Mortality following noncardiac surgery assessed by the Saint Louis University Score (SLUScore) for hypotension: a retrospective observational cohort study.

BACKGROUND: The Saint Louis University Score (SLUScore) was developed to quantify intraoperative blood pressure trajectories and their associated risk for adverse outcomes. This study examines the prevalence and severity of intraoperative hypotension described by the SLUScore and its relationship with 30-day mortality in surgical subtypes. METHODS: This retrospective analysis of perioperative data included surgical cases performed between January 1, 2010, and December 31, 2020. The SLUScore is calculated from cumulative time-periods for which the mean arterial pressure is below a range of hypotensive thresholds. After calculating the SLUScore for each surgical procedure, we quantified the prevalence and severity of intraoperative hypotension for each surgical procedure and the association between intraoperative hypotension and 30-day mortality. We used binary logistic regression to quantify the potential contribution of intraoperative hypotension to mortality. RESULTS: We analysed 490 982 cases (57.7% female; mean age 57 yr); 33.2% of cases had a SLUScore>0, a median SLUScore of 13 (inter-quartile range [IQR] 7-21), with 1.19% average mortality. The SLUScore was associated with mortality in 12/14 surgical groups. The increases in the odds ratio for death within 30 days of surgery per SLUScore increment were: all surgery types 3.5% (95% confidence interval [95% CI] 3.2-3.9); abdominal/transplant surgery 6% (95% CI 1.5-10.7); thoracic surgery1.5% (95% CI 1-3.3); vascular surgery 3.01% (95% CI 1.9-4.05); spine/neurosurgery 1.1% (95% CI 0.1-2.1); orthopaedic surgery 1.4% (95% CI 0.7-2.2); gynaecological surgery 6.3% (95% CI 2.5-10.1); genitourinary surgery 4.84% (95% CI 3.5-6.15); gastrointestinal surgery 5.2% (95% CI 3.9-6.4); gastroendoscopy 5.5% (95% CI 4.4-6.7); general surgery 6.3% (95% CI 5.5-7.1); ear, nose, and throat surgery 1.6% (95% CI 0-3.27); and cardiac electrophysiology (including pacemaker procedures) 6.6% (95% CI 1.1-12.4). CONCLUSIONS: The SLUScore was independently, but variably, associated with 30-day mortality after noncardiac surgery.

Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial.

Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

Tertiary lymphoid structures and B cells: An intratumoral immunity cycle.

The generation of anti-tumor immunity in the draining lymph nodes is known as the cancer immunity cycle. Accumulating evidence supports the occurrence of such a cycle at tumor sites in the context of chronic inflammation. Here, we review the role of tertiary lymphoid structures (TLS) in the generation of T and B cell immunities, focusing on the impact of B cells that undergo full maturation, resulting in the generation of plasma cells (PCs) producing high-affinity IgG and IgA antibodies. In this context, we propose that antibodies binding to tumor cells induce macrophage or natural killer (NK)-cell-dependent apoptosis. Subsequently, released antigen-antibody complexes are internalized and processed by dendritic cells (DCs), amplifying antigen presentation to T cells. Immune complexes may also be fixed by follicular DCs (FDCs) in TLS, thereby increasing memory B cell responses. This amplification loop creates an intra-tumoral immunity cycle, capable of increasing sensitivity of tumors to immunotherapy even in cancers with low mutational burden.

Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.

Standardized Pathology Screening of Mature Tertiary Lymphoid Structures in Cancers.

Mature tertiary lymphoid structures (mTLSs) are organized lymphoid structures containing B lymphocytes admixed to CD23+ follicular dendritic cells. Their presence has been linked to improved survival and sensitivity to immune checkpoint inhibitors in several cancers, emerging as a promising pancancer biomarker. However, the requirements for any biomarker are clear methodology, proven feasibility, and reliability. In 357 patients' samples, we studied tertiary lymphoid structures (TLSs) parameters using multiplex immunofluorescence (mIF), hematoxylin-eosin-saffron (HES) staining, double CD20/CD23 staining, and single CD23 immunohistochemistry. The cohort included carcinomas (n = 211) and sarcomas (n = 146), gathering biopsies (n = 170), and surgical specimens (n = 187). mTLSs were defined as TLSs containing either a visible germinal center on HES staining or CD23+ follicular dendritic cells. Focusing on 40 TLSs assessed using mIF, double CD20/CD23 staining was less sensitive than mIF to assess maturity in 27.5% (n = 11/40) but was rescued by single CD23 staining in 90.9% (n = 10/11). In 97 patients, several samples (n = 240) were reviewed to characterize TLS distribution. The likelihood of finding TLSs in surgical material was 6.1 higher than in biopsy and 2.0 higher in primary samples than in metastasis after adjustment with a type of sample. Interrater agreement rates over 4 examiners were 0.65 (Fleiss kappa, 95% CI [0.46, 0.90]) for the presence of TLS and 0.90 for maturity (95% CI [0.83, 0.99]). In this study, we propose a standardized method to screen mTLSs in cancer samples using HES staining and immunohistochemistry that can be applied to all specimens.

