IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin-4 in an m6A-dependent manner.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often leads to a poor prognosis due to metastasis. The investigation of N6-methyladenosine (m6A) methylation, a crucial RNA modification, and its role in ccRCC, particularly through the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), revealed significant insights. We found that IGF2BP2 was notably downregulated in ccRCC, which correlated with tumor aggressiveness and poor prognosis. Thus, IGFBP2 has emerged as an independent prognostic factor of ccRCC. Moreover, a strong positive correlation was observed between the expression of IGF2BP2 and Netrin-4. Netrin-4 was also downregulated in ccRCC, and its lower levels were associated with increased malignancy and poor prognosis. Overexpression of IGF2BP2 and Netrin-4 suppressed the invasion and migration of ccRCC cells, while Netrin-4 knockdown reversed these effects in ccRCC cell lines. RNA immunoprecipitation (RIP)-quantitative polymerase chain reaction validated the robust enrichment of Netrin-4 mRNA in anti-IGF2BP2 antibody immunoprecipitates. MeRlP showed significantly increased Netrin4 m6A levels after lGF2BP2 overexpression. Moreover, we found that IGF2BP2 recognized and bound to the m6A site within the coding sequence of Netrin-4, enhancing its mRNA stability. Collectively, these results showed that IGF2BP2 plays a suppressive role in the invasion and migration of ccRCC cells by targeting Netrin-4 in an m6A-dependent manner. These findings underscore the potential of IGF2BP2/Netrin-4 as a promising prognostic biomarker and therapeutic target in patients with ccRCC metastasis.

RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China.

OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.

Sarcopenia is associated with leukopenia in urothelial carcinoma patients who receive tislelizumab combined with gemcitabine and cisplatin therapy.

BACKGROUND: In the era of combination therapy, there has been limited research on body composition. Specific body composition, such as sarcopenia, possesses the potential to serve as a predictive biomarker for toxic effects and clinical response in patients with urothelial carcinoma (UC) undergoing tislelizumab combined with gemcitabine and cisplatin (T + GC). MATERIALS AND METHODS: A total of 112 UC patients who received T + GC were selected at the Affiliated Hospital of Xuzhou Medical University from April 2020 to January 2023. Baseline patient characteristics and detailed hematological parameters were collected using the electronic medical system and laboratory examinations. The computed tomography images of patients were analyzed to calculate psoas muscle mass index (PMI). We evaluated the association between sarcopenia (PMI < 4.5 cm2/m2 in men; PMI < 3.3 cm2/m2 in women) and both hematological toxicity and tumor response. RESULTS: Overall, of the 112 patients (65.2% male, median age 56 years), 43 (38.4%) were defined as sarcopenia. Patients with sarcopenia were notably older (p = 0.037), more likely to have hypertension (p = 0.009), and had poorer ECOG-PS (p = 0.027). Patients with sarcopenia were more likely to develop leukopenia (OR 2.969, 95% CI 1.028-8.575, p = 0.044) after receiving at least two cycles of T + GC. However, these significant differences were not observed in thrombocytopenia and anemia. There were no significant differences in the tumor response and grade 3-4 hematological toxicity between patients with sarcopenia and those without sarcopenia. CONCLUSIONS: Patients with sarcopenia were more likely to develop leukopenia after receiving T + GC. There were no notable alterations observed in relation to anemia or thrombocytopenia. No significant difference was found between the sarcopenia group and non-sarcopenia group in terms of tumor response and grade 3-4 hematological toxicity.

The addition of tislelizumab to gemcitabine and cisplatin chemotherapy increases thrombocytopenia in patients with urothelial carcinoma: A single-center study based on propensity score matching.

