Assessing Functional Outcomes of Partial Versus Radical Nephrectomy for T1b-T2 Renal Masses: Results from a Multi-institutional Collaboration.

BACKGROUND: Deterioration of renal function is associated with increased all-cause mortality. In renal masses larger than 4 cm, whether partial versus radical nephrectomy (PN vs. RN) might affect long-term functional outcomes is unknown. This study tested the association between PN versus RN and postoperative acute kidney injury (AKI), recovery of at least 90% of the preoperative estimated glomerular filtration rate (eGFR) at 1 year, upstaging of chronic kidney disease (CKD) one stage or more at 1 year, and eGFR decline of 45 ml/min/1.73 m2 or less at 1 year. METHODS: Data from 23 high-volume institutions were used. The study included only surgically treated patients with single, unilateral, localized, clinical T1b-2 renal masses. Multivariable logistic regression analyses were performed. RESULTS: Overall, 968 PN patients and 325 RN patients were identified. The rate of AKI was lower in the PN versus the RN patients (17% vs. 58%; p < 0.001). At 1 year after surgery, for the PN versus the RN patients, the rate for recovery of at least 90% of baseline eGFR was 51% versus 16%, the rate of CKD progression of ≥ 1 stage was 38% versus 65%, and the rate of eGFR decline of 45 ml/min/1.73 m2 or less was 10% versus 23% (all p < 0.001). Radical nephrectomy independently predicted AKI (odds ratio [OR], 7.61), 1-year ≥ 90% eGFR recovery (OR, 0.30), 1-year CKD upstaging (OR, 1.78), and 1-year eGFR decline of 45 ml/min/1.73 m2 or less (OR, 2.36) (all p ≤ 0.002). CONCLUSIONS: For cT1b-2 masses, RN portends worse immediate and 1-year functional outcomes. When technically feasible and oncologically safe, efforts should be made to spare the kidney in case of large renal masses to avoid the hazard of glomerular function loss-related mortality.

Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis.

Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-ß (TGF-ß) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-ß overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-ß signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae.

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension.

Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr∆end) and held them in an environmental chamber with 10% FiO2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.

Soluble galectin-3 is associated with premature myocardial infarction.

BACKGROUND: Inflammatory responses are pivotal in the initiation and development of premature atherosclerotic lesions. Galectin-3 represents a valuable biomarker for both progression and destabilization of atherosclerotic lesions. This study aims to assess the involvement of galectin-3 in premature myocardial infarction. DESIGN: In this multicentre case-control study, we assessed circulating galectin-3 levels in 144 patients comprising 72 consecutive survivors of acute myocardial infarction (≤ 40 years) and 72 hospital controls frequency matched for age, gender and centre. RESULTS: Patients with acute myocardial infarction showed significantly higher galectin-3 levels as compared to controls in the acute phase of acute myocardial infarction (2552 ± 1992 vs. 1666 ± 829 pg/mL; P < 0·001) as well as in the stable phase 1 year after the index event (3692 ± 1774 vs. 1666 ± 829 pg/mL; P < 0·001). Circulating galectin-3 was significantly and independently associated with premature myocardial infarction in the logistic regression analysis (acute phase: adj. OR per 1-SD change 2·03, 95% CI 1·30-3·19; P = 0·002; stable phase: adj. OR of 6·54 (95% CI 2·56-16·68; P < 0·001). Moreover, we observed a significant correlation between circulating galectin-3 and leucocyte count (r = 0·35, P < 0·001), non-HDL cholesterol (r = 0·23, P = 0·014) and HDL cholesterol (r = -0·29, P = 0·002). CONCLUSION: We demonstrated that elevated levels of circulating galectin-3 are strongly associated with premature myocardial infarction. Galectin-3 might serve as link between dyslipidaemia as driving force of plaque formation with inflammation as initiator of plaque rupture in patients with premature acute myocardial infarction.

Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension.

OBJECTIVE: Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. APPROACH AND RESULTS: Mice with an endothelial cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell-specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. CONCLUSIONS: In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell-specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.

Real-World Results of Cabozantinib Given as Alternative Schedule in Metastatic Renal Cell Carcinoma.

BACKGROUND: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. OBJECTIVE: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. PATIENTS: This is a single center retrospective study from the Medical University of Vienna. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. RESULTS: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC criteria, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. CONCLUSIONS: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety.

Primary retroperitoneal lymph node dissection for clinical stage II seminoma: A systematic review and meta-analysis of safety and oncological effectiveness.

