dressing performance was evaluated at each change, and weekly for up to four weeks or until the wound healed, if this was in less than four weeks. The main outcome measure was dressing performance, wound bed and periwound skin condition. RESULTS: A total of 15 patients, aged 26-87 years, were enrolled; 10 patients (66.7%) presented with chronic wounds including venous leg ulcers (VLUs), arterial leg ulcer, one mixed leg ulcer, pressure ulcer (PU), and diabetic foot ulcers (DFUs). The remaining wounds (33.3%) were postsurgical complex wounds healing by secondary intention, located in the upper leg, foot, abdomen, and sacrum. Mean wound area was 22.6±36.6cm2 (range: 1.3-144.0cm2). Treated wounds showed complete granulation in eight (53.0%) wounds, 75% granulation coverage in two (13.3%) wounds, 50% coverage in three (20.3%), and 25% coverage in two (13.3%) wounds. Patients evaluated the dressing effectiveness as 'excellent' or 'very good' in 45% of cases, 'moderate' in 45%, and 'poor' in 10% of cases. Results of Visual Analogue Scale (VAS) showed 70% of patients rated their pain as 'low' and 30% as 'moderate' at dressing removal. Clinicians' evaluation of dressing ability to absorb and retain wound exudate was rated 'excellent' or 'very good' in 80% of cases, and moderate in 20% and poor in 10% of cases. Overall, clinicians' impression of the dressing performance was reported as 'excellent' or 'very good' in 80% of cases and 'moderate' in 20% of cases. No patient had to be removed from the study due to adverse events directly related to the dressing or its performance. CONCLUSION: These clinical findings suggest the new gelling fibre dressing to be safe and effective in wound treatment of complex (non-healing) surgical or chronic wounds, to manage exudate effectively, and to optimise the conditions of wounds healing by secondary intention.

[Use of Negative Pressure Wound Therapy with Instillation and Dwell Time for Wound Treatment - Results of an Expert Consensus Conference]. / Einsatz der Vakuuminstillationstherapie für die Wundbehandlung ­ Ergebnis einer Expertenkonsensuskonferenz.

Rinsing wounds with wound cleansing solutions has long been a recognised cornerstone in wound management as a means of removing cell debris and surface pathogens in wound exudates. In combination with surgical debridement and topical negative pressure wound therapy (NPWT), this can facilitate the intended progression from the inflammatory to the proliferative phase of wound healing. Procedures of topical negative pressure wound therapy with instillation and a defined exposure/dwell-time of topical solutions under cyclic compression and decompression with foam dressings (NPWTi-d) can remove cellular remnants and debris that may inhibit the healing process. At the same time, it can aid in reducing the bacterial load in contaminated or infected wounds. Since this newer technique is now commercially available and increasingly widespread, recommendations for the proper use and clinical indications were developed by a panel of interdisciplinary experts in the course of a consensus meeting. Although the level of evidence from expert opinions is low, general guidelines for a safe and effective use of NPWTi-d can be worked out that can be of assistance to the clinician. The consensus recommendations derived from this meeting include the objectives of the treatment, the administration modalities of NPWTi-d, the indications for various wounds, including their contraindications, therapy settings, as well as the use of topical instillation solutions, volume and duration (dwell time) based on current scientific data, optimal treatment duration and future developments of the NPWTi-d.

The Physiological Incubation Biosimulator (PIBS): An Improved Ex Vivo Experimental Setup for the Mechanical Stability of Biological Sealants in Surgical Procedures.

BACKGROUND: Tissue-bound fibrin sealants are used in a wide array of surgical procedures. The microenvironmental interaction between sealant and application site is often poorly evaluated due to a lack of suitable experimental models. METHODS: A physiological incubation biosimulator (PIBS) was developed to test biological sealants in an ex vivo setup under physiological conditions comparable to the microenvironment at application site (temperature, humidity, pressure). PIBS was validated by a study on the effectiveness of TachoSil for leak closure at pancreatic resection sites. Defined defects in a thoracic membrane of porcine origin were sealed by TachoSil. Integrity of the sealing was tested in the presence of active pancreatic fluid over 60 minutes. Heat-inactivated pancreatic fluid and electrolyte solution served as controls. The time to leakage was recorded and experimental groups were analyzed by Kaplan-Meier analysis. RESULTS: PIBS produced reliable results. TachoSil lead to a leakage rate of 96% after incubation with active pancreatic fluid (p = 34), which was significantly higher compared with heat-inactivated pancreatic fluid (p = 34, 52%) or electrolyte solution (p = 20, 19%). CONCLUSION: PIBS is an effective tool to evaluate microenvironmental effects on the adhesive strength of biomaterials. Tissue sealing effect of TachoSil is diminished in a "pancreatic" microenvironment rich with pancreatic enzymes. Our results might therefore explain the reason of the findings of randomized controlled trials recently published on this subject.

Dose-dependent role of novel agents emodin and BTB14431 in colonic cancer treatment in rats.

