bluuebunny/crossref_metadata_2025 huggingface dataset:
UriFind assay and association with whole course management of urothelial carcinoma in a large multicentric, prospective China cohort.
Authors: Chen Xu , Liu Zheng , Zhou Liqun , Fan Jinhai , Ruan Weimei , Wang Hong , Wei Qiang , Chen Haige , Xu Tao , Li Lei , Wang Shaogang , Tan Wanlong , Xu Abai , Zhong Jianmei , Li Xia , Chen Zhiwei , Bibikova Marina , Fan Jian-Bing , Huang Jian , Lin Tianxin
Published: June 2023

e16588

Background: The gold standard to diagnose and monitor urothelial carcinoma is cystoscopy, which is invasive and painful. The currently available non-invasive methods to detect urothelial carcinoma are either of unsatisfying sensitivity or limited specificity in China. Previously, a DNA methylation assay, termed UriFind, was developed, and showed a compelling sensitivity and specificity in a retrospective cohort. This study aimed to further validate its performance in a large multicentric, prospective China cohort. Methods: Patients involved in the whole course of UC management were recruited in this cohort. The cohort contained 931 patients diagnosed with urothelial carcinoma (UC), and 994 controls with benign diseases and 78 healthy participants from 12 hospitals across China. Urine samples were collected before the therapy, and analyzed with quantitative PCR of ONECUT2 and VIM methylation (UriFind), FISH and urinary cytology. Sensitivity, specificity, accuracy, PPV and NPV of these assays were evaluated as compared to the diagnostic gold standard of cystoscopy, histology results or clinical diagnosis. Results: The UC group of the cohort consisted of 683 non-muscle invasive UC (73.4%), 203 muscle invasive UC (21.8%) and 45 unavailable stage (4.8%). The patients of low, high-grade UC and unavailable grade were 244(26.2%), 651(69.9%) and 36 (3.9%), respectively. Overall sensitivity, specificity, accuracy, PPV and NPV of UriFind was 82.3%, 91.2%, 87.3%, 88.1% and 86.7%, respectively. The specificity of healthy participants was 100%. The overall sensitivity and accuracy of UriFind were significantly higher than urine cytology (40% and 55.7%) and FISH (68.2% and 73.6%), while the specificity was similar to cytology (93.9%) and FISH (87.3%). Importantly, UriFind achieved a great improvement of sensitivity in whole course management, including low grade tumor (56.1%), small and single tumor (63.3%), residual tumor after therapy (71.4%) and recurrent tumor (84.3%). Conclusions: The performance of UriFind is well validated with significantly higher sensitivity and accuracy than urine cytology and FISH in UC detection in this cohort with 2003 cases. This assay facilitates whole course management of urothelial carcinoma, which may reduce the burden of cystoscopy and unnecessary second TURBT. Clinical trial information: NCT04314245 .
Tislelizumab (Tisle) combined with/without gemcitabine and cisplatin (GC) as adjuvant therapy in patients at high risk after upper urothelial carcinoma (UTUC) surgery: A real-world study.
Authors: Yang Xiaojian , Quan Penghe , Yu Changjiang
Published: June 2023

e16592

Background: In China, UTUC affects 9.3% - 19.9% of urothelial carcinoma(UC) patients(Pts), comparing to 5%-10% in western countries. Radical nephroureterectomy (RNU) is the standard of care for locally advanced UTUC; however, patient prognosis remains suboptimal, and previous studies have shown a controversial survival benefit of postoperative adjuvant chemotherapy in pts with UTUC. Immune checkpoint inhibitors(ICI) have been demonstrated to improve disease-free survival (DFS) in pts after adjuvant therapy for UC, but the data from UTUC studies is limited. This study is intended to evaluate real-world study data on whether Tisle with/without GC is able to achieve better survival benefit in pts with UTUC. Methods: UTUC pts with clinical diagnosis of T1N1 or T2-T4aN0-1M0, ECOG ps of 0-1, could tolerate surgery and had adequate renal functional reserve after surgery. Enrolled pts underwent RNU surgery and adjuvant therapy was started within 90 days after surgery. ICI: 200 mg in day1(D1), Q3w regimen, when to discontinue the drug was assessed by clinicians, and the reasons for disease progression and intolerable toxicity; GC chemotherapy: gemcitabine 1000 mg/m2 D1, D8, cisplatin 70 mg/m2 D2, up to 6 (0-6) cycles. Primary endpoint: 3-year Overall survival (OS) rate; secondary endpoints included 5-year OS rate, tumor-related survival (CSS) and safety. Results: A total of 60 pts received the above treatment from Jan 2020 to Dec 2022, of whom 5 pts were considered to have metastases at initial diagnosis at further evaluation and were finally evaluated for safety only. Fifty-five pts were evaluable for response, with a median follow-up time of 21.5 (3-33) months, and 70.91% (39/55) of pts were followed up for more than 12 months. The OS rate was 93.14% at 1 year and 76.21% at 2 years. Tisle was administered for a median of 6 (1-14) cycles, with a 7.19% and 24.79% lower risk of death at 1 and 2 years in pts with Tisle ≥ 3 cycles compared with pts with Tisle < 3 cycles (HR: 0.368, 95% CI (0.076-1.781); p = 0.162). GC was administered for a median of 3 (0-6) cycles, with a 3.7% and 24.8% lower risk of death at 1 and 2 years in pts with GC＞2 cycles compared with pts with GC≤2 cycles (HR: 0.218, 95% CI (0.045-0.970); p = 0.110). The incidence of treatment-related adverse reactions (trAEs) of any grade was 91.64%; the incidence of trAEs of grade 3-4 was 18.33%, mainly manifested as leukopenic, gastrointestinal reaction and thrombocytopenia. The incidence of immune-related adverse reactions (irAEs) was 25%, and no irAEs of grade 3 or higher were found. The enrollment and follow-up of the present study are currently ongoing. Conclusions: Encouraging efficacy data and safety have been preliminarily observed with adjuvant Tisle with/without GC chemotherapy in high-risk pts after UTUC surgery. Final results also need to be observed in further studies.
CarePoint assay in the management of bladder cancer: A pilot study.
Authors: Chang Sam S. , Linehan Jennifer , Scarpato Kristen R. , Bassett Jeffrey C. , Brenneman Rodney
Published: June 2023

