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Background/Objectives: ABO-incompatible live-donor kidney transplantation (ABOi-LDKT) has become an established treatment for end-stage renal disease. Non-inferiority in the long-term graft function compared to ABO-compatible live-donor kidney transplantations (ABOc-LDKTs) has been shown. However, the assumed burden due to complications owing to increased immunosuppression inherent to ABOi-LDKTs has not yet been quantified. The aim of this study was to determine if ABOi-LDKT recipients suffer from additional morbidity and whether the resulting burden is justified. Methods: We retrospectively analyzed 45 matched pairs of ABOi-LDKTs and ABOc-LDKTs transplanted over a twenty-year period from January 2000 to March 2020. The number and duration of postoperative readmissions, surgical complication rates according to Clavien–Dindo and its comprehensive complication index (CCI), kidney function, occurrence of new-onset diabetes, and infections as well as tumor incidence were analyzed. Results: Patient and graft survival, as well as graft function, were comparable between the two groups. There were no significant differences in terms of complications, readmission rates, and length of readmission, as well as infection and rejection rates. The median CCIs for ABOi-LDKTs and ABOc-LDKTs at primary discharge and 3, 6, 12, and >12 months were 20.9 vs. 20.9 (p = 0.363), 31.4 vs. 33.7 (p = 0.438), 33.7 vs. 33.7 (p = 0.875), 20.9 vs. 33.1 (p = 0.25), and 27.1 vs. 31.9 (p = 0.163), respectively. Conclusions: ABOi-LDKT seems safe, with comparable outcome, complication, and readmission rates to ABOc-LDKT. In recipients with ABOi living donors, transplantation should not be delayed solely due to concerns over increased perioperative risks. [ABSTRACT FROM AUTHOR]

Simple Summary: In solid tumors, hypoxia activates pathways associated with tumor progression and induces alterations in the immune microenvironment such as the upregulation of programmed cell death-ligand 1 (PD-L1). Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors which are all considered to have metastatic potential independent of their initial clinical presentation. However, the relationship between hypoxia and PD-L1 regulation in PPGLs is still largely unexplored. We show that PD-L1 expression in head and neck paragangliomas (HNPGLs) undergoing embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%). Consistently, significantly more HNPGLs with embolization were positive for the hypoxia-marker HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without embolization (median nuclear HIF-2α positivity: 0%). Our findings suggest, that hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and may thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors. Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Peritoneal metastases have a poor prognosis, and one potential treatment option is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). The specific role of HIPEC is still poorly defined. In this cross-sectional study, we systematically analyzed all HIPEC trials registered on ClinicalTrials.gov to identify current research areas and to provide a perspective on expected outcomes. Only 11% (n = 26) of HIPEC trials registered on ClinicalTrials.gov (n = 234) have been published. The registered trials are very heterogeneous regarding methodological approaches and study designs. Currently, research is being conducted on 20 different drugs. The most studied cancers in HIPEC trials are peritoneal metastatic colorectal tumors, gastric cancer, and ovarian cancer. Introduction: Over the past two decades, cytoreductive surgery and HIPEC has improved outcomes for selected patients with peritoneal metastasis from various origins. This is a cross-sectional study with descriptive analyses of HIPEC trials registered on ClinicalTrials.gov. This study aimed to characterize clinical trials on HIPEC registered on ClinicalTrials.gov with the primary objective of identifying a trial focus and to examine whether trial results were published. Methods: The search included trials registered from 1 January 2001 to 14 March 2022. We examined the associations of exposure variables and other trial features with two primary outcomes: therapeutic focus and results reporting. Results: In total, 234 clinical trials were identified; 26 (11%) were already published, and 15 (6%) trials have reported their results but have not been published as full papers. Among ongoing nonpublished trials, 81 (39%) were randomized, 30 (14%) were blinded, n = 39 (20%) were later phase trials (i.e., phases 3 and 4), n = 152 (73%) were from a single institution, and 91 (44%) had parallel groups. Most of the trials were recruiting at the time of this analysis (75, 36%), and 39 (20%) were completed but had yet to publish results. In total, 68% of the trials focused on treatment strategies, and 53% investigated the oncological outcome. The most studied neoplasms for HIPEC trials were peritoneally metastasized colorectal cancer (32%), gastric cancer (29%), and ovarian cancer (26%). Twenty different drugs were analyzed in these clinical trials. Conclusions: Many study results are awaited from ongoing HIPEC trials. Most HIPEC trials focused on gastric, colorectal, or ovarian cancer. Many clinical trials were identified involving multiple entities and chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Peritoneal cancer is best addressed by a multimodal treatment approach, including cytoreductive surgery, systemic immunochemotherapy, and intraperitoneal chemotherapy (HIPEC, PIPAC). The present Swiss Peritoneal Cancer Group comprehensive treatment algorithms offer consensus guidance for interdisciplinary care of patients with peritoneal cancer from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include straight complete surgical resection, multimodal neoadjuvant treatment, HIPEC and PIPAC, and referral to palliative care. These state-of-the-art algorithms have been endorsed by all Swiss clinicians routinely involved in the multimodal care of patients with peritoneal cancer of gastrointestinal origin. Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic neuroendocrine tumors (pNET) are a heterogeneous and challenging entity, and today's guidelines offer a variety of treatment modalities, while surgery has a clear role for patients with resectable tumors and early stages, advanced, or metastatic pNET may benefit from treatments that were evaluated in randomized controlled studies during the last year. With this review, we aim to provide an updated view on treatment options for metastatic pNET. Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have emerged recently and shown benefits in randomized trials. Today, liver surgery is an option for advanced pNETs if the tumor has a favorable prognosis, reflected by a low to moderate proliferation index (G1 and G2). Surgery in this well-selected population may prolong progression-free and overall survival. Optimal selection of a treatment plan for an individual patient should be considered in a multidisciplinary tumor board. However, while current guidelines offer a variety of modalities, there is so far only a limited focus on the right timing. Available data is based on small case series or retrospective analyses. The focus of this review is to highlight the right time-point for surgery in the setting of the multimodal treatment of an advanced pancreatic neuroendocrine tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical and locoregional treatments of peritoneal metastasis, e.g., from colorectal cancer, has gained increasing acceptance after the publication of excellent patient outcomes from many groups around the world. Apart from systemic chemotherapy and surgical removal of the tumor, locoregional therapies such as HIPEC or PIPAC may improve tumor control. Understanding the molecular characteristics of peritoneal metastasis is crucial to evolve future therapeutic strategies for peritoneal metastasis. This includes the genetic background of PM, which is often different from other sites of metastasis, and promotes peritoneal dissemination and the growth of tumor cells. Growing knowledge and insight into the physiology of the peritoneal tumor microenvironment and the specific role of the immune system in this compartment may provide a critical step to move locoregional therapy to the next level. This review summarizes the current knowledge and highlights the molecular characteristics of peritoneal metastasis. Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. The advent of better systemic treatment, a better understanding of prognostic factors, and finally, the advent of novel loco-regional therapies, has opened the door for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged survival of patients with peritoneal metastasis. This has triggered a significant body of research, leading to the molecular characterization of PM, which may further help in the development of novel treatments. This review summarizes current evidence on peritoneal metastasis and explores potential novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of peritoneal surface malignancies (PSM) has dramatically evolved during the past two decades. Indications, treatment protocols, surgical techniques and the application of HIPEC in the prophylactic setting were evaluated in the surgical community. Nevertheless, the current results of the PRODIGE-7 trial disfavored the application of HIPEC for PSM of colorectal cancer and raised uncertainty among surgeons. On the other hand, cytoreductive surgery and HIPEC represent state-of-the-art therapy for peritoneal mesothelioma (except the sarcomatoid-subtype) and pseudomyxoma peritonei. Comparing the literature is cumbersome due to the variety of HIPEC protocols and differences in indication settings. This article aims to provide an insight into the impact of different HIPEC protocols, different indication settings and the implementation of pre-HIPEC laparoscopy on patients' morbidity rates and outcomes and serves as guidance for surgeons dealing with these patients in order to guarantee high-quality treatment. (1) Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy provide survival benefits to selected patients. We aimed to report our experience and the evolution of our peritoneal surface malignancy program. (2) Methods: From June 2005 to June 2017, 399 patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy at the Tübingen University Hospital were analyzed from a prospectively collected database. (3) Results: Peritoneal metastasis from colorectal cancer was the leading indication (group 1: 28%; group 2: 32%). The median PCI was 15.5 (range, 1–39) in group 1 and 11 (range, 1–39) in group 2 (p = 0.002). Regarding the completeness of cytoreduction (CC), a score of 0 was achieved in 63% vs. 69% for group 1 and 2, respectively (p = 0.010). Median overall survival rates for patients in group 1 and 2 for colon cancer, ovarian cancer, gastric cancer and appendix cancer were 34 and 25 months; 45 months and not reached; 30 and 16 months; 39 months and not reached, respectively. The occurrence of grade-III and -IV complications slightly differed between groups (14.5% vs. 15.6%). No 30-day mortality occurred. (4) Conclusions: Specialized centers are able to provide low-morbidity cytoreductive surgery and hyperthermic intraperitoneal chemotherapy without mortality. Strict patient selection during the time period significantly improved CC scores. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer treatments are increasingly based on therapeutic antibodies to clear tumors. While in vivo mouse models are useful to predict effectiveness of human antibodies it is not completely clear how useful these models are to test antibodies engineered with enhanced effector functions designed for humans. One of the changes considered for many new antibody-based drugs is the removal of fucose (resulting in afucosylated IgG) which enhances IgG-Fc receptor (FcγR) mediated effector functions in humans through FcγRIIIa. Here we show that afucosylated human IgG1 also have enhanced effector functions against peritoneal metastasis of melanoma cells in mice through the evolutionary related mouse FcγRIV. This shows that afucosylated human IgG is functionally recognized across species and shows that mouse tumor models can be used to assess the therapeutic potential of afucosylated IgG1. Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies. [ABSTRACT FROM AUTHOR]