To evaluate the oncological outcomes and safety of primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) II seminomatous testicular germ cell tumor (TGCT). A literature search using PubMed, Scopus, and Cochrane Library was conducted on July 2023 to identify relevant studies according to the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) guidelines. The pooled recurrence rate and treatment-related complications were calculated using a random effects model. Overall 8 studies published between 1997 and 2023 including a total of 355 patients were selected for systematic review and meta-analysis with the overall median follow-up of 38 months. The overall and infield recurrence rate were 0.14 (95% CI: 0.08-0.22) and 0.04 (95% CI: 0.00-0.11), respectively. The overall pooled rate of ≥ Clavien Dindo grade III complications was 0.04 (95% CI: 0.01-0.10); there was no significant heterogeneity (I^2 = 35.10%, P = 0.19). Antegrade ejaculation was preserved with the overall pooled rate of 0.98 (95% CI: 0.95-1.00); there was no significant heterogeneity on Chi-square and I2 tests (I^2 = 0.00%, P = 0.58). Primary RPLND is a safe and effective treatment option for patients with CS II seminomatous TGCT resulting highly promising cure rates combined with low treatment-associated adverse events, at medium-term follow-up. However, owing to the lack of comparative studies to the current standard of care and the limited follow-up, individual decision must be made with the informed patient in a shared decision process together with a multidisciplinary team.

Metastatic Organotropism Differential Treatment Response in Urothelial Carcinoma: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

CONTEXT: The optimal therapeutic agent with respect to metastatic sites is unclear in advanced urothelial carcinoma (UC). OBJECTIVE: To investigate the metastatic organotropism differential treatment response in patients with advanced or metastatic UC. EVIDENCE ACQUISITION: A systematic search and network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The primary endpoints of interest were the objective response rate, overall survival (OS), and progression-free survival with respect to different metastatic sites. EVIDENCE SYNTHESIS: Twenty-six trials comprising 9082 patients met our eligibility criteria, and a formal NMA was conducted. Durvalumab plus tremelimumab as first-line systemic therapy was significantly associated with better OS than chemotherapy in visceral metastasis (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.67-0.98). Pembrolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with visceral metastasis (HR 0.75, 95% CI 0.60-0.95). Atezolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with liver metastasis (in the population of >5% of tumor-infiltrating immune cells) and lymph node metastasis (HR 0.51, 95% CI 0.28-0.96, and HR 0.59, 95% CI 0.37-0.96, respectively). CONCLUSIONS: Administration of immune-oncology treatments with respect to metastatic sites in patients with advanced or metastatic UC might have a positive impact on survival outcomes in both the first- and the second-line setting. Nevertheless, further investigations focusing on metastatic organotropism differential response with reliable oncological outcomes are needed to identify the optimal management strategy for these patients. PATIENT SUMMARY: Although the supporting evidence for oncological benefits of therapeutic systemic agents with respect to metastatic sites is not yet strong enough to provide a recommendation in advanced or metastatic urothelial carcinoma, clinicians may take into account tumor organotropism only in discussion with the patient fully informed on the optimal treatment decision to be taken.

Pretreatment serum C-reactive protein levels predict benefit from multimodality treatment including radical surgery in malignant pleural mesothelioma: a retrospective multicenter analysis.

OBJECTIVE: To evaluate the prognostic and predictive relevance of pretreatment serum C-reactive protein (CRP) in malignant pleural mesothelioma (MPM) patients. BACKGROUND: MPM is a rare but aggressive disease with poor treatment outcome. Therapeutic decision is challenging, and predictive biomarkers for better treatment stratification are urgently needed. METHODS: Clinical data, including survival and pretreatment CRP levels, were retrospectively collected from 115 patients with histologically proven MPM. Patients with any evidence for infectious disease were excluded. The association between CRP levels and survival was analyzed using Cox models adjusted for clinical and pathological factors. RESULTS: Median pretreatment CRP of all patients was 1.19 mg/dL (range: 0.00-22.62 mg/dL). Patients with elevated CRP levels (≥1 mg/dL; n = 62, 53.9%) had a significantly shorter overall survival compared with those with normal CRP (hazard ratio [HR] 2.81, 95% confidence interval [CI] 1.82-4.33; P < 0.001). In multivariate survival analyses, elevated CRP was confirmed as an independent prognostic factor in MPM (HR 2.07, 95% CI 1.23-3.46; P = 0.01). Most interestingly, we observed a significant interaction between CRP and treatment modality (P < 0.001). Among patients with normal CRP levels, radical tumor resection within multimodality therapy was associated with distinctly prolonged overall survival when compared with treatment protocols without surgery (HR 7.26, 95% CI 3.40-15.49; P < 0.001). In contrast among patients with elevated CRP, no survival benefit was achieved by radical surgery within multimodality approaches (HR 0.911, 95% CI 0.53-1.58; P = 0.74). CONCLUSIONS: Our results suggest that multimodality regimens including radical resection increase survival selectively in MPM patients with normal pretreatment serum CRP levels.

Recent pharmacological approaches for the treatment of renal cell carcinoma.