e16593

Background: Bladder cancer afflicts over 700,000 patients in the US and is one of the most expensive cancers to treat. Given a recurrence rate of up to 70%, regular often prolonged surveillance is required. In addition to urine based tests, current standard evaluation includes cystoscopy which is burdensome for patients and physicians; there has long been a need for a reliable non-invasive alternative diagnostic tool. While there is a wealth of literature on urinary biomarkers, no single biomarker has demonstrated consistent high sensitivity and specificity. Methods: The CarePoint Assay, a point-of-care (POC) tool, can perform multiple biomarker tests simultaneously. In this study, urine was collected from patients undergoing urologic evaluation for hematuria from three separate institutions. The urine was sent for central evaluation and the CarePoint Assay was used to detect the bladder cancer biomarker BTA. POC results were then compared to results from a highly sensitive 6-hour ELISA. The accuracy of distinguishing high-grade tumors, low-grade tumors and no tumor present were compared between the two methods. Results: The CarePoint Assay demonstrated excellent correlation with the ELISA in detecting biomarker levels and distinguishing high-grade tumors as well as a superior specificity (88% versus 77%) for ELISA, sensitivity (52% vs. 72%) for ELISA and a limit of detection of 2.55 ng/mL (16 picomolar). Conclusions: With this high performance, the CarePoint Assay has the ability to detect and multiplex multiple other bladder cancer biomarkers with higher sensitivity and specificity. Additional biomarker analysis using the CarePoint Assay may yield the medically desired higher levels of sensitivity and specificity for a non-invasive point-of-care bladder cancer test, ultimately limiting the patient burden of bladder cancer surveillance.
Performance of the OncoUrine test on the predictive capacity of non-muscle-invasive bladder cancer patients who are candidates for repeated transurethral resection.
Authors: Yang Xiao , Cai Lingkai , Liang Yiming , Xin Yaqun , Ma Tonghui , Lyu Qiang
Published: June 2023

e16595

Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of high-risk non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. But so far, no diagnostic tests able to improve patients’ stratification exist to reduce negative biopsy ratio of re-TURBT. To evaluate the value of the OncoUrine test for the predictive capacity of biopsy findings on re-TURBT, a prospective multi-center clinical trial was designed. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). Between December 2020 and September 2022, patients with a confirmed diagnosis of high-risk NMIBC at three study centers were enrolled. The inclusion criteria were ≥age 22 years old, prepare for re-TURBT following EAU guidelines, able to produce 100 ml of morning urine, and able to consent. Urine samples were collected from the enrolled patients for the OncoUrine tests before re-TURBT, and the test results were compared with the pathological results to calculate the performance. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. Results: Out of 109 patients enrolled, 93 were eligible for the performance analysis. In 33 cases, residual tumors were confirmed while the remaining 60 patients was found to have a result of negative pathological section. In the overall OncoUrine test results, variants from 11 genes showed positive mutations. TERT C228T, TP53, TERT C250T, ERBB2 and PIK3CA were on the top 5 of the list with other mutations from FGFR3, KRAS, HRAS, ERBB3, ERCC2, U2AF1, and ROHA. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the OncoUrine test for predicting pathological diagnosis were 81.8% (27/33), 81.7% (49/60), 89.1% (49/55), and 71.1% (27/38), respectively. Conclusions: Even for high-risk patients for whom re-TURBT is currently recommended, the OncoUrine test can accurately differentiate between cases with incomplete primary surgeries and those with no residual tumors. An interventional clinical trial is needed to further confirm the clinical value of this urine-based biopsy method on improving the selections of NMIBC patients. Clinical trial information: NCT05112523 .
A novel approach to the treatment of high-risk non–muscle-invasive bladder cancer: Combining immune checkpoint inhibitor (ICI) and microtubule inhibitor (MTI).
Authors: Hu Hailong , Niu Yuanjie , Li Hong Zheng , Shen Chong , Huang Shiwang , Qie Yunkai , Wu Zhouliang , Zhao Gangjian , Zhang Zhe , Jia Kaipeng , An Zesheng , Chen Houyuan , Guo Shizheng , Bai Yiduo
Published: June 2023