PURPOSE: Whether the addition of tislelizumab to gemcitabine and cisplatin (GC) chemotherapy increases the incidence of myelosuppression has not been well established. This study identified the risk factors for the development of myelosuppression in patients with urothelial carcinoma (UC) after receiving GC chemotherapy with or without tislelizumab. MATERIALS AND METHODS: We enrolled 192 UC patients who received GC with or without tislelizumab at the Affiliated Hospital of Xuzhou Medical University between July 2014 and November 2022. Patient baseline characteristics were included in the statistical analyses after adjusting for previously reported risk factors affecting survival using propensity score matching (1:1). Binary logistic regression analysis was used to identify the risk factors associated with posttreatment myelosuppression. RESULTS: A total of 192 patients were enrolled, of whom 96 were treated with tislelizumab plus gemcitabine and cisplatin (T + GC) and 96 with GC alone. The incidence of leukopenia, anemia, and thrombocytopenia of any grade was 50.0%, 70.8%, and 42.7%, respectively, in the T + GC group and 41.7%, 72.9%, and 20.8%, respectively, in the GC group. In multivariate analysis, patients aged over 70 years (OR = 2.486, 95% CI: 1.067-5.792, p = 0.035) and those who received T + GC (OR = 3.119, 95% CI: 1.576-6.173, p = 0.001) were more likely to develop thrombocytopenia. Patients aged over 70 years (OR = 3.213, 95% CI: 1.254-8.237, p = 0.015) were more likely to develop anemia, and patients with renal insufficiency (OR = 2.105, 95% CI: 1.035-4.280, p = 0.040) were more likely to develop leukopenia. Eventually, 99 (51.6%) patients with UC successfully completed all the treatment cycles. CONCLUSIONS: This study demonstrates that the addition of tislelizumab to GC chemotherapy led to a considerable increase in the occurrence of thrombocytopenia, whereas no significant changes were observed regarding anemia or leukopenia. It is crucial to fully inform patients at increased risk for myelosuppression of potential risks and closely monitor changes in their blood routines.

Neoadjuvant androgen deprivation therapy combined with abiraterone acetate in patients with locally advanced or metastatic prostate cancer: When to perform radical prostatectomy?

The surgical timing after neoadjuvant androgen-deprivation therapy (ADT) plus abiraterone acetate (AA) for patients with locally advanced or metastatic prostate cancer (PCa) is unknown. We divided patients with locally advanced or metastatic PCa into three groups according to prostate-specific antigen (PSA) nadir after neoadjuvant ADT plus AA: group 1 (PSA ≤ 0.2 ng/ml), group 2 (0.2 < PSA ≤ 4.0 ng/ml), and group 3 (PSA > 4.0 ng/ml).The median PSA baseline levels in groups 1, 2, 3 were 118.42 (32.03-457.78), 143.48 (17.7-8100.16), and153.35 (46.44-423.31) ng/ml, respectively. The median times of progression to CRPC in groups 1, 2,and 3 were 30, 26, and 26 months, respectively. Compared to patients with PSA nadir >0.2 ng/ml, patients with PSA nadir <0.2 ng/ml presented with longer PFS (p = 0.048).Our results suggested that, in patients with locally advanced or metastatic PCa, the time to progression to CRPC was longer after radical prostatectomy when PSA decreased below 0.2 ng/ml using neoadjuvant ADT plus AA.

Free Ferrous Protoporphyrin and Reactive Oxygen Species Status of Voided Urine Predicts Higher Stage in Urothelial Carcinoma.

