Keisuke Shigeta

• Doctor of Medicine
• Medical Doctor at Keio University

Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib inhibitor is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent path...

Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resis...

Purpose Treatment of pancreatic ductal adenocarcinoma (PDAC) has been advanced by the development of KRAS inhibitors. Despite this progress, PDAC invariably develop resistance to these agents through multiple mechanisms. In this study, we investigated the role of the oncogenic MUC1-C (M1C) protein in mediating the resistance of PDAC cells to KRAS i...

The APOBEC3 (A3) genes encoding cytidine deaminases evolved in mammals to restrict retroviral replication. The MUC1 gene appeared in mammals to protect barrier tissues from viral infections. There is no known involvement of the MUC1 encoded MUC1-C/M1C protein in the regulation of A3s. We found that induction of MUC1-C in NSCLC cells treated with EG...

Latent Epstein-Barr Virus (EBV) infection promotes cancers derived from B-lymphocytes and epithelial cells by mechanisms that largely remain unclear. EBV-encoded nuclear antigen 1 (EBNA1) is uniformly expressed in EBV-associated cancers; however, how EBNA1 contributes to cancer progression is not known. The MUC1 gene evolved in mammals to protect b...

Androgen receptor-positive prostate cancer (PC), castration-resistant prostate cancer (CRPC), and neuroendocrine prostate cancer (NEPC) invariably become resistant to treatment with targeted and cytotoxic agents. Multiple pathways have been identified as being responsible for these pleiotropic mechanisms of resistance. The mucin 1 (MUC1) gene is ab...

Treatment of hormone receptor (HR)-positive, HER2-negative breast cancer (HR+/HER2− BC) is limited by resistance to endocrine therapy (ET) and CDK4/6 inhibitors. There is no known common pathway that confers resistance to these agents. We report that (i) the MUC1 gene is upregulated in HR+/HER2− BCs and (ii) the MUC1-C protein regulates estrogen re...

Background The MUCIN 1 (MUC1) gene evolved in mammals to protect barrier tissues from biotic and abiotic insults. MUC1 encodes a transmembrane MUC1-C subunit that is activated in response to the loss of homeostasis and promotes proliferative, inflammatory, and remodeling responses necessary for wound repair. However, in contrast to its protective f...

Bladder cancer is the 10th most common and 13th most deadly cancer worldwide, with urothelial carcinomas being the most common type. Distinguishing between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) is essential due to significant differences in management and prognosis. MRI may play an important diagnostic...

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a...

Bladder cancer (BC), predominantly comprising urothelial carcinomas (UCs), ranks as the tenth most common cancer worldwide. UCs with variant histology (variant UC), including squamous differentiation, glandular differentiation, plasmacytoid variant, micropapillary variant, sarcomatoid variant, and nested variant, accounting for 5–10% of cases, exhi...

The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating...

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demon...

Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. In this study, we performed a systematic review following the Minds...

Purpose The diagnostic accuracy of computed tomography urography for upper tract urothelial carcinoma is high; however, difficulties are associated with precisely assessing the T stage. Preoperative tumor staging has an impact on treatment options for upper tract urothelial carcinoma. We herein attempted to identify preoperative factors that predic...

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression...

Background and purpose Neoadjuvant chemotherapy (NAC) is a well-established standard practice in invasive bladder cancer (BCa), however patient selection remains challenging. High expression of vasohibin-1 (VASH1), an endogenous regulator of angiogenesis, has been reported in high-grade and advanced BCa; however, its prognostic value for chemothera...

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression...

69 Background: Although several evidence revealed that upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expressions follow favorable outcomes, the relationship between immune cell markers and FGFR3 expression remains unknown. We aimed to clarify FGFR3 based immune microenvironment and to inve...

Background: The diagnostic performance of contrast medium-free biparametric magnetic resonance imaging (bpMRI; combining T2-weighted imaging [T2WI] and diffusion-weighted imaging [DWI]) for evaluating variant-histology urothelial carcinoma (VUC) remains unknown. Objective: To compare the diagnostic performance of bpMRI and multiparametric MRI (m...

Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the prod...

The value of the Vesicle Imaging-Reporting and Data System (VI-RADS) in the diagnosis of muscle-invasive bladder cancer (MIBC) for urothelial carcinoma with variant histology (VUC) remains unknown. We retrospectively evaluated 360 consecutive patients with bladder cancer (255 pure urothelial carcinoma [PUC] and 69 VUC) who underwent multiparametric...