e16596

Background: Pts with multiple or tumors with large invasion areas that are incompletely resectable through TURBT would be recommended for radical cystectomy in the clinical treatment. The KEYNOTE-057 and SWOG S1605 studies have illuminated the efficacy of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). This trial was designed to evaluate the efficacy and safety of tislelizumab (ICI) plus nab-paclitaxel (MTI) in HR-NMIBC pts. Methods: TRUCE-02 is a single-arm phase II study testing systemic tislelizumab 200mg on days 1 plus nab-paclitaxel 200mg on days 2 every 3 weeks (Q3W) for one year for NMIBC pts with incompletely resectable tumor by TURBT. Here we report the results for all eligible patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate when pts received 3 or 4 cycles of therapy. Duration of complete response (DOR), cystectomy-free survival (CFS), overall survival (OS), and progression-free survival (PFS) using Kaplan-Meier methods (KM) were secondary endpoints. Results: Between July 2020 and December 2022, 69 pts were enrolled and included in the safety analysis, and, of those, 56 pts were eligible and included in the efficacy analysis. 34 (60.7%; 95% CI 46.8%, 73.2%) out of 56 pts achieved CR condition when completing 3 or 4 treatment cycles. At 12 months, the estimated DOR after CR was 88.1% (95% CI 76.2%, 99.9%); the median DOR was not reached. At 18 months, the estimated CFS was 70.0% (95% CI 58.1%, 84.3%), OS was 90.6% (95% CI 82.9%, 99.0%), and PFS was 74.4% (95% CI 62.5%,80.0%); the median CFS, OS, and PRS were not reached. 65 (94%) of 69 pts had treatment-related adverse events (trAEs). The most common trAEs were alopecia 47(68%), fatigue 44(64%), and rash 25(36%). 8 grade 3-4 trAEs occurred in 6 (9%) pts, including adrenal insufficiency in 2 (3%), rash in 1 (1%), myalgia or arthralgia in 1 (1%), increased creatine kinase isoenzyme in 1 (1%), hepatic enzymes increase in 1 (1%), increased glutamyl transpeptidase in 1 (1%), and decreased white blood cell count in 1 (1%). No trAE-related death was reported. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a durable and clinically meaningful activity in treating HR-NMIBC. The safety profile was consistent with that of previous experience and no new safety concerns. Clinical trial information: NCT04730232 .
Clinical performance of Bladder EpiCheck methylation test for active surveillance of non-muscle invasive bladder cancer: Systematic review and meta-analysis.
Authors: HSIA YUANPING , Chiang Cho Hsien , Chiang Cho Han , Chiang Cho Hung , Wang Shih-Syuan , Chang Yu-Cheng , Jaroenlapnopparat Aunchalee , Shiah Her-Shyong
Published: June 2023

e16597

Background: Non-muscle invasive bladder cancer (NMIBC) has a favorable 5-year survival, but up to 60% of patients experience cancer recurrence within the first year of diagnosis. The current gold standard for active surveillance is periodic cystoscopy, but this is expensive and invasive. An alternative non-invasive method involves urine cytology, but it has poor sensitivity. Recently developed urine-based molecular diagnostics such as the EpiCheck (Nucleix, Rehovot, Israel) test offers non-invasive and quick testing for active surveillance. In this systematic review and meta-analysis, we aimed to evaluate the diagnostic value of Bladder EpiCheck in active surveillance of NMIBC. Methods: We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies published between 1 January 2010 and 31 December 2022. The primary outcome was the sensitivity / negative predictive value (NPV) and specificity (PPV) of Bladder EpiCheck in active surveillance of NMIBC. We also performed a subgroup analysis to evaluate the performance of EpiCheck in detecting the recurrence of high-grade and low-grade NMIBC. Results: Our systematic search identified 110 articles, from which 6 studies were included in the final analysis. Compared with urine cytology, EpiCheck had a higher pooled sensitivity (73% [95% CI: 59-83] vs. 51% [95% CI: 30-72]) and NPV (90% [95% CI: 79.5-95.2] vs. 84% [95 % CI: 69-92]. However, EpiCheck had a lower pooled specificity (63% [95% CI: 48-76] vs. 97% [95% CI: 89-99]) and PPV (63% [95% CI: 48-76] vs. 85% [95 % CI: 69-94] than urine cytology. Similarly in subgroup analysis, EpiCheck had a higher pooled sensitivity than urine cytology in detecting both high-grade (86% [95% CI: 78-91] vs. 63% [95% CI: 43-80]) and low-grade (44% [95% CI: 34-55] vs. 13% [95% CI: 7-23]) NMIBC. Conclusions: The Bladder EpiCheck test has a better sensitivity than urine cytology and may be utilized as a part of the active surveillance strategy for NIMBC recurrence.
Neutrophil extracellular trap as a predictive marker to cisplatin-based chemotherapy for patients with muscle-invasive bladder cancer.
Authors: Shang Bing-Qing , Gu Zhaoru , Qu Wang , Xie Rui-Yang , Wu Jie , Zhou Ai-Ping , Shou Jianzhong
Published: June 2023

e16600

Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in both the neoadjuvant and first-line settings. However, the efficacy of MIBC for chemotherapy is only about 40%~60%. Patients without clear benefits from cisplatin-based chemotherapy still suffer from the potential toxicity, possibly missing the timing for other effective treatments. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In bladder cancer, NETs were involved in radio-resistance, but the predictive role of chemotherapy is unclear. This study constructed a NET-related signature that predicted chemotherapy efficacy for MIBC patients. Methods: Transcriptome datasets were obtained from the transurethral resection of bladder tumor (TURBT) and metastatic lesion specimens. A dataset (GSE169455) of 149 MIBC patients who received preoperative cisplatin-based chemotherapy (neoadjuvant or induction) was enrolled for the training cohort. We used the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model to select candidate molecules based on the 250 NETs-initial biomarkers collected from the literature, and further developed a NETs-associated signature score (NETs-score) for therapeutic response prediction. The dataset reported by Taber A et al. of 96 MIBC patients who received cisplatin-based chemotherapy (neoadjuvant or first-line) was used as a validation cohort. Immunohistochemistry (IHC) was conducted to evaluate the potential role of NET-related genes in 51 patients who received neoadjuvant chemotherapy at our center from 2012 to 2019. Results: We constructed the NETs-score with 11 NETs-related genes by the LASSO Cox model. A higher NET score was observed in non-responders compared to responders in the training cohort (P<0.001). These results were confirmed in the validation cohort (P=0.006). Moreover, high NETs-score indicated reduced recurrence-free survival (RFS) [HR=2.07, 95% CI (1.26-3.40), P=0.003], cancer-specific survival (CSS) [HR=1.87, 95% CI (1.12-3.12), P=0.014], and overall survival (OS) [HR=1.83, 95% CI (1.13-2.94), P=0.012] among MIBC patients. Furthermore, in the IHC cohort, citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analysis [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Conclusions: In conclusion, our study suggested that NET was a predictive and prognostic biomarker for MIBC patients with cisplatin-based chemotherapy. [Table: see text]
A phase II study of toripalimab combined with gemcitabine-cisplatin as neoadjuvant therapy for patients with muscle-invasive bladder cancer (MIBC).
Authors: Xu Abai , Xu Peng , Chen Chunxiao , Liu Zhe , Jiang Ning , Bi Enguang , Cao Manming , Chen BinShen , LIU Chunxiao
Published: June 2023

