Publications by authors named "Tomomi Fujii"

109 Publications

Prostate diseases and microbiome in the prostate, gut, and urine.

Prostate Int 2022 Jun 29;10(2):96-107. Epub 2022 Mar 29.

Department of Urology, Kashihara, Nara, 634-8522, Japan.

The microbiome in various organs involves a vast network that plays a key role in the health and wellness of the human body. With recent advances in biological technologies such as high-throughput sequencing, transcriptomics, and metabolomics, it appears that the microbial signature varies dynamically among individuals, creating various roles in metabolism, local and systemic inflammation, and host immunity. Urinary and genital organs, including the prostate, seminal vesicles, and urinary bladder, are reservoirs of several bacterial, viral, and fungal communities. Accumulating evidence has suggested profound roles for the gut, urinary, and intraprostate microbiomes in genitourinary benign and malignant diseases. This review article addresses microbiome-related evidence for three major diseases involved in prostate cancer: chronic prostatitis (CP), benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Symptomatic CP is known as CP/chronic pelvic pain syndrome. CP is one of the most common prostate diseases in young men, accounting for 8% of all men visiting a urologic clinic. Although oral medication is the gold standard therapy for patients with BPH, approximately 13% of men present with clinical progression within 4 years after the initiation of treatment, with 5% requiring surgical intervention. The identification of proinflammatory cytokines and pathogens responsible for the clinical progression of BPH is still underway. Several topics regarding the association between PCa and the microbiome are discussed in this review as follows: i) intraprostatic microbiome and the risk of PCa, ii) gut microbiome and PCa, iii) gut microbiome and the risk of radiation-induced side effects, iv) isoflavone intake and equol-producing intestinal flora on PCa, and v) the inhibitory effect of daidzein and equol on tumor growth and progression of PCa. Further studies are required for a comprehensive understanding between the urogenital microbiome and prostate pathogenesis to facilitate the development of preventive and therapeutic approaches for prostate diseases.
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http://dx.doi.org/10.1016/j.prnil.2022.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052083PMC
June 2022

Association between urine 6-sulfatoxy-melatonin level and intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer.

Support Care Cancer 2022 Apr 14. Epub 2022 Apr 14.

Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Purpose: The level of 6-sulfatoxy-melatonin (SaMT), a metabolite of melatonin, in first-void morning urine reflects blood melatonin levels from the previous night. We investigated the association between urine SaMT and sleep quality deterioration in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin induction therapy (iBCG).

Methods: We enrolled 51 patients who received iBCG once weekly for 6 or 8 weeks. Patient-reported outcomes were assessed with questionnaires including the International Prostate Symptom Score (IPSS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQC30). Questionnaires were completed before (baseline), during, at completion, and 1 and 3 months after iBCG. Melatonin and SaMT levels at baseline were measured in serum and first-void morning urine samples, respectively.

Results: Based on changes in the QLQC30 insomnia subscale, 28 (55%) patients experienced sleep quality deterioration (deterioration group). Urine SaMT values in the deterioration group were lower than those in the non-deterioration group (P = 0.0015; 7.5 vs 15.4 ng/mg creatinine, respectively). Nocturia scores in the non-deterioration group decreased over time, while those of the deterioration group remained high after completion of iBCG. A binary logistic regression analysis revealed that low urine SaMT levels (≤ 9.6 ng/mg creatinine), high IPSS nocturia scores at baseline, and high IPSS storage subscores at baseline were associated with BCG-induced sleep quality deterioration.

Conclusions: This study confirmed the association among urine SaMT levels, nocturia, and sleep disturbance in patients with NMIBC who receive iBCG. We should be aware of treatment-induced impairments to aid in appropriate decision-making.
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http://dx.doi.org/10.1007/s00520-022-07043-0DOI Listing
April 2022

Evaluation of DNA/RNA quality from cell block of malignant mesothelioma and lung adenocarcinoma.

Diagn Cytopathol 2022 Jun 5;50(6):273-283. Epub 2022 Apr 5.

Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara, Japan.

Malignant mesothelioma (MM) is a rare and highly lethal tumor that arises from mesothelial tissue on the surface of the chest and abdominal cavity. Cytological examination of body fluids, including pleural fluid and ascites, is essential for the differentiation of malignant mesothelioma from other carcinomas, such as lung and gastrointestinal carcinomas and metastatic tumors. To evaluate the effectiveness of cell block preparation procedures, which are used for immunocytochemical staining and genetic panel analysis of tumor-specific gene mutations, we used various fixatives. We also evaluated the effects of immunostaining, and the quality of nucleic acids for genetic analysis.