PURPOSE: This study was conducted to evaluate the correlation between the free ferrous protoporphyrin and reactive oxygen species (FH and ROS) combined test and the tumor grade and stage in a pathologically confirmed uroepithelial carcinoma (UC) patient population. PATIENTS AND METHODS: In this retrospective study, we enrolled patients newly diagnosed with UC between May 2020 and June 2021. All patients were classified as FH(+) and ROS(+), FH(+) and ROS(-), or FH(-) and ROS(-), based on the FH and ROS combined test of voided urine. Demographic information, pathological results, and status of the FH and ROS combined test were reviewed retrospectively. The relationship between FH and ROS combined test status and tumor stage and grade was evaluated using logistic regression. RESULTS: This study included 120 UC patients with a median age of 69 years (interquartile range [IQR] 62-77 years). Eighteen patients (15%) were diagnosed with upper tract urothelial carcinoma, and the others (85%) were diagnosed with bladder cancer. The pathological stages for those with FH(+) and ROS(+) at diagnosis were 25.0% Ta, 45.8% T1, and 29.2% ≥T2. The pathological stages for those with FH(+) and ROS(-) at diagnosis were 23.5% Ta, 35.3% T1, and 41.2% ≥T2. The pathological stages for those with FH(-) and ROS(-) at diagnosis were 52.6% Ta, 26.3% T1, and 21.1% ≥T2. After adjusting for clinical factors, including age, sex, and smoking history, FH(+) and ROS(-) were independent risk factors for muscle-invasive UC (≥T2 stage) at diagnosis (odds ratio [OR] 3.379; 95% confidence interval [CI] 1.103-10.355; P=0.033) in the univariate and multivariate logistic regression analyses. CONCLUSION: Among patients with newly diagnosed UC, FH(+) and ROS(-) might have an association with a more advanced pathological stage. This finding may help differentiate between patients with aggressive diseases and those who may benefit from organ-sparing surgery.

How to Perform Intravesical Chemotherapy after Second TURBT for Non-Muscle-Invasive Bladder Cancer: A Single-Center Experience.

PURPOSE: The objective of this study aimed to explore whether the original IVC regimen should be continued after the second TURBT or whether the IVC induction phase should be restarted from the beginning. METHODS: A retrospective analysis was performed on 137 patients who underwent a second TURBT at the Affiliated Hospital of Xuzhou Medical University between April 2014 and June 2022. Based on the pathological findings, patients were divided into two groups: group A patients, who did not have a residual tumor on pathological examination after the second TURBT; and group B patients, who had residual tumor. Recurrence was determined using cystoscopy and imaging every three months. The endpoint was recurrence-free survival. RESULT: In the entire cohort, there was a statistically significant difference in the RFS between patients in the two IVC regimens (p = 0.029). The RFS of patients in group B1 was significantly lower than that of patients in group B2 (p = 0.009). There was no significant difference in RFS between the subgroups A1 and A2 (p = 0.560). Multivariate Cox regression analysis confirmed that the IVC regimen after a second TURBT (p = 0.012) and T stage after a second TURBT (p = 0.005) were both independent predictors for patient RFS. CONCLUSION: If the pathological findings of the second TURBT specimen is benign, patients can continue their previous treatment regimen without restarting an IVC induction phase. Unnecessary IVC can be avoided in these patients. In contrast, for patients with residual tumors in the second TURBT specimen, the need to restart the IVC induction phase should be emphasized to improve patient prognosis.

Second Primary Renal Cell Carcinoma With Nonrenal Malignancies: An Analysis of 118 Cases and a Review of Literature.

OBJECTIVES: To evaluate the nature, diagnosis, treatment and prognosis of second primary renal cell carcinoma (SPRCC). MATERIALS AND METHODS: We retrospectively collected data from 118 patients with SPRCC. Clinical characteristics, imaging features and treatments were analyzed and comparisons between SPRCC and renal metastases (RM) were made. RESULTS: SPRCC accounts for 11.4% of all RCC. The most common types of extrarenal malignancies included lung, colorectal, breast and gynecological cancers. The median age was 58.5 years old, and 61.0% (72/118) of the patients were male. About 5.1% of the patients presented with symptoms. The average tumor diameter was 4.4 cm (1-8.4 cm). The diagnostic specificity of enhanced computed tomography (CT) was 80.1%. When comparing with RM, more patients with stage I-II extrarenal malignancy and less patients with bilateral, multiple, and endogenic renal masses on computed tomography were found in the SPRCC group. A total of 110 SPRCC patients underwent surgery, including 48 radical nephrectomies and 62 partial nephrectomies. The median overall survival time was 117 months. Female, asymptomatic status, no distant metastasis, and surgical treatment predicted a better survival. CONCLUSIONS: SPRCC are not uncommon, and it should be considered during the follow-up of patients with nonrenal malignancy. The differential diagnosis between SPRCC and RM was mainly based on imaging and puncture biopsy.

