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.

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.

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.