Publications by authors named "Jimpei Miyakawa"

24 Publications

  • Page 1 of 1

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Cancer Cell 2021 Jun;39(6):793-809.e8

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
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http://dx.doi.org/10.1016/j.ccell.2021.05.008DOI Listing
June 2021

Smaller decline of renal function after nephroureterectomy predicts poorer prognosis of upper tract urothelial carcinoma: a multicentre retrospective study.

Jpn J Clin Oncol 2021 May 28. Epub 2021 May 28.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan.

Purpose: Renal function is frequently impaired in the patients with upper tract urothelial carcinoma. We aimed to evaluate the impact of renal function and its change after surgery on survival rates in patients with upper tract urothelial carcinoma after nephroureterectomy.

Methods: The study cohort comprised 755 patients with upper tract urothelial carcinoma who underwent nephroureterectomy between 1995 and 2016 at nine hospitals in Japan. Estimated glomerular filtration rate was calculated using the three-variable Japanese equation for glomerular filtration rate estimation from serum creatinine level and age. Outcomes were recurrence-free, cancer-specific and overall survivals. Univariate and multivariate Cox proportional hazards regression analyses were used.

Results: Median patients' age was 72 years old. Pre- and post-surgical median estimated glomerular filtration rate were 55.5 and 42.9 ml/min/1.73 m2, respectively. Median estimated glomerular filtration rate decline after surgery, which represents function of the affected side kidney, was 13.1 ml/min/1.73 m2. The 5-year recurrence-free, cancer-specific and overall survivals were 68.3, 79.4 and 74.0%, respectively. Multivariate analysis indicated that lower preoperative estimated glomerular filtration rate and estimated glomerular filtration rate decline were associated with poorer recurrence-free, cancer-specific and overall survivals, but post-operative estimated glomerular filtration rate was not. Estimated glomerular filtration rate decline was more significant poor-prognosticator than preoperative estimated glomerular filtration rate. Proportions of the patients with estimated glomerular filtration rate <60 ml/min/1.73 m2 before surgery were 50.6 and 73.2% in organ-confined disease and locally advanced disease, respectively (P < 0.0001). After surgery, they were 91.6 and 89.8%, respectively (P = 0.3896).

Conclusions: Lower preoperative renal function, especially of the affected side kidney, was significantly associated with poor prognosis after nephroureterectomy for upper tract urothelial carcinoma. Many patients with locally advanced disease have reduced renal function at diagnosis and even more after surgery.
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http://dx.doi.org/10.1093/jjco/hyab081DOI Listing
May 2021

Squamous differentiation is a potential biomarker predicting tumor progression in patients treated with pembrolizumab for urothelial carcinoma.

Pathol Res Pract 2021 Mar 8;219:153364. Epub 2021 Feb 8.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address:

Immune checkpoint inhibitor (ICI) is widely used and highly effective for some cancer patients but may result in disease progression in others. Hyperprogressive disease in particular is characterized by an acceleration of tumor growth during ICI therapy and has been reported in patients including those with urothelial carcinoma. Biomarkers predicting treatment efficacy are crucial to avoid tumor progression and unnecessary adverse effects. This study aims to clarify the predictors of disease progression for ICI treatment in patients with urothelial carcinoma. We analyzed the response pattern of 23 urothelial carcinomas treated with pembrolizumab and its association with pathological features and potential immunohistochemical markers including EGFR, MDM2, p53, p16, and programmed cell death ligand-1 (PD-L1) expression and CD8- and CD204-positive cell infiltration. During ICI therapy, 13 (57 %) patients showed progressive disease including 6 (26 %) with hyperprogressive disease. Notably, squamous differentiation combined with MAC387 expression was observed exclusively in cases with progressive disease (6 of 13, 46 %); it was not present in cases with stable disease or partial/complete response (0 of 10, p = 0.0019). All tumors with squamous differentiation showed positive staining for EGFR. Additionally, the loss of p16 expression occurred more frequently in cases with progressive disease (8 of 13, 62 %) than in other cases (3 of 10, 30 %), but this finding did not reach statistical significance. Squamous differentiation was also significantly associated with shorter overall survival. Based on our observations, squamous differentiation may be a novel biomarker for predicting disease progression in patients with urothelial carcinoma who receive pembrolizumab.
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http://dx.doi.org/10.1016/j.prp.2021.153364DOI Listing
March 2021

Impact of Initial Computed Tomography Findings on Management of Atypical Urinary Cytology of the Upper Urinary Tract.