Methods: Cell blocks were prepared using the malignant mesothelioma cell lines MESO4 and H226 and non-small cell lung carcinoma cell line HCC78. The cells were fixed using 10% neutral buffered formalin and four different fixatives for liquid cytology. Fixed cells were formed into cell clusters using sodium alginate or centrifugation, and paraffin-embedded cell blocks were prepared.

Results: Cell blocks were morphologically evaluated by hematoxylin and eosin and immunocytological staining, and the nucleic acid quality was evaluated by DNA/RNA extraction, qPCR, and next-generation sequence analysis. D2-40 and WT1 staining differed depending on the fixation solution and the cell cluster formation method; however, the degree of nucleic acid degradation was not impaired by any method.

Conclusion: Although the morphological evaluation of cytology specimens is affected by the method of cell block preparation, it is still useful for nucleic acid extraction and gene panel analysis, as long as there are sufficient amounts of tumor cells.
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http://dx.doi.org/10.1002/dc.24960DOI Listing
June 2022

5-Aminolevulinic acid overcomes hypoxia-induced radiation resistance by enhancing mitochondrial reactive oxygen species production in prostate cancer cells.

Br J Cancer 2022 Apr 1. Epub 2022 Apr 1.

Department of Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan.

Background: The naturally occurring amino acid 5-aminolevulinic acid (5-ALA) is a precursor of protoporphyrin IX (PpIX) biosynthesised in the mitochondria. When accumulated PpIX is excited by light (wavelength of 625-635 nm), reactive oxygen species (ROS) are generated. Here, we investigated whether 5-ALA may increase the sensitisation of prostate cancer (PCA) cells to radiotherapy through the generation of ROS via its metabolite, PpIX.

Methods: Effect of 5-ALA on PC-3 and DU-145 PCA cell lines treated with ionising radiation (IR) was examined in vitro and in vivo with assessment by clonogenic assay, mitochondrial function and ROS production under normoxia or hypoxia condition.

Results: 5-ALA enhanced intra-mitochondrial ROS production immediately after exposure to IR and decreased mitochondrial membrane potential via increase of intra-cellular PpIX. IR with 5-ALA induced mitochondrial dysfunction and increased ATP production, switching energy metabolism to the quiescence. Under hypoxic condition, ROS burst and mitochondrial dysfunction were induced by IR with 5-ALA resulting reducing cancer stemness and radiation resistance.

Conclusion: These results suggest that combined therapy with 5-ALA and radiation therapy is a novel strategy to improve the anti-cancer effects of radiation therapy for PCA.
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http://dx.doi.org/10.1038/s41416-022-01789-4DOI Listing
April 2022

A prospective, single-arm trial of fluorescent ureteroscopy-assisted thulium-holmium:YAG dual laser ablation for upper urinary tract cancer: Study protocol of the FLUAM trial.

Contemp Clin Trials Commun 2022 Apr 2;26:100902. Epub 2022 Mar 2.

Department of Urology, Nara Medical University, Kashihara, Nara, Japan.

Background: Latest guidelines recommend kidney-sparing management as the primary treatment option for selected patients with upper urinary tract urothelial carcinoma (UTUC). One of the biggest issues of ureteroscopic laser ablation (ULA) is a high rate of surgical site recurrence, which is largely attributed to residual lesions at the initial ULA. Another clinical issue is a significant lack of non-invasive reliable detection tools of urinary recurrent tumors in this treatment setting.

Methods: The FLUAM trial is a prospective, single-center, single-arm pilot trial to investigate the efficacy of 5-aminolevulinic acid-mediated photodynamic diagnosis (ALA-PDD)-assisted ULA for localized UTUC and the usefulness of the UroVysion® assay (multiprobe fluorescence in situ hybridization) as a monitoring test after the kidney-sparing treatment. After the screening and registration, a total of 20 patients with localized UTUC will undergo the initial ALA-PDD-assisted ULA followed by the second look ALA-PDD-assisted ureteroscopic examination. The primary endpoint is progression-free survival. Secondary endpoints include patient reported outcomes, diagnostic accuracy of UroVysion assay to detect tumor recurrence, adverse events, and safety of the intervention.

