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ZusammenfassungDas Ampullenkarzinom stellt eine seltene, jedoch in seiner Inzidenz steigende Entität gastrointestinaler Tumoren dar. Aufgrund der anatomischen Lokalisation führt es vergleichsweise früh im Erkrankungsprozess zu einer biliären Gangobstruktion, wodurch eine schnellere Diagnosestellung erleichtert und eine bessere Prognose bedingt werden. Adenome der Ampulla hepatopancreatica und der Papilla duodeni major stellen Vorläuferläsionen des Ampullenkarzinoms dar und besitzen ein 30–40%iges Risiko zur malignen Transformation. Diese Entartungstendenz begründet die Notwendigkeit zur vollständigen/kompletten Abtragung im Rahmen der endoskopischen Therapie. Der Erfolg der endoskopischen Papillektomie wird durch eine Ausdehnung des Befundes in den Pankreashauptgang oder Ductus choledochus erschwert. Endoskopisch nicht sanierbare Adenome und Ampullenkarzinome stellen Indikationen für chirurgische Therapieverfahren dar. Grundsätzlich sollte für benigne Befunde die transduodenale Papillenresektion bervorzugt werden, für maligne Befunde stellt die Pankreaskopfresektion mit systematischer Lymphadenektomie und Level-II-Dissektion des Mesopankreas die onkologisch korrekte Operation dar. Prognostische Faktoren beim Ampullenkarzinom sind: der pankreatobiliäre Subtyp, eine Lymphknoteninfiltration und eine Perineuralscheideninvasion. Die Differenzierung in histopathologische Subtypen gewinnt zunehmend in der Indikationsstellung zur Systemtherapie an Bedeutung. Der Einsatz der neoadjuvanten und adjuvanten Therapie für das Ampullenkarzinom konnte bisher nicht klar definiert werden. Jedoch scheinen Patienten mit dem pankreatobiliären Subtyp oder anderen prognoselimitierenden Faktoren von einer adjuvanten Therapie zu profitieren. Zukünftige Studien werden zur zielgerichteten Therapiefestlegung benötigt.

Objective Hepatobiliary surgery bares obstacles to informed consent for the patients due to its complexity and related risk of postoperative complications. 3D visualization of the liver has been proven to facilitate comprehension of the spatial relationship between anatomical structures and to assist in clinical decision-making. Our objective is to utilize individual 3D-printed liver models to enhance patient satisfaction with surgical education in hepatobiliary surgery. Design, setting We conducted a prospective, randomized pilot study comparing 3D liver model-enhanced (3D-LiMo) surgical education against regular patient education during preoperative consultation at the department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany. Participants Of 97 screened patients, undergoing hepatobiliary surgery, 40 patients were enrolled from July 2020 to January 2022. Results The study population (n = 40) was predominantly of male gender (62.5%) with a median age of 65.2 years and a high prevalence of preexisting diseases. Underlying disease, warranting hepatobiliary surgery, was malignancy in the majority of cases (97.5%). Patients in the 3D-LiMo group were more likely to feel very thoroughly educated and exhibited a higher level of satisfaction following surgical education than the control group (80 vs. 55%, n.s.; 90 vs. 65%, n.s.; respectively). Applying 3D models was also associated with enhanced understanding of the underlying disease with regard to amount (100% vs. 70%, p = 0.020) and location of liver masses (95 vs. 65%, p = 0.044). 3D-LiMo patients also demonstrated enhanced understanding of the surgical procedure (80 vs. 55%, n.s.), leading to better awareness for the occurrence of postoperative complications (88.9, vs. 68.4%, p = 0.052). Adverse event profiles were similar. Conclusion In conclusion, individual 3D-printed liver models increase patient satisfaction with surgical education and facilitate patients’ understanding of the surgical procedure as well as awareness of postoperative complications. Therefore, the study protocol is feasible to apply to an adequately powered, multicenter, randomized clinical trial with minor modifications.

In this study, we aimed to apply the cytokine IL-36γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36γ (IL-36γ-OVs), leveraging unique synergism between OV and IL-36γ’s ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36γ-OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36-γ-armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36γ-OV increased the number of tumor antigen-specific CD4+ and CD8+ T cells and the therapeutic efficacy depended on both CD8+ and CD4+ T cells. These results demonstrate that these IL36γ-armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.