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we conducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-muscle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recur...

Purpose Bi-parametric magnetic resonance imaging (bpMRI) with diffusion-weighted images has wide utility in diagnosing clinically significant prostate cancer (csPCa). However, bpMRI yields more false-negatives for PI-RADS category 3 lesions than multiparametric (mp)MRI with dynamic-contrast-enhanced (DCE)-MRI. We investigated the utility of synthet...

Background: Although the administration of neoadjuvant chemotherapy has been associated with improved prognosis in patients with muscle-invasive bladder cancer, the therapeutic effects of adjuvant chemotherapy remain unknown in real-world settings. Therefore, we herein evaluated the clinical outcomes of adjuvant chemotherapy in pT3/4 muscle-invasi...

Purpose To assess the impact of the updated Bosniak classification (BC2019) for cystic renal masses (CRMs) on interobserver agreement between radiologists and urologists and the diagnostic value of adding MRI to CT examination (combined CT/MRI). Method This study included 103 CRMs from 83 consecutive patients assessed using contrast-enhanced CT an...

Objectives There is no recommended observation time for patients who have undergone radical prostatectomy for prostate cancer. This study was undertaken to determine the postoperative observation time by investigating the hazard rate for prostate-specific antigen failure and other-cause death using Weibull analysis. Methods We included 612 patient...

Limited information is currently available on predictors of upper tract urothelial carcinoma (UTUC) recurrence in non-muscle-invasive bladder cancer (NMIBC) patients according to smoking history, although smoking probably contributes to urothelial carcinogenesis. Therefore, the present study aimed to identify independent predictors of UTUC recurren...

Limited information is currently available on predictors of upper tract urothelial carcinoma (UTUC) recurrence in non-muscle-invasive bladder cancer (NMIBC) patients according to smoking history, although smoking probably contributes to urothelial carcinogenesis. Therefore, the present study aimed to identify independent predictors of UTUC recurren...

Background The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive bladder cancer (NMIBC) recurrence and progression are controversial and our aim is to investigate their associations.Methods We identified 300 NMIBC patients who underwent initial TURBT wit...

Objective The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (R...

Purpose We herein compared the diagnostic performance of Vesical Imaging-Reporting and Data System (VI-RADS) scoring with diagnostic cystoscopy and evaluated diagnostic accuracies based on tumor locations. Materials and Methods Among 112 bladder cancer patients who underwent multiparametric magnetic resonance imaging and diagnostic cystoscopy preo...

Background: The relationship between guideline adherence for radical cystectomy of non-muscle-invasive bladder cancer and patient prognoses currently remains unclear. We investigated whether guideline adherence at the time of non-muscle-invasive bladder cancer affects the oncological outcomes of bladder cancer patients who underwent radical cystec...

Objective: To investigate whether dose reductions in cisplatin due to renal dysfunction were associated with worse clinical outcomes in metastatic urothelial carcinoma (UC) patients. Patients and methods: One hundred and fifty one metastatic UC patients who received first-line gemcitabine plus cisplatin (GC) salvage chemotherapy without a previo...

Introduction: Our aim is to evaluate whether previous non-urothelial malignant history affects the clinical outcomes of patients with non-muscle invasive bladder cancer (NMIBC). Patients and methods: We identified 1097 cases treated by transurethral resection of bladder tumors for initially diagnosed NMIBC at our four institutions between 1999 a...

Background: It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or...

Background: Radical nephroureterectomy (RNU) with the concomitant excision of the distal ureter and bladder cuff is the current standard of care for the treatment of muscle invasive and/or high-risk upper tract urothelial carcinoma (UTUC). In small uncontrolled studies, laparoscopic RNU has been suggested to be associated with better perioperative...

We aimed to clarify the clinical characteristics and oncological outcomes of upper tract urothelial carcinoma (UTUC) patients who developed muscle‐invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa‐4N0‐2M0 UTUC patients who underwent RNU and clarified the risk factors for MIBC progression after initial intr...

Background: Prophylactic urethrectomy at the time of radical cystectomy is frequently recommended for patients with bladder cancer at a high risk of urethral recurrence without definitive evidence. The present study attempted to clarify the survival benefits of performing prophylactic urethrectomy. Methods: We identified 214 male patients who we...

