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10 pages, 1022 KiB

Open AccessArticle

Oncological Outcomes in Patients with Metastatic Urothelial Carcinoma after Discontinuing Pembrolizumab as a Second-Line Treatment: A Retrospective Multicenter Real-World Cohort Study

by Toyohiro Yamada, Keita Nakane, Torai Enomoto, Masayuki Tomioka, Tomoki Taniguchi, Takashi Ishida, Kaori Ozawa, Kimiaki Takagi, Hiroki Ito, Shinichi Takeuchi, Makoto Kawase, Kota Kawase, Daiki Kato, Manabu Takai, Koji Iinuma, Shigeaki Yokoi, Masahiro Nakano and Takuya Koie

Biomedicines 2022, 10(9), 2243; https://doi.org/10.3390/biomedicines10092243 - 9 Sep 2022

Cited by 3 | Viewed by 1465

Abstract

The treatment options are currently limited, and the oncological outcomes remain unclear, for patients with metastatic urothelial carcinoma (mUC) with or without third-line systemic therapy. We aimed to evaluate the oncological outcomes in real-world daily clinical practice after platinum-based chemotherapy followed by pembrolizumab [...] Read more.

The treatment options are currently limited, and the oncological outcomes remain unclear, for patients with metastatic urothelial carcinoma (mUC) with or without third-line systemic therapy. We aimed to evaluate the oncological outcomes in real-world daily clinical practice after platinum-based chemotherapy followed by pembrolizumab for mUC. This retrospective, multicenter cohort study included patients with mUC who received second-line pembrolizumab in Japan. The patients were divided into the treatment group (those who received third-line treatment) and the BSC group (those who did not receive other treatments). The primary endpoint of this study was to evaluate the oncological outcomes. Of 126 patients enrolled in this study, 40 received third-line therapy. The median follow-up period was 8.0 months. The median overall survival (OS) times were nine months in the BSC group and 17 months in the treatment group (p < 0.001). The median progression-free survival (PFS) times were 4 months in the BSC group and 14 months in the treatment group (p < 0.001). In the multivariate analysis, performance status and liver metastasis were significantly associated with OS. Third-line therapy may have clinical potential advantages for improving the oncological outcomes in patients with mUC. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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9 pages, 819 KiB

Open AccessArticle

Subsequent Systemic Therapy following Platinum and Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma

by Joohyun Hong, Hyun Hwan Sung, Byong Chang Jeong and Se Hoon Park

Biomedicines 2022, 10(8), 2005; https://doi.org/10.3390/biomedicines10082005 - 18 Aug 2022

Viewed by 1399

Abstract

Treatment of metastatic urothelial carcinoma (mUC) after failure with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) remains controversial. To explore the role of subsequent systemic therapy, medical records from 436 patients who were consecutively treated with chemotherapy for mUC between May 2017 and [...] Read more.

Treatment of metastatic urothelial carcinoma (mUC) after failure with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) remains controversial. To explore the role of subsequent systemic therapy, medical records from 436 patients who were consecutively treated with chemotherapy for mUC between May 2017 and April 2021 were collected from a single-center cancer registry. The primary endpoint was overall survival (OS), and progression-free survival (PFS) and response rate (RR) were also assessed. Among the 318 patients who failed both platinum and ICIs, subsequent therapy was delivered to 166 (52%) patients: taxanes (n = 56), platinum rechallenge (n = 46), pemetrexed (n = 39), and clinical trials (n = 25). Objective responses to third-line therapy were noted in 50 patients (RR, 30%; 95% CI, 23–37%). The patients who were enrolled in clinical trials and treated with platinum rechallenge were significantly more likely to respond than those treated with taxanes or pemetrexed. The median PFS and OS were 3.5 months (95% CI, 2.9–4.2 months) and 9.5 months (95% CI, 8.1–11.0 months), respectively. Similar to RR, PFS and OS were longer for the patients who were enrolled in clinical trials. Based on multivariate analyses, good performance status and enrollment in clinical trials are associated with benefits from subsequent therapy for pretreated mUC. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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10 pages, 1601 KiB