Activation of B cells in Tertiary Lymphoid Structures in cancer: Anti-tumor or anti-self?

Whereas T cells in the tumor microenvironment have been the main focus as cancer controlling cells and targets of immunotherapies, B cells have recently gained strong attention. Being associated to Tertiary Lymphoid Structures (TLS) located at the vicinity of tumor nests, the fate of B cell depends on TLS maturity. In immature TLS they may evolve as regulatory B cells producing immunosuppressive cytokines and promote tumor growth. In mature TLS with a germinal center, B cells are selected, amplified, undergo affinity maturation and isotypic switching, resulting in plasma cell generation and production of anti-tumor antibodies. In that case, they are associated with longer patient's survival and therapeutic response to immunotherapy. Identification of tumor specific, or tumor overexpressed, antigens recognized by "in situ" produced antibodies and their discrimination from self-antigens induced by ICI treatments is a major challenge to develop novel antibody-based immunotherapies.

Antenatal corticosteroids and perinatal outcome in late fetal growth restriction: analysis of prospective cohort.

OBJECTIVE: To evaluate the role of antenatal administration of corticosteroids for fetal lung maturation on the short-term perinatal outcome of pregnancy complicated by late fetal growth restriction (FGR). METHODS: This cohort study was a secondary analysis of a multicenter prospective observational study, the TRUFFLE-2 feasibility study, conducted between 2017 and 2018 in 33 European perinatal centers. The study included women with a singleton pregnancy from 32 + 0 to 36 + 6 weeks of gestation with a fetus considered at risk for FGR, defined as estimated fetal weight (EFW) and/or fetal abdominal circumference < 10th percentile, or umbilicocerebral ratio (UCR) ≥ 95th percentile or a drop of more than 40 percentile points in abdominal circumference measurement from the 20-week scan. For the purposes of the current study, we identified women who received a single course of steroids to improve fetal lung maturation before delivery. Each exposed pregnancy was matched with one that did not receive antenatal corticosteroids (ACS) (control), based on gestational age at delivery and birth weight. The primary adverse outcome was a composite of abnormal condition at birth, major neonatal morbidity or perinatal death. RESULTS: A total of 86 pregnancies that received ACS were matched to 86 controls. The two groups were similar with respect to gestational age (33.1 vs 33.3 weeks), EFW (1673 vs 1634 g) and UCR (0.68 vs 0.62) at inclusion, and gestational age at delivery (35.5 vs 35.9 weeks) and birth weight (1925 vs 1948 g). No significant differences were observed between the exposed and non-exposed groups in the incidence of composite adverse outcome (28% vs 24%; P = 0.73) or any of its elements. CONCLUSION: The present data do not show a beneficial effect of steroids on short-term outcome of fetuses with late FGR. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Impact of intravenous fish oil on omega-3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) can lead to intestinal failure-associated liver disease (IFALD). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA-derived and DHA-derived oxylipins could contribute to this protective effect. METHODS: We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA-derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish-oil PN. RESULTS: EPA plus DHA in erythrocytes (the Omega-3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega-3-Index to 12.75%. EPA-derived and DHA-derived CYP-dependent and LOX-dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. CONCLUSIONS: This study shows that fish oil-containing PN leads to primarily CYP- and LOX-dependent n-3 PUFA-derived inflammation-dampening oxylipins arising from EPA and DHA. Within this short (16-week) study, there were no significant changes in inflammation and clinical readout parameters.

Spatial transcriptomics.

Spatial transcriptomics, with other spatial technologies, has enabled scientists to dissect the organization and interaction of different cell types within the tumor microenvironment. We asked experts to discuss some aspects of this technology from revealing the tumor microenvironment and heterogeneity, to tracking tumor evolution, to guiding tumor therapy, to current technical challenges.

