CXCR2/Snail-1-Induced Epithelial-Mesenchymal Transition in the Formation and Progression of RCC with Inferior Vena Cava Tumour Thrombus.

BACKGROUND: Renal cell carcinoma (RCC), a common and highly invasive malignant tumour, presents clinical challenges due to its propensity for easy metastasis. Inferior vena cava tumour thrombus is a common RCC complication significantly impacting patient prognosis. This study investigates C-X-C chemokine receptor type 2 (CXCR2)/Snail-1-induced epithelial-mesenchymal transition (EMT) in RCC with inferior vena cava tumour thrombus. METHODS: Tissues from 51 RCC patients were analysed for CXCR2 and Snail-1 Messenger Ribonucleic Acid (mRNA) levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Elevated levels of both were observed in tumour and inferior vena cava tumour thrombus tissues. Using Short Hairpin RNA (shRNA) technology, we inhibited CXCR2 and Snail-1 expression to investigate their impact on EMT, invasiveness, and metastatic potential in RCC cells. RESULTS: Compared with that in the Short Hairpin RNA-Negative Control (ShNC) group, inhibition of CXCR2 and Snail-1 suppressed the degree of EMT, invasiveness, and metastatic ability of RCC cells (p < 0.01). Further mechanistic studies showed that CXCR2/Snail-1 participated in the formation and progression of RCC by regulating the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathways. Additionally, compared with that in the ShNC group, knockdown of CXCR2 and Snail-1 significantly inhibited the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9; p < 0.01), thereby regulating the metastasis of RCC. CONCLUSIONS: Our findings suggest that CXCR2/Snail-1-induced EMT plays an important role in the formation and progression of RCC with inferior vena cava tumour thrombus. CXCR2/Snail-1 participates in the invasion and metastasis of RCC by regulating the expression of multiple signalling pathways and related genes. These results provide new insights and directions for the treatment of RCC.

High serum sodium predicts immunotherapy response in metastatic renal cell and urothelial carcinoma.

OBJECTIVES: The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. METHODS: We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. RESULTS: We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. CONCLUSIONS: Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities.

Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Patient's self-reported quality of life as a prognostic factor in metastatic renal cell carcinoma initially treated with TKI: nomogram proposal.

BACKGROUND: Numerous prognostic factors have been described for metastatic renal cell carcinoma (mRCC). There are nomograms to assist in clinical decision-making and inform patients of their disease progression. However, they have a limited capacity and moderate concordance rates. Performance status (PS) is one of the most widely used prognostic factors and most closely related to overall survival (OS), but this is a subjective assessment based solely on the clinician's opinion. Patients must be at the center of care. Patient-reported outcomes (PROs) have shown benefits but are not widespread in daily clinical practice. METHODS: We analyzed 78 consecutive patients diagnosed with mRCC who initiated treatment at our institution between September 2012 and September 2019. We performed a descriptive analysis of the sample's baseline characteristics and the NCCN FKSI 19 questionnaire. We also conducted a survival analysis. RESULTS: The baseline FKSI 19 score demonstrates its prognostic potential, HR of 0.94 (95% CI 0.92-0.97). Our prognostic model would include: FKSI < 58 (HR 3.61 95% CI 1.97-6.61), anemia, thrombocytosis, non-clear cell histology, and metastatic hepatic involvement. AUC 0.86 (95%CI 0.77-0.95). CONCLUSION: Although it would need external validation, the proposed nomogram could be an alternative to other previously described models. The NCCN FKSI 19 baseline score could replace the clinician's subjective determination of PS. CLINICAL TRIAL REGISTRATION: Not applicable.

Validation of the Lung Immune Prognostic Index (LIPI) as a prognostic biomarker in metastatic renal cell carcinoma.

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is associated with immune checkpoint inhibitors (ICI) outcomes across different solid tumors, particularly in non-small cell lung cancer. Data regarding the prognostic and/or predictive role of LIPI in metastatic renal cell carcinoma (mRCC) are still scarce. The aim of this study was to evaluate whether LIPI could be predictive of survival in mRCC patients. METHODS: We used patient level data from three different prospective studies (NIVOREN trial: nivolumab; TORAVA trial: VEGF/VEGFR-targeted therapy (TT); CheckMate 214: nivolumab-ipilimumab vs sunitinib). LIPI was calculated based on a derived neutrophils/(leukocyte-neutrophil) ratio > 3 and lactate-dehydrogenase >upper limit of normal, classifying patients into three groups (LIPI good, 0 factors;LIPI intermediate (int), 1 factor;LIPI poor, 2 factors) and/or into two groups (LIPI good, 0 factors;LIPI int/poor, 1-2 factors) according to trial sample size. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: In the Nivolumab dataset (n = 619), LIPI was significantly associated with OS (LIPI-good 30.1 vs 13.8 months in the LIPI int/poor; HR= 0.47) and PFS (HR=0.74). In the VEGF/VEGFR-TT dataset (n = 159), only a correlation with PFS was observed. In the CheckMate214 dataset (n = 1084), LIPI was significantly associated with OS (nivolumab-ipilimumab OS LIPI good vs int/poor: HR=0.55, p < 0.0001; sunitinib: OS LIPI good vs int/poor: 0.38, p < 0.0001) in both treatment groups in univariate and multivariate analysis. CONCLUSIONS: Pretreatment-LIPI correlated with worse survival outcomes in mRCC treated with either ICI or antiangiogenic therapy, confirming LIPI's prognostic role in mRCC irrespective of systemic treatment used.

