Characterization of embryonic stem cell transplantation immunobiology using molecular imaging

Given their self-renewing and pluripotent capabilities, embryonic stem cells (ESCs) are well-poised as a cellular source for tissue regeneration therapy. Successful in vitro differentiation of both mouse (m) and human (h) ESCs into multiple somatic cell types has been reported, including cardiomyocytes, neurons and pancreatic islet cells. However, the host immune response against transplanted ESCs is not well characterized. In fact, controversy remains as to whether ESCs have immune-privileged properties. The scope of the current thesis is to gain insight into immunological aspects of transplantation of embryonic stem cells or their differentiated progeny by using molecular imaging techniques to follow cell fate. Specifically, this thesis presents evidence that: (1) molecular imaging can be used to quantify organ and ESC survival following transplantation and non-invasively follow donor graft fate; (2) ESCs express MHC and co-signaling molecules that are upregulated upon differentiation; (3) mESCs and hESCs can trigger potent cellular and humoral immune responses following allogeneic and/or xenogeneic transplantation, leading to rejection; and (4) immunosuppressive drugs can significantly mitigate the host immune response to prolong hESC survival in immunocompetent mice. These results clearly indicate that ESC immunogenicity is a significant hurdle that must be overcome before successful clinical application can be accomplished.UBL - phd migration 201

Advances in Diagnostic and Intraoperative Molecular Imaging of Pancreatic Cancer

Surgical oncolog

Molecular targeted positron emission tomography imaging and radionuclide therapy of pancreatic ductal adenocarcinoma

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, mainly due to difficulty in early detection of the disease by current imaging modalities. In this review, we discuss the more specific diagnostic imaging modality that evaluates the presence of specific tumour tracers via positron emission tomography. In addition, we review the available therapeutic applications of these tumour-specific tracers. Pancreatic ductal adenocarcinoma (PDAC) has an inauspicious prognosis, mainly due to difficulty in early detection of the disease by the current imaging modalities. The upcoming development of tumour-specific tracers provides an alternative solution for more accurate diagnostic imaging techniques for staging and therapy response monitoring. The future goal to strive for, in a patient with PDAC, should definitely be first to receive a diagnostic dose of an antibody labelled with a radionuclide and to subsequently receive a therapeutic dose of the same labelled antibody with curative intent. In the first part of this paper, we summarise the available evidence on tumour-targeted diagnostic tracers for molecular positron emission tomography (PET) imaging that have been tested in humans, together with their clinical indications. Tracers such as radiolabelled prostate-specific membrane antigen (PSMA)-in particular, F-18-labelled PSMA-already validated and successfully implemented in clinical practice for prostate cancer, also seem promising for PDAC. In the second part, we discuss the theranostic applications of these tumour-specific tracers. Although targeted radionuclide therapy is still in its infancy, lessons can already be learned from early publications focusing on dose fractioning and adding a radiosensitiser, such as gemcitabine.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Clinical translation and implementation of optical imaging agents for precision image-guided cancer surgery

Introduction The field of tumor-specific fluorescence-guided surgery has seen a significant increase in the development of novel tumor-targeted imaging agents. Studying patient benefit using intraoperative fluorescence-guided imaging for cancer surgery is the final step needed for implementation in standard treatment protocols. Translation into phase III clinical trials can be challenging and time consuming. Recent studies have helped to identify certain waypoints in this transition phase between studying imaging agent efficacy (phase I-II) and proving patient benefit (phase III). Trial initiation Performing these trials outside centers of expertise, thus involving motivated clinicians, training them, and providing feedback on data quality, increases the translatability of imaging agents and the surgical technique. Furthermore, timely formation of a trial team which oversees the translational process is vital. They are responsible for establishing an imaging framework (camera system, imaging protocol, surgical workflow) and clinical framework (disease stage, procedure type, clinical research question) in which the trial is executed. Providing participating clinicians with well-defined protocols with the aim to answer clinically relevant research questions within the context of care is the pinnacle in gathering reliable trial data. Outlook If all these aspects are taken into consideration, tumor-specific fluorescence-guided surgery is expected be of significant value when integrated into the diagnostic work-up, surgical procedure, and follow-up of cancer patients. It is only by involving and collaborating with all stakeholders involved in this process that successful clinical translation can occur. Aim Here, we discuss the challenges faced during this important translational phase and present potential solutions to enable final clinical translation and implementation of imaging agents for image-guided cancer surgery.Surgical oncolog