BACKGROUND: BTB14431 is an in silico homolog to emodin. Both were found to possess anti-tumor effects in vitro. The aim of this work was to analyze the tumor suppressing effects of both molecules in an intraperitoneal (ip) and intravenous (iv) treated rat model (WAG-Rij). METHODS: A tumor cell suspension (CC531) was applied at the cecum after laparotomy and at the back. The rats where treated twice a day over 1 week with BTB14431, emodin and isotone sodium chloride solution (control). Treatment was applied iv or ip in a variety of dosages. Peripheral blood samples were taken before tumor application and on day 7. Twenty-one days after the last day of therapy animals were euthanized and tumor growth was evaluated. RESULTS: Data showed an insignificant decrease of tumor growth after iv and ip treatment with low doses of BTB14431 and emodin. Differential blood analysis showed apoptosis. Increased doses of emodin clearly raised mortality rate. CONCLUSIONS: Apoptosis was verified but no tumor-suppressing effects could be observed for iv and ip treatment with both agents in contrast to in vitro studies in our model. Establishing a successful ip treatment model for emotion and BTB14331 requires further studies.

Quality of life and need for care in patients with an ostomy: a survey of 2647 patients of the Berlin OStomy-Study (BOSS).

BACKGROUND: Although ostomies are sometimes necessary, it is unclear which type of ostomy is advantageous for quality of life (QoL). In an observational study of 2647 patients, QoL after colostomy (CS) and small bowel stoma (SBS) formation was evaluated. METHODS: The European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30 and CR-38 questionnaires were used. Patient characteristics, retrospective information about the ostomy and previous treatments, and current stoma-related complications were recorded. All questionnaires were distributed and collected by stoma therapists at the homecare company PubliCare®. RESULTS: In all, 1790 patients had a CS, and 756 had an SBS. The mean Global Health Score (mGHS-a general QoL indicator) was 52.33 in CS and 49.40 in SBS patients (p = 0.004), but the effect size (Cohen's d) was 0.1. In SBS patients, all functional scores were lower and most of the symptom scores were higher. CONCLUSIONS: QoL differed significantly for CS and SBS patients, but the effect size was marginal. The care of certain patient groups, particularly (female) patients who receive emergency surgeries, must be improved. More professional education and guidance are necessary for a larger proportion of patients. This survey provided reference data for quality of life in patients with an ostomy.

Conversion cholecystectomy in patients with acute cholecystitis-it's not as black as it's painted!

BACKGROUND: Although laparoscopic cholecystectomy is recommended as standard treatment for acute cholecystitis, in 10-30 % a conversion to open cholecystectomy is required. Among some surgeons, this is still perceived as a "complication." The aim of our study was to define characteristics and outcome of patients with acute cholecystitis undergoing conversion cholecystectomy. METHODS: Over a 9-year period, 464 consecutive patients undergoing cholecystectomy for acute cholecystitis were analyzed for demographic, preoperative, intraoperative, histopathological, and laboratory findings and surgical outcome parameters. RESULTS: Patients with conversion cholecystectomy were characterized by younger age, lower American Society of Anesthesiologists (ASA) score, and less cardiac comorbidities compared to patients with primary open cholecystectomy. Severity of inflammation on the clinical and histopathological level was similar and comparable. Overall complication rate, mortality, and median hospital stay were significantly lower compared to those of primary open cholecystectomy group. CONCLUSIONS: There are no disadvantages for patients undergoing conversion cholecystectomy compared to primary open cholecystectomy. The outcome is influenced by general condition and comorbidities rather than by the surgical approach. Underlying fear of conversion should not avoid a laparoscopic approach in patients with acute cholecystitis.

Maintenance Therapy for Pancreatic Cancer, a New Approach Based on the Synergy between the Novel Agent GP-2250 (Misetionamide) and Gemcitabine.

The novel Oxathiazinane derivative GP-2250 (Misetionamide) displays antineoplastic activity in vitro and in vivo, as previously shown in pancreatic cancer cells and in patient-derived mouse xenografts (PDX). Currently, GP 2250 is under phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC). GP-2250 in combination with Gemcitabine displays a high synergistic capacity in various primary and established pancreatic cancer cell lines. Additionally, in the eight PDX models tested, the drug combination was superior in reducing tumor volume with an aggregate tumor regression (ATR) of 74% compared to Gemcitabine alone (ATR: 10%). Similarly, in a PDX maintenance setting following two weeks of treatment with nab-Paclitaxel plus Gemcitabine, the combination of GP-2250 plus Gemcitabine resulted in outstanding tumor control (ATR: 79%) compared to treatment with Gemcitabine alone (ATR: 60%). Furthermore, GP-2250 reduced the ratio of tumor-initiating CD133+ markers on the surface of PDAC cells in spheroid cultures, indicating a possible mechanism for the synergistic effect of both substances. Considering the high tolerability of GP 2250, these results may open up a new approach to maintenance therapy with GP-2250/Gemcitabine combination following nab-Paclitaxel plus Gemcitabine as first-line treatment.

Differential miRNA and Protein Expression Reveals miR-1285, Its Targets TGM2 and CDH-1, as Well as CD166 and S100A13 as Potential New Biomarkers in Patients with Diabetes Mellitus and Pancreatic Adenocarcinoma.