Mortality Increases When Radical Nephrectomy is Delayed More Than 60 Days for T3 Renal Cell Carcinoma.

Background: Radical nephrectomy is widely accepted as the default management option for patients with T3 renal cell carcinoma (RCC). However, it may require a certain time before surgery for various reasons. There are concerns that the delay in surgery may affect postoperative outcomes. The present study aimed to evaluate the impact of surgical wait time on survival in patients with T3 RCC. Methods: We retrospectively selected 138 patients with T3 RCC who underwent radical surgery between July 2009 and December 2019. Surgical wait time was defined as the period from initial imaging diagnosis to surgery. Patients were divided into the following 2 groups according to wait time: short-wait group(≤60 days), and long-wait group (>60 days). The clinical and pathological characteristics were evaluated. The overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) of each group were calculated and compared. Age, gender, interval, tumor size, pathological grade, Eastern Cooperative Oncology Group performance status (ECOG PS), surgical approach, year of surgery, and pathological type were included in the multivariable model. Results: This study included 91 male (65.9%) and 47 female (34.1%) patients. The median age of all patients was 60 years (interquartile range [IQR] 52-68 years). The median body mass index is 22.2 kg/m2 (IQR 18.9-24.7  kg/m2). There were 128 patients (92.8%) with pT3a disease and 10 patients (7.3%) with pT3b disease. The median surgical wait time for all patients was 16 days (IQR 10-77 days). The median surgical wait time of the short- and long-wait groups was 12 days (IQR 8-16 days) and 92 days (IQR 79-115 days), respectively. Until the last follow-up, 54 patients died. Among them, 49 patients (90.7%) died of tumor-related causes, and 5 patients (9.3%) died of other causes. There are 1 and 4 cases in the short-wait and long-wait groups, respectively. There were no significant differences in gender, ECOG PS, American society of anesthesiologists score, Charlson comorbidity index, clinical T stage, clinical N stage, and body mass index. And there were no significant differences in tumor size, surgical approach, year of surgery, pathological type, tumor grade, pathological T stage, pathological N stage, and venous involvement between the 2 groups. OS, CSS, and RFS were compared. The 5-year OS of the short- and long-wait time groups were 65.0% and 40.9%, respectively (P = .030). The 5-year CSS rates of the short- and long-wait time groups were 68.7% and 51.5%, respectively (P = .012). The 5-year RFS rates of the short- and long-wait time groups were 61.5% and 46.8%, respectively (P = .119). Multivariable analysis revealed that surgical wait time interval and tumor size were independent risk factors for OS and that wait time was also an independent risk factor for CCS. Conclusion: Delay in radical surgery beyond 60 days can negatively affect OS in patients with T3 RCC.

Impact of Surgical Wait Time on Survival in Patients With Upper Urinary Tract Urothelial Carcinoma With Hydronephrosis.

