Bioprosthetic aortic valve replacement in patients aged 50 years old and younger: Structural valve deterioration at long-term follow-up. Retrospective study.

Background: Structural valve deterioration (SVD) remains the major determinant of bioprosthesis durability. The aim of this study was to investigate the SVD incidence, predictors and outcomes in patients aged 50 years and younger after bioprosthetic aortic valve replacement (bAVR). Methods: We retrospectively analyzed 73 consecutive patients ≤50 years old who underwent bioprosthetic AVR at our center between 2005 and 2015. Median age at surgery was 44 (interquartile range [IQR]: 39-47) years. Follow-up was 93.2% complete at a median time of 7.2 (IQR: 5.5-9.5) years. Cumulative follow-up was 545.5 valve-years. Bioprosthesis SVD was determined by strict echocardiographic assessment. Results: The overall survival-rate at 10/15 years and freedom from SVD at 10/12.5 years were 89.6 ± 5.2%/81.5 ± 9.1% and 73.5 ± 8.2%/41.9 ± 18.9%, respectively. SVD occurred at a median time of 8.2 (IQR: 6.0-9.9) years after bAVR. Age was not found as an independent predictor for SVD at the multivariable model, despite a higher rate of SVD in the age group ≤30 years. Freedom from reoperation due to SVD at 10/15 years was 71.3 ± 14.1%/13.6 ± 12.3%. Reoperation was performed at a median time of 10.0 (IQR: 8.9-11.9) years since first bAVR and was associated with a 100% 12-month survival. Conclusions: In our study, the rate and time of SVD occurrence were comparable to those of other studies' older age groups. Strict echocardiographic monitoring of valve performance is mandatory to set the appropriate timing of eventual reoperation. This attitude can improve outcomes of bAVR in younger patients.

Dual drug targeting to kill colon cancers.

INTRODUCTION: Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair-wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. OBJECTIVES: To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. METHODS: The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro-cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. RESULTS: Colon cancer cells in non-adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro-apoptotic Bcl-2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. CONCLUSION: By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro-survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro-survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations.

Novel Transcatheter Mitral Prosthesis Designed to Preserve Physiological Ventricular Flow Dynamics.

BACKGROUND: Current mitral bioprostheses are akin to the aortic valve and therefore abolish the left ventricular (LV) physiological vortex. We evaluated the hemodynamic performance and the effects on intraventricular flow dynamics (IFD) of a novel mitral bioprosthesis that presents an innovative design mimicking the native valve. METHODS: A D-shaped self-expandable stent-bovine pericardium monoleaflet valve was designed to provide physiological asymmetric intraventricular flow. Transapical implantation was consecutively performed in 12 juvenile sheep. Postimplant studies using Doppler echocardiography and IFD using echo particle imaging velocimetry were obtained immediately after the implantation and at 3 months to assess the hemodynamic performance of the prostheses. RESULTS: There were 3 deaths during follow-up, 1 due to valve misplacement because of poor imaging visualization and 2 not valve related. The mean transvalvular gradient and effective orifice area were 2.2 ± 1.2 mm Hg and 4.0 ± 1.1 cm2 after implantation and 3.3 ± 1.5 mm Hg and 3.5 ± 0.5 cm2 at 3 months, respectively. LV vortex dimension, orientation, and physiological anticlockwise rotation were preserved compared with preoperative normal LV flow pattern. One animal showed a moderate paravalvular leak, others mild or none. LV outflow tract obstruction, valve thrombosis, and hemolysis were not observed. CONCLUSIONS: Our preclinical in vivo results confirm the good hemodynamic performance of this new transcatheter bioprosthesis with preservation of the physiological IFD. Clinical studies are needed to document whether these characteristics will foster LV recovery and improve the clinical outcome of patients with mitral regurgitation.

Coronary Artery Perforation, Subepicardial Hematoma, and Cardiac Tamponade After Complex Percutaneous Coronary Intervention.

This report presents the case of fissured subepicardial hematoma and cardiac tamponade after coronary artery perforation during a complex percutaneous intervention. Surgical therapy was required to achieve hemostasis because a percutaneous sealing result was insufficient. Prompt recognition and cardiac surgery availability are essential for patient survival in such situations. (Level of Difficulty: Beginner.).

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial.

INTRODUCTION: Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC. METHODS: Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria. RESULTS: 27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response. CONCLUSIONS: Early-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

Poly (ADP-ribose) polymerase inhibitors in solid tumours: Systematic review and meta-analysis.

BACKGROUND: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt). METHODS: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied. RESULTS: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51-0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16-1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80-0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43-0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours. CONCLUSION: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.

Tumor Type Agnostic Therapy Carrying BRAF Mutation: Case Reports and Review of Literature.