e16602

Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care in MIBC with improved pathologic response (PaR) and overall survival (OS) compared to radical cystectomy (RC) alone. The efficacy of PD-1 inhibitor in combination with chemotherapy as a new neoadjuvant treatment option for MIBC still needs further confirmation. This study evaluated the efficacy and safety of toripalimab (an anti-PD-1 monoclonal antibody) combined with gemcitabine-cisplatin (GC) as neoadjuvant therapy for patients with MIBC. Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Toripalimab (240mg, d1) combined with GC (gemcitabine 1000mg/m2 d1,d8 plus cisplatin 35mg/m2 d1,d2) every 21 days, up to 4 cycles. RC was performed within 6 weeks after the last dose treatment. The primary endpoint was PaR (≤ pT1,N0). Secondary endpoints were PFS at 2 years and safety. Results: Between Apr 2021 and Jun 2022, 16 pts (4 pts cT2, 11 pts cT3, 1 pts cT4) were enrolled and received 4 cycles of neoadjuvant therapy, with median age of 63.5 and 75% male. 14 of the 16 pts underwent RC and two declined RC. Among 14 evaluable pts, PaR ≤pT1N0 was achieved in 12 pts (85.71%, 4 were pT0, 8 were pT1/a/is). Survival data are not yet mature. The most common adverse events (AEs) of any grade were anemia (14/16; 87.5%) and nausea/vomiting (11/16; 68.75%). One had Grade≥3 AEs (hemorrhagic shock) while on study that was unrelated to GC or toripalimab. Five pts experienced grade 1-2 immune related AEs, including thyroiditis (3/16, 18.75%) and rash (2/16,12.5%). Conclusions: Neoadjuvant toripalimab combined with GC showed promising safety and efficacy in MIBC with significant pathologic downstaging rates. Clinical trial information: NCT04861584 .
Detection of bladder cancer relapse after TURBT through urinary tumor DNA analysis: A prospective real-world evidence study.
Authors: Zhang Ruiyun , Zang Jingyu , Tang Haoran , Xie Feng , Zhang Yue , Jin Di , Qian Lei , Zhang Tianxiang , Jia Shidong , Zhuang Guanglei , Chen Haige
Published: June 2023

e16605

Background: Bladder cancer is a common malignancy and detection of tumor recurrence is important to improve patient outcomes. Transurethral resection of bladder tumor (TURBT) is the standard treatment for early-stage bladder cancer, but the molecular detection of disease relapse remains a challenge. Reliable and non-invasive methods for monitoring the molecular changes in urine are crucial for timely intervention and disease management. Methods: In this study, 108 patients with early-stage bladder cancer who were selected for detection of disease relapse after the 1st TURBT (median timing 4.8 months after TURBT) were prospectively enrolled. The molecular recurrence in these patients was detected from the urinary tumor DNA (utDNA) using a targeted next-generation sequencing (NGS) assay (PredicineCARE). This assay identifies somatic alterations in utDNA, including single nucleotide variations (SNVs), gene fusions and copy number variations (CNVs), and based on these variations, the tumor fraction was called to identify molecular relapse in the patients. Results: 77 out of 108 (71.3%) patients were found to be tumor positive in utDNA with a tumor fraction ≥ 0.5%. The assay identified 525 SNVs and 32 CNVs in the tumor positive patients. The most frequently mutated genes in the urine samples were TP53 (38%), TERT (32%), KMT2D (28%), ARID1A (19%), FGFR3 (19%), PIK3CA (14%) and ERBB2 (12%). Conclusions: This study demonstrates the feasibility of using urine ctDNA assay to detect molecular recurrence in early-stage bladder cancer patients treated by TURBT. This information can be used to improve patient outcomes by enabling early detection of tumor recurrence and guiding treatment decisions. The findings of this study highlight the promising potential of urine-based NGS assays for cancer detection and disease surveillance.
A meta-analysis of local-regional therapy (LRT) in liver metastases from genitourinary cancers.
Authors: Behara Murali Ranjani , Findakly Dawood , Wang Jue
Published: June 2023