Conclusion: The goal of this trial is to determine the potential benefit of ALA-PDD assistance in patients who undergo the ULA. The evidence of this novel technique is still limited. The results are expected to change the standard of care and lead to better management of localized UTUC.

Trial Registration: This clinical trial was prospectively registered with the Japan Registry of Clinical Trials on 23 June 2021. The reference number is jRCTs051210042, nara0023 (Certified Review Board of Nara Medical University).
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http://dx.doi.org/10.1016/j.conctc.2022.100902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897668PMC
April 2022

A clinicopathologic and molecular analysis of five cases of bronchiolar adenoma with rare mutations.

Pathol Int 2022 May 2;72(5):273-282. Epub 2022 Mar 2.

Department of Surgical Pathology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar-type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non-classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal-type BAs and two distal-type BAs. NRAS codon 12/13 mutation and EML4 exon 20-ALK exon 20 fusion were found in two of the three proximal-types. BRAF V600E mutation was found in one of the two distal-types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2-84 months) of follow-up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma.
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http://dx.doi.org/10.1111/pin.13213DOI Listing
May 2022

Significant Improvement of Prognosis After the Advent of Immune Checkpoint Inhibitors in Patients with Advanced, Unresectable, or Metastatic Urothelial Carcinoma: A Propensity Score Matching and Inverse Probability of Treatment Weighting Analysis on Real-World Data.

Cancer Manag Res 2022 16;14:623-635. Epub 2022 Feb 16.

Department of Urology, Nara Medical University, Kashihara, Nara, 634-8522, Japan.

Purpose: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment.

Patients And Methods: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model.

Results: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age <70 years), those who received radical surgery, and those without visceral metastasis.

Conclusion: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.
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http://dx.doi.org/10.2147/CMAR.S348899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8858764PMC
February 2022

Involvement of enhanced expression of classical complement C1q in atherosclerosis progression and plaque instability: C1q as an indicator of clinical outcome.

PLoS One 2022 27;17(1):e0262413. Epub 2022 Jan 27.

Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, Japan.

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0262413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794146PMC
February 2022

Mirabegron Reduces Urinary Frequency and Improves Overactive Bladder Symptoms at 3 Months After I-brachytherapy for Prostate Cancer: An Open-Labeled, Randomized, Non-Placebo-Controlled Study.

Urology 2022 03 29;161:87-92. Epub 2021 Dec 29.

Department of Urology, Nara Medical University, Nara, Japan.

Objective: To evaluate the additional effects of mirabegron to alpha-1 adrenergic antagonist on lower urinary tract symptoms of patients who underwent I-brachytherapy for prostate cancer.

Patients And Methods: Patients who underwent I-brachytherapy for prostate cancer (cT1-cT3aN0M0) in a single institute between September 2016 and October 2018 were enrolled in the randomized, non-placebo, open-labeled, paralleled study. Patients were randomly distributed (1:1) to combination group (tamsulosin (0.2 mg/day) plus mirabegron (50 mg/day)) or tamsulosin-alone group after I -brachytherapy by envelope method. The primary endpoint was the change from baseline in mean voided volume per micturition 3 months after I brachytherapy. The secondary endpoints included the changes from baseline of International Prostate Symptom Score, Overactive Bladder Symptom Score, and Expanded Prostate Cancer Index Composite scores and 24 hours urinary frequency after 3 months after I brachytherapy.

Results: The mean changes in volume voided per micturition in the combination (n = 108) and tamsulosin-alone (n = 110) groups were -62.5 (standard deviation, ±53.8) and -68.0 (standard deviation, ±52.7), respectively (P = .17). The change in Overactive Bladder Symptom Score in combination group (P = .02) was more moderate than in tamsulosin-alone group; and 24 hour urinary frequency in combination group was lower (P = .03) than in tamsulosin-alone group. Retention rates within 3 months after I-brachytherapy in the mirabegron and tamsulosin-alone groups were 7.3% (9/122) and 6.0% (7/118), respectively (P = .80).