Safety and efficacy of nivolumab therapy in patients with metastatic renal cell carcinoma and impaired kidney function.

INTRODUCTION: Patients with renal insufficiency, usually defined as those with creatinine clearance < 40 mL/min, were excluded from pivotal clinical trials, especially in studies involving nivolumab therapy in patients with renal cell carcinoma (RCC). The aim of the study is to evaluate the efficacy and safety of nivolumab in patients with metastatic RCC (mRCC) stratified according to creatinine clearance. MATERIAL AND METHODS: Data from mRCC patients treated with nivolumab were retrospectively analyzed. Patients were classified into two categories according to their estimated glomerular filtration rate (eGFR); the first category (C1) included patients with eGFR < 40 mL/min/1.73 m2 and the second category (C2) included those with eGFR ≥ 40 mL/min/1.73 m2. RESULTS: Of the 95 patients enrolled, 1. group included 26 patients (27.4%) and 2. group included 69 patients (72.6%). None of the pts in category 1 were on hemodialysis. Overall incidence of adverse events was not statistically different between the two groups (P = .469). The overall response rate ORR was 50% in the first group and 42.0% in the second group (P = .486). Median overall survival (OS) was longer with 23.3 months in the 2. group versus 11 months in the 1. group (P = .415). CONCLUSION: Renal insufficiency is a common problem in patients with advanced renal cancer since they often undergo nephrectomy and their renal function may also worsen while receiving tyrosine kinase inhibitor therapy. We found that there is no significant difference in the safety and efficacy of nivolumab treatment between two groups. Nivolumab appears to be a safe and effective agent in patients with renal impairment.

Surgical management of renal cell carcinoma with subhepatic inferior vena cava tumor thrombus: a case report and review of the literature.

BACKGROUND: Renal cell carcinomas are the most common form of kidney cancer in adults. In addition to metastasizing in lungs, soft tissues, bones, and the liver, it also spreads locally. In 2-10% of patients, it causes a thrombus in the renal or inferior vena cava vein; in 1% of patients thrombus reaches the right atrium. Surgery is the only curative option, particularly for locally advanced disease. Despite the advancements in laparoscopic, robotic and endovascular techniques, for this group of patients, open surgery continues to be among the best options. CASE REPORT: Here we present a case of successful tumor thrombectomy from the infrahepatic inferior vena cava combined with renal vein amputation and nephrectomy. Our patient, a 58 year old Albanian woman presented to the doctors office with flank pain, weight loss, fever, high blood pressure, night sweats, and malaise. After a comprehensive assessment, which included urine analysis, complete blood count, electrolytes, renal and hepatic function tests, as well as ultrasonography and computed tomography, she was diagnosed with left kidney renal cell carcinoma involving the left renal vein and subhepatic inferior vena cava. After obtaining informed consent from the patient we scheduled her for surgery, which went well and without complications. She was discharged one week after to continue treatment with radiotherapy, chemotherapy, and immunotherapy. CONCLUSION: Open surgery is a safe and efficient way to treat renal cell carcinoma involving the renal vein and inferior vena cava. It is superior to other therapeutic modalities. When properly done it provides acceptable long time survival and good quality of life to patients.

The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma: a retrospective cohort study.

PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.

Renal Cell Carcinoma Metastasis to the Penis: A Case Report and Literature Review.

Metastasis to the penis from renal cell carcinoma (RCC) or any other primary cancer site is unusual; when it does occur, it often involves multiple organs. A 75-year-old man presented with penile pain and swelling. Three months earlier, he had open radical nephrectomy with thrombectomy and was diagnosed with clear-cell RCC with tumor thrombosis in the inferior vena cava. The follow-up imaging indicated metastasis to the penis, prompting a total penectomy due to worsening pain. The excised mass displayed features consistent with metastatic RCC. This case underscores the need to consider rare metastatic sites, such as the metastasis of RCC to the penis, in RCC patients.

Sweet syndrome with peripheral neuropathy in a patient with metastatic clear cell renal cell carcinoma.