Early detection of PDAC remains challenging due to the lack of early symptoms and the absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics signatures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used Western blotting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal distributions were performed using one-way ANOVA followed by Tukey's post hoc test, and pairwise tests were performed using t-tests. p ≤ 0.05 was considered statistically significant. Protein clusters of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium-binding protein A13 (S100A13), and tumor necrosis factor-ß (TNF-ß) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166, and S100A13 as potential meaningful biomarker candidates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with the identifier PXD053169.

Intraoperative Wound Irrigation for the Prevention of Surgical Site Infection After Laparotomy: A Randomized Clinical Trial by CHIR-Net.

Importance: Surgical site infections frequently occur after open abdominal surgery. Intraoperative wound irrigation as a preventive measure is a common practice worldwide, although evidence supporting this practice is lacking. Objective: To evaluate the preventive effect of intraoperative wound irrigation with polyhexanide solution. Design, Setting, and Participants: The Intraoperative Wound Irrigation to Prevent Surgical Site Infection After Laparotomy (IOWISI) trial was a multicenter, 3-armed, randomized clinical trial. Patients and outcome assessors were blinded to the intervention. The clinical trial was conducted in 12 university and general hospitals in Germany from September 2017 to December 2021 with 30-day follow-up. Adult patients undergoing laparotomy were eligible for inclusion. The main exclusion criteria were clean laparoscopic procedures and the inability to provide consent. Of 11 700 screened, 689 were included and 557 completed the trial; 689 were included in the intention-to-treat and safety analysis. Interventions: Randomization was performed online (3:3:1 allocation) to polyhexanide 0.04%, saline, or no irrigation (control) of the operative wound before closure. Main Outcome and Measures: The primary end point was surgical site infection within 30 postoperative days according to the US Centers for Disease Control and Prevention definition. Results: Among the 689 patients included, 402 were male and 287 were female. The median (range) age was 65.9 (18.5-94.9) years. Participants were randomized to either wound irrigation with polyhexanide (n = 292), saline (n = 295), or no irrigation (n = 102). The procedures were classified as clean contaminated in 92 cases (8%). The surgical site infection incidence was 11.8% overall (81 of 689), 10.6% in the polyhexanide arm (31 of 292), 12.5% in the saline arm (37 of 295), and 12.8% in the no irrigation arm (13 of 102). Irrigation with polyhexanide was not statistically superior to no irrigation or saline irrigation (hazard ratio [HR], 1.23; 95% CI, 0.64-2.36 vs HR, 1.19; 95% CI, 0.74-1.94; P = .47). The incidence of serious adverse events did not differ among the 3 groups. Conclusions and Relevance: In this study, intraoperative wound irrigation with polyhexanide solution did not reduce surgical site infection incidence in clean-contaminated open abdominal surgical procedures compared to saline or no irrigation. More clinical trials are warranted to evaluate the potential benefit in contaminated and septic procedures, including the emergency setting. Trial Registration: drks.de Identifier: DRKS00012251.

The effect of GP-2250 on cultured virus-negative Merkel cell carcinoma cells: preliminary results.

BACKGROUND: Even in the novel immunotherapy era, Merkel cell carcinoma (MCC) remains challenging in its treatment. Apart from Merkel cell polyomavirus (MCPyV) associated MCC, this cancer is linked in about 20% of cases to ultraviolet-induced mutational burden frequently causing aberrations in Notch and PI3K/AKT/mTOR signalling pathways. The recently developed agent GP-2250 is capable to inhibit growth of cells of different cancers, including pancreatic neuroendocrine tumors. The objective of the present study was to investigate the effects of GP-2250 on MCPyV-negative MCC cells. METHODS: Methods We employed three cell lines (MCC13, MCC14.2, MCC26) which were exposed to different GP-2250doses. GP-2250's effects on cell viability, proliferation, and migration were evaluated by means of MTT, BrdU, and scratch assays, respectively. Flow cytometry was performed for the evaluation of apoptosis and necrosis. Western blotting was implemented for the determination of AKT, mTOR, STAT3, and Notch1 protein expression. RESULTS: Cell viability, proliferation, and migration decreased with increasing GP-2250 doses. Flow cytometry revealed a dose response to GP-2250 in all three MCC cell lines. While the viable fraction decreased, the share of necrotic and in a smaller amount the apoptotic cells increased. Regarding Notch1, AKT, mTOR, and STAT3 expression a comparatively time- and dose-dependent decrease of protein expression in the MCC13 and MCC26 cell lines was observed. By contrast, Notch1, AKT, mTOR, and STAT3 expression in MCC14.2 was scarcely altered or even increased by the three dosages of GP-2250 applied. CONCLUSIONS: The present study indicates GP-2250 having anti-neoplastic effects in MCPyV-negative tumor cells in regard to viability, proliferation, and migration. Moreover, the substance is capable of downregulating protein expression of aberrant tumorigenic pathways in MCPyV-negative MCC cells.

New Therapy Options for Neuroendocrine Carcinoma of the Pancreas-The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo.

Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250mono) and Gemcitabine (Gemmono), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gemmono and GP-2250mono showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250mono and Gemmono showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.