Conclusion: Tamsulosin and mirabegron combination therapy after I-brachytherapy did not improve voided volume per micturition compared to tamsulosin-only treatment. However, it could improve frequent urination and overactive bladder symptoms.
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http://dx.doi.org/10.1016/j.urology.2021.12.018DOI Listing
March 2022

Correlation of MTAP Immunohistochemistry With CDKN2A Status Assessed by Fluorescence In Situ Hybridization and Clinicopathological Features in CNS WHO Grade 2 and 3 Meningiomas: A Single Center Cohort Study.

J Neuropathol Exp Neurol 2022 01;81(2):117-126

From the Department of Diagnostic Pathology, Nara Medical University, Nara, Japan.

CDKN2A homozygous deletion has occasionally been reported in atypical and anaplastic meningiomas and is considered as one of the genetic alterations commonly involved in their recurrence and malignant progression. Methylthioadenosine phosphorylase (MTAP) immunohistochemistry is a promising surrogate marker for CDKN2A homozygous deletion in different cancers but has not been examined in meningiomas. We performed CDKN2A FISH and MTAP immunohistochemistry on specimens from 30 patients with CNS WHO grade 2 (n = 27) and 3 (n = 3) meningiomas, including specimens from primary and recurrent tumors and then determined whether MTAP immunohistochemistry correlated with CDKN2A homozygous deletion and clinicopathological features. CDKN2A homozygous deletion was detected in 12% (3/26) of CNS WHO grade 2 and 67% (2/3) of CNS WHO grade 3 meningiomas; 3 cases exhibited temporal and/or spatial heterogeneity. MTAP loss was in excellent concordance with CDKN2A homozygous deletion (sensitivity; 100%, specificity; 100%). MTAP loss/CDKN2A homozygous deletion correlated with cellular proliferation (mitotic rate; p = 0.001, Ki-67 labeling index; p = 0.03) and poor prognosis (overall survival; p = 0.01, progression free survival; p < 0.001). Thus, MTAP immunostaining can be a surrogate marker for CDKN2A homozygous deletion in meningiomas, and MTAP loss/CDKN2A homozygous deletion may be an important prognostic factor for meningiomas.
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http://dx.doi.org/10.1093/jnen/nlab127DOI Listing
January 2022

Clinical Impact of Subclinical Interstitial Fibrosis or Tubular Atrophy in 1-Hour Allograft Biopsy for Remnant Renal Function in Living Kidney Donors: A Prospective Observational Study.

Transplant Proc 2021 Dec 28;53(10):2833-2840. Epub 2021 Oct 28.

Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.

Background: Preservation of remnant renal function (RRF) is one of the major concerns among living kidney donors (LKDs). A comprehensive assessment is needed to predict the RRF. In this prospective study, we investigated the roles of histologic findings from a 1-hour allograft biopsy in predicting the RRF.

Methods: Our prospective study included 116 LKDs who underwent donor nephrectomy (DN) at our institute. Clinical and radiographic data were obtained from their medical charts. Renal volume parameters were calculated using the preoperative computed tomographic images in the volume analyzer SYNAPSE VINCENT image analysis system. Tissues obtained from allograft biopsy were examined. RRF was defined as the estimated glomerular filtration rate (eGFR) 12 months after DN.

Results: Of 116 LKDs, 95 were finally evaluated. The median age of the LKDs at DN and the preoperative eGFR were 57 years and 80.0 mL/min/1.73 m, respectively. In the histologic analysis, 68 allografts (71.6%) had nonspecific findings involving the glomerulus, vessel, and tubulointerstitium. Interstitial fibrosis or tubular atrophy (IF/TA) was the only significant predictive factor for RRF (P = .039). No significant association was found between renal volume parameters and IF/TA, whereas remnant renal volume adjusted by body weight (RRV/BW) tended to be relatively correlated with IF/TA (P = .072). Furthermore, LKDs with subclinical IF/TA tended to have decreased RRV/BW compared with those without subclinical IF/TA (P = .088).

Conclusions: Our findings suggested that the presence of IF/TA could be a predictive factor for RRF after DN. Further research establishing the predictive model for RRF is warranted to improve the outcomes of LKDs.
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http://dx.doi.org/10.1016/j.transproceed.2021.09.018DOI Listing
December 2021

Evaluation and diagnostic value of next-generation sequencing analysis of residual liquid-based cytology specimens of pancreatic masses.

Cancer Cytopathol 2022 03 19;130(3):202-214. Epub 2021 Oct 19.

Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan.