Gadoxetic acid-enhanced magnetic resonance imaging significantly influences the clinical course in patients with colorectal liver metastases

Surgical oncolog

Overview and future perspectives on tumor-targeted positron emission tomography and fluorescence imaging of pancreatic cancer in the era of neoadjuvant therapy

Simple Summary Patients diagnosed with pancreatic cancer have a poor prognosis at time of diagnosis, with a 5-year survival rate of merely 10%. The only treatment with curative intent is surgical resection of the tumor and adjacent tumor-containing lymph nodes. To improve surgical outcome and survival, additional (imaging) tools are needed that support complete surgical tumor resection. Firstly, more accurate monitoring of tumor response to neoadjuvant treatment and subsequent determination of resectability is needed. Secondly, an imaging tool is needed for intraoperative guidance allowing accurate identification, delineation, and complete resection of the tumor and suspected lymph nodes. Therefore, both tumor-targeted PET/CT before surgery and real time fluorescence-guidance during surgery could be helpful to improve patient outcome. This review focusses on literature considering tumor-targeted PET/CT and near-infrared fluorescence (NIRF) imaging. Several tumor-targeted agents are under clinical evaluation, and several other promising agents are currently tested preclinically, both with promising results. Their additional diagnostic value and feasibility for future implementation in standard clinical care of PDAC has yet to be established in phase III clinical trials. Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient's treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins.Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

HEALTHCARE PROCESS OF THE PATIENT WITH ACUTE PANCREATITIS

Akutni pankreatitis je nagla upala gušterače koja se može javiti u blagom ili teškom obliku. Ova nagla upala se u gotovo 80% prijema u bolnicu pripisuje postojanju žučnih kamenaca ili konzumaciji alkohola. Žučni kamenci kao uzrok budu 1,5 puta češći kod žena, dok se alkohol kao uzrok u muškaraca pojavljuje šest puta više nego kod žena. Žučni kamenci najčešće začepe otvor pankreatičnog voda ili se na neko vrijeme zaustave u Oddijevu sfinkteru uzrokujući time upalu dok svakodnevna konzumacija alkohola također može dovesti do začepljenja malih vodova. Jaki bolovi se javljaju najčešće naglo nakon konzumacije prekomjerne količine obroka ili alkohola u gornjem srednjem dijelu abdomena. Osim što je bol nagla, pacijenti je opisuju kao probadajuću bol koja se širi u leđa. Može se javiti mučnina kao i nagon na povraćanje, u većini slučajeva popratnu uz temperaturu. Bolesnik se javlja u hitni trakt radi jakih bolova koji se ne smanjuju te se podvrgava daljnjoj dijagnostici. Laboratorijskim pretragama ne može se potvrditi dijagnoza akutnog pankreatitisa ali povišenom razinom enzima gušterače tu dijagnozu možemo potkrijepiti. Daljnjim radiološkim pretragama (rendgen abdomena, kompjutorizirana tomografija) dokazuje se mogućnost postojanja žučnih kamenaca kao i promjene u veličini i strukturi gušterače. Sa utvrđenom dijagnozom akutnog pankreatitisa, osoba se zaprima na odjel gdje se prekida daljnji unos hrane i pića kako bi se smanjila daljnja proizvodnja enzima u gušterači. Svu potrebnu tekućinu i ostale hranjive tvari nadoknađuju se intravenskim putem. U cijelom procesu liječenja ključna je i medicinska sestra koja najprije može uočiti eventualne promjene koje se mogu javiti kod pacijenta, kao što su primjerice smanjeno mokrenje, otežano disanje te stagniranje ili pogoršavanje intenziteta boli unatoč primijenjenoj analgetskoj terapiji.Acute pancreatitis is a sudden pancreatic inflammation occurring in mild or severe form. This sudden inflammation in almost 80% of admission to the hospital is attributed to the existence of gallstones or drinking alcohol. The gallstones as a cause of Acute pancreatitis are 1.5 times more common in women, while alcohol as a cause is present men appears six times more than in women. Gallstones usually close the pancreatic opening or stop for a while in Oddies sphincter causing it to inflate ,while daily alcohol consumption also leads to clogging of small lines. Strong pain usually are occurring suddnely after eating excessive meals or presence of alcohol in the upper mid-section of the abdomen. Apart pain is acute, patients are describeing as a stabbing kind of pain that is spreading in their back. There can be nausea and vomiting, in most cases accompanied by temperature. The patient is coming to an emergency with severe pain that does not diminish and undergoes further diagnosis. Laboratory examinations can not confirm the diagnosis of acute pancreatitis but elevated pancreatic enzyme levels can be supported by this diagnosis. Further radiological examinations (X-ray abdomena, computerized tomography) are proveing the possibility of gallstones as well as changes in the size and structure of the pancreas. With established diagnosis of acute pancreatitis, a person is hospitalized in intensice care where further food and drink intake is discontinued in order to reduce further enzyme production in the pancreas. All the necessary fluid and other nutrients are compensated by the intravenous. Throughout the process of treatment, role of nurse is also crucial to notice possible changes that may occur in the patient, such as decreased urination, difficulty breathing and stagnation or aggravation of pain intensity despite analgesic therapy