Hepatobiliary surgery is technically challenging due to a complex internal anatomy, further amplified by recent advancements in resection techniques. 3D visualization of the liver has been proven to facilitate comprehension of the spatial relationship between anatomical structures and to assist in clinical decision making. The aim of this study was to evaluate the educational and satisfiable value of individual 3D-printed liver models during surgical education. In this prospective, monocentric, randomized, controlled trial, n=40 patients, undergoing liver surgery, were enrolled and either randomized to standard (control group) or 3D liver model-enhanced (3D-LiMo) education before surgery. Primary endpoint was patient satisfaction following surgical education. Secondary endpoints included patients’ apprehension and satisfaction in the ongoing process, occurrence of postoperative complications as well as length of hospital stay. Patients in the 3D-LiMo group were more likely to feel very thoroughly educated and exhibited a higher level of satisfaction following surgical education than the control group (80 vs. 55%, n.s.; 90% vs. 65%, n.s.; respectively). Applying 3D models was also associated with enhanced understanding of the underlying disease with regard to amount (100% vs. 70%, p=0.020) and location of liver masses (95% vs. 65%, p=0.044). 3D-LiMo patients also demonstrated enhanced understanding of the surgical procedure (80% vs. 55%, n.s.), leading to better awareness for the occurrence of postoperative complications (88.9%, vs. 68.4%, p=0.052). In conclusion, individual 3D printed liver models increase patient satisfaction with surgical education and facilitate patients’ understanding of the surgical procedure as well as awareness of postoperative complications.

Ampullary carcinoma belongs to the cluster of periampullary cancers and is a rare, but increasing form of gastrointestinal malignancy. Due to the location of the tumour, occurrence of biliary obstruction is common. Symptoms due to the compression of the biliary tract facilitate early diagnosis, evoking a better prognosis. Adenomas of the ampulla of Vater and major duodenal papilla are precursor lesions and possess a risk of 30-40% to progress into a malignancy. Therefore, en-bloc resection is warranted for all ampullary adenomas. Endoscopic papillectomy is aggravated by extension into the pancreatic duct or common bile duct. Surgical resection is indicated whenever endoscopic resection is incomplete or infiltrative growth is suspected. Transduodenal ampullectomy is an alternative to extensive oncological resection in the absence of malignancy. Pancreatoduodenectomy (or Whipple procedure) with systemic lymphadenectomy and mesopancreas excision is the standard procedure of all ampullary carcinomas and incompletely excised adenomas by minimally invasive procedures. The indication for extensive surgical resection includes suspicion of infiltration in endoscopic ultrasound or evidence of malignancy in frozen section during transduodenal ampullectomy. Negative prognostic indicators are implicated by the pancreatobiliary subtype, lymph node metastases and perineural invasion. Differentiation of the different histopathological subtypes thereby increases in clinical relevance. Evidence based guidelines for the clinical practice of neoadjuvant and adjuvant treatment for ampullary carcinoma have yet to be defined. According to the literature available, patients with the pancreatobiliary subtyp or association with other negative prognostic factors seem to benefit from systemic therapy. Further studies are warranted.Das Ampullenkarzinom stellt eine seltene, jedoch in seiner Inzidenz steigende Entität gastrointestinaler Tumoren dar. Aufgrund der anatomischen Lokalisation führt es vergleichsweise früh im Erkrankungsprozess zu einer biliären Gangobstruktion, wodurch eine schnellere Diagnosestellung erleichtert und eine bessere Prognose bedingt werden. Adenome der Ampulla hepatopancreatica und der Papilla duodeni major stellen Vorläuferläsionen des Ampullenkarzinoms dar und besitzen ein 30–40%iges Risiko zur malignen Transformation. Diese Entartungstendenz begründet die Notwendigkeit zur vollständigen/kompletten Abtragung im Rahmen der endoskopischen Therapie. Der Erfolg der endoskopischen Papillektomie wird durch eine Ausdehnung des Befundes in den Pankreashauptgang oder Ductus choledochus erschwert. Endoskopisch nicht sanierbare Adenome und Ampullenkarzinome stellen Indikationen für chirurgische Therapieverfahren dar. Grundsätzlich sollte für benigne Befunde die transduodenale Papillenresektion bervorzugt werden, für maligne Befunde stellt die Pankreaskopfresektion mit systematischer Lymphadenektomie und Level-II-Dissektion des Mesopankreas die onkologisch korrekte Operation dar. Prognostische Faktoren beim Ampullenkarzinom sind: der pankreatobiliäre Subtyp, eine Lymphknoteninfiltration und eine Perineuralscheideninvasion. Die Differenzierung in histopathologische Subtypen gewinnt zunehmend in der Indikationsstellung zur Systemtherapie an Bedeutung. Der Einsatz der neoadjuvanten und adjuvanten Therapie für das Ampullenkarzinom konnte bisher nicht klar definiert werden. Jedoch scheinen Patienten mit dem pankreatobiliären Subtyp oder anderen prognoselimitierenden Faktoren von einer adjuvanten Therapie zu profitieren. Zukünftige Studien werden zur zielgerichteten Therapiefestlegung benötigt.