BACKGROUND AND OBJECTIVES: Due to the inevitability of waiting time for surgery, this problem seems to have become more pronounced since the outbreak of COVID-19, and due to the high incidence of preoperative hydronephrosis in upper urinary tract urothelial carcinoma (UTUC) patients, it is particularly important to explore the impact of preoperative waiting time and hydronephrosis on upper urinary urothelial carcinoma. METHODS: 316 patients with UTUC who underwent radical surgery at a high-volume center in China between January 2008 and December 2019 were included in this study. We retrospectively collected the clinicopathologic data from the medical records, including age, sex, smoking history, ECOG performance status (ECOG PS), body mass index (BMI), tumor location and size, number of lesions, T stage, N stage, surgical approach and occurrence of hydronephrosis, lymph node invasion, lymph node dissection, surgical margin, tumor necrosis, infiltrative tumor architecture, lymphovascular invasion and concomitant bladder cancer. Surgical wait time was defined as the interval between initial imaging diagnosis and radical surgery of UTUC. Hydronephrosis was defined as abnormal dilation of the renal pelvis and calyces due to obstruction of the urinary system. Firstly, all patients were divided into short-wait (<31 days), intermediate-wait (31-90 days) and long-wait (>90 days) groups according to the surgical wait time. The clinicopathological characteristics of each group were evaluated and the survival was compared. For patients with hydronephrosis, we subsequently divided them into two groups: short-wait (≤60 days) and long-wait (>60 days) groups according to the surgical wait time. Univariate and multivariate COX regression analysis were performed to evaluate the prognostic risk factor for patients with hydronephrosis. RESULTS: A total of 316 patients with UTUC were included in this study with a median surgical wait time of 22 days (IQR 11-71 days). Of the 316 patients, 173 were classified into the short-wait group (54.7%), 69 into the intermediate-wait group (21.8%) and 74 into the long-wait group (23.5%). The median follow-up time for all patients was 43 months (IQR 28-67months). The median surgical wait times of the short-wait, intermediate-wait and long-wait group were12 days (IQR 8-17days), 42days (IQR 37-65days) and 191days (IQR 129-372days), respectively. The 5-year overall survival (OS) of all patients was 54.3%. The 5-year OS of short-wait, intermediate-wait and long-wait groups were 56.4%, 59.3% and 35.1%, respectively (P=0.045). The 5-year cancer-specific survival (CSS) of short-wait, intermediate-wait and long-wait groups were 65.8%, 70.9% and 39.6%, respectively (P=0.032). In the subgroup analysis, we divided 158 UTUC patients with hydronephrosis into short-wait group (≤60 days) and long-wait group (> 60 days), 120 patients were included in the short-wait group and 38 patients in the long-wait group. The median surgical wait times of the short-wait and long-wait group were 14days (IQR 8-28days) and 174days (IQR 100-369days), respectively. The 5-year OS of long-wait group was significantly lower than the OS of short-wait group (44.2% vs. 55.1%, P =0.023). The 5-year CSS of long-wait and short-wait group were 49.1% and 61.7%, respectively (P=0.041). In multivariate Cox regression analysis of UTUC patients with hydronephrosis, surgical wait time, tumor grade, pathological T stage, and tumor size were independent risk factors for OS and CSS. Lymph node involvement was also a prognostic factor for CSS. CONCLUSION: For patients with UTUC, the surgical wait time should be limited to less than 3 months. For UTUC patients with hydronephrosis, the OS and CSS of patients with surgical wait time of more than 60 days were relatively shorted than those of patients with surgical wait time of less than 60 days.

Safety of Prolonged Wait Time for Nephrectomy for Clinically Localized Renal Cell Carcinoma.

BACKGROUND: There is usually a surgical wait time before nephrectomy for patients with clinically localized renal cell carcinoma, and many factors can influence this preoperative wait time. A relatively prolonged wait time may cause tumor progression. Therefore, we assessed the effect of preoperative wait time on the prognosis of patients with clinically localized renal cell carcinoma. METHODS: The outcomes of 561 patients with clinically localized renal cell carcinoma who underwent nephrectomy between July 2011 and March 2017 were retrospectively evaluated. According to the wait time before surgery, we divided the patients into three groups: short-wait group (≤ 30 days), intermediate-wait group (> 30 and ≤ 90 days), and long-wait group (>90 days). The clinicopathological characteristics were evaluated, and the survival rates of the three groups were compared. RESULTS: This study included 370 male (66%) and 191(34%) female patients, with a median age of 64 years. There were 520 patients with stage T1 and 41 patients with stage T2 tumors. The median interval between diagnosis and surgery was 21 days. There were no significant differences in age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, tumor size, surgical approach, surgical procedure, pathological subtype, tumor stage, tumor grade, and residual tumor among the three groups. Overall survival(OS) and cancer-specific survival (CSS) were comparable; the 5-year OS of the short-, intermediate-, and long-wait time groups were 84.2%, 82.0%, and 89.8%, respectively (P=0.732). The 5-year CSS rates of the short-, intermediate-, and long-wait time groups were 87.1%, 88.9%, and 90.4%, respectively (P=0.896). Multivariate analysis revealed that wait time was not an independent prognostic factor for OS or CSS. CONCLUSION: Prolonged surgical wait time (> 90 days) does not influence survival in patients with clinically localized renal cell carcinoma.

