Method for providing information for predicting likelihood of bladder cancer recurrence

Abstract

The present invention relates to a method for providing information for predicting the likelihood of bladder cancer recurrence, which provides information that patients who have undergone transurethral resection of a bladder tumor and test positive for suspicious high-grade urothelial carcinoma (SHGUC) or high-grade urothelial carcinoma (HGUC) in a urine cytology test have a higher likelihood of bladder cancer recurrence compared with patients who do not test positive.

Description

Methods for providing information to predict the likelihood of bladder cancer recurrence

[0001] The present invention relates to a method for providing information for predicting the possibility of bladder cancer recurrence.

[0002]

[0003] The risk of recurrence increases when residual cancer cells remain in the bladder after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC).

[0004] To predict the likelihood of bladder cancer recurrence, cystoscopy is performed after TURBT. This method directly visualizes the bladder to check for recurrence. Cystoscopy uses imaging tests such as ultrasound, CT, and MRI to identify abnormalities within the bladder. While these imaging tests provide additional information, they can miss small lesions. Furthermore, cystoscopy is an invasive procedure, which can cause discomfort to the patient and carries a risk of infection.

[0005] Accordingly, methods to monitor bladder cancer recurrence using biomarkers such as NMP22, BTA stat, and UroVysion FISH have been introduced. However, although biomarkers may be useful in certain situations, their sensitivity and specificity may be limited.

[0006] In other words, existing technologies suffer from limitations in sensitivity and specificity, the inconvenience of invasive testing, high costs, and difficulties in removing residual cancer cells. Therefore, the introduction of new methods to address these issues is necessary.

[0007]

[0008] The present invention aims to provide a novel method for providing information for predicting the possibility of bladder cancer recurrence.

[0009]

[0010] 1. A method for providing information for predicting the possibility of bladder cancer recurrence, which provides information that patients who underwent transurethral resection of a bladder tumor and tested positive for SHGUC (suspected high-grade urothelial carcinoma) or HGUC (high-grade urothelial carcinoma) in urine cytology have a higher possibility of bladder cancer recurrence than patients who did not.

[0011] 2. In the above 1, the urine cytology test is a method for providing information for predicting the possibility of bladder cancer recurrence, which examines cells discharged through urine after continuously injecting physiological saline into the bladder of a patient who has undergone transurethral resection of a bladder tumor.

[0012] 3. A method for providing information for predicting the possibility of bladder cancer recurrence, wherein the above saline solution injection is performed for 6 to 24 hours.

[0013]

[0014] The present invention can provide a novel method for early prediction of bladder cancer recurrence.

[0015]

[0016] Figure 1. Kaplan-Meier recurrence-free survival (RFS) graphs compared the RFS rates of the negative group, LGUN+AUC group, and SHGUC+HGUC group. The negative group showed a longer RFS than the SHGUC+HGUC group (p=0.013). LGUN, low-grade urothelial neoplasm; AUC, atypical urothelial cells; SHGUC, suspected high-grade urothelial carcinoma; HGUC, high-grade urothelial carcinoma.

[0017]

[0018] The present invention is described in detail below.

[0019]

[0020] The present invention relates to a method for providing information for predicting the possibility of bladder cancer recurrence, which provides information that patients who have undergone transurethral resection of a bladder tumor and are positive for SHGUC (suspected high-grade urothelial carcinoma) or HGUC (high-grade urothelial carcinoma) in a urine cytology test have a higher possibility of bladder cancer recurrence than patients who are not.

[0021] Transurethral resection of bladder tumor (TURBT) is an endoscopic surgery performed to remove tumors in the bladder.

[0022] Patients who underwent resection are those diagnosed with bladder cancer and underwent resection to remove the tumor.

[0023] Urine cytology is a noninvasive test to detect residual tumor cells and predict bladder cancer recurrence after transurethral resection of bladder tumor (TURBT) in patients with bladder cancer, such as non-muscle-invasive bladder cancer (NMIBC).

[0024] Urine cytology testing can be performed, for example, on patients who have undergone transurethral resection of a bladder tumor by continuous saline infusion (OCSI) into the bladder to remove as many residual cancer cells as possible, and then examining the cells excreted in the urine.

[0025] Saline infusions can be performed, for example, overnight, for 6 to 24 hours, or for 6 to 12 hours.

[0026] Urine cytology may be performed 1 day after transurethral resection of a bladder tumor.

[0027] Urine cytology results can be classified as, for example, Negative for high-grade urothelial carcinoma (Negative), Low-grade urothelial neoplasm (LGUN), Atypical urothelial cells (AUC), Suspicious for high-grade urothelial carcinoma (SHGUC), and High-grade urothelial carcinoma (HGUC).

[0028] The risk of malignancy according to the above classification may be, for example, 0% to 10% for high-grade urothelial carcinoma negative, 5% to 20% for low-grade urothelial neoplasm (LGUN), 8% to 35% for atypical urothelial cells (AUC), 50% to 90% for high-grade suspicious for high-grade urothelial carcinoma (SHGUC), and 90% or more for high-grade urothelial carcinoma (HGUC).