e16606

Background: Liver metastases (Mets) from genitourinary cancers are difficult to treat and many of them are resistant to systemic therapy. Local-Regional Therapies (LRT) are becoming popular in treating Liver Mets. In this Meta-analysis, we analyze the outcomes of LRT for Liver Mets from Genitourinary Cancers. Methods: We searched PubMed, Google scholar for case reports, case studies, retrospective studies with patients who underwent LRT like Radiofrequency Ablation (RF), Chemoembolization (CE), Microwave Ablation (MA), Cryoablation for liver metastases for from Genitourinary Cancers including Prostate Cancer (PC), Testicular Cancer (TC) and Renal Cell Cancer (RCC). We also included 3 patients from Dignity Health Cancer Center, Phoenix, AZ. Results: Total number of patients in the study is 54, 3 of them from our Center. 39 are men and 15 are women. Mean and median age of the patients was 62.3, 65 years respectively. Number of patients with RCC, PC, TC are 43, 6, 5 respectively. 28 patients had CE, 23 had RFA and 3 had MA with the total number of procedures being 144, 41 and 5 respectively. Mean survival for all the patients is 62.7 months, mean survival for RCC, TC and PC are 68.9, 45.8 and 24.4 months respectively. Median number of systemic therapies received by the patients prior to getting LRT was 2 (range 1-4). We used RECIST criteria to quantify the benefit from LRT, 23 patients had Complete Response (CR), 6 had Partial Response (PR), 14 had Stable Disease (SD) and 8 had Progressive Disease (PD), there was no data for 2 patients. 43 patients had Clinical Benefit. We present a case of castration resistant metastatic PC from our facility. A 78-year man diagnosed metastatic PC in 2007 who had Prostatectomy, salvage radiation, intermittent androgen deprivation and Combined deprivation therapy. But his PSA continued to rise, flutamide was added. In 2017, he had liver metastasis, had RFA twice for 2 liver lesions and had CR. He continues to be on relugolix with good quality of life. Patients in the study are people with advanced metastatic cancer who underwent various systemic therapies like chemotherapy, radiation, immunotherapy and hormonal therapy prior to getting the LRT. LRT was done as the patients failed or did not tolerate systemic therapies. The mean survival for RCC patients in the study group is greater than the average survival of stage IV RCC, the lower mean survival for PC and TC can be explained by the limited number of this patient population in the study. Conclusions: Combination of LRT with systemic therapy for previously heavily treated Liver Mets from genitourinary cancers is a promising strategy for patients with otherwise poor prognosis. [Table: see text]
Outcomes of renal function and efficacy in patients with muscle invasive bladder cancer treated by tislelizumab-based immunochemotherapy.
Authors: Li Hong Zheng , Niu Yuanjie , Hu Hailong , An Zesheng , Shen Chong , Wu Zhouliang , Qie Yunkai , Chen Houyuan , Zhao Gangjian , Huang Shiwang , Bai Yiduo , Guo Shizheng , Li Peng , Lin Yuda
Published: June 2023

e16608

Background: The occurrence PD-1 ICIs brings a new era of treatment for bladder cancer (BC). Although the safety and efficacy of most PD-1 ICIs have been certified progressively, whether they can be used in patients (pts) with renal impairment is always a concern for clinicians. Consequently, we intend to investigate the variation of renal function and efficacy of PD-1 ICIs based immunochemotherapy for pts with muscle invasive bladder cancer (MIBC) and renal insufficiency in short term. Methods: Our study relied on population of the TRUCE-01 trial (NCT04730219), an open-label, single-arm phase II study of tislelizumab based immunochemotherapy in pts with MIBC. Data of pts, including demographic information, imaging and pathological assessment of efficacy, and serum creatinine (SCr) level in baseline, after the first, second and third cycle (C1, C2 and C3) of treatment was collected and analyzed retrospectively. We calculated at estimated glomerular filtration rate (eGFR) according to CKD-EPI formula 2009, and divided pts into different groups according to baseline eGFR, in reference to CKD categories in the K-DIGO 2012 guidelines. Results: 74 pts have been included in our research in total. The median age was 69.5 years (IQR 61.7-75.0) and 56 (75.7%) were male. Median SCr in baseline was 77.4umol/L (IQR 67.8-96.6), while median eGFR was 84.6 (IQR 63.6-94.0) (the unit of eGFR is mL/min/1.73 m2). At baseline, 25 pts were classified as G1 (eGFR≥90), 36 as G2(eGFR <90 and≥60), 12 as G3 (eGFR <60 and ≥30), and 1 as G4 (eGFR <30 and≥15). No significant difference was found in eGFR between pts with CKD G1-2 in comparison to baseline and after C1, C2, C3 of treatment (All p>0.05). In pts with CKD G3-4, it is notable that eGFR may improve when the C1, C2 and C3 completed, in comparison to the baseline (p=0.087, p=0.046, p=0.114 in Wilcoxson test, p=0.082 in Repeated Measures ANOVA). 48 (64.9%) pts received 3 cycles of ICIs and underwent an operation. 24 of 48 (50%) pts received radical cystectomy (RC) and others were treated by maximal TURBT. All of them have conducted efficacy evaluation by both radiographic test and pathology. It is noted that no statistical difference in outcomes between Group G1-2 and G3-4 (p=0.772). Conclusions: Despite renal impairment is common in pts with MIBC, PD-1 immunotherapy is generally safe for kidney of MIBC patients with renal insufficiency and have no influence on efficacy in the short term. The potential improvement in eGFR of patients with worse renal function and its mechanism is essential to be revealed and verified. [Table: see text]
Efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy in patients with high-risk UTUC.
Authors: Niu Yuanjie , Li Hong Zheng , Hu Hailong , An Zesheng , Shen Chong , Wu Zhouliang , Qie Yunkai , Bai Yiduo , Zhao Gangjian , Chen Houyuan , Guo Shizheng
Published: June 2023