Metastases to the Kidney: An Analysis of 35 Cases and a Review of Literature.

INTRODUCTION: In addition to being rare, metastases to the kidney present clinicians with issues regarding their treatment. MATERIALS AND METHODS: We retrospectively analyzed 35 cases of diagnosed renal metastases. The clinical characteristics, imaging features, pathological features, diagnosis, and treatment were analyzed, and Kaplan-Meier methods and Cox regression analysis were used to calculate overall survival (OS) and influencing factors. RESULTS: The average age of the patients was 62 years, and 40% presented with symptoms. The most common primary tumor was lung cancer (60%), and two patients had renal metastases coexisting with renal cell carcinoma. The average interval from primary tumor to renal metastasis was 29.4 months. Only 45.5% of the patients who underwent enhanced computerized tomography were diagnosed with renal metastases. Renal biopsy was performed in 16 patients (45.7%), leading to a diagnosis in 15 (93.8%). Twenty-one patients (60%) received surgical treatment, and median recurrence free survival of these patients was 7 months (95% CI, 5 to 12). Overall, the median OS was 44 months for patients who underwent renal surgery, and 52 months for patients who did not (P = 0.672). However, for patients without metastases at other sites, surgery could significantly prolong OS (P = 0.001). CONCLUSION: Although rare, the possibility of renal metastasis should be considered after finding renal tumors in patients with primary tumors in other organs, and can be diagnosed by imaging examination and puncture biopsy. For patients without other metastases, surgical intervention can be considered for the renal lesions.

Microscopic hematuria predicts lower stage in patients with upper tract urothelial carcinoma.

BACKGROUND: The aim of this study was to assess the association between the severity of hema-turia (microscopic or gross) and the tumor stage and grade in a population of histopathologically confirmed upper tract urothelial carcinoma (UTUC) patients. PATIENTS AND METHODS: We conducted a multicenter, observational study of patients who were newly diagnosed with UTUC between January 2011 and December 2016. Demographic information, pathology, and the status of hematuria were retrospectively reviewed. The association between the severity of hematuria and the tumor stage and grade was evaluated using logistic regression. RESULTS: The UTUC patients presented with gross hematuria (GH, 76.7%), microscopic hematuria (MH, 11.1%), and no hematuria (12.2%) at the time of diagnosis. The pathological stages at diagnosis for those with MH were Ta in 5.1%, T1 in 47.5%, and ≥T2 in 47.5%. The stages at diagnosis for those with GH were Ta in 1.7%, T1 in 35.5%, and ≥T2 in 62.7%. On univariate and multivariate logistic regression analyses, after adjusting for clinical factors such as age, gender, and smoking history, GH was an independent risk factor for muscle-invasive UTUC (≥T2 disease) at diagnosis (OR 1.89, 95% CI 1.073-3.329; P=0.027). High-grade tumor was found in 47.8% of patients with GH and 39.0% of those with MH. The severity of hematuria was not associated with tumor grade. CONCLUSION: We are the first to report evidence that microscopic hematuria at presentation accurately predicts lower pathological stage in patients with newly diagnosed UTUC. Earlier detection of disease, before the development of GH, may influence the treatment decision and survival. The type of hematuria at the time of diagnosis does not impact the tumor grade.

Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.

PURPOSE: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL). METHODS: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. RESULTS: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations. CONCLUSION: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

Risk factors for survival in patients with von Hippel-Lindau disease.