Urol Int 2021 28;105(7-8):619-623. Epub 2021 Jan 28.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: Management of patients with atypical urinary cytology (class III) of the upper urinary tract is often complicated because some patients develop upper urinary tract urothelial carcinoma (UTUC). Here, we aimed to help define the optimal management of these patients.

Methods: We investigated 31 patients who underwent retrograde ureteropyelography (RP) and were diagnosed with atypical findings of upper urinary tract cytology.

Results: UTUC was revealed in 17 of 31 patients during the follow-up period of 1 year or longer. Tumor-like lesions and wall thickening in the upper urinary tract on initial computed tomography (CT) were significant predictors of UTUC (p = 0.0002 and p = 0.012, respectively). All 11 patients with tumor-like lesions and 3 of 8 patients with wall thickening on initial CT underwent nephroureterectomy, and UTUC was confirmed histologically. Moreover, 3 of 12 patients with hydronephrosis only or with normal findings later went on to develop UTUC. Repeated RP performed within 6 months from the initial RP was able to distinguish patients with UTUC from those without, even in individuals with normal CT findings.

Discussion/conclusion: Repeated RP based on initial CT findings is recommended in patients with atypical urinary cytology of the upper urinary tract. Nephroureterectomy without repeated RP may be warranted in patients with tumor-like lesions on initial CT findings.
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http://dx.doi.org/10.1159/000512978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315664PMC
January 2021

Impact of age, body mass index, and renal function for severe hypotension caused by oral 5-aminolevulinic acid administration in patients undergoing transurethral resection of bladder tumor.

Photodiagnosis Photodyn Ther 2021 Mar 8;33:102179. Epub 2021 Jan 8.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Severe hypotension is a notable adverse event caused by administration of 5-aminolevulinic acid (5-ALA) during photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT). Hypotension can be prolonged following induction of anesthesia and may require continuous administration of a vasopressor. Here, we investigated the risk factors for severe hypotension caused by oral administration of 5-ALA.

Methods: A total of 128 patients with bladder tumors who underwent PDD-TURBT using 5-ALA were included in this study. Clinicopathological data were collected retrospectively and the correlations between the incidence of severe hypotension and clinicopathological factors were analyzed.

Results: Severe hypotension developed in 8 cases (6.3 %). Age ≥ 80 years, body mass index (BMI) ≥ 25 (kg/m), and estimated glomerular filtration rate (eGFR) < 45 (mL/min/1.73 m) were significantly correlated with severe hypotension (P = 0.003, 0.017, and 0.027, respectively). Severe hypotension developed in 1 of 89 cases (1.1 %) which have 0 or 1 risk factor, and in 3 of 31 cases (9.7 %) which have 2 risk factors, whereas it developed in 4 of 8 cases (50 %) which have all risk factors. Patients with all risk factors developed severe hypotension significantly more frequently compared with patients with 1 or fewer risk factors (P < 0.001).

Conclusion: Age ≥ 80 years, BMI ≥ 25, and eGFR < 45 are risk factors for severe hypotension in PDD-TURBT using 5-ALA. The risk of developing severe hypotension is extremely high in patients who have all factors. Adjustment of the 5-ALA dose may be desirable in those patients.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102179DOI Listing
March 2021

An autopsy case of prostatic rhabdomyosarcoma with DICER1 hotspot mutation.