e16609

Background: Urothelial carcinomas (UCs) are the sixth most common tumor. Among them, UTUCs are uncommon, accounting for only 5-10% of UCs. Currently, radical nephroureterectomy (RNU) remains the gold standard of treatment for UTUC. Neoadjuvant chemotherapy treatment can be used for specific UTUC patients, especially for highly staged and/or grade tumors, such as kidneys with potentially decreased renal function after RNU. Neoadjuvant therapy is a series of treatments administered preoperatively for UTUC, mainly chemotherapy, and in recent years, novel therapies of immunotherapy have emerged. Since conventional cisplatin neoadjuvant regimens also require high preoperative renal function, neoadjuvant chemotherapy regimens such as immunotherapy provide more effective and feasible treatments for patients who are intolerant to current cisplatin chemotherapy regimens. However, there is a lack of valuable studies worldwide on novel regimens such as immunotherapy for UTUC. The aim of this study was to explore a novel preoperative neoadjuvant regimen of immunotherapy combined with chemotherapy for UTUC. To further observe the feasibility and effectiveness of this regimen in the field. Methods: 9 high-risk UTUC patients were included in this study. Among them, 7 had unilateral ureteral tumors. 1 had a unilateral renal pelvic tumor. 1 had unilateral pelvic ureteral tumor. Among them, 2 were combined with bladder tumor. All patients were given 3 cycles of tislelizumab 200 mg combined with albumin paclitaxel 200 mg after a thorough evaluation. The treatment cycles were 21 days. Imaging evaluation and surgical resection were given within 15-20 days after the end of the last treatment cycle. Results: 3 patients underwent radical nephroureterectomy with postoperative pathology suggesting SD status of the tumor. 1 patient underwent ureteral reimplantation with tumor-negative postoperative pathology (cCR) and 2 patients underwent ureteroscopic biopsy, 1 of whom had tumor-negative pathology (cCR). 2 patients declined surgical treatment with RNU, one patient had imaging confirmation that the tumor was in SD, and the other showed no evidence of tumor presence on imaging and cytology (cCR). 1 patient was treated intermittently for grade 2 myocardial adverse effects (the remaining patients had adverse effects mostly limited to grade 1, with alopecia and malaise as common symptoms). Conclusions: The characteristics of epithelial carcinoma of the upper urinary tract have led to a reduced intention of some patients to undergo RNU treatment after the completion of NAC treatment. Although the present study failed to obtain ideal pathological information after RNU, the clinical treatment effect (cCR 30%) presented in combination with imaging and cytological results reveals to some extent the promising prospect of future UTUC patients treated with NAC.
Early postoperative outcomes in stent vs stent-less ileal conduits after radical cystectomies.
Authors: Shah Yash , Simhal Rishabh , Wang Kerith Ruoyao , Prebay Zachary , Lallas Costas D. , Simon Daniel P , Gomella Leonard G. , Shah Mihir S
Published: June 2023

e16612

Background: Placing stents at the ureteroileal anastomosis for radical cystectomy with ileal conduit (RCIC) diversion has been common practice for the vast majority of urologists. Recently, the practice has been called into question, as some institutions have shifted to not stenting their ileal conduits for patient comfort and convenience. In this study, we aim to investigate the difference in 30-day outcomes between patients who did and did not receive ureteroileal stents after RCIC. Methods: RCs performed between 2019-2020 were identified in NSQIP and the corresponding cystectomy-targeted database. Baseline demographics, comorbidities, and operative parameters were compared via Pearson’s chi-square and t-tests between stented and stent-less RCICs. Outcomes of interest included rates of urinary tract infections (UTIs), acute kidney injury (AKI), renal failure requiring dialysis, anastomotic leaks, ureteral obstruction, ureteral fistula formation, need for reoperation, and 30-day hospital readmissions. Outcomes were compared using Pearson’s chi-square. All statistical tests were two tailed, p<0.05 considered significant. Results: 3,865 RCICs were identified, of which 446 (11.5%) were stent-less. There was no difference in baseline demographics, comorbidities, or operative parameters between the stented and stent-less group, with the notable exceptions that significantly more stent-less patients had robotic-assisted instead of open RCs compared to the stented group (33% vs 21%, p<0.001), and significantly more stent-less patients were preoperatively on dialysis compared to the stented group (4.9% vs 0.5%, p<0.001). There was no significant difference in 30-day rates of UTIs, AKIs, renal failure, anastomotic leaks, ureteral obstruction, ureteral fistula formation, need for reoperation, and readmissions between the stented and stent-less cohorts. Conclusions: Stent-less ileal conduits have recently emerged in popularity. This study represents the largest multi-institutional analysis comparing outcomes between traditionally stented and stent-less RCICs, and shows that there is no significant difference in outcomes. Given the added cost and patient discomfort of ureteroileal stents, this study may indicate that these stents may not play as significant of a role in preventing early complications as previously thought. These findings warrant further investigation.
Phase Ib neoadjuvant CG0070 and nivolumab (N) for cisplatin (C)-ineligible muscle invasive bladder cancer (MIBC).
Authors: Li Roger , Spiess Philippe E. , Sexton Wade J. , Poch Michael Adam , Zemp Logan , Pow-Sang Julio M. , Zhang Jingsong , Dhillon Jasreman , Borjas Gustavo , Naidu Shreyas U , Dorman Denise , Burke James M. , Mule James J , Conejo-Garcia Jose , Jain Rohit K.
Published: June 2023

