BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study.

Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to emerge. In this proof-of-concept study, we performed a detailed correlative analysis of the mutational and immunological landscapes in a series of 23 consecutive kidney cancer patients. We discovered that a high infiltration with CD8 + T cells was not dependent on the number of driver mutations but rather on the presence of specific mutational events, namely pathogenic mutations in PTEN or BAP1. This observation encouraged us to compare mechanisms of T cell suppression in the context of four different genetic patterns, i.e., the presence of multiple drivers, a PTEN or BAP1 mutation, or the absence of detectable driver mutations. We found that ccRCCs harboring a PTEN or BAP1 mutation showed the lowest level of Granzyme B positive tumor-infiltrating lymphocytes (TILs). A multiplex immunofluorescence analysis revealed a significant number of CD8 + TILs in the vicinity of CD68 + macrophages/monocytes in the context of a BAP1 mutation but not in the context of a PTEN mutation. In line with this finding, direct interactions between CD8 + TILs and CD163 + M2-polarized macrophages were found in BAP1-mutated ccRCC but not in tumors with other mutational patterns. While an absence of driver mutations was associated with more CD8 + TILs in the vicinity of FOXP3 + Tregs and CD68 + monocytes/macrophages, the presence of multiple driver mutations was, to our surprise, not found to be strongly associated with immunosuppressive mechanisms. Our results highlight the role of genetic alterations in shaping the immunological landscape of ccRCC. We discovered a remarkable heterogeneity of mechanisms that can lead to T cell suppression, which supports the need for personalized immune oncological approaches.

Study protocol of REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I): a prospective observational study of antibiotic prophylaxis practice for patients undergoing major abdominal surgery.

INTRODUCTION: Surgical site infections (SSIs) are among the most common complications after abdominal surgery and develop in approximately 20% of patients. These patients suffer a 12% increase in mortality, underlying the need for strategies reducing SSI. Perioperative antibiotic prophylaxis is paramount for SSI prevention in major abdominal surgery. Yet, intraoperative redosing criteria are subjective and whether patients benefit from it remains unclear. METHODS AND ANALYSIS: The REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I) study is a single-centre, prospective, observational study investigating redosing of antibiotic prophylaxis in 300 patients undergoing major abdominal surgery. Adult patients scheduled for major abdominal surgery will be included. Current practice of redosing regarding number and time period will be recorded. Postoperative SSIs, nosocomial infections, clinically relevant infection-associated bacteria, postoperative antibiotic treatment, in addition to other clinical, pharmacological and economical outcomes will be evaluated. Differences between groups will be analysed with analysis of covariance. ETHICS AND DISSEMINATION: RESISTAAS I will be conducted in accordance with the Declaration of Helsinki and internal, national and international standards of GCP. The Medical Ethics Review Board of Heidelberg University has approved the study prior to initiation (S-404/2021). The study has been registered on 7 February 2022 at German Clinical Trials Register, with identifier DRKS00027892. We plan to disseminate the results of the study in a peer-reviewed journal. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00027892.

Routine Postoperative Antibiotic Prophylaxis Offers No Benefit after Hepatectomy-A Systematic Review and Meta-Analysis.

BACKGROUND: Prophylactic antibiotics are frequently administered after major abdominal surgery including hepatectomies aiming to prevent infective complications. Yet, excessive use of antibiotics increases resistance in bacteria. The aim of this systematic review and meta-analysis is to assess the efficacy of prophylactic antibiotics after hepatectomy (postoperative antibiotic prophylaxis, POA). METHOD: This systematic review and meta-analysis were completed according to the current PRISMA guidelines. The protocol has been registered prior to data extraction (PROSPERO registration Nr: CRD42021288510). MEDLINE, Web of Science and CENTRAL were searched for clinical reports on POA in hepatectomy restrictions. A random-effects model was used for synthesis. Methodological quality was assessed with RoB2 and ROBINS-I. GRADE was used for the quality of evidence assessment. RESULTS: Nine comparative studies comprising 2987 patients were identified: six randomized controlled trials (RCTs) and three retrospectives. POA did not lead to a reduction in postoperative infective complications or have an effect on liver-specific complications-post-hepatectomy liver failure and biliary leaks. POA over four or more days was associated with increased rates of deep surgical site infections compared to short-term administration for up to two days (OR 1.54; 95% CI [1.17;2.03]; p = 0.03). Routine POA led to significantly higher MRSA incidence as a pathogen (p = 0.0073). Overall, the risk of bias in the studies was low and the quality of evidence moderate. CONCLUSION: Routine POA cannot be recommended after hepatectomy since it does not reduce postoperative infection or liver-specific complications but contributes to resistance in bacteria. Studies into individualized risk-adapted antibiotic prophylaxis strategies are needed to further optimize perioperative treatment in liver surgery.

Kidney Cancer Models for Pre-Clinical Drug Discovery: Challenges and Opportunities.

Renal cell carcinoma (RCC) is among the most lethal urological malignancies once metastatic. The introduction of immune checkpoint inhibitors has revolutionized the therapeutic landscape of metastatic RCC, nevertheless, a significant proportion of patients will experience disease progression. Novel treatment options are therefore still needed and in vitro and in vivo model systems are crucial to ultimately improve disease control. At the same time, RCC is characterized by a number of molecular and functional peculiarities that have the potential to limit the utility of pre-clinical model systems. This includes not only the well-known genomic intratumoral heterogeneity (ITH) of RCC but also a remarkable functional ITH that can be shaped by influences of the tumor microenvironment. Importantly, RCC is among the tumor entities, in which a high number of intratumoral cytotoxic T cells is associated with a poor prognosis. In fact, many of these T cells are exhausted, which represents a major challenge for modeling tumor-immune cell interactions. Lastly, pre-clinical drug development commonly relies on using phenotypic screening of 2D or 3D RCC cell culture models, however, the problem of "reverse engineering" can prevent the identification of the precise mode of action of drug candidates thus impeding their translation to the clinic. In conclusion, a holistic approach to model the complex "ecosystem RCC" will likely require not only a combination of model systems but also an integration of concepts and methods using artificial intelligence to further improve pre-clinical drug discovery.

Is metabolic syndrome a risk factor in hepatectomy? A meta-analysis with subgroup analysis for histologically confirmed hepatic manifestations.

BACKGROUND: Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy. METHODS: The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed. RESULTS: The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low. CONCLUSION: Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications-PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF. TRIAL REGISTRATION: PROSPERO Nr: CRD42021253768.