Pathol Int 2021 Jan 28;71(1):102-108. Epub 2020 Oct 28.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Somatic hotspot DICER1 mutations, which frequently coexist with germline inactivating mutation (i.e., DICER1 syndrome), have been identified in various types of benign and malignant conditions. Herein, we report an autopsy case of prostatic rhabdomyosarcoma (RMS) with a hotspot DICER1 c.5125G>A (p.D1709N) mutation. A 26 year-old man presented with a prostatic mass, hematuria, and urinary retention. He underwent total pelvic exenteration, colostomy, ileal conduit construction and partial urethrectomy. Five months postoperatively, he developed multiple metastases to the lungs, brain, iliopsoas muscles and bones. He died of respiratory failure, and autopsy was performed. Microscopically, the tumor was primarily composed of uniform primitive mesenchymal cells infiltrating to the prostate with cambium layer. Rhabdomyoblasts and anaplastic cells were focally observed. Immunohistochemically, tumor cells were positive for desmin, myogenin, PAX7, HMGA2. Multinodular goiter was detected at autopsy. Because the morphology is similar to pleuropulmonary blastoma and DICER1-mutant RMS of the female genital tract, we tested and identified a hotspot DICER1 mutation with Sanger sequencing. Recognizing DICER1-mutant tumor is important because of its frequent association with germline DICER1 inactivation and potential therapeutic implication. Further research is needed to clarify whether this case can be classified as embryonal RMS with anaplasia or 'DICER1-associated sarcoma'.
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http://dx.doi.org/10.1111/pin.13042DOI Listing
January 2021

B7-H3 expression in upper tract urothelial carcinoma associates with adverse clinicopathological features and poor survival.

Pathol Res Pract 2020 Dec 21;216(12):153219. Epub 2020 Sep 21.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

B7-H3, a member of the B7 superfamily, is an immune checkpoint molecule. An association between B7-H3 expression and poor survival has been reported in many types of cancer. However, its prognostic value in patients with upper tract urothelial carcinoma (UTUC) has not yet been reported. The aim of this study was to examine the clinical significance of tumor B7-H3 expression in UTUC. B7-H3 positivity was observed in 36 of 271 cases (13 %) by immunohistochemistry and was significantly associated with several adverse clinicopathological features such as tumor grade, tumor stage, and lymph node metastasis. In addition, B7-H3 positivity was significantly associated with shorter metastasis-free survival and cancer-specific survival. We also found that B7-H3/programmed cell death ligand-1 (PD-L1) co-positivity was significantly associated with worse prognosis. These results suggest the utility of B7-H3 positivity and B7-H3/PD-L1 co-positivity as novel prognostic biomarkers in UTUC, and the potential usefulness of B7-H3 targeted therapy for patients with UTUC, the effect of which may be enhanced by combination with programmed cell death-1 /PD-L1 blockade.
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http://dx.doi.org/10.1016/j.prp.2020.153219DOI Listing
December 2020

Latent prostate cancer among Japanese males: a bibliometric study of autopsy reports from 1980-2016.

Jpn J Clin Oncol 2021 Jan;51(1):156-159

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo.

Prostate cancer is one of the most common malignancies, but a substantial portion remains latent throughout the patients' lifetime. Analysis of temporal change in the latent prostate cancer pool would be beneficial for clinical decision-making, but longitudinal autopsy studies are rare. We conducted a hand-search of the Annual of Pathological Autopsy Cases in Japan from 1980 to 2016 for cases of latent prostate cancer. Of 570 997 males aged 30 or older, latent prostate cancer was detected in 12 562 patients (2.2%). Proportion of detected cases correlated strongly with 'aging rate', the percentage of population aged 65 or older (squared Pearson's correlation coefficient r2 = 0.972, P value <0.0001). Temporal increase in proportion was also seen in each age group as well. This continuous growth reinforces evidence from past Japanese reports on latent prostate cancer. The rapidly rising ageing rate of Japan may forecast further increase in the latent prostate cancer pool moving forward.
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http://dx.doi.org/10.1093/jjco/hyaa161DOI Listing
January 2021

Inverted papilloma of the urinary bladder shows fluorescence on photodynamic diagnosis using 5-aminolevulinic acid.