Open AccessArticle

The Impact of Neutrophil-to-Lymphocyte Ratio after Two Courses of Pembrolizumab for Oncological Outcomes in Patients with Metastatic Urothelial Carcinoma

by Risa Tomioka-Inagawa, Keita Nakane, Torai Enomoto, Masayuki Tomioka, Tomoki Taniguchi, Takashi Ishida, Kaori Ozawa, Kimiaki Takagi, Hiroki Ito, Shinichi Takeuchi, Makoto Kawase, Kota Kawase, Daiki Kato, Manabu Takai, Koji Iinuma, Shigeaki Yokoi, Masahiro Nakano and Takuya Koie

Biomedicines 2022, 10(7), 1609; https://doi.org/10.3390/biomedicines10071609 - 6 Jul 2022

Cited by 9 | Viewed by 1436

Abstract

We focused on the therapeutic effect of pembrolizumab for metastatic urothelial carcinoma (mUC) and evaluated predictive factors for improving clinical outcomes. We conducted a retrospective multicenter cohort study of patients with mUC who received pembrolizumab. The endpoint was to evaluate the association between [...] Read more.

We focused on the therapeutic effect of pembrolizumab for metastatic urothelial carcinoma (mUC) and evaluated predictive factors for improving clinical outcomes. We conducted a retrospective multicenter cohort study of patients with mUC who received pembrolizumab. The endpoint was to evaluate the association between clinicopathological features and oncological outcomes. A total of 160 patients were enrolled in this study and were divided into two groups: the responder and the non-responder group, according to the best response. They were followed up for a median period of 10 months. The median overall (OS) and progression-free survival (PFS) in this study were 17 and 4 months, respectively. The responder group did not achieve median OS and it was 10 months in the non-responder group (p < 0.001). Similarly, the responder group did not achieve PFS, and it was 2 months in the non-responder group (p < 0.001). Regarding the neutrophil-to-lymphocyte ratio (NLR) after two courses of administration of pembrolizumab, patients with NLR < 3.24 had significantly better oncological outcomes than those with NLR ≥ 3.24. Multivariate analysis showed a significant association between NLR after two courses of pembrolizumab and OS. Therefore, the absolute value of NLR after two courses of pembrolizumab was a significant predictive factor for oncological outcomes. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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11 pages, 903 KiB

Open AccessArticle

Clinical Implication of Preoperative Renal Function on Oncological Outcomes in Patients with Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy

by Tae Heon Kim, Hyun Hwan Sung, Jong Jin Oh, Seok Ho Kang, Ho Kyung Seo, Bumsik Hong, Ja Hyeon Ku and Byong Chang Jeong

Biomedicines 2022, 10(6), 1340; https://doi.org/10.3390/biomedicines10061340 - 7 Jun 2022

Cited by 1 | Viewed by 1610

Abstract

This study aims to evaluate the impact of preoperative renal function on oncological outcomes in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). We performed a retrospective analysis of patients who underwent RNU between 2000 and 2012 at six [...] Read more.

This study aims to evaluate the impact of preoperative renal function on oncological outcomes in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). We performed a retrospective analysis of patients who underwent RNU between 2000 and 2012 at six academic centers. The patients were stratified into two groups based on preoperative renal function: eGFR < 60 mL/min/1.73 m² (chronic kidney disease; CKD) and eGFR ≥ 60 mL/min/1.73 m² (non-CKD). We investigated oncological outcomes, including overall survival, cancer-specific survival, and progression-free survival dichotomized by preoperative renal function. Multivariable Cox proportional hazards regression was used to determine if preoperative CKD was associated with oncological outcomes. In total, 1733 patients were eligible for the present study (CKD = 707 and non-CKD = 1026). Significant differences were noted in the clinical and pathologic features among the two groups, including age, sex, tumor localization, pathological T stage, tumor grade, and number of patients who received adjuvant chemotherapy. The estimated five-year overall survival (79.4 vs. 67.5%, log-rank p < 0.001), cancer-specific survival (83.5 vs. 73.6%, log-rank p < 0.001), and progression-free survival (74.6 vs. 61.5%, log-rank p < 0.001) were significantly different between the two groups, longer in the non-CKD group. Upon multivariable analysis, preoperative CKD status was associated with increased risk of overall mortality, cancer-specific mortality, and progression (p = 0.010, p = 0.016, and p = 0.008, respectively). UTUC patients with preoperative CKD had a higher risk of poor overall survival, cancer-specific survival, and progression-free survival after RNU than those without CKD. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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15 pages, 3222 KiB