e16613

Background: CG0070 is a replication-competent oncolytic adenovirus engineered to target RB deficient tumor cells and to express GM-CSF. CG0070 has previously demonstrated safety and efficacy against BCG-exposed high risk non-muscle invasive bladder cancer through tumor lysis and anti-tumor immune activation. We tested the safety and efficacy of CG0070 in combination with N as neoadjuvant therapy for MIBC in C-ineligible patients in this study (NCT04610671). Methods: C-ineligible pts with MIBC (cT2-4a, N≤1) were enrolled. Pts received 6 weekly intravesical CG0070 (1x1012vp) and 2 doses of N at wks 2 and 6, followed by radical cystectomy (RC). The primary objective is safety of CG0070+N as measured by CTCAEv5.0. Secondary objective is to assess pathologic response (PaR) (pT0N0) and 1yr event free survival (EFS). Exploratory objectives include the assessment of correlation between PaR with baseline 1) E2F expression; 2) immune infiltration; 3) PD-L1 expression; and 4) TLS expression. Results: Between Nov 2020 and Feb 2023, 21 pts were enrolled with median age 75yrs, 81% male, 33% > cT2; 1 pt refused RC but was included in the ITT population. Treatment was stopped after 1 infusion of CG0070 in 1 pt due to treatment unrelated worsening of renal function. The overall rate of >grade 3 AEs was 12/20 (60%), and the vast majority were related to RC (83%). Immune related AEs were seen in 1 pt, who had grade 2 autoimmune thyroiditis. There was no delay in time to RC and no unexpected surgical complications from treatment. Overall, 1 pt was unevaluable for efficacy, 2 pts progressed prior to RC, PaR was observed in 8/15 (53%) evaluable pts, and an additional pt had negative post-treatment biopsy but refused RC. On exploratory analysis, treatment response correlated with increased maturation of tertiary lymphoid structures and immunogenicity to bespoke tumor neoantigens. Conclusions: Neoadjuvant CG0070+N is safe and effective in C-ineligible pts with MIBC. This combination was well tolerated without any delays in RC and induced an overall response rate of 50%. Clinical trial information: NCT04610671 .
A single institution experience of multimodality radiation therapy for muscle-invasive bladder cancer.
Authors: Nair Monica , Scarborough Jessica , Gupta Shilpa , Gilligan Timothy D. , Nizam Amanda , Ornstein Moshe Chaim , Echle Jessica , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D. , Scott Jacob , Mian Omar Y.
Published: June 2023

e16614

Background: We studied a cohort of patients with localized muscle invasive bladder cancer (MIBC) who received organ preserving trimodality therapy (TMT) as definitive treatment at a single high-volume institution. Methods: A retrospective cohort analysis was performed for 231 bladder cancer patients treated with definitive radiation or chemoradiation therapy from 2006 to 2022 at a single institution. We assessed overall and disease-free survival as defined by any type of cancer recurrence. We analyzed survival outcomes based on stage, pathologic features, and patient characteristics. Results: 184 of 231 patients in this cohort received either definitive radiation therapy alone or with chemoradiation and had adequate follow-up data for analysis. The median overall survival for these 184 patients was 37mo (95%CI 28-67). Disease free survival (DFS) had a median time of 36mo (95% CI 23-69). On univariate analysis neither tumor size nor hydronephrosis showed a significant association with local recurrence. The presence of carcinoma in situ (CIS) was associated with shorter time to local recurrence (Log-Rank p = 0.039). Nine patients (4.9%) required cystectomy after initial definitive radiation therapy. When overall survival was compared between patients offered radical cystectomy who proceeded with definitive multimodal radiation therapy and radical cystectomy ineligible patients, there was a significantly longer overall survival for the cystectomy eligible patients (median 86mo (95%CI 35-206) vs median 31mo (95%CI 24-44), Log-Rank p = 0.0016). No differences were observed in cancer specific survival between cystectomy eligible and ineligible patients. Conclusions: Multimodality bladder preservation demonstrated cancer specific survival outcomes comparable to published radical cystectomy series. The presence of CIS at baseline was associated with increased local recurrence, but not CSS or OS. Eligibility for radical cystectomy was associated with longer overall survival in patients treated with TMT, highlighting the limitations of retrospective comparisons of all-cause mortality between different treatment approaches. Disease specific survival endpoints, propensity matching analyses, or randomized prospective trials are needed to draw comparative efficacy conclusions.
Prognostic value of DNA damage repair and tolerance factors in patients with muscle-infiltrating urothelial carcinoma.
Authors: Palacka Patrik , Holickova Andrea , Roska Jan , Vallova Miroslava , Biro Csaba , Slopovsky Jan , Orasova Eveline , Mardiak Jozef , Kajo Karol , Chovanec Miroslav
Published: June 2023

e16615

Background: Cisplatin (CDDP) is the key agent in treatment of muscle-infiltrating urothelial carcinomas (MIUCs). However, around a half of patients do not respond to combined chemotherapy based on this agent what might be caused by an increased capacity to repair CDDP-induced DNA damage. The objective of this study was to determine the levels of selected DNA repair and tolerance factors in patients with MIUC to reveal their potential prognostic value. Methods: We have evaluated the bladder tumors from 86 subjects reviewed by trained pathologists. Median age was 67 years (range 37-84 years), 75.6% were males. All patients had MIUCs. To detect the XPA, XPF, POLI, REV3L, and POLH levels in primary tumors, immunohistochemistry was used. Study population was divided into two groups by positivity defined as 76-100% (negative vs positive tumors). Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: At median follow-up of 20.6 months (1.0-212.5 months), 86.1% of patients died. Median OS of subjects with tumors stained negative for XPA, XPF, REV3L, and POLH did not differ significantly from patients with positive staining for these proteins, with hazard ratios (HRs) being 0.61, 0.62, 0.98, and 0.72, respectively. Patients with tumor negative for POLI expression had significantly ( p = 0.0334) better median OS of 23.5 months (range 17.3-47.3 months) compared to subjects with tumor stained positive for expression of this protein [median OS of 17.6 months (range 13.6-21.3 months)] (HR = 0.61, 95%, CI 0.39-0.97). Conclusions: In this study, we showed a clear correlation between higher POLI expression in primary tumor tissue and inferior outcome in MIUC patients. Hence, we believe that the expression level of POLI might represent a prognostic biomarker and potentially constitute promising therapeutic target.
Molecular and immune analysis of adrenocortical carcinoma (ACC): Implications for immune checkpoint inhibition (ICI).
Authors: Nazha Bassel , Gandhi Nishant , Naqash Abdul Rafeh , Hadfield Matthew James , Zhuang Tony , Brown Jacqueline T. , Carthon Bradley Curtis , Barata Pedro C. , Agarwal Neeraj , Soares Heloisa P. , Kucuk Omer , Goldman Jamie , Lou Emil , Abdulla Farah Rukshana , Oberley Matthew James , Farrell Alex Patrick , Master Viraj A. , Bilen Mehmet Asim
Published: June 2023