INTRODUCTION: Therapies combining either two immune check-point inhibitors (ICIs) or an ICI and a tyrosine kinase inhibitor (TKI) have been shown to improve overall survival (OS), progression-free survival (PFS) and objective response rates (ORR) in metastatic renal cell carcinoma (mRCC); moreover, unprecedented rates of complete remission (CR) have been reported. AREAS COVERED: Among six randomized trials of ICI combinations, four have outperformed the TKI sunitinib in terms of OS. The CheckMate 214 trial investigated the combination of nivolumab (a programmed cell death protein 1 [PD-1] inhibitor) and ipilimumab (a cytotoxic T-lymphocyte antigen-4 [CTLA-4)] inhibitor). Three other trials evaluated combinations of an ICI and a TKI. These combinations are: 1) pembrolizumab (PD-1 inhibitor) plus axitinib, 2) nivolumab plus cabozantinib, and 3) pembrolizumab plus lenvatinib. This short review addresses the findings of these trials, comparing outcomes and discussing the challenges of decision-making in clinical practice. EXPERT OPINION: Not all patients benefit from ICI combinations. Predictive biomarkers and new therapeutic approaches are urgently needed to overcome treatment failures. A growing understanding of immune escape mechanisms and the interplay between the immune response and the gut microbiota may offer additional rescue strategies beyond ICIs and TKIs.

A neutrophil-B-cell axis impacts tissue damage control in a mouse model of intraabdominal bacterial infection via Cxcr4.

Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multiorgan failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a mouse model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils include upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted disease tolerance by improving tissue damage control via the suppression of neutrophils' tissue-damaging properties. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue damage control and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis.

Long-term outcome and risk assessment in premature acute myocardial infarction: A 10-year follow-up study.

BACKGROUND: Premature acute myocardial infarction (AMI) is a rare disease carrying significant morbidity and mortality. Existing data on outcome in these patients is based on retrospective analysis of angiographic reports or refer to time periods with incomparable treatment regimes, making them unusable for risk assessment in times of widespread use of reperfusion therapy. Aim of this study was to assess the outcome of premature AMI in a prospectively recruited study population enrolled in the times of modern reperfusion therapy. METHODS: We included 102 consecutive AMI survivors (≤40years) in this prospective multicentre study. Outcome was assessed via retrieval query of the Austrian Death Registry and the centralized patient management system of Vienna. RESULTS: During a median follow up time of 10.3years (IQR:8.9-11.1), 23% of all patients experienced MACE, of those 6% died, 17% experienced re-AMI and 5% patients an ischemic stroke. Furthermore, forty patients underwent cardiac re-catheterization and twenty-five needed recurrent revascularization. MACE were associated among the classic cardiovascular risk factors with elevated levels of HbA1c (adj. HR 1.32; 95%CI 1.06-1.64; P=0.012), total cholesterol (adj. HR 2.16; 95%CI 1.27-3.48; P=0.004), and c-reactive protein (adj. HR 1.67; 95%CI 1.29-2.17; P=0-003) for an increase of 1-standard deviation. CONCLUSION: Although myocardial re-infarction was the driving force of morbidity in premature myocardial infarction, we observed an excellent long-term survival opposed to previous reports. We found that persistence risk factors rather than the clinical risk profile at baseline influences the outcome in these patients, emphasizing the importance of secondary prevention in young patients after AMI.

Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: The PCSK9-REACT study.

BACKGROUND: Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme might be associated with increased activation of platelets. We aimed to assess the relationship between PCSK9 levels, platelet reactivity and ischemic outcomes. METHODS: Consecutive ACS patients receiving prasugrel or ticagrelor and undergoing percutaneous coronary intervention (PCI) were enrolled in a prospective, observational study. Adenosine diphosphate (ADP)-induced platelet aggregation was determined by Multiplate Analyzer in the maintenance phase of treatment with prasugrel or ticagrelor. Major adverse cardiovascular events (MACEs) defined as composite of cardiovascular death, myocardial infarction, unstable angina, stent thrombosis, repeat revascularization, ischemic stroke were evaluated at 12months. RESULTS: A direct association was found between increased PCSK9 serum levels and platelet reactivity (r=0.30; p=0.004). When assessed according to tertile values of PCSK9, there was a significant increase in platelet reactivity in the upper vs lower tertile (p=0.02). Clinical outcome was available at follow-up in 178 subjects. In the upper PCSK9 tertile 13/59 (22.03%) patients experienced a clinical MACE at one year, vs 2/59 (3.39%) patients in the lower PCSK9 tertile. At one-year follow-up, PCSK9 was independently associated with increased ischemic MACEs: hazard ratio for upper vs lower PCSK9-level tertile was 2.62 (95% confidence interval 1.24-5.52; p=0.01). CONCLUSIONS: These findings suggest that increased PCSK9 levels are associated with higher platelet reactivity and are a possible predictor of ischemic events in ACS patients undergoing PCI.

Splenectomy is modifying the vascular remodeling of thrombosis.

BACKGROUND: Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. METHODS AND RESULTS: We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (CTEPH), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte-platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine-enriched phospholipids specifically inhibited endothelial proliferation and sprouting. CONCLUSIONS: After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in CTEPH.