Surgical outcomes of laparoscopic and open resection of benign liver tumours in the Netherlands: a nationwide analysis

Background: Data on surgical outcomes of laparoscopic liver resection (LLR) versus open liver resection (OLR) of benign liver tumour (BLT) are scarce. This study aimed to provide a nationwide overview of postoperative outcomes after LLR and OLR of BLT. Methods: This was a nationwide retrospective study including all patients who underwent liver resection for hepatocellular adenoma, haemangioma and focal nodular hyperplasia in the Netherlands from 2014 to 2019. Propensity score matching (PSM) was applied to compare 30-day overall and major morbidity and 30-day mortality after OLR and LLR. Results: In total, 415 patients underwent BLT resection of whom 230 (55.4%) underwent LLR. PSM for OLR and LLR resulted in 250 matched patients. Median (IQR) length of stay was shorter after LLR than OLR (4 versus 6 days, 5.0-8.0, p < 0.001). Postoperative 30-day overall morbidity was lower after LLR than OLR (12.0% vs. 22.4%, p = 0.043). LLR was associated with reduced 30-day overall morbidity in multivariable analysis (aOR:0.46, CI:0.22-0.95, p = 0.043). Both 30-day major morbidity and 30-day mortality were not different. Conclusions: LLR for BLT is associated with shorter hospital stay and reduced overall morbidity and is preferred if technically feasible.Transplant surger

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study

Background: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation.Methods: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery.Results: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy.Conclusion: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Factors associated with failure to rescue after liver resection and impact on hospital variation: a nationwide population-based study

Background: Failure to rescue (FTR) is defined as postoperative complications leading to mortality. This nationwide study aimed to assess factors associated with FTR and hospital variation in FTR after liver surgery.Methods: All patients who underwent liver resection between 2014 and 2017 in the Netherlands were included. FTR was defined as in-hospital or 30-day mortality after complications Dindo grade >= 3a. Variables associated with FTR and nationwide hospital variation were assessed using multivariable lo-gistic regression.Results: Of 4961 patients included, 3707 (74.4%) underwent liver resection for colorectal liver me-tastases, 379 (7.6%) for other metastases, 526 (10.6%) for hepatocellular carcinoma and 349 (7.0%) for biliary cancer. Thirty-day major morbidity was 11.5%. Overall mortality was 2.3%. FTR was 19.1%. Age 65-80 (aOR: 2.86, CI:1.01-12.0, p = 0.049), ASA 3+ (aOR:2.59, CI: 1.66-4.02, p < 0.001), liver cirrhosis (aOR:4.15, CI:1.81-9.22, p < 0.001), biliary cancer (aOR:3.47, CI: 1.73-6.96, p < 0.001), and major resection (aOR:6.46, CI: 3.91-10.9, p < 0.001) were associated with FTR. Postoperative liver failure (aOR: 26.9, CI: 14.6-51.2, p < 0.001), cardiac (aOR: 2.62, CI: 1.27-5.29, p = 0.008) and thromboembolic complications (aOR: 2.49, CI: 1.16-5.22, p = 0.017) were associated with FTR. After case-mix correction, no hospital variation in FTR was observed.Conclusion: FTR is influenced by patient demographics, disease and procedural burden. Prevention of postoperative liver failure, cardiac and thromboembolic complications could decrease FTR.Surgical oncolog