Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression of immune checkpoint receptors (PD-L1 and VISTA), markers of systemic inflammation, thrombosis in the tumor area, and the tumor budding in the group of 107 patients diagnosed with pancreatic adenocarcinoma in a single center. The high expression of PD-L1 on tumor cells (TCs) was associated with worse overall survival (OS, p = 0.041, log-rank). On the contrary, high PD-L1 or VISTA on tumor-associated immune cells (TAICs) was correlated with better OS (p = 0.006 and p = 0.008, respectively, log-rank). The joint status of PD-L1 on TCs and TAICs stratified patients into three prognostic groups. The cases with high-grade budding were characterized by higher PD-L1 expression on TCs (p = 0.008) and elevated systemic inflammatory markers. Moreover, budding was identified as the independent prognostic factor in multivariate Cox regression analysis (HR = 2.87; 95% CI = 1.75−4.68; p < 0.001). To conclude, the pattern of PD-L1 and VISTA expression was associated with survival in univariate analysis. Tumor budding accurately predicts outcomes in pancreatic cancer and should be incorporated into routine histopathological practice.

Kidney Transplantation in Patients After Bariatric Surgery: High-Volume Bariatric and Transplant Center Experience.

BACKGROUND: Kidney transplantation (KTx) is the best type of treatment for patients with end-stage renal disease (ESRD). Unfortunately, obesity may be a contraindication for transplantation. Our study aimed to evaluate the results of KTx in patients who had bariatric surgery (BS) prior to transplantation. METHODS: A single center, with experience in bariatric and transplant surgery, presents a retrospective study of 13 patients who received a kidney transplant after a gastric bypass (GB) operation between 2012 and 2019. RESULTS: Thirteen patients, who were potential candidates for KTx, were previously qualified for BS because of a body mass index (BMI) > 35 kg/m2. Additionally, all patients had arterial hypertension, 60% of patients had diabetes, and 30% of patients had coronary artery disease. Patients were activated on the waiting list when their BMI was < 35 kg/m2. KTx was performed between 5 and 29 months after BS. One patient needed reoperation due to a urinary leak and another patient needed reoperation because of a high-pressure lymphocele. We diagnosed 2 delayed graft functions (DGFs) and 1 acute rejection. One patient died for reasons independent of surgery. The KTx observation period ranged from 3 to 8 years. Currently, 11 patients has stable renal function: creatinine concentration is 0.8-1.8 mg/dL and BMI is between 23 and 35 kg/m2. CONCLUSIONS: Despite the small group of patients, we can assume that kidney transplantation can be safely performed in patients with end-stage renal disease (ESRD) who have previously undergone gastric bypass (GB) as a graft bridging procedure. In some cases, BS may be the only chance of getting an organ.

Comprehensive cancer-oriented biobanking resource of human samples for studies of post-zygotic genetic variation involved in cancer predisposition.

The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver. The choice was based on the high incidence of these cancers and/or frequent fatal outcome. We also collect age-matched normal controls. Our still ongoing collection originates from five clinical centers and after nearly 2-year cooperation reached 1711 patients and controls, yielding a total of 23226 independent samples, with an average of 74 donors and 1010 samples collected per month. The predominant diagnosis is breast carcinoma, with 933 donors, followed by colorectal carcinoma (383 donors), prostate carcinoma (221 donors), bladder carcinoma (81 donors), exocrine pancreatic carcinoma (15 donors) and metachronous colorectal cancer metastases to liver (14 donors). Forty percent of the total sample count originates from macroscopically healthy cancer-neighboring tissue, while contribution from tumors is 12%, which adds to the uniqueness of our collection for cancer predisposition studies. Moreover, we developed two program packages, enabling registration of patients, clinical data and samples at the participating hospitals as well as the central system of sample/data management at coordinating center. The approach used by us may serve as a model for dispersed biobanking from multiple satellite hospitals. Our biobanking resource ought to stimulate research into genetic mechanisms underlying the development of common cancers. It will allow all available "-omics" approaches on DNA-, RNA-, protein- and tissue levels to be applied. The collected samples can be made available to other research groups.