Photodiagnosis Photodyn Ther 2020 Jun 18;30:101766. Epub 2020 Apr 18.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Photodynamic diagnosis (PDD) of non-muscle invasive bladder cancer using 5-aminolevulinic acid (5-ALA) has recently attracted attention as a diagnostic method for observing cancer lesions based on fluorescence emission using a fluorescent endoscope. However, there are few reports of false positives associated with benign bladder neoplasms. Here, we provide report of two cases of inverted papillomas of the bladder that were fluorescent on PDD using 5-ALA. In each case, a surface-smooth, pedunculated bladder tumor was observed, which fluoresced red on PDD after oral administration of 5-ALA. Histopathological findings demonstrated inverted papilloma of the bladder. Although inverted papilloma of the bladder is usually regarded as a benign neoplasm, some recent studies have revealed that it could be a risk factor for urothelial carcinoma. Our present report may support the hypothesis that inverted papilloma of the bladder has malignant potential.
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http://dx.doi.org/10.1016/j.pdpdt.2020.101766DOI Listing
June 2020

Fluorescence Detection of Prostate Cancer by an Activatable Fluorescence Probe for PSMA Carboxypeptidase Activity.

J Am Chem Soc 2019 07 21;141(26):10409-10416. Epub 2019 Jun 21.

AMED-CREST, Japan Agency for Medical Research and Development , 1-7-1 Otemachi , Chiyoda-ku, Tokyo , 100-0004 , Japan.

Prostate cancer (PCa) is a common malignant tumor among adult males, and convenient intraoperative detection of PCa would reduce the risk of leaving positive surgical margins, especially during nerve-sparing procedures. To achieve rapid, fluorescence-based visualization of PCa, we focused on the glutamate carboxypeptidase (CP) activity of prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein that is attracting attention as a PCa biomarker. Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO (lowest unoccupied molecular orbital) energy level to quench the fluorophore through photoinduced electron transfer, we designed and synthesized a first-in-class activatable fluorescence probe for CP activity of PSMA. The developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from PCa patients and is expected to be useful for rapid intraoperative detection and diagnosis of PCa.
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http://dx.doi.org/10.1021/jacs.9b04412DOI Listing
July 2019

The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count.

Cancer Med 2018 09 31;7(9):4330-4338. Epub 2018 Jul 31.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Programmed cell death ligand-1 (PD-L1) is a ligand for programmed cell death-1 (PD-1) that negatively regulates T-cell activation and plays a crucial role in suppressing anti-tumor host immunity. Although PD-L1 is a promising immunotherapy target in various cancers, including urothelial carcinoma (UC), the prognostic significance of PD-L1 in UC is unclear. As platelets help protect tumor cells from immune elimination in the circulatory system, we hypothesized that tumor PD-L1 and circulating platelets might synergistically promote tumor metastasis, and that the prognostic significance of PD-L1 might vary according to platelet count. We immunohistochemically examined tumor PD-L1 expression in 271 patients with upper tract UC, which revealed PD-L1 positivity in 31 of 271 cases (11%). The associations of tumor PD-L1 expression with outcomes varied among patients with high or low platelet counts (P  < 0.004). Among patients with high platelet counts (N = 136), PD-L1 positivity (N = 15) was significantly associated with shorter metastasis-free survival (univariate hazard ratio [HR]: 6.23, 95% confidence interval [CI]: 2.95-13.1; multivariate HR: 2.68, 95% CI: 1.27-5.64) and shorter overall survival (univariate HR: 4.92, 95% CI: 2.14-11.3, multivariate HR: 2.78, 95% CI: 1.19-6.51). In contrast, among patients with low platelet counts (N = 135), PD-L1 positivity (N = 16) was not significantly associated with these outcomes. Our results suggest that tumor PD-L1 expression and platelet count might interact and help regulate tumor progression. Although a larger prospective study is needed to validate our findings, this relationship is important to consider, as immunotherapies targeting the PD-1/PD-L1 axis have gained significant attention as promising therapies for UC.
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http://dx.doi.org/10.1002/cam4.1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143937PMC
September 2018

Prognostic significance of neutrophil-to-lymphocyte ratio in collecting duct carcinoma.