Background: Liquid-based cytology (LBC) is a widely used method for processing specimens obtained by endoscopic biopsy. This study evaluated next-generation sequencing (NGS) analysis of LBC specimens to improve the diagnostic accuracy of pancreatic lesions.

Methods: Upon the diagnosis of a suspected pancreatic mass, LBC residues were used retrospectively. The quantity and quality of DNA extracted from residual LBC samples were evaluated, and an NGS analysis targeting 6 genes (KRAS, GNAS, TP53, CDKN2A, SMAD4, and PIK3CA) was performed.

Results: The library was prepared from LBC specimens taken from 52 cases: 44 were successful, and 8 preparations failed. An analysis of DNA quantity and quality suggested that the success or failure of NGS implementation depended on both properties. The final diagnosis was achieved by a combination of the pathological analysis of the surgical excision or biopsy material with clinical information. Among the 33 cases of pancreatic ductal adenocarcinoma (PDAC), KRAS, TP53, CDKN2A, and SMAD4 mutations were identified in 31 (94%), 16 (48%), 3 (9%), and 2 (6%), respectively. Among the 11 benign cases, only a KRAS mutation was identified in 1 case. On the basis of NGS results, 18 of 33 PDACs (55%) were classified as highly dysplastic or more, and 10 of 11 benign lesions were evaluated as nonmalignant, which was consistent with the final diagnosis.

Conclusions: NGS analysis using LBC specimens from which DNA of appropriate quantity and quality has been extracted could contribute to improving the assessment of pancreatic tumor malignancies and the application of molecular-targeted drugs.
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http://dx.doi.org/10.1002/cncy.22525DOI Listing
March 2022

Treatment and prognosis of patients with both cancer and impaired decision-patient with both cancer and dementia making as a symptom of dementia.

Geriatr Gerontol Int 2021 Dec 15;21(12):1105-1110. Epub 2021 Oct 15.

Department of Clinical Oncology, Ehime University Graduate School of Medicine, Toon, Japan.

Aim: In our aging society, the number of patients with both cancer and dementia has recently been increasing. One of the major clinical questions is whether patients with dementia could receive appropriate cancer treatment. The purpose of this study is to know the prognosis of patients with both cancer and impaired decision-making as a symptom of dementia, and to discuss the proper cancer treatment of the patients with dementia.

Methods: Patients newly diagnosed with both cancer and impaired decision-making as a symptom of dementia at Ehime University Hospital between January 2010 and December 2016 were reviewed. The data of patients with cancer were retrospectively analyzed using an electronic medical record system.

Results: In total, 9354 cases were diagnosed with cancer in the Ehime University Hospital over 7 years, and only 105 (1.1%) cases with impaired decision-making as a symptom of dementia were recorded by medical professionals, probably due to poor attention to the cognitive functions of patients with cancer. Analysis of the cancer prognosis of these patients showed that a better prognosis was seen in patients with any therapeutic interventions than in those with no treatment for the cancer itself. However, the prognosis of patients was not significantly different between standard and non-standard treatments.

Conclusions: This study suggests that the poor interest of medical professionals in the cognitive function of patients with cancer at the time of diagnosis of cancer and the lack of any guidelines for patients with both cancer and dementia are major problems in our aging society. Geriatr Gerontol Int 2021; 21: 1105-1110.
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http://dx.doi.org/10.1111/ggi.14292DOI Listing
December 2021

Intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer: functional outcome assessment based on a questionnaire survey and actigraphy.

Support Care Cancer 2022 Jan 16;30(1):887-895. Epub 2021 Aug 16.

Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Purpose: We investigated sleep parameters and patient-reported outcomes before, during, and after induction Bacillus Calmette-Guerin therapy using questionnaires and actigraphy in patients with non-muscle invasive bladder cancer.

Methods: We investigated 10 patients who received Bacillus Calmette-Guerin therapy once weekly for 8 weeks. The International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, Functional Assessment of Cancer Therapy-Bladder, and multi-item Short Form-8 tools were used to assess patient-reported outcomes. Participants completed all questionnaires before (baseline), at the 4th and 8th doses, and 1 month after the last Bacillus Calmette-Guerin dose. The MotionWatch8 was fastened to patients' waist throughout the study. Composite sleep quality was determined based on sleep duration, efficiency, and fragmentation.

Results: We observed a transient increase in frequency/nocturia subscores and the insomnia subscore. The number of patients