Benefitial role of electrochemotherapy in locally advanced pancreatic cancer - radiological perspective.

Irreversible electroporation (IRE) of locally advanced pancreatic cancer is an increasingly used method for unresectable pancreatic cancer that can be used in cytoreduction followed by surgical treatment and shows promising results in palliative care. IRE is an ablative technique where electric pulses cause damage to the cell membrane leading to apoptosis without the destruction of stroma. The application of IRE increases the concentration of hydrophobic regimens like bleomycin within the tumor, what could improve the effectiveness of treatment. This fusion of those two treatments is called electrochemotherapy. In this review, the authors will discuss the radiological perspective of possible beneficial role of irreversible electroporation in relation with chemotherapy in pancreatic cancer treatment.

Partial pancreatic resection along the embryological fusion plane - no longer a fantasy.

BACKGROUND: The embryological connection between the dorsal and ventral pancreatic regions divides the pancreas into two segments. This anatomical dependence allows segmental pancreatic resection through the embryological fusion plane (EFP). The advantages of limited pancreatic resection are the preservation of the natural continuity and function of the gastrointestinal tract and the avoidance of the metabolic and endocrine consequences of total resection of the pancreas and the duodenum. MATERIALS AND METHODS: Two patients are described who underwent anatomicalsegmentectomyof the pancreatic head along the EFP for the treatment of pancreatic cystic tumor and main duct IPMN. The authors suggested diagnostic and intraoperative management leading to qualification for pancreatic resection along the EFP. RESULTS: Pancreas and duodenum sparing surgery is an opportunity for patients in terms of the post-operative quality of life. Indications for this kind of surgery are limited and case selection is very difficult. The procedure for embryological bud resection is highly complicated includes a high rate of possible complications. On the other hand high volume centers may offer this procedure at an acceptable rate of complications in selected cases. CONCLUSIONS: Accurate diagnosis with a vascular anatomy and biliary and pancreatic duct configuration give grounds to analyze pancreas-sparing surgery. The operation plan requires careful 3D planning and an experienced team. Bipolar electrocautery, micro surgical tools and intraoperative cholangiography and pancreatography are helpful.

Can Disturbed Liver Perfusion Revealed in p-CT on the First Day of Acute Pancreatitis Provide Information about the Expected Severity of the Disease?

BACKGROUND: The aim of the study was to evaluate the prognostic properties of perfusion parameters of liver parenchyma based on computed tomography (CT) of patients with acute pancreatitis (AP) made on the first day of onset of symptoms, to assess their usefulness in identifying patients with increased risk of the development of severe AP. METHODS: 79 patients with clinical symptoms and biochemical criteria indicative of AP underwent perfusion computed tomography (p-CT) within 24 hours after onset of the symptoms. Perfusion parameters in 41 people who developed a severe form of AP were compared with parameters in 38 patients in whom the course of AP was mild. RESULTS: Statistical differences in the liver perfusion parameters between the group of patients with mild and severe AP were shown. The permeability-surface area product was significantly lower, and the hepatic arterial fraction was significantly higher in the group of patients with progression of AP. CONCLUSIONS: Based on the results, it seems that p-CT performed on the first day from the onset of AP is a method that, by revealing disturbances in hepatic perfusion, can help in identifying patients with increased risk of the development of severe AP.

New Oxidovanadium(IV) Coordination Complex Containing 2-Methylnitrilotriacetate Ligands Induces Cell Cycle Arrest and Autophagy in Human Pancreatic Ductal Adenocarcinoma Cell Lines.

Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3-), N-(2-carbamoylethyl)iminodiacetate (ceida3-) and N-(phosphonomethyl)-iminodiacetate (pmida4-) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy. The results showed that these oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2), but not on non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE) over the concentration range of 10⁻25 µM, following 48 h incubation. Furthermore, molecular mechanisms of cytotoxicity of [4-NH2-2-Me(Q)H][VO(bcma)(H2O)]2H2O (T1) were dependent on antiproliterative activity, increased ROS generation, cell cycle arrest in G2/M phase with simultaneous triggering of the p53/p21 pathway, binucleation, and induction of autophagy. Our study indicates that oxidovanadium(IV) coordination complexes containing 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer.

Cost-effectiveness of benign Wirsung duct strictures treatment in chronic pancreatitis.

INTRODUCTION: Chronic pancreatitis (CP) is an important problem for modern medicine, the healthcare system (Poland - NFZ) and the national insurance system (Poland - ZUS). The chronic nature of the disease, the lack of targeted treatment and the low mortality rate lead to an accumulation of patients who demand expensive treatment, both conservative and invasive. Rising costs in health care are forcing the need for a more cost-effective method of treatment. AIM: The primary aim of this study was to perform a retrospective calculation of costs in both surgical and endoscopic treatment, hospital stay, healthcare, and public insurance of patients suffering from chronic pancreatitis. Parallel quality of life analysis was performed. It was possible to develop a cost-effective therapeutic algorithm for patients with an uncomplicated stricture of Wirsung's duct within the Polish health care system. RESULTS: In Poland, the hospital costs of endoscopic treatment of patients with chronic pancreatitis were higher than those of the surgical treatment group despite both resulting in a similar life quality. CONCLUSIONS: From a cost-effectiveness perspective, it was shown that surgical intervention is a more cost-effective therapy than endotherapy. Furthermore, patients with benign stricture of the main pancreatic duct in chronic pancreatitis should not be treated with endotherapy for longer than 12 months.

Surgical decompression of Wirsung duct reduces serum concentration of SPINK1 in patients with chronic pancreatitis.

OBJECTIVES: The primary aim of this study was to determine the blood levels of SPINK1 in patients with chronic pancreatitis (CP) submitted to surgical or endoscopic decompression of pancreatic duct (PD). Additionally, we measured trypsin activity levels. METHODS: Two groups were identified, surgical (group A) and endoscopic (group B). Levels of SPINK1 and trypsin activity were measured at baseline and 6 months after pancreatic duct decompression and then compared within the groups. SPINK1 levels were determined with Human ELISA Kit. RESULTS: Group A and B were made up of 30 and 28 patients, respectively. Baseline features of the groups were similar. A decrease in SPINK1 levels was significant only in group A 46.88 to 16.10 ng/mL (p = 0.001). On the contrary, trypsin activity changed significantly in group B 40.01 to 34.92 mU/mL (p = 0.01). Patients of group A showed a significant increase in BMI, before and after treatment. The pain score pre- and post-treatment reduced significantly in both groups (p < 0.001). CONCLUSIONS: We demonstrate for the first time a significant decrease of SPINK1 levels after surgical decompression of PD and a reduction of trypsin activity analysis after endoscopic decompression. The meaning of this phenomena is yet to be explained and it should be further explored.

Pancreatic cancer - summary of the session of 6th International Pancreatic Days in Gdynia 27-30 October 2016.

The session participants were Prof. Caroline Verbeke (CV) from The Department of Pathology Oslo University and Prof. Marcus Wolfgang Büchler (WMB) from the Department of General, Visceral and Transplantation Surgery at the University Hospital Heidelberg. The participants had to assume the problem of the surgical treatment of pancreatic cancer with the reflection to radicality.

Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process.