A female patient in her 70s with a newly diagnosed clear cell renal cell carcinoma (ccRCC) with osseous metastasis presented with sudden onset erythematous painful blistering skin lesions on the dorsum of both hands, with associated intermittent fever episodes. Blood tests showed elevated inflammatory marker levels (C reactive protein 257.8 mg/dL, leucocytes 17.79×109/L, with 94% neutrophils). Histologically, there was predominately neutrophil dermal infiltrate without leucocytoclastic vasculitis. The diagnostic criteria of Sweet syndrome were fulfilled. A week later, the patient developed abrupt left-hand palsy, which was confirmed as a medial and ulnar sensorimotor axonal peripheral neuropathy of paraneoplastic origin. The patient was prescribed a course of oral high-dose steroids, which significantly improved the skin lesions. The peripheral nerve palsy improved after 3 months. This case describes the two very rare concurrent paraneoplastic manifestations of ccRCC occurring simultaneously, which have been rarely reported.

Preliminary Investigation of a Rapid and Feasible Therapeutic Drug Monitoring Method for the Real-Time Estimation of Blood Pazopanib Concentrations.

Pazopanib is a multi-kinase inhibitor used to treat advanced/metastatic renal cell carcinoma and advanced soft tissue tumors; however, side effects such as diarrhea and hypertension have been reported, and dosage adjustment based on drug concentration in the blood is necessary. However, measuring pazopanib concentrations in blood using the existing methods is time-consuming; and current dosage adjustments are made using the results of blood samples taken at the patient's previous hospital visit (approximately a month prior). If the concentration of pazopanib could be measured during the waiting period for a doctor's examination at the hospital (in approximately 30 min), the dosage could be adjusted according to the patient's condition on that day. Therefore, we aimed to develop a method for rapidly measuring blood pazopanib concentrations (in approximately 25 min) using common analytical devices (a tabletop centrifuge and a spectrometer). This method allowed for pazopanib quantification in the therapeutic concentration range (25-50 µg/mL). Additionally, eight popular concomitant medications taken simultaneously with pazopanib did not interfere with the measurements. We used the developed method to measure blood concentration in two patients and obtained similar results to those measured using the previously reported HPLC method. By integrating it with the point of care and sample collection by finger pick, this method can be used for measurements in pharmacies and patients' homes. This method can maximize the therapeutic effects of pazopanib by dose adjustment to control adverse events.

External validation of a red cell-based blood prognostic score in patients with metastatic renal cell carcinoma treated with first-line immunotherapy combinations.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling.

Renal cell carcinoma (RCC) spreading to the larynx: an unusual condition.

A man in his mid-70s, heavy smoker with chronic alcohol consumption and a chronic exposure to insecticides and burning of crop residues was referred to the surgical oncology department because of a 4-month onset of hoarseness, dyspnoea and laryngeal stridor. He had a history of left nephrectomy due to Fuhrman IV clear cell renal cancer 2 years ago. The patient underwent a bronchoscopy which identified a deforming tumour of the left vallecula, occlusion of 90% of the lumen and did not allow a safe biopsy. Following discussion between the oncological team, total laryngectomy and bilateral neck dissection of levels II, III, IV and V were performed, finding a transglottic tumour of approximately 4×3 cm with extension to the right anterolateral thyroid cartilage. The pathology report described metastatic RCC. The patient recovered well postoperatively and started systemic therapy with a vascular endothelial growth factor receptors inhibitor.

Prognostic outcomes in patients with metastatic renal cell carcinoma receiving second-line treatment with tyrosine kinase inhibitor following first-line immune-oncology combination therapy.

OBJECTIVES: This study aimed to assess the prognostic outcomes in mRCC patients receiving second-line TKI following first-line IO combination therapy. METHODS: This study retrospectively included 243 mRCC patients receiving second-line TKI after first-line IO combination therapy: nivolumab plus ipilimumab (n = 189, IO-IO group) and either pembrolizumab plus axitinib or avelumab plus axitinib (n = 54, IO-TKI group). Oncological outcomes between the two groups were compared, and prognostication systems were developed for these patients. RESULTS: In the IO-IO and IO-TKI groups, the objective response rates to second-line TKI were 34.4% and 25.9% (p = 0.26), the median PFS periods were 9.7 and 7.1 months (p = 0.79), and the median OS periods after the introduction of second-line TKI were 23.1 and 33.5 months (p = 0.93), respectively. Among the several factors examined, non-CCRCC, high CRP, and low albumin levels were identified as independent predictors of both poor PFS and OS by multivariate analyses. It was possible to precisely classify the patients into 3 risk groups regarding both PFS and OS according to the positive numbers of the independent prognostic factors. Furthermore, the c-indices of this study were superior to those of previous systems as follows: 0.75, 0.64, and 0.61 for PFS prediction and 0.76, 0.70, and 0.65 for OS prediction by the present, IMDC, and MSKCC systems, respectively. CONCLUSIONS: There were no significant differences in the prognostic outcomes after introducing second-line TKI between the IO-IO and IO-TKI groups, and the histopathology, CRP and albumin levels had independent impacts on the prognosis in mRCC patients receiving second-line TKI, irrespective of first-line IO combination therapies.