Jpn J Clin Oncol 2018 Jul;48(7):692-694

Department of Urology, Graduate School of Medicine, The University of Tokyo.

Collecting (Bellini) duct carcinoma of the kidney is a rare lethal tumor, and its prognostic factors remain unclear. The present study investigated the prognostic significance of neutrophil-to-lymphocyte ratio, which has recently been recognized as a readily available prognostic marker in various malignancies, in patients with collecting duct carcinoma. Of 11 patients who were pathologically diagnosed with collecting duct carcinoma at our institution, nine died of collecting duct carcinoma, one died of a postoperative complication, and one was alive, with a median follow-up period of 6 (range: 0-97) months. Both univariate and multivariate analyses associated neutrophil-to-lymphocyte ratio ≥4 (median) with worse cancer-specific survival. Notably, the sole surviving patient maintained a low neutrophil-to-lymphocyte ratio (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that neutrophil-to-lymphocyte ratio might serve as a useful biomarker for collecting duct carcinoma as well as other malignancies.
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http://dx.doi.org/10.1093/jjco/hyy076DOI Listing
July 2018

Clinical significance of random bladder biopsy in primary T1 bladder cancer.

Mol Clin Oncol 2018 May 8;8(5):665-670. Epub 2018 Mar 8.

Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

The clinical significance of random bladder biopsies in primary non-muscle-invasive bladder cancer is unclear. The present study investigated the significance of positive random bladder biopsies in primary T1 NMIBC. The present study retrospectively reviewed the records of 71 patients with primary pT1N0M0 bladder cancer who underwent transurethral resection of the bladder tumor (TURBT) and concomitant random bladder biopsy. A total of 12 patients who received cystectomy immediately following the TURBT were excluded, and the remaining 59 patients were included in the analysis. Random bladder biopsy was defined as a cold-cup biopsy of pre-specified normal-looking areas in the bladder. The association of clinicopathological factors, including random biopsy results, with intravesical recurrence were assessed by univariate and multivariate Cox proportional hazards analyses. Of the 59 patients, 15 (25%) demonstrated carcinoma (CIS) lesions on random bladder biopsy: Five (33%) in biopsy specimens alone and the remaining 10 (67%) in biopsy and TUR specimens. Positive random biopsy was associated with preoperative positive urine cytology (P=0.011) and small size of the main tumor (P=0.008). Multivariate analysis demonstrated positive random biopsy as the sole independent poor prognostic factor for intravesical recurrence (hazard ratio: 4.69, P=0.014). The five patients who had CIS detected in biopsy specimens alone had worse, although non-significantly worse, recurrence-free survival compared with those with CIS detected in biopsy and TUR specimens (P=0.100). In conclusion, positive bladder random biopsy, equivalent to the presence of CIS, was an independent predictor of recurrence in primary T1 bladder cancer. Given that one-third of CIS lesions could not have been detected without biopsy, random bladder biopsy should be considered for patients with T1 tumors.
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http://dx.doi.org/10.3892/mco.2018.1587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920156PMC
May 2018

Preoperative chronic kidney disease is predictive of oncological outcome of radical cystectomy for bladder cancer.

World J Urol 2018 Feb 28;36(2):249-256. Epub 2017 Nov 28.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: To evaluate the impact of preoperative chronic kidney disease (CKD) on oncological outcomes after radical cystectomy (RC) for bladder cancer.