BACKGROUND: Precision medicine is based on molecular and genotypic patient characterization to define specific target treatment. BRAF mutation is an oncogenic driver, and the Cancer Genome Atlas has identified BRAF mutations in different cancer types. Tumor type agnostic therapy is based on targeting genomic alterations, regardless of tumor origin. In this context, novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape in solid tumors have been investigated. Case presentation, Case 1: The first case is chemotherapy-refractory, BRAF V600E mutated intrahepaticcholangiocarcinoma treated with vemurafenib and cobimetinib as third line therapy. In this setting the dual BRAF and MEK inhibition resulted in improved progression-free survival and quality of life; Case 2: The second case shows aBRAF G466A mutated Bellini duct carcinoma (BDC), treated with dabrafenib and trametinib in second line therapy. The disease remained under control for 11 months after the first relapse. DISCUSSION: In the literature there is strong evidence that melanoma, colorectal cancer, non small cell lung cancer and anaplastic thyroid cancer with BRAF mutations are good targets for BRAF/MEK pathway inhibitors. The VE-BASKET and ROAR basket trials explored the efficacy of vemurafenib and the combination of dabrafenib/trametinib, respectively, in BRAF V600 mutation-positive cancers other than melanoma, papillary thyroid cancer, colorectal cancer and non small cell lung cancer. Within the concept of tumor type agnostic therapy, we decided to treat our BRAF-mutated tumors with the association of BRAF and MEK inhibitors. CONCLUSIONS: Our results confirm the emerging importance of molecular tumor profiling for the successful management of cancer, and the potential of BRAF-targeted therapy in the treatment of rare solid tumors with poor prognosis and no clinical benefit from systemic therapies with.

Early Changes of the Standardized Uptake Values (SUVmax) Predict the Efficacy of Everolimus-Exemestane in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Background: The mTORC1 inhibitor everolimus has been approved in combination with the aromatase inhibitor exemestane for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (HR+ mBC) progressing on prior therapy with a non-steroidal aromatase inhibitor. To date, no predictive biomarkers of tumor sensitivity/resistance for everolimus-based treatments have been identified. We hypothesized that precocious changes in the Standardized Uptake Volume (∆SUV%), as assessed by 18F-Fluorodeoxyglucosepositron-emission tomography (18F-FDG PET/CT), may be a marker of everolimus efficacy. Methods: This was a retrospective study including 31 HR+ HER2- patients treated with everolimus and exemestane in two Italian centers between 2013 and 2018. The objective of the study was to investigate ∆SUV% as a predictive marker of everolimus antitumor efficacy. 18F-FDG PET/CT scans were performed at baseline and after three months of treatment. Patients were defined as long responders (LRs) if disease progression occurred at least 10 months after treatment initiation and long survivors (LSs) if death occurred later than 36 months after starting therapy. ROC analysis was used to determine the optimal cut-off values of ∆SUV% to distinguish LRs from non-LRs and LSs from non-LSs. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: The SUVmax values decreased significantly from baseline to 3 months after therapy (p = 0.003). Dynamic changes of SUVmax (Delta SUV) had a higher accuracy in discriminating long-responders from non-long-responders (AUC = 0.67, Delta SUV cut-off = 28.8%) respects to its ability to identify long survivors from no-long survivors (AUC = 0.60, Delta SUV cut-off = 53.8%). Patients were divided into groups according to the Delta SUV cut-offs and survival outcomes were evaluated: patients with a decrease of ∆SUV% ≥ 28.8% had significantly better PFS (10 months-PFS: 63.2%, 95% CI: 37.9-80.4% and 16.7%, 95% CI: 2.7-41.3% respectively, p = 0.005). As regard as OS, patients with ∆SUV% ≥ 53.8% had longer OS when compared to patients with ∆SUV% < 53.8% (36 month-OS: 82.5% vs. 45.9% vs. p = 0.048). Conclusion: We found two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients, which would achieve long-term benefit or long-term survival during everolimus-exemestane therapy. These results warrant further validation in prospective studies and should be integrated with molecular biomarkers related to tumor metabolism and mTORC1 signaling.

Features of degenerative mitral valve prolapse in the North East of China: repair characteristics, and short-term follow-up results.

BACKGROUND: We aimed to assess the clinical and echocardiographic characteristics of patients who underwent surgery for degenerative mitral valve prolapse (MVP) in our center, and its relation to outcomes. METHODS: We enrolled 117 consecutive patients from North-East China with an echocardiographic diagnosis of MVP related mitral regurgitation (MR) between April 2018 and November 2019. A complexity scoring system was used for valve anatomy, and patients were re-evaluated at 3-6 months after surgery. RESULTS: Most patients (57.3%) were 40-59 years old. Ejection fraction was <60% in one third, and pulmonary hypertension was present in 64.3% of operated patients. Etiology was myxomatous in 58.9%, with flail as main lesion. Leaflet involvement was posterior in 59.8% patients, anterior in 32.5%, bileaflet in 6%, and commissural in 25.6%. Lesion score was intermediate in >50% of patients, and myxomatous lesions scored higher compared to fibroelastic deficiency (FED). Degree of MR left atrial volume and estimated wedge pressure were significantly higher in intermediate and complex lesions. Repair was performed in 93/101 patients (95.8% success rate). No in-hospital major adverse events, nor deaths at follow-up were reported. Residual MR was ≤ mild in 86.7% of patients at follow-up and was associated with FED etiology and complex lesions. CONCLUSIONS: Compared to Western countries, in our sample of Chinese population degenerative severe MR occurred in younger patients. The MVP lesion characteristics are similar, can be accurately detected by non-invasive preoperative evaluation, allowing predictable results. Advanced tailored repair techniques allow excellent immediate and short-term results regardless of the underlying complexity.