A Transparency Checklist for Carbon Footprint Calculations Applied within a Systematic Review of Virtual Care Interventions.

Increasing concerns about climate change imply that decisions on the digitization of healthcare should consider evidence about its carbon footprint (CF). This study aims to develop a transparency catalogue for reporting CF calculations, to compare results, and to assess the transparency (reporting quality) of the current evidence of virtual care (VC) intervention. We developed a checklist of transparency criteria based on the consolidation of three established standards/norms for CF calculation. We conducted a systematic review of primary studies written in English or German on the CF of VC interventions to check applicability. Based on our checklist, we extracted methodological information. We compared the results and calculated a transparency score. The checklist comprises 22 items in the aim, scope, data and analysis categories. Twenty-three studies out of 1466 records were included, mostly addressing telemedicine. The mean transparency score was 38% (minimum 14%, maximum 68%). On average, 148 kg carbon dioxide equivalents per patient were saved. Digitization may have co-benefits, improving care and reducing the healthcare CF. However, the evidence for this is weak, and CF reports are heterogeneous. Our transparency checklist may serve as a reference for developing a standard to assess the CF of virtual and other healthcare and public health services.

Intraoperative hypotension is associated with persistent acute kidney disease after noncardiac surgery: a multicentre cohort study.

BACKGROUND: Whilst intraoperative hypotension is associated with postoperative acute kidney injury (AKI), the link between intraoperative hypotension and acute kidney disease (AKD), defined as continuing renal dysfunction for up to 3 months after exposure, has not yet been studied. METHODS: We conducted a retrospective multicentre cohort study using data from noncardiac, non-obstetric surgery extracted from a US electronic health records database. Primary outcome was the association between intraoperative hypotension, at three MAP thresholds (≤75, ≤65, and ≤55 mm Hg), and the following two AKD subtypes: (i) persistent (initial AKI incidence within 7 days of surgery, with continuation between 8 and 90 days post-surgery) and (ii) delayed (renal impairment without AKI within 7 days, with AKI occurring between 8 and 90 days post-surgery). Secondary outcomes included healthcare resource utilisation for patients with either AKD subtype or no AKD. RESULTS: A total of 112 912 surgeries qualified for the study. We observed a rate of 2.2% for delayed AKD and 0.6% for persistent AKD. Intraoperative hypotension was significantly associated with persistent AKD at MAP ≤55 mm Hg (hazard ratio 1.1; 95% confidence interval: 1.38-1.22; P<0.004). However, IOH was not significantly associated with delayed AKD across any of the MAP thresholds. Patients with delayed or persistent AKD had higher healthcare resource utilisation across both hospital and intensive care admissions, compared with patients with no AKD. CONCLUSIONS: Intraoperative hypotension is associated with persistent but not delayed acute kidney disease. Both types of acute kidney disease appear to be associated with increased healthcare utilisation. Correction of intraoperative hypotension is a potential opportunity to decrease postoperative kidney injury and associated costs.

B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome.

B cells are a major component of the tumour microenvironment, where they are predominantly associated with tertiary lymphoid structures (TLS). In germinal centres within mature TLS, B cell clones are selectively activated and amplified, and undergo antibody class switching and somatic hypermutation. Subsequently, these B cell clones differentiate into plasma cells that can produce IgG or IgA antibodies targeting tumour-associated antigens. In tumours without mature TLS, B cells are either scarce or differentiate into regulatory cells that produce immunosuppressive cytokines. Indeed, different tumours vary considerably in their TLS and B cell content. Notably, tumours with mature TLS, a high density of B cells and plasma cells, as well as the presence of antibodies to tumour-associated antigens are typically associated with favourable clinical outcomes and responses to immunotherapy compared with those lacking these characteristics. However, polyclonal B cell activation can also result in the formation of immune complexes that trigger the production of pro-inflammatory cytokines by macrophages and neutrophils. In complement-rich tumours, IgG antibodies can also activate the complement cascade, resulting in the production of anaphylatoxins that sustain tumour-promoting inflammation and angiogenesis. Herein, we review the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation as well as the potential of B cells and TLS as prognostic and predictive biomarkers. We also discuss novel therapeutic approaches that are being explored with the aim of increasing mature TLS formation, B cell differentiation and anti-tumour antibody production within tumours.

Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. MATERIALS AND METHODS: Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. RESULTS: Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. CONCLUSION: SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

The expression and role of tenascin C in abdominal aortic aneurysm formation and progression.