Methods: We reviewed the medical records of patients with urothelial bladder carcinoma who underwent RC with curative intent at seven hospitals between 1990 and 2013. After excluding patients with a history of upper urinary tract urothelial cancer or neoadjuvant chemotherapy, we analyzed 594 cases for the study. Preoperative estimated glomerular filtration rate (eGFR) was calculated using the three-variable Japanese equation for GFR estimation from serum creatinine level and age. Patients were divided into four groups of different CKD stages based on eGFR values (mL/min/1.73 m), i.e., ≥ 60 (CKD stages G1-2), 45-60 (G3a), 30-45 (G3b), and < 30 (G4-5). Survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses addressed survivals after RC.

Results: Median age of patients was 67 years. Patients were classified into CKD stages: G1-2 (n = 388; 65.3%), G3a (n = 122; 20.5%), G3b (n = 51; 8.6%), and G4-5 (n = 33; 5.6%). During a median follow-up of 4.0 years, 200 and 164 patients showed cancer progression and died of bladder cancer, with the 5-year progression-free survival (PFS) and cancer-specific survival (CSS) of 64.9 and 70.2%, respectively. On multivariate analyses, CKD stages of G3b or greater, advanced pT stage, lymph node metastasis, and positive lymphovascular invasion were independent poor prognostic factors for PFS and CSS.

Conclusions: We demonstrated that the advanced preoperative CKD stage was significantly associated with poor oncological outcomes of the bladder cancer after RC.
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http://dx.doi.org/10.1007/s00345-017-2141-2DOI Listing
February 2018

Loss of Stromal Antigen 2 (STAG2) Expression in Upper Urinary Tract Carcinoma: Differential Prognostic Effect According to the Ki-67 Proliferating Index.

Ann Surg Oncol 2017 Dec 2;24(13):4059-4066. Epub 2017 Oct 2.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Inactivating mutation and consequent expression loss of stromal antigen 2 (STAG2, also known as SA2), a component of the cohesion complex, is one of the most common genetic aberrations in urothelial carcinoma. However, the clinicopathologic or prognostic significance of STAG2 alterations in upper tract urothelial carcinoma (UTUC) is largely unknown.

Methods: This study immunohistochemically examined the expression of STAG2 in 171 patients with UTUC. The correlations of STAG2 loss with clinicopathologic features and patients' prognoses were examined.

Results: Loss of STAG2 expression was observed in 28 cases (16%). Loss of STAG2 was significantly correlated with histological low grade, papillary architecture, noninvasive tumors, absence of concomitant carcinoma in situ, and lower Ki-67 expression. Loss of STAG2 alone was not significantly associated with patients' prognoses in either the uni- or multivariate analysis. However, STAG2 loss was significantly associated with worse clinical outcome in UTUC with high Ki-67 proliferation indexes, but not in UTUC with low Ki-67 expression.

Conclusions: Loss of STAG2 was generally associated with less aggressive features in UTUC. However, the STAG2 loss was an ominous sign in the subpopulation with higher Ki-67 proliferation indexes. Examining both STAG2 and Ki-67 status may be useful for identifying aggressive clinical behavior of UTUC.
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http://dx.doi.org/10.1245/s10434-017-6097-7DOI Listing
December 2017

Oncologic Outcome of Metastasectomy for Urothelial Carcinoma: Who Is the Best Candidate?

Ann Surg Oncol 2017 Sep 7;24(9):2794-2800. Epub 2017 Jul 7.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC.

Methods: This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan-Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival.

Results: Metastasectomy was performed for pulmonary (n = 23), nodal (n = 7), and other (n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival.

Conclusions: Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered.
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http://dx.doi.org/10.1245/s10434-017-5970-8DOI Listing
September 2017

Diagnostic utility of Ki-67 immunohistochemistry in small endoscopic biopsies of the ureter and renal pelvis.