Expression patterns and clinical significance of the potential cancer stem cell markers OCT4 and NANOG in colorectal cancer patients.

Colorectal cancer (CRC) is one of the most important malignancies and causes of cancer-related deaths worldwide. Cancer stem cell markers identification could be helpful to acquire important prognostic information and develop new treatment regimens. This study aimed to evaluate the expression of OCT4 and NANOG in CRC patients and their clinical significance.Totally 359 CRC samples were stained for OCT4 and NANOG expression using tissue microarray. The correlation between their expression and clinical and pathological features was explored.The majority of CRC cases showed low-level expression of OCT4 (80%) and NANOG (75%). Lower expression of OCT4 was more often detected in CRC cases with no vascular involvement (P = .01). Also, a trend found between low level of OCT4 expression and absence of distant metastasis or lymph node involvement (P = .07 and P = .09, respectively). Surprisingly, a significant positive correlation was observed between NANOG expression and cellular differentiation (P = .05). Our combined analysis demonstrated that OCT4 low/NANOG low phenotype has frequently seen in colorectal cancer cases with no vascular invasion (P = .05).Our observations indicated that higher expression of OCT4 and NANOG can confer malignant and aggressive behavior to CRC. Evaluation of the co-expression of these cancer stem cell markers can serve a new diagnostic and prognostic approach in CRC patients. These findings also suggested that simultaneous expression of OCT4 and NANOG can be considered as a therapeutic marker for targeted therapy of CRC, especially in advanced stages.

Immune system and angiogenesis-related potential surrogate biomarkers of response to everolimus-based treatment in hormone receptor-positive breast cancer: an exploratory study.

PURPOSE: mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity. METHODS: We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study. RESULTS: The circulating levels of CD3+/CD8+, CD3+/CD4+, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p < 0.001, p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p < 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after. CONCLUSIONS: Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.

Impact of BMI on the outcome of metastatic breast cancer patients treated with everolimus: a retrospective exploratory analysis of the BALLET study.

INTRODUCTION: Reliable biomarkers of response to mTOR inhibition are yet to be identified. As mTOR is heavily implicated in cell-metabolism, we investigated the relation between BMI variation and outcomes in metastatic breast cancer (mBC) patients treated with everolimus. RESULTS: we found a linear correlation between everolimus exposure duration and BMI/weight decrease. Patients exhibiting >2 kg weight loss or >3% BMI decrease from baseline at the end of treatment (EOT) had a statistically significant improvement in PFS. Interestingly, a similar BMI/weight decrease within the first 8 weeks of therapy identified patients at higher risk of progression. PATIENTS AND METHODS: we performed a retrospective analysis of patients enrolled in the BALLET trial who progressed during the study. Primary end-point was progression-free survival (PFS). Secondary end-point was the identification of other predictors of response. CONCLUSION: A >3% weight loss at EOT is associated with better outcome in mBC patients treated with everolimus. On the contrary, a significant early weight loss represents a predictor of poor survival and could therefore be used as an early negative prognostic marker. As PI3K-inhibition also converges onto mTOR, these findings might extend to patients treated with selective PI3K inhibitors and warrant further investigation.

Association between neutropenia and response to ramucirumab and paclitaxel in patients with metastatic gastric cancer.

The aim of this study was to evaluate if the occurrence of neutropenia is correlated with response to ramucirumab plus paclitaxel for metastatic gastric cancer. This is a retrospective study of patients treated with ramucirumab plus paclitaxel. Fifty-three patients were evaluated. Among these, 10 patients (26.5%) developed grade ≥3 neutropenia. Patients with grade ≥3 neutropenia reported a progression-free survival of 6.6 months (95% confidence interval 3.3-8.4) and overall survival of 11 months (95% confidence interval 5.9-13.1) vs. 4.4 months (95% confidence interval 3.9-5.2) and 8.7 months (95% confidence interval 7.8-10.1) respectively in patients' group with lower grade events. Our analysis seems to suggest that the occurrence of neutropenia predicts response to treatment with ramucirumab and paclitaxel.

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.

Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.

Corticosteroid switch after progression on abiraterone acetate plus prednisone.

INTRODUCTION: Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone. MATERIALS AND METHODS: The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. RESULTS: A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. CONCLUSION: Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone.

Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

BACKGROUND: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. METHODS: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. RESULTS: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36-0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72-0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57-0.74; p < 0.001) in patients with PD-L1 positive tumours. CONCLUSIONS: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.