[0029] Urine cytology test results can be categorized into, for example, the Negative group, the LGUN+AUC group, and the SHGUC+HGUC group. The recurrence-free survival (RFS) rates for each group can be compared using the Kaplan-Meier method. For example, the median RFS for the Negative group may not be reached, the median RFS for the LGUN+AUC group may be 400 to 800 days, and the median RFS for the SHGUC+HGUC group may be 250 to 450 days.

[0030] Patients who test positive for SHGUC (suspected high-grade urothelial carcinoma) or HGUC (high-grade urothelial carcinoma) in urine cytology are patients suspected of having high-grade urothelial carcinoma or confirmed to have high-grade urothelial carcinoma.

[0031] High-grade urothelial carcinoma is a highly malignant type of cancer that arises from the epithelial cells of the urinary tract, and can occur in the bladder, ureter, renal pelvis, and urethra.

[0032] The present invention can provide information that patients positive for SHGUC (suspected high-grade urothelial carcinoma) or HGUC (high-grade urothelial carcinoma) have a higher risk of bladder cancer recurrence compared to patients who are not positive.

[0033] Patients who do not have this may be those who have undergone transurethral resection of a bladder tumor but have negative urine cytology for SHGUC (suspected high-grade urothelial carcinoma) or HGUC (high-grade urothelial carcinoma).

[0034]

[0035] The present invention will be described in more detail with reference to the following examples.

[0036]

[0037] Example

[0038] Materials and Methods

[0039] Study population and inclusion / exclusion criteria

[0040] Patients diagnosed with NMIBC who underwent TURBT at Gyeongsang National University Hospital from January 2016 to May 2020 were included. All TURBT procedures were performed by three urologists, each with more than 5 years of TURBT experience at the time of the first patient's surgery in 2016. Patients aged 40 years or older who underwent OCSI after TURBT and underwent urine cytology examination on postoperative day 1 were included in this study. Exclusion criteria were as follows: patients with non-urothelial tumor pathology at the initial TURBT, tumor stage T2, lymph node metastasis or distant metastasis on imaging, patients who received intravesical chemotherapy (mitomycin C, epirubicin, gemcitabine), and patients who underwent repeat TURBT without surveillance.

[0041]

[0042] definition

[0043] The date of diagnosis was defined as the date of the initial TURBT. Recurrence was defined as the presence of bladder cancer in the pathology report following additional TURBT after the date of diagnosis. The date of recurrence was defined as the date of the TURBT performed at the time of recurrence. The time to recurrence was defined as the period from the date of diagnosis to the date of recurrence.

[0044]

[0045] Data collection and grouping

[0046] Data from the included participants were analyzed considering factors such as sex, age, smoking status, diabetes status, hypertension status, pT stage and grade, BCG injection status, urine cytology results 1 day before and after OCSI, date of diagnosis, and date of recurrence. Patients who underwent TURBT and underwent urine cytology after OCSI were divided into three groups based on urine cytology results: the negative group, the LGUN+AUC group, and the SHGUC+HGUC group. Baseline characteristics were compared between the three groups. Recurrence-free survival (RFS) rates were also compared among the three groups.

[0047] * LGUN: Low-Grade Urothelial Neoplasm

[0048] AUC: Atypical Urothelial Cells

[0049]

[0050] Statistical analysis

[0051] Statistical analysis was performed using IBM SPSS software version 21.0 (IBM Corp.). One-way analysis of variance (ANOVA) was used to compare numerical variables, and Pearson's chi-square test was used to compare categorical variables. Means and standard deviations were calculated for numerical variables, and frequencies and percentages were calculated for categorical variables. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic factors for recurrence. A p-value <0.05 was considered statistically significant.

[0052]

[0053] Ethics Statement

[0054] The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Gyeongsang National University Hospital (Approval Number: 2020-06-011). Due to the retrospective study design, which included anonymized data, the IRB waived the requirement for informed consent.

[0055]

[0056] result

[0057] Table 1 shows the baseline characteristics of the 172 patients included in this study. The mean age was 71.74 years, and the mean follow-up period was 857.92 days.

[0058] When the baseline characteristics of patients classified into three groups according to urine cytology results were compared, pT stage and grade showed significant differences among the three groups (p=0.001), but other factors did not show significant differences (Table 2).

[0059] Regarding RFS in the three groups, the median RFS was not reached in the negative group. The median RFS was 615.00 days in the LGUN+AUC group and 377.00 days in the SHGUC+HGUC group. Survival analysis showed that the negative group had a longer RFS than the SHGUC+HGUC group (p=0.013). However, no significant difference in RFS was observed between the negative group and the LGUN+AUC group (p=0.278) or between the LGUN+AUC group and the SHGUC+HGUC group (p=0.260) (Fig. 1).