Pathol Res Pract 2017 Jul 20;213(7):737-741. Epub 2017 Apr 20.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Diagnosis of upper urinary tract urothelial carcinoma in ureteroscopic biopsies is challenging. Therefore, an immunohistochemical marker that can differentiate between malignant and benign urothelium and predict final pathological features is necessary. In this study, we investigated Ki-67 expression in 26 ureteroscopic biopsies of the ureter and renal pelvis diagnosed with urothelial carcinoma (UC) and in 13 biopsies with non-neoplastic urothelium, using digital image analysis. The median Ki-67 labeling index was 1.5% (range: 0.2-13.9%) in non-neoplastic urothelial specimens and 15.0% (range: 0.2-61.3%) in UC specimens (p=0.0001). In 12 of 26 (46%) UC specimens, the Ki-67 labeling index was more than 20%. By contrast, the Ki-67 labeling index was less than 5% in 11 of 13 (85%) non-neoplastic urothelial specimens. Ki-67 expression in ureteroscopic biopsies was significantly correlated with high tumor grade (p=0.013), concomitant carcinoma in situ (p=0.011), and stromal invasion (p=0.048) in surgical resection specimens. Our data suggested that Ki-67 may provide supplemental, objective evidence that can aid diagnosis of upper urinary tract UC in ureteroscopic biopsy specimens. Determination of Ki-67 expression in ureteroscopic biopsy specimens is potentially helpful in clinical decision making for patients with suspected upper urinary tract UC.
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http://dx.doi.org/10.1016/j.prp.2017.04.009DOI Listing
July 2017

Efficacy of post-nephroureterectomy cisplatin-based adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: a multi-institutional retrospective study.

World J Urol 2017 Oct 10;35(10):1569-1575. Epub 2017 Apr 10.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: To evaluate the efficacy of adjuvant systemic chemotherapy for locally advanced (pT3-4pN0/xM0) upper tract urothelial carcinoma (UTUC).

Materials And Methods: We retrospectively reviewed the medical records of 109 patients with pT3-4pN0/xM0 UTUC who had undergone radical nephroureterectomy between 1996 and 2013 at our four institutions. The patients were divided into two groups: those who received adjuvant chemotherapy (AC group) and those who did not (surgery-alone: SA group). All chemotherapy regimens were cisplatin-based. Cox proportional hazards regression models addressed the associations between clinicopathological factors and recurrence-free survival (RFS) and cancer-specific survival (CSS).

Results: Forty-three (39.5%) out of the 109 patients underwent one to four cycles of adjuvant chemotherapy after nephroureterectomy. Median follow-up was 46.5 months. There were no significant differences in the background characteristics of the two groups, except for age. Recurrence developed in 11 (25.6%) and 29 (43.9%) patients in the AC and SA groups, respectively. Ultimately, six (14.0%) and 18 (27.3%) patients in the AC and SA groups, respectively, died of disease progression. On univariate analysis, hydronephrosis, nuclear grade, lymphovascular invasion, and adjuvant chemotherapy were significantly associated with both RFS and CSS. Charlson comorbidity index was associated only with CSS. On multivariate analysis, adjuvant chemotherapy was the only independent factor associated with improved RFS (p = 0.0178, HR = 0.41). Moreover, adjuvant chemotherapy (p = 0.0375, HR = 0.33), lower nuclear grade (p = 0.0070), and the absence of hydronephrosis (p = 0.0493) were independently associated with better CSS.

Conclusion: Locally advanced (pT3-4pN0/xM0) UTUC patients who underwent cisplatin-based adjuvant chemotherapy demonstrated better RFS and CSS than those without adjuvant chemotherapy.
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http://dx.doi.org/10.1007/s00345-017-2032-6DOI Listing
October 2017

Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

Pathol Res Pract 2016 Sep 18;212(9):833-7. Epub 2016 May 18.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary.
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http://dx.doi.org/10.1016/j.prp.2016.04.014DOI Listing
September 2016

Prognostic significance of serum neuron-specific enolase in small cell carcinoma of the urinary bladder.

World J Urol 2017 Jan 14;35(1):97-103. Epub 2016 May 14.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: Small cell carcinoma of the urinary bladder (SCCB) is known for its aggressive clinical features and poor prognosis. No prognostic factor has been established so far. The aim of this study was to assess the significance of possible prognostic factors, including serum neuron-specific enolase (NSE), an established biomarker for small cell lung carcinoma.