BACKGROUND: Historically, von Hippel-Lindau (VHL) disease is characterised by a poor survival. Although genotype-phenotype correlation has been described in many studies, the risk factors for VHL survival remain unclear. This study aims to evaluate the median survival of Chinese patients with VHL disease and explore whether VHL survival is influenced by genetic and clinical factors. METHODS: In this retrospective study, we recruited 340 patients from 127 VHL families. Kaplan-Meier plot and Cox regression model were used to evaluate the median survival and assess how survival was influenced by birth year, birth order, sex, family history, mutation type, onset age and first presenting symptom. RESULTS: The estimated median life expectancy for Chinese patients with VHL disease was 62 years. Patients with early-onset age, positive family history and truncating mutation types had poorer overall and VHL-related survival. Patients with haemangioblastoma as their first presenting symptom were related to a higher risk of death from central nervous system haemangioblastoma than those with abdominal lesions (HR 8.84, 95% CI 2.04 to 38.37, P=0.004). CONCLUSIONS: This largest VHL survival analysis indicates that onset age, family history, mutation type and first presenting symptom have an effect on the survival of patients with VHL disease, which is helpful to genetic counselling and clinical decision-making.

Concurrent renal cell carcinoma and urothelial carcinoma: long-term follow-up study of 27 cases.

BACKGROUND: To investigate the clinical manifestation, diagnosis, treatment, and outcome of simultaneous occurrence of renal cell carcinoma (RCC) and urothelial carcinoma. METHODS: Twenty-seven consecutive patients with synchronous renal cell carcinoma and urothelial carcinoma treated in two tertiary medical centers from March 2005 to December 2015 were retrospectively reviewed. Their clinical, pathological, and prognostic features were evaluated. Kaplan-Meier curves were used to estimate overall survival. RESULTS: The median age was 69 years (range, 37-79 years). Seventeen patients presented with macroscopic hematuria, and 10 patients were asymptomatic. B-ultrasound, computed tomography (CT), and cystoscopy initially indicated RCC concurrent with ipsilateral upper tract urothelial carcinoma (UTUC) in 5 cases, RCC concurrent with contralateral UTUC in 1 case, RCC concurrent with bladder tumor in 17 cases, RCC concurrent with both ipsilateral UTUC and bladder tumor in 1 case, RCC in 2 cases and ureter carcinoma in 1 case. Different treatments were performed. The median follow-up time after surgery was 23 months. For patients with synchronous RCC and bladder tumor, there was no significant survival difference between patients treated with partial nephrectomy and radical nephrectomy. During follow up, four patients died of RCC, three patients died of non-oncological disease, one patient died of ureter carcinoma. The 3-year overall survival rate was 80.8%. CONCLUSIONS: Concurrence of RCC and urothelial carcinoma is clinically rare. Treatments should be individualized. The prognosis for a patient with synchronous RCC and urothelial carcinoma is possibly associated with the more aggressive one.

Renal Arterial Pseudoaneurysm and Renal Arteriovenous Fistula Following Partial Nephrectomy.

INTRODUCTION: Renal arterial pseudoaneurysm (RAP) and renal arteriovenous fistula (RAVF) are rare but can cause fatal bleeding. MATERIALS AND METHODS: A retrospective review was conducted for patients undergoing partial nephrectomy (PN) in our department. The clinical features and treatment methods were analysed, and the relationships between RAP/RAVF and the surgical methods and R.E.N.A.L. score were investigated. RESULTS: Eleven patients were diagnosed with RAP/RAVF (9 with RAP and 2 with RAVF). The incidence of RAP/RAVF after laparoscopic PN showed no significant difference compared to that after open PN (p = 0.47). A low R.E.N.A.L. score was present in 6 patients, while an intermediate/high score was present in the other 5 patients. The major clinical manifestations included haematuria and haemorrhagic shock, and the median time of occurrence was 8 days after the operation. Six patients underwent an ultrasound examination. Of the 4 patients who underwent enhanced CT, 2 patients were diagnosed with RAP. All 11 patients were diagnosed by renal angiography and were cured after super-selective arterial embolization. The serum creatinine levels before and after embolization showed no significant differences (p = 0.14). CONCLUSIONS: RAP/RAVF may not have any relationship with the surgical procedure or R.E.N.A.L. score. Renal angiography and super-selective arterial embolization are the preferred methods for diagnosing and treating RAP/RAVF.