[0060] Univariate and multivariate Cox regression analyses revealed that multifocality and high grade (TaHG and T1HG) were independent prognostic factors for recurrence. The hazard ratios were 2.430 (95% confidence interval [CI] 1.312–4.499, p=0.005), 2.908 (95% CI 1.361–6.212, p=0.006), and 2.883 (95% CI 1.277–6.507, p=0.011), respectively. SHGUC+HGUC was not an independent prognostic factor for recurrence (Table 3).

[0061]

[0062]

[0063]

[0064] Baseline characteristics of all patients (n=172)

[0065] Values ​​are presented as mean ± standard deviation or number (%).

[0066] pT, pathologic T stage; TaLG, noninvasive papillary carcinoma and low grade; TaHG, noninvasive papillary carcinoma and high grade; CIS, urothelial carcinoma in situ; T1LG, lamina propria invasion and low-grade tumor; T1HG, lamina propria invasion and high-grade tumor; BCG, bacillus Calmette-Guérin; Preop., before surgery; LGUN, low-grade urothelial neoplasm; AUC, atypical urothelial cell; SHGUC, suspected high-grade urothelial carcinoma; HGUC, high-grade urothelial carcinoma; Postop., after surgery.

[0067]

[0068]

[0069]

[0070] Comparison of baseline characteristics between three groups classified according to urine cytology results (post-OCSI)

[0071] Values ​​are presented as mean ± standard deviation or number (%).

[0072] OCSI, continuous saline irrigation; LGUN, low-grade urothelial neoplasm; AUC, atypical urothelial cells; SHGUC, suspected high-grade urothelial carcinoma; HGUC, high-grade urothelial carcinoma; pT, pathologic T stage; TaLG, noninvasive papillary carcinoma and low grade; TaHG, noninvasive papillary carcinoma and high grade; CIS, urothelial carcinoma in situ; T1LG, low-grade tumor with invasion of lamina propria; T1HG, high-grade tumor with invasion of lamina propria; BCG, bacillus Calmette-Guérin.

[0073]

[0074]

[0075]

[0076] Univariate and multivariate Cox regression analyses for recurrence

[0077] HR, hazard ratio; CI, confidence interval; pT, pathologic T stage; TaLG, noninvasive papillary carcinoma and low grade; TaHG, noninvasive papillary carcinoma and high grade; CIS, urothelial carcinoma in situ; T1LG, lamina propria invasion and low-grade tumor; T1HG, lamina propria invasion and high-grade tumor; Preop., before surgery; LGUN, low-grade urothelial neoplasm; AUC, atypical urothelial cell; SHGUC, suspected high-grade urothelial carcinoma; HGUC, high-grade urothelial carcinoma; OCSI, continuous saline irrigation.

[0078]

[0079] In one study, patients who underwent OCSI after TURBT and had a negative urine cytology result had a longer recurrence-free survival (RFS) than those with high-grade urothelial carcinoma (HGUC) or suspected high-grade urothelial carcinoma (SHGUC). Specifically, the median RFS in the negative group was not reached, while the median RFS in the LGUN+AUC group was 615 days and the median RFS in the SHGUC+HGUC group was 377 days.

[0080] Survival analysis results showed that the negative group had a longer RFS than the SHGUC+HGUC group (p=0.013), indicating that urine cytology results are useful in predicting the risk of bladder cancer recurrence.

[0081] Meanwhile, univariate and multivariate Cox regression analyses confirmed that multiplicity and high grade (TaHG and T1HG) were independent prognostic factors for recurrence.

[0082] The hazard ratio (HR) was 2.430 (95% CI 1.312-4.499, p=0.005) for multifocality, 2.908 (95% CI 1.361-6.212, p=0.006) for high grade (TaHG), and 2.883 (95% CI 1.277-6.507, p=0.011) for high grade (T1HG). SHGUC+HGUC was not an independent prognostic factor for recurrence.

[0083] Furthermore, we confirmed that urine cytology results were associated with bladder cancer recurrence in NMIBC patients who underwent OCSI after TURBT. Specifically, cases with SHGUC or HGUC showed earlier recurrence than those with negative results, suggesting that urine cytology may be a valuable tool for predicting the risk of bladder cancer recurrence.

Claims

1. A method for providing information for predicting the possibility of bladder cancer recurrence, which provides information that among patients who underwent transurethral resection of a bladder tumor, patients who are positive for SHGUC (Suspicious for High-Grade Urothelial Carcinoma) or HGUC (High-Grade Urothelial Carcinoma) in urine cytology tests have a higher possibility of bladder cancer recurrence than patients who are not.

2. A method for providing information for predicting the possibility of bladder cancer recurrence according to claim 1, wherein the urine cytology test is performed by continuously injecting saline solution into the bladder of a patient who has undergone transurethral resection of a bladder tumor and then examining cells discharged through urine.

3. A method for providing information for predicting the possibility of bladder cancer recurrence, wherein the saline solution injection according to claim 1 is performed for 6 to 24 hours.

Images