Methods: We retrospectively reviewed 31 patients with primary SCCB treated at our eight affiliate institutions between 2001 and 2014. The association of various clinicopathological factors at diagnosis, including the serum NSE value, with cancer-specific survival (CSS) was assessed. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively.

Results: Nineteen (61.3 %) died of SCCB during the follow-up, with a median survival time of 12.7 months. Prognostic factors were analyzed for the 25 patients after excluding six with missing data. Univariate analysis demonstrated that stage (extensive disease) and serum NSE ≥25 ng/ml were significantly associated with worse CSS. Multivariate analysis identified increased serum NSE value as a sole independent predictor of CSS (hazard ratio 18.52, p = 0.0022).

Conclusions: Serum NSE value at diagnosis was an independent prognostic factor for primary SCCB and may serve as a useful biomarker in the management of SCCB.
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http://dx.doi.org/10.1007/s00345-016-1846-yDOI Listing
January 2017

Radiation-induced esophagitis exacerbated by everolimus.

Case Rep Oncol 2013 May 15;6(2):320-4. Epub 2013 Jun 15.

Departments of Medical Oncology, Toranomon Hospital, Tokyo, Japan.

Background: Everolimus, a potent mammalian target of rapamycin (mTOR) inhibitor, has shown anticancer activity against various types of cancer, including renal cell carcinoma (RCC); however, little information is available on the efficacy and safety of the combination of everolimus and radiotherapy. We report a case of radiation-induced esophagitis that might have been exacerbated by the sequential administration of everolimus.

Case Presentation: A 63-year-old Japanese man with RCC complained of back pain, and magnetic resonance imaging revealed vertebral metastases. He received radiotherapy (30 Gy/10 fractions) to the T6-10 vertebrae. Everolimus was administered immediately after the completion of radiotherapy. One week later, he complained of dysphagia, nausea and vomiting. An endoscopic examination of the esophagus showed erosive esophagitis in the middle to lower portions of his thoracic esophagus, corresponding to the irradiation field.

Conclusion: Clinicians should be aware that everolimus might lead to the unexpected exacerbation of radiation toxicities.
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http://dx.doi.org/10.1159/000353309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725027PMC
May 2013

[Efficacy and safety of maintenance intravesical instillation therapy with bacillus Calmette-Guerin and epirubicin for non-muscle invasive bladder cancer].

Hinyokika Kiyo 2013 Mar;59(3):153-7

The Department of Urology, Toranomon Hospital.

The objectives of this study were to evaluate the efficacy and toxicity of maintenance intravesical instillation therapy with bacillus Calmette-Guerin (BCG) and epirubicin for non-muscle invasive bladder cancer. From April 1999 to March 2010, 27 eligible patients were enrolled in this study. After receiving one cycle of epirubicin (100 mg/100 ml) by intravesical instillation, all patients received 6 weekly alternate intravesical instillation of BCG (80 mg/50 ml) and epirubicin (50 mg/50 ml), followed by 10 monthly instillations. Among the 27 patients, 19 were men and 8 were women, with a median age of 62.4 years (range, 37-78 years). Tumor pathologic stage was pTa in 25 patients, pT1 in 2 and there were no concomitant carcinoma in situ cases. Median follow-up was 37.1 months (range, 11-82 months). The 3- year recurrence-free and progression-free survival rates were 75.3% and 96.1%, respectively. Furthermore, a high completion rate of 81.5% was achieved in this study. Adverse events of grade 3 or higher occurred in 3 patients (11.1%), 1 patient had anaphylaxis. There were no treatment-related deaths. Maintenance intravesical instillation therapy with BCG and epirubicin is a favorable therapeutic option for non-muscle invasive bladder cancer. Given the safety and benefit profile found in this study, appropriate patient selection is warranted in the future.
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March 2013
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