Shorter telomere length increases age-related tumor risks in von Hippel-Lindau disease patients.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age-related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age-related risks for the five major VHL-associated tumors were evaluated using Kaplan-Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age-adjusted telomere length ≤ 0.44) suffered higher age-related risks for VHL-associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age-related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL-associated tumors.

Clinicopathologic Features and Prognosis of Sporadic Bilateral Renal Cell Carcinoma: A Series of 148 Cases.

INTRODUCTION: The purpose of this study was to investigate the clinicopathologic features, treatment, and prognosis of sporadic bilateral renal cell carcinoma (RCC). PATIENTS AND METHODS: A total of 148 patients with sporadic bilateral RCC treated in our center from June 1986 to December 2015 were included in this retrospective study. Their clinicopathologic features and treatments were evaluated. The survival and prognostic factors were assessed based on data from follow-up. RESULTS: The median age was 54 years (range, 31-78 years). There were 88 patients with synchronous bilateral RCC and 60 with metachronous bilateral RCC. The median interval between bilateral tumors of metachronous bilateral RCC was 75.5 months. There was no significant difference in tumor size, nuclear grade, or T stage between metachronous tumors (P = .385, P = .544, and P = .263, respectively). Of 148 patients, 124 patients underwent bilateral surgery, 16 underwent unilateral surgery, and 8 patients did not undergo surgery. Of the 317 tumors with pathologic results, 297 (93.7%) were clear-cell subtype. A total of 136 (91.9%) patients were followed-up, and the median follow-up period was 77 months (range, 2-398 months). During follow-up, 38 (27.9%) patients died. The 5-year overall survival rate was 85.9%. The median survival time of patients with no surgery was 5 months. Older age (P = .001), bilateral nonoperative treatment (P < .001), higher T stage (P < .001), and multifocality (P = .02) were related to worse prognosis in multivariate analysis. CONCLUSION: In metachronous bilateral RCC, the latter occurrence does not bear a significantly worse pathologic biology. The prognosis of sporadic bilateral RCC with no surgery is poor. The overall oncologic results of patients with sporadic bilateral RCC are comparable with that of patients with unilateral RCC.

Cytoreductive nephrectomy with thrombectomy before targeted therapy improves survival for metastatic renal cell carcinoma with venous tumor thrombus: a single-center experience.

BACKGROUND: The aim of the study is to evaluate the role of cytoreductive nephrectomy (CN) with thrombectomy before targeted molecular therapy (TMT) on survival in metastatic renal cell carcinoma (mRCC) with venous tumor thrombus. METHODS: We performed a retrospective analysis of 47 patients treated in our center from April 2008 to October 2014. In the study, 20 patients underwent CN with thrombectomy followed by targeted therapy (group 1); 15 patients received targeted therapy alone (group 2); and 12 patients underwent CN with thrombectomy alone (group 3). The overall survival (OS) and cancer-specific survival (CSS) were calculated according to the Kaplan-Meier survival curve method, and prognostic variables were assessed by Cox regression analyses. RESULTS: The median follow-up times of group 1, group 2, and group 3 were 24.5, 12, and 6.5 months, respectively. During follow-up, in both group 1 and group 3, 12 patients died. In group 2, 14 patients died. The median OS of group 1, group 2, and group 3 was 22, 12, and 6 months, respectively (P < 0.001). Compared with surgery alone and targeted therapy alone, patients with cytoreductive surgery before targeted therapy had statistically better survival benefits (P < 0.001, P = 0.009, respectively). On univariate analysis, the number of metastatic sites (P = 0.004) was a statistically significant prognostic factor influencing OS. CONCLUSIONS: Our single-center experience showed that CN with thrombectomy before targeted therapy improved the survival of patients with mRCC with venous tumor thrombus. The number of metastatic sites was an independent prognostic factor influencing OS.