Open AccessArticle

Effective Radiosensitization of Bladder Cancer Cells by Pharmacological Inhibition of DNA-PK and ATR

by Ahmed Ali Chughtai, Julia Pannhausen, Pia Dinger, Julia Wirtz, Ruth Knüchel, Nadine T. Gaisa, Michael J. Eble and Michael Rose

Biomedicines 2022, 10(6), 1277; https://doi.org/10.3390/biomedicines10061277 - 30 May 2022

Cited by 4 | Viewed by 1964

Abstract

This study aims at analyzing the impact of the pharmacological inhibition of DNA damage response (DDR) targets (DNA-PK and ATR) on radiosensitization of bladder cancer cell lines of different molecular/histological subtypes. Applying DNA-PK (AZD7648) and ATR (Ceralasertib) inhibitors on SCaBER, J82 and VMCUB-1 [...] Read more.

This study aims at analyzing the impact of the pharmacological inhibition of DNA damage response (DDR) targets (DNA-PK and ATR) on radiosensitization of bladder cancer cell lines of different molecular/histological subtypes. Applying DNA-PK (AZD7648) and ATR (Ceralasertib) inhibitors on SCaBER, J82 and VMCUB-1 bladder cancer cell lines, we revealed sensitization upon ionizing radiation (IR), i.e., the IC₅₀ for each drug shifted to a lower drug concentration with increased IR doses. In line with this, drug exposure retarded DNA repair after IR-induced DNA damage visualized by a neutral comet assay. Western blot analyses confirmed specific inhibition of targeted DDR pathways in the analyzed bladder cancer cell lines, i.e., drugs blocked DNA-PK phosphorylation at Ser2056 and the ATR downstream mediator CHK1 at Ser317. Interestingly, clonogenic survival assays indicated a cell-line-dependent synergism of combined DDR inhibition upon IR. Calculating combined index (CI) values, with and without IR, according to the Chou–Talalay method, confirmed drug- and IR-dose-specific synergistic CI values. Thus, we provide functional evidence that DNA-PK and ATR inhibitors specifically target corresponding DDR pathways retarding the DNA repair process at nano-molar concentrations. This, in turn, leads to a strong radiosensitizing effect and impairs the survival of bladder cancer cells. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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21 pages, 4629 KiB

Open AccessArticle

Targeted Inhibition of O-Linked β-N-Acetylglucosamine Transferase as a Promising Therapeutic Strategy to Restore Chemosensitivity and Attenuate Aggressive Tumor Traits in Chemoresistant Urothelial Carcinoma of the Bladder

by Hye Won Lee, Mi Ju Kang, Young-Ju Kwon, Sama Abdi Nansa, Eui Hyun Jung, Sung Han Kim, Sang-Jin Lee, Kyung-Chae Jeong, Youngwook Kim, Heesun Cheong and Ho Kyung Seo

Biomedicines 2022, 10(5), 1162; https://doi.org/10.3390/biomedicines10051162 - 18 May 2022

Cited by 3 | Viewed by 2487

Abstract

Acquisition of acquired chemoresistance during treatment cycles in urothelial carcinoma of the bladder (UCB) is the major cause of death through enhancing the risk of cancer progression and metastasis. Elevated glucose flux through the abnormal upregulation of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) controls [...] Read more.