OBJECTIVES: Up-regulation of tenascin C (TNC), a matricellular protein, produced mainly by vascular smooth muscle cells (VSMC), is associated with the progression and dilation of abdominal aortic aneurysms (AAA). The aims of this study were (i) to evaluate whether serum levels of TNC in patients with AAA patients correlate with aortic diameter and (ii) to clarify the role of TNC in formation and progression of AAA in a murine model. METHODS: In 15 patients with AAA serum levels of TNC were measured and correlated with aortic diameters. Moreover, in a murine calcium chloride AAA model, the impact of TNC deficiency on AAA diameter was evaluated. Finally, human VSMC were incubated with TNC to clarify its regulating potential. RESULTS: In the clinical cohort, there was a trend of correlation between serum TNC levels and AAA diameter (P = 0.055). TNC knock out mice with AAA showed significantly lower diameter ratios compared to the wild-type group (WT) 3 weeks (P < 0.05) and 10 weeks (P < 0.05) after AAA induction. Immunohistochemistry revealed increased TNC expression in aortic tissue from WT with AAA as compared sham-operated mice. Furthermore, WT with AAA showed a more disrupted Elastin structure than TNC knock out mice 10 weeks after AAA induction. In human aortic VSMC, TNC incubation induced expression of remodelling associated proteins. CONCLUSIONS: TNC might play a causative role in the formation, dilation and progression of AAA. Our results indicate that TNC might be a biomarker as well as a potential therapeutic target in the treatment of AAA.

B cells and cancer.

Tumor-infiltrating B cells complement T cell-mediated antitumor immunity. A panel of experts share their views on the complexity of B cells within the tumor microenvironment, the variety of mechanisms by which these cells control tumor growth, their organization in tertiary lymphoid structures, and their association with immunotherapy response.

Association of perioperative hypotension with subsequent greater healthcare resource utilization.

STUDY OBJECTIVE: Determine if perioperative hypotension, a modifiable risk factor, is associated with increased postoperative healthcare resource utilization (HRU). DESIGN: Retrospective cohort study. SETTING: Multicenter using the Optum® electronic health record database. PATIENTS: Patients discharged to the ward after non-cardiac, non-obstetric surgeries between January 1, 2008 and December 31, 2017 with six months of data, before and after the surgical visit. INTERVENTIONS/EXPOSURE: Perioperative hypotension, a binary variable (presence/absence) at an absolute MAP of ≤65-mmHg, measured during surgery and within 48-h after, to dichotomize patients with greater versus lesser hypotensive exposures. MEASUREMENTS: Short-term HRU defined by postoperative length-of-stay (LOS), discharge to a care facility, and 30-day readmission following surgery discharge. Mid-term HRU (within 6 months post-discharge) quantified via number of outpatient and emergency department (ED) visits, and readmission LOS. MAIN RESULTS: 42,800 distinct patients met study criteria and 37.5% experienced perioperative hypotension. After adjusting for study covariates including patient demographics and comorbidities, patients with perioperative hypotension had: longer LOS (4.01 vs. 3.83 days; LOS ratio, 1.05; 95% CI, 1.04-1.06), higher odds of discharge to a care facility (OR, 1.18; 95% CI, 1.12-1.24; observed rate 22.1% vs. 18.1%) and of 30-day readmission (OR, 1.22; 95% CI, 1.11-1.33; observed rate 6.2% vs. 5.0%) as compared to the non-hypotensive population (all outcomes, p < 0.001). During 6-month follow-up, patients with perioperative hypotension showed significantly greater HRU regarding number of ED visits (0.34 vs. 0.31 visits; visit ratio, 1.10; 95% CI, 1.05-1.15) and readmission LOS (1.06 vs. 0.92 days; LOS ratio, 1.15; 95% CI, 1.07-1.24) but not outpatient visits (10.47 vs. 10.82; visit ratio, 0.97; 95% CI, 0.95-0.99) compared to those without hypotension. There was no difference in HRU during the 6-month period before qualifying surgery. CONCLUSIONS: We report a significant association of perioperative hypotension with an increase in HRU, including additional LOS and readmissions, both important contributors to overall medical costs.

Association of AXL and PD-L1 Expression with Clinical Outcomes in Patients with Advanced Renal Cell Carcinoma Treated with PD-1 Blockade.