Objectives: To investigate the relationship between radiation doses in prostate brachytherapy and deterioration of erectile function in patients with localized prostate cancer. Methods: A longitudinal survey study was carried out among 261 prostate cancer patients who received prostate brachytherapy. A total of 48 patients were potent at baselin...

Purpose: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. Methods: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwe...

Mucin 1 C‐terminal subunit (MUC1‐C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1‐C of urothelial cancer (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1‐C oncoprotein in UC cell...

Objectives To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions.Methods This stud...

PurposeUsing conditional survival (CS) analysis, we investigated whether the duration of survival without biochemical recurrence (BCR) of prostate cancer after laparoscopic radical prostatectomies (LRP) affected the BCR rate. We also investigated the impact of well-known risk factors for BCR.Methods Between 2002 and 2014, 627 consecutive patients u...

BackgroundA previous comparative study in Japan has demonstrated that the two consecutive UroVysion tests are useful tools to detect the presence of bladder cancer during follow-up after transurethral resection, but they also presented their high rates of false-positive results. Here, we aimed to evaluate the relationship between the UroVysion test...

Purpose We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab. Methods Our study population comprised 78 patients diagnosed w...

Bacillus Calmette-Guérin induction with or without maintenance is the gold standard therapy for intermediate-/high-risk non-muscle-invasive bladder cancer; however, one-third of patients treated with adequate bacillus Calmette-Guérin therapy do not achieve sufficient responses, and this is referred to as "bacillus Calmette-Guérin failure." The term...

Background Since smoking has a causal relationship not just with oncological outcomes but also with aggravating the general health conditions of upper tract urothelial carcinoma (UTUC) survivors, our specific aim is to introduce an individualized risk-based surveillance regimen which interacts with smoking status. Methods We identified 714 non-met...

Objective: Our specific aim was to introduce the TachoSil binding suturing technique for renal cell carcinoma (RCC) patients when closing the parenchymal defect after tumor excision during laparoscopic partial nephrectomy (LPN), which is a novel technique for reducing the risk of developing subsequent pseudoaneurysm (PA). Methods: We identified...

Background The current guideline lacks evidence for creating individualized surveillance strategies for upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). Objective To create a novel risk model and to simulate individualized surveillance duration that dynamically illustrates the changing risk relationship of U...

Background This study aimed to investigate the long-term oncologic outcomes of laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) for patients with clinical and pathologic T3N0M0 upper tract urothelial carcinoma (UTUC). Methods Among 375 UTUC patients who underwent radical nephroureterectomy, this study ident...

Accidental hypothermia is defined as a core body temperature <35°C. Even with the use of multiple active rewarming methods, it has a high mortality rate. No standard treatment strategy for moderate or severe hypothermia in the absence of cardiac arrest has yet been established. We herein report three patients with severe or moderate accidental hypo...

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Background Our specific aim was to investigate the prognostic value of effective duration of first androgen deprivation therapy (ADT) and to evaluate the clinical impact on early docetaxel administration with oncological outcomes in castration-resistant prostate cancer (CRPC) patients treated with docetaxel. Methods We identified 148 mCRPC patient...

Purpose Since a conditional survival (CS) analysis provides better estimates of survival times at each follow-up, we aimed to assess changes in conditional intravesical recurrence-free survival (IVRFS) rates after radical nephroureterectomy (RNU) and how the impact of well-known risk factors evolves over time, particularly in localized upper tract...

Objective: To evaluate the impact of pneumoperitoneum time on intravesical recurrence (IVR) in upper tract urothelial carcinoma (UTUC) patients who underwent laparoscopic radical nephroureterectomy (LRNU). Patients and methods: We identified 129 UTUC patients who underwent LRNU at our three institutions from 2004 to 2014. We evaluated the associ...

Background The association of peripheral monocyte count and prostate cancer progression is not well characterized. Objective Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated wit...

Our aim was to evaluate the effect of visceral obesity and impact of severe hydronephrosis on surgical complexity in patients undergoing laparoscopic radical nephroureterectomy (LRNU). From January 2000 to December 2013, 169 patients underwent radical nephroureterectomy at our institution. We retrospectively reviewed the medical records of 70 patie...