Acquisition of acquired chemoresistance during treatment cycles in urothelial carcinoma of the bladder (UCB) is the major cause of death through enhancing the risk of cancer progression and metastasis. Elevated glucose flux through the abnormal upregulation of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) controls key signaling and metabolic pathways regulating diverse cancer cell phenotypes. This study showed that OGT expression levels in two human UCB cell models with acquired resistance to gemcitabine and paclitaxel were significantly upregulated compared with those in parental cells. Reducing hyper-O-GlcNAcylation by OGT knockdown (KD) markedly facilitated chemosensitivity to the corresponding chemotherapeutics in both cells, and combination treatment with OGT-KD showed more severe growth defects in chemoresistant sublines. We subsequently verified the suppressive effects of OGT-KD monotherapy on cell migration/invasion in vitro and xenograft tumor growth in vivo in chemoresistant UCB cells. Transcriptome analysis of these cells revealed 97 upregulated genes, which were enriched in multiple oncogenic pathways. Our final choice of suspected OGT glycosylation substrate was VCAN, S1PR3, PDGFRB, and PRKCG, the knockdown of which induced cell growth defects. These findings demonstrate the vital role of dysregulated OGT activity and hyper-O-GlcNAcylation in modulating treatment failure and tumor aggression in chemoresistant UCB. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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Review

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15 pages, 1287 KiB

Open AccessReview

The Current Progress and Future Options of Multiple Therapy and Potential Biomarkers for Muscle-Invasive Bladder Cancer

by Ying Shi, Bryan J. Mathis, Yayun He and Xiong Yang

Biomedicines 2023, 11(2), 539; https://doi.org/10.3390/biomedicines11020539 - 13 Feb 2023

Cited by 4 | Viewed by 4059

Abstract

Bladder cancer is a common disease in men and the elderly. Current treatment paradigms include radical resection of the bladder and lymph nodes or transurethral resection, both supported by chemotherapy and/or radiation. New modalities, such as illumination-based therapies are also being translationally pursued. [...] Read more.

Bladder cancer is a common disease in men and the elderly. Current treatment paradigms include radical resection of the bladder and lymph nodes or transurethral resection, both supported by chemotherapy and/or radiation. New modalities, such as illumination-based therapies are also being translationally pursued. However, while survival rates have increased due to combined therapies (particularly chemotherapy, radiation, immune checkpoint inhibitors, and surgery), a lack of diagnostic markers leads clinical professionals to rely on frequently invasive and expensive means of monitoring, such as magnetic resonance imaging or bladder cystoscopy. To improve real-time diagnostic capabilities, biomarkers that reflect both the metabolic and metastatic potential of tumor cells are needed. Furthermore, indicators of therapy resistance would allow for rapid changes in treatment to optimize survival outcomes. Fortunately, the presence of nanoscale extracellular vesicles in the blood, urine, and other peripheral fluids allow for proteomic, genomic, and transcriptomic analyses while limiting the invasiveness of frequent sampling. This review provides an overview of the pathogenesis and progression of bladder cancer, standard treatments and outcomes, some novel treatment studies, and the current status of biomarker and therapy development featuring exosome-based analysis and engineering. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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15 pages, 311 KiB

Open AccessReview

Bacteria for Treatment: Microbiome in Bladder Cancer

by Kyungchan Min, Hyun Tae Kim, Eun Hye Lee, Hansoo Park and Yun-Sok Ha

Biomedicines 2022, 10(8), 1783; https://doi.org/10.3390/biomedicines10081783 - 25 Jul 2022

Cited by 6 | Viewed by 2445

Abstract

The human body contains a variety of microbes. The distribution of microbes varies from organ to organ. Sequencing and bioinformatics techniques have revolutionized microbial research. Although previously considered to be sterile, the urinary bladder contains various microbes. Several studies have used urine and [...] Read more.

The human body contains a variety of microbes. The distribution of microbes varies from organ to organ. Sequencing and bioinformatics techniques have revolutionized microbial research. Although previously considered to be sterile, the urinary bladder contains various microbes. Several studies have used urine and bladder tissues to reveal the microbiome of the urinary bladder. Lactic acid-producing bacteria, such as Bifidobacterium, Lactobacillus, and Lactococcus, are particularly beneficial for human health and are linked to bladder cancer. This review highlights the analysis protocols for microbiome research, the studies undertaken to date, and the microbes with therapeutic potential in bladder cancer. Full article

(This article belongs to the Special Issue Advances in Urothelial Cancer)

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