Background The number of liver resections is constantly rising over the last decades. Despite the reduction of overall mortality and morbidity in liver surgery, biliary leakage is still a relevant postoperative complication that can lead to a fatal postoperative course. Aim of this analysis is the identification of specific risk factors for postoperative biliary complications after liver resections and the development of a predictive biliary leakage risk score. Methods A single-center, retrospective analysis of 844 liver resections performed in the Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, between 1/2013 and 12/2019 is conducted to identify risk factors for postoperative biliary leakage and a risk score for biliary leakage after hepatectomy is established based on multivariate regression. The score has been validated by an independent validation cohort consisting of 142 patients. Results Overall morbidity is 43.1% with 36% surgical complications and an overall mortality of 4.3%. Biliary leakage occurred in 15.8% of patients. A predictive score for postoperative biliary leakage based on age, major resection, pretreatment with FOLFOX/cetuximab and operating time is created. Patients are stratified to low ( 15%) risk with a sensitivity of 67.4% and a specificity of 70.7% in development cohort and a specificity of 68.2% and sensitivity of 75.8% in validation cohort. Conclusions The presented score is robust and has been validated in an independent patient cohort. Depending on the calculated risk, prevention or early treatment can be initiated to avoid bile leakage and to improve postoperative course.

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1hiTim-3+ CD8+ T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.

Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

Although autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple kidney cysts, the most frequent cause of death in ADPKD patients is cardiovascular disease. ADPKD is linked to mutations in PKD1 or pkd2, the genes that encode for the proteins polycystin 1 and polycystin 2 (PC1 and PC2, respectively). The cardiovascular complications have been assumed to be a consequence of renal hypertension and activation of renin/angiotensin/aldosterone (RAAS) pathway. However, the expression of PC1 and PC2 in cardiac tissue suggests additional direct effects of these proteins on cardiac function. We previously reported that zebrafish lacking PC2 develop heart failure, and that heterozygous Pkd2+/− mice are hypersensitive to acute β-adrenergic receptor (βAR) stimulation. Here, we investigate the effect of cardiac stress (prolonged continuous βAR stimulus) on Pkd2+/− mice. After βAR stimulation for 7 days, wild-type (WT) mice had increased left ventricular mass and natriuretic peptide (ANP and BNP) mRNA levels. The WT mice also had upregulated levels of PC2 and chromogranin B (CGB, an upstream regulator of BNP). Conversely, Pkd2+/− mice had increased left ventricular mass, but natriuretic peptide and CGB expression levels remained constant. Reversal of the increased cardiac mass was observed in WT mice 3 days after cessation of the βAR stimulation, but not in Pkd2+/− mice. We suggest that cardiac stress leads to upregulation of the PC2-CGB-BNP signaling axis, and this pathway regulates the production of cardio-protective natriuretic peptides. The lack of a PC2-dependent cardio-protective function may contribute to the severity of cardiac dysfunction in Pkd2+/− mice and in ADPKD patients.