PURPOSE: A minority of patients currently respond to single-agent immune-checkpoint blockade (ICB), and strategies to increase response rates are urgently needed. AXL is a receptor tyrosine kinase commonly associated with drug resistance and poor prognosis in many cancer types, including in clear-cell renal cell carcinoma (ccRCC). Recent experimental cues in breast, pancreatic, and lung cancer models have linked AXL with immune suppression and resistance to antitumor immunity. However, its role in intrinsic and acquired resistance to ICB remains largely unexplored. EXPERIMENTAL DESIGN: In this study, tumoral expression of AXL was examined in ccRCC specimens from 316 patients who were metastatic receiving the PD-1 inhibitor nivolumab in the GETUG AFU 26 NIVOREN trial after failure of antiangiogenic therapy. We assessed associations between AXL and patient outcomes following PD-1 blockade, as well as the relationship with various markers, including PD-L1; VEGFA; the immune markers CD3, CD8, CD163, and CD20; and the mutational status of the tumor-suppressor gene von Hippel-Lindau (VHL). RESULTS: Our results show that high AXL-expression level in tumor cells is associated with lower response rates and a trend to shorter progression-free survival following anti-PD-1 treatment. AXL expression was strongly associated with tumor-PD-L1 expression, especially in tumors with VHL inactivation. Moreover, patients with tumors displaying concomitant PD-L1 expression and high AXL expression had the worst overall survival. CONCLUSIONS: Our findings propose AXL as candidate factor of resistance to PD-1 blockade, and provide compelling support for screening both AXL and PD-L1 expression in the management of advanced ccRCC.See related commentary by Hahn et al., p. 6619.

Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma.

Context: The number of prognostic markers for clear cell renal cell carcinoma (ccRCC) has been increasing regularly over the last 15 years, without being integrated and compared. Objective: Our goal was to perform a review of prognostic markers for ccRCC to lay the ground for their use in the clinics. Evidence Acquisition: PubMed database was searched to identify RNA and protein markers whose expression level was reported as associated with survival of ccRCC patients. Relevant studies were selected through cross-reading by two readers. Evidence Synthesis: We selected 249 studies reporting an association with prognostic of either single markers or multiple-marker models. Altogether, these studies were based on a total of 341 distinct markers and 13 multiple-marker models. Twenty percent of these markers were involved in four biological pathways altered in ccRCC: cell cycle, angiogenesis, hypoxia, and immune response. The main genes (VHL, PBRM1, BAP1, and SETD2) involved in ccRCC carcinogenesis are not the most relevant for assessing survival. Conclusion: Among single markers, the most validated markers were KI67, BIRC5, TP53, CXCR4, and CA9. Of the multiple-marker models, the most famous model, ClearCode34, has been highly validated on several independent datasets, but its clinical utility has not yet been investigated. Patient Summary: Over the years, the prognosis studies have evolved from single markers to multiple-marker models. Our review highlights the highly validated prognostic markers and multiple-marker models and discusses their clinical utility for better therapeutic care.

Intracellular Factor H Drives Tumor Progression Independently of the Complement Cascade.

The complement system is a powerful and druggable innate immune component of the tumor microenvironment. Nevertheless, it is challenging to elucidate the exact mechanisms by which complement affects tumor growth. In this study, we examined the processes by which the master complement regulator factor H (FH) affects clear cell renal cell carcinoma (ccRCC) and lung cancer, two cancers in which complement overactivation predicts poor prognosis. FH was present in two distinct cellular compartments: the membranous (mb-FH) and intracellular (int-FH) compartments. Int-FH resided in lysosomes and colocalized with C3. In ccRCC and lung adenocarcinoma, FH exerted protumoral action through an intracellular, noncanonical mechanism. FH silencing in ccRCC cell lines resulted in decreased proliferation, due to cell-cycle arrest and increased mortality, and this was associated with increased p53 phosphorylation and NFκB translocation to the nucleus. Moreover, the migration of the FH-silenced cells was reduced, likely due to altered morphology. These effects were cell type-specific because no modifications occurred upon CFH silencing in other FH-expressing cells tested: tubular cells (from which ccRCC originates), endothelial cells (human umbilical vein endothelial cells), and squamous cell lung cancer cells. Consistent with this, in ccRCC and lung adenocarcinoma, but not in lung squamous cell carcinoma, int-FH conferred poor prognosis in patient cohorts. Mb-FH performed its canonical function of complement regulation but had no impact on tumor cell phenotype or patient survival. The discovery of intracellular functions for FH redefines the role of the protein in tumor progression and its use as a prognostic biomarker or potential therapeutic target.See article by Daugan et al., p. 891 (36).