e16617

Background: ACC is a rare and aggressive malignancy. Response rates to ICI are low with scarce yet promising durable responses. Molecular ACC subtypes have been reported based on The Cancer Genome Atlas (TCGA). Here we report the mutational and immune landscapes of ACC obtained from a real-world patient dataset. Methods: DNA (592-gene or whole exome; N=215) and RNA sequencing (whole transcriptome; N=121) were performed for ACC specimens submitted to Caris Life Sciences (Phoenix, AZ). PD-L1+ expression was tested by IHC (SP142; ≥1%). Hierarchical agglomerative clustering (HAC) analysis was performed on a pre-defined set of immune genes. Specimens grouped into immune-high/intermediate (IH) and immune-low (IL) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate immune cell infiltrates. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q<0.05). Results: Overall, the most frequent mutations were in TP53 (37%), CTNNB1 (18.7%), ATRX (12.1%), NF1 (9.6%), and RB1 (8.75%), consistent with previous reports. Further, 6.4% of tumors were PD-L1+, 6.1% TMB-high (≥ 10 mut/MB), and 5.9% dMMR/MSI-H. 38.2% of tumors were biopsied from metastatic sites (M). Compared to M, primary (P) specimens had a higher prevalence of TP53 (43.4 vs 26.9%, p<0.05) and TERT promoter mutations (11.1 vs 0%, p=0.08), and a lower prevalence of SMARCB1 (0 vs 3.7%, p=0.054) and BRCA2 (0 vs 3.8%, p=0.056) mutations. Interestingly, M lesions were enriched for HAVCR2 expression (1.3-fold, p<0.05), as well as infiltration of monocytes (1.8-fold, q<0.05) and endothelial cells (1.4-fold, q<0.05). HAC based segregation of tumors based on immune activity was corroborated by a general enrichment of immune cell infiltrates in the IH tumors. IH tumors were enriched for common immunotherapy-related biomarkers (TMB-high, dMMR/MSI-H and PD-L1 positivity), along with a higher prevalence of TP53 and ATRX mutations, while CTNNB1 mutation and CDK4 copy number amplification were less common in IH tumors. Conclusions: Querying a large real-world ACC patient dataset, we find somatic alterations and a low prevalence of ICI-related biomarkers (<10%), consistent with previous reports. Monocyte and endothelial cell infiltration in metastatic tumors suggests an immunosuppressive phenotype compared to primary tumors. Finally, identification of molecular alterations in tumors with distinct immune phenotypes may facilitate development of new therapeutic strategies in ACC. [Table: see text]
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced bladder cancer.
Authors: Chen Haige , Qian Lei
Published: June 2023

e16619

Background: Previous studies have shown that intra-tumor heterogeneity (ITH) can lead to drug resistance to tumor therapy, which is associated with poor prognosis of solid tumors. However, studies on the correlation between ITH and immunotherapy efficacy in patients with advanced bladder cancer (BLCA) are still lacking. Methods: Bioconductor R package Maftools was used to analyze somatic variants of advanced BLCA from an independent cohort (Miao-249 study cohort, PMID: 30150660) with data from 27 patients who underwent whole-exome sequencing. The ITH score was measured using the mutant-allele tumor heterogeneity (MATH) algorithm to analyze the difference in the genetic profile between the ITH score high (ITH-H) and ITH score low (ITH-L) groups, its association with tumor mutational burden (TMB), and the effect of ITH on the prognosis of immunotherapy. Results: There were significant differences in gene mutation spectrum between ITH-H and ITH-L groups. The genes with the highest mutation frequency in ITH-H group were TP53 (57.14%), DNAH5 (38.1%), TNRC18 (38.1%), TTN (38.1%), CSMD3 (33.33%), MDN1 (33.33%), MRPL49 (33.33%), and MUC19 (33.33%), while the genes with the highest mutation frequency in ITH-L group were KDM6A (83.33%), TP53 (66.67%), CALN1 (50%), MICAL2 (50%), MTOR (50%), NINL (50%), PCDHA (50%), and RMIBP2 (50%). The objective response rate (ORR) of immunotherapy was 66.66% and 42.86% for the patients with ITH-L and ITH-H subgroup. The ITH-L patients had significantly improved median overall survival (mOS) than the ITH-H group (not reach versus 12.3 months, hazard ratio (HR) = 6.65, 95%CI 0.86−51.36, P = 0.037). There was no significant difference in median TMB levels between ITH-L and ITH-H groups (8 Muts/Mb versus 7.6 Muts/Mb, P = 0.97). The TMB high (TMB-H) patients had no significantly better mOS than the TMB low (TMB-L) group (not reach versus 9.07 months, HR = 0.33, 95%CI 0.07−1.49, P = 0.13). A pooled analysis of ITH and TMB show that mOS in the ITH-L+ TMB-H group was numerically better than that in the ITH-H+TMB-H, ITH-H+TMB-L, and ITH-L+TMB-L group (not reach versus 15.6 months versus 7.1 months versus not reach, HR-1.57, 95CI 0−Inf, P = 0.1). Conclusions: The results suggest that ITH may be independent of TMB and a positive predictor of immunotherapy in patients with advanced BLCA.