The pancreatic cancer is the fourth leading cause of cancer-related death and characterized by one of the lowest five-year survival rate. The current therapeutic options are demonstrating minimal effectiveness, therefore studies on new potential anticancer compounds, with non-significant side effects are highly desirable. Recently, it was demonstrated that vanadium compounds, in particular organic derivatives, exhibit anticancer properties against different type of tumor as well as favorable biodistribution from a pancreatic cancer treatment perspective. In this research, we showed selective cytotoxic effect of vanadium complexes, containing phenanthroline and quinoline as an organic ligands, against human pancreatic ductal adenocarcinoma cell line (PANC-1), compared to non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE). Results exhibited that vanadium complexes inhibited autophagy process in selective cytotoxic concentration as well as caused the cell cycle arrest in G2/M phase associated with mitotic catastrophe and increased level of reactive oxygen species (ROS). Moreover, in higher concentration, vanadium derivatives induced a mix type of cell death in PANC-1 cells, including apoptotic and necroptotic process. Our investigation emphasizes the anticancer potential of vanadium complexes by indicating their selective cytotoxic activity, through different process posed by alternative type of cell deaths to apoptosis-resistant cancer cells. Further studies supporting the therapeutic potential of vanadium in pancreatic cancer treatment is highly recommended.

NOTES. Study on patients' perspective.

INTRODUCTION: Rapid development of minimally invasive surgery has led to escalation of the demands placed on health care professionals. Nowadays the patient is the one to choose where and how she/he wants to be operated on. Perioperative and postoperative quality of life is the most common item impacting the patients' choice. Laparoscopic surgery is undoubtedly advantageous in several applications; however a further improvement of medical services has been introduced: the NOTES technique. This novel surgical approach definitively eliminates the problem of having scars. Though NOTES is still in the clinical trial stage, it might become an alternative for selected procedures soon. At this point it is necessary to define the patients' expectations and preferences. AIM: To evaluate patients' opinions on the four surgical approaches: open, laparoscopic, transvaginal and transgastric. MATERIAL AND METHODS: For this purpose a special questionnaire was designed and one hundred randomly selected women were asked to complete it. RESULTS: The laparoscopic access was preferable in most aspects, closely followed by the transvaginal access. Open and transgastric approaches were considered as dangerous and disadvantageous. CONCLUSIONS: Currently NOTES is a possible reality of tomorrow for some procedures. The transvaginal access was scored as "attractive", "cosmetically attractive" and "technologically advanced", as opposed to the transgastric access. The fact of manipulation in the intimate region requires thorough attention in future NOTES studies. Though the patients currently prefer the laparoscopic approach, this study proves that further development of transvaginal NOTES technology is acceptable and to some extent desired by the patients.

Introduction of new technique of single-port transgastric access for repeated debridement of infected pancreatic necrosis.

In this article we introduce a novel technique of repeated single-port transgastric debritment of walledoff pancreatic necrosis using TriPort™ Access System. The presented technique seems an appealing and innovative approach to the treatment of walled-off pancreatic necrosis in acute pancreatitis patients. Studies proving feasibility, safety and efficiency are necessary to elucidate real value of the technique.

Analysis of intraoperative transfusions of red blood cell concentrates in adults.

BACKGROUND: Transfusion of red blood cell (RBC) concentrates is the most common allogeneic transplantation. The aim of the study was to analyse the indications for RBC transfusions, compared to the estimated intraoperative blood loss and the actual requirements for blood transfusion. METHODS: We retrospectively analysed the files of 250 adult patients who were transfused over the year 2006, during various general, oncologic, trauma, vascular, plastic and thoracic surgical procedures. Preoperative screening was done in a hospital laboratory, whereas postoperative haemoglobin concentration and haematocrit were assessed at the bedside using a co-oximeter. RESULTS: The majority of RBC transfusions were started at relatively high haemoglobin concentrations (mean 5.6 mmol L⁻¹), contrary to the current guidelines. A high correlation coefficient (r=0.82) was found between the estimated blood loss and the volume of RBCs transfused; therefore we concluded that the observed blood loss was the main factor in transfusion decisions. CONCLUSIONS: Despite enormous progress in transfusion science, the current practice in our institution is still far from ideal; RBCs are frequently transfused too early and without a real indication.