Progression-free survival after front line, second line and third line in patients with follicular lymphoma treated in clinical practice.

BACKGROUND: The modern-day therapeutic landscape for follicular lymphoma (FL) includes a number of highly effective therapies. PATIENTS AND METHODS: We set out to determine progression-free survival (PFS) after front line, second line, and third line of therapy on the basis of relevant biological characteristics and therapeutic choices. Patients (n = 743, 51% females, median 60 years old) diagnosed with grade 1-2 FL between 1997 and 2016 in nine institutions were included. RESULTS: The median PFS1, PFS2, and PFS3 were 8.1 years (95% confidence interval [CI]: 7-9.3 years), 4.2 years (95% CI: 2.8-5.6 years) and 2.2 years (95% CI 1.7-2.8 years). We found longer PFS1 for (1) females, (2) younger age, (3) lower-risk follicular lymphoma international prognostic index (FLIPI), (4) standard intensity (over low intensity) regimens and (5) immunochemotherapy strategies and (6) maintenance rituximab. We found a shorter PFS2 for patients who received front-line immunochemotherapy. Older age at diagnosis correlated with a shorter PFS3. Intensity of front-line chemotherapy, maintenance, or POD24 status did not correlate with PFS2 or PFS3 in this dataset. INTERPRETATION: With current immunochemotherapy strategies, the natural course of FL is characterized by shorter-lasting remissions after each relapse. It will be interesting to see whether new therapies can alter this pattern.

Front-line and second-line treatment for mantle cell lymphoma in clinical practice: A multicenter retrospective analysis.

BACKGROUND: There are few reports of clinical practice treatment patterns and efficacy in mantle cell lymphoma (MCL). MATERIALS AND METHODS: We retrospectively studied a large, multicenter, cohort of patients with MCL diagnosed between 2000 and 2020 in eight institutions. RESULTS: 536 patients were registered (73% male, median of 70 years). Front-line treatment was based on high-dose cytarabine, bendamustine, and anthracyclines in 42%, 12%, and 15%, respectively. The median PFS for all patients was 45 months; 68, 34, and 30 months for those who received high-dose cytarabine-based, bendamustine-based and anthracycline-based therapy. 204 patients received second-line. Bendamustine-based treatment was the most common second-line regimen (36% of patients). The median second-line PFS (sPFS) for the entire cohort was 14 months; 19, 24, and 31 for bendamustine-, platinum-, and high-dose cytarabine-based regimens, with broad confidence intervals for these latter estimates. Patients treated with cytarabine-based therapies in the front-line and those with front-line PFS longer than 24 months had a substantially superior sPFS. CONCLUSION: Front-line treatment in this cohort of MCL was as expected and with a median PFS of over 3.5 years. Second-line treatment strategies were heterogeneous and the median second-line PFS was little over 1 year.

Gut microbiome-derived bacterial extracellular vesicles in patients with solid tumours.

INTRODUCTION: Gut microbiome-derived nanoparticles, known as bacterial extracellular vesicles (bEVs), have garnered interest as promising tools for studying the link between the gut microbiome and human health. The diverse composition of bEVs, including their proteins, mRNAs, metabolites, and lipids, makes them useful for investigating diseases such as cancer. However, conventional approaches for studying gut microbiome composition alone may not be accurate in deciphering host-gut microbiome communication. In clinical microbiome research, there is a gap in the knowledge on the role of bEVs in solid tumor patients. OBJECTIVES: Analyzing the functionality of bEVs using (meta)genomics and proteomics could highlight the unique aspects of host-gut microbiome interactions in solid tumor patients. Therefore, we performed a comparative analysis of the proteome and microbiota composition of gut microbiome-derived bEVs isolated from patients with solid tumors and healthy controls. METHODS: After isolating bEVs from the feces of solid tumor patients and healthy controls, we performed spectrometry analysis of their proteomes and next-generation sequencing (NGS) of the 16S gene. We also investigated the gut microbiomes of feces from patients and controls using 16S sequencing and used machine learning to classify the samples into patients and controls based on their bEVs and fecal microbiomes. RESULTS: Solid tumor patients showed decreased microbiota richness and diversity in both the bEVs and feces. However, the bEV proteomes were more diverse in patients than in the controls and were enriched with proteins associated with the metabolism of amino acids and carbohydrates, nucleotide binding, and oxidoreductase activity. Metadata classification of samples was more accurate using fecal bEVs (100%) compared with fecal samples (93%). CONCLUSION: Our findings suggest that bEVs are unique functional entities. There is a need to explore bEVs together with conventional gut microbiome analysis in functional cancer research to decipher the potential of bEVs as cancer diagnostic or therapeutic biomarkers.

Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?

BACKGROUND: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions. OBJECTIVE: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature. CONCLUSIONS: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations. PATIENT SUMMARY: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.

Estimating the Lifetime Treatment Burden of Patients With Follicular Lymphoma: A Retrospective Study Using Real-World Multicenter Data.

PURPOSE: Although follicular lymphoma is characterized by long natural history and frequent relapses, data on the number of patients receiving subsequent therapy lines are scarce. To perform reliable health economical calculations for various treatment options, data regarding the lifetime number of therapy courses are needed. The purpose of this study was to use real-world data to create a model that could estimate the treatment burden over a 20-year period. MATERIALS AND METHODS: We performed a 20-year simulation on the basis of retrospectively obtained multicenter data of 743 patients with follicular lymphoma. The simulation was carried out in two steps: First, a competing risk model on the basis of Weibull distribution was used to simulate the state transitions from diagnosis onward and from first-line therapy onward. Then, the data were completed by imputing on the basis of the existing data. Completion of data was repeated for 1,000 times to estimate reliability. RESULTS: In 20 years, 97% (2.5-97.5 percentile range: 96%-98%), 66% (61%-70%), 34% (30%-41%), and 15% (9%-18%) of the patients received first-line, second-line, third-line, and fourth-line therapies, respectively. The median number of therapy lines received by each patient was two. CONCLUSION: Despite long remissions, approximately two thirds of the patients receive at least two lines and one-third at least three lines of therapy during their lifetime.

Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations.

BACKGROUND: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia). METHODS: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy. RESULTS: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas. CONCLUSIONS: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events.

BACKGROUND: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. METHODS: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. RESULTS: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT -/AE + group, 26.7% in the RT -/AE - group and 18.3% in the RT + /AE - group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT -/AE - and RT + /AE - groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT -/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582-0.935; p = 0.012, and HR 0.620; 95% CI 0.499-0.769; p < 0.001, respectively). CONCLUSIONS: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.

FDG-PET/CT-guided rebiopsy may find clinically unsuspicious transformation of follicular lymphoma.

AIM: The purpose of the study was to evaluate the clinical impact of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) followed by a new biopsy from the site with maximum standardized uptake value (SUVmax) in case of high maximal SUV values, in detecting clinically unsuspected histologic transformations (HT) of follicular lymphoma (FL). METHODS: This retrospective study included all the patients who had undergone FDG-PET/CT during primary diagnosis or relapse of FL between 2010 and 2020 at Oulu University Hospital. RESULTS: The diagnosis changed from an indolent disease to a transformed lymphoma in >10% (7/63) of the patients who underwent diagnostic FDG-PET/CT. The HT risk associated with high SUVmax (>10) was 24% (7 of 29 performed biopsies). Four out of these seven patients with verified HT had no previous clinical suspicion of transformation. CONCLUSION: Our results suggest that a rebiopsy based on a high SUVmax in diagnostic FDG-PET/CT is valuable in detecting clinically unsuspected HT of FL.

Survival of patients with mantle cell lymphoma in the rituximab era: Retrospective binational analysis between 2000 and 2020.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab- and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.

Health-Related Quality of Life Outcomes With Two Different Starting Doses of Lenvatinib in Combination With Everolimus for Previously Treated Renal Cell Carcinoma.

BACKGROUND: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560). PATIENTS AND METHODS: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method. RESULTS: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales. CONCLUSIONS: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.

Mortality among patients with low-grade follicular lymphoma: A binational retrospective analysis.

BACKGROUND: The life expectancy of patients with follicular lymphoma (FL) has improved considerably since the introduction of rituximab. This study examined the proportion of deaths from progressive lymphoma and the impact of FL on survival compared with that in the general population. METHODS: Altogether, 749 patients with grades 1 and 2 FL in 9 institutions between 1997 and 2016 were enrolled. Competing risk models were used to estimate the cumulative incidences of deaths from progressive lymphoma and from other reasons. Excess mortality was analyzed with respect to the corresponding background populations standardized for age and sex using the excess mortality model based on the penalized spline approach. RESULTS: The median follow-up duration was 69 months (range, 0-226 months). The estimated 10-year overall, disease-specific, and net survival rates were 72.4%, 86.6%, and 86.4%, respectively. The cumulative incidence of deaths from progressive lymphoma was slightly smaller than that of other causes in the study population (estimated 10-year cumulative incidences: 12.3% [95% CI, 9.6%-15.3%] and 15.4% [95% CI, 12.2%-18.8%], respectively). Excess mortality was observed for up to 10 years after diagnosis, and it slightly increased with time. CONCLUSIONS: Deaths from progressive lymphoma are nearly as common as deaths from other causes in FL patients during the rituximab era. Despite the improvements in survival, there was evidence of excess mortality resulting from FL for at least 10 years after diagnosis.

Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial.

BACKGROUND: Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. OBJECTIVE: To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor-targeted therapy (prior anti-programmed death-1/programmed death ligand-1 therapy permitted). INTERVENTION: Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. RESULTS AND LIMITATIONS: The ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25-39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27-42]; odds ratio: 0.88; 90% CI 0.59-1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. CONCLUSIONS: The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. PATIENT SUMMARY: In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.

Female patients with follicular lymphoma have a better prognosis if primary remission lasts over 24 months.

Findings regarding the role of sex in follicular lymphoma (FL) are contradictory and the prognostic value of sex among patients with early progression of disease (POD) remains unclear. We collected real-life data from nine hospitals in Finland and Spain including 1020 FL patients to study the influence of sex on disease outcome. The median follow-up duration was 67 months (range 0-226 months). Female patients showed better progression-free survival (PFS) (hazard ratio [HR], 0.720; 95% confidence interval [CI], 0.588-0.881), disease-specific survival (DSS) (HR, 0.653; 95% CI, 0.448-0.951), and overall survival (OS) (HR, 0.653; 95% CI, 0.501-0.853) than male patients. However, there were no significant sex differences in prognosis in patients with early POD. This study strengthens the understanding that male sex is an adverse prognostic factor for FL. However, this difference does not apply to patients with early POD.

Novel Angiogenesis Markers as Long-Term Prognostic Factors in Patients With Renal Cell Cancer.

OBJECTIVE: To evaluate Ang-2 expression alone and in combination with expression of cell proliferation and cell survival markers (MIB-1 and Bcl-2) and angiogenesis markers (VEGFR3 and CD31), and the associations of these markers with renal cell cancer (RCC) in long-term survival. PATIENTS AND METHODS: Our study included 224 patients with RCC who were treated before the availability of antiangiogenic agents between 1985 and 1995, at the Pirkanmaa Hospital District in Finland. All tumor samples were reclassified and reevaluated by an experienced uropathologist, and parallel tissue microarrays (TMA) were performed for immunohistochemical analysis. Kaplan-Meier's survival estimation method and Cox proportional hazards models were used for survival analysis. RESULTS: The percentage of Ang-2 expression in the tumor area varied from 0.07 to 25.65. Ang-2 expression was significantly associated with the tumor grade and stage, as well as the MIB-1, Bcl-2, and VEGFR3 expression (P = .042, P = .019, P = .039, P = .013, and P = .005, respectively). The highest Ang-2 expression predicted better survival, P < .05. High Bcl-2 and low MIB-1 expression combined with Ang-2 expression was associated with better survival. Multivariate analysis showed poorer survival in patients with low Ang-2 or high MIB-1 expressions: HR 1.89, 95% CI 1.16 to 3.08, P = .010 and HR 2.20, 95% CI 1.36 to 3.54, P = .001, respectively. CONCLUSIONS: Very high Ang-2 expression was associated with better survival in patients with RCC. Ang-2 expression correlated with tumor stage and grade, but it was still an independent prognostic factor in a multivariate analysis.

[Treatment and prevention of iphosphamide-induced encephalopathy]. / lfosfamidin aiheuttama enkefalopatia.

Iphosphamide is a chemotherapeutic that is used in the treatment of many cancer types. It causes encephalopathy in as many as 27% of patients. Drug interactions increase the probability of encephalopathy. Aprepitant, which is used in the prevention of chemotherapy-induced nausea and vomitus, is one of the problematic drugs. The treatment of encephalopathy includes discontinuation of iphosphamide, the use of methylene blue and correction of electrolytes. If iphosphamide is still useful, methylene blue can be used prophylactically to prevent encephalopathy.

Combined Angiogenesis and Proliferation Markers' Expressions as Long-Term Prognostic Factors in Renal Cell Cancer.

OBJECTIVES: The aim of this study was to evaluate the expression of MIB-1, BCL-2, VEGFR3, and CD31 and their associations with long-term survival in patients with renal cell cancer (RCC). PATIENTS AND METHODS: This study consisted of 224 RCC patients who underwent radical nephrectomy from 1985 to 1995. Follow-up continued for up to over 20 years. MIB-1 and BCL-2 expression were analyzed alone, and additionally, the expression of MIB-1, BCL-2, VEGFR3, and CD31 were combined in pairs using the following groups: low/low, low/high, high/low, and high/high. RESULTS: Low BCL-2 expression (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.42-3.31; P < .001 compared with high BCL-2 in univariate analysis) and high MIB-1 expression (HR, 2.05; 95% CI, 1.32-3.19; P = .001 in multivariate analysis) were found to associate for poorer survival in RCC. In multivariate analysis, the combination of high MIB-1/low BCL-2 was associated with poor survival compared with low MIB-1/high BCL-2 (HR, 3.20; 95% CI, 1.66-6.17; P = .001), and the combination of low VEGFR3/high CD31 was associated with poor survival (HR, 2.48; 95% CI, 1.29-4.78; P = .007) compared with high VEGFR3/high CD31. CONCLUSIONS: Compared with high BCL-2 expression in combination with low or high MIB-1, VEGFR3, or CD31 expression, low BCL-2 expression in combination with low or high MIB-1, VEGFR3, or CD31 expression has poorer survival in the long-term follow-up of patients with RCC. Analysis of MIB-1, BCL-2, VEGFR3, and CD31 expression might be a useful additional marker to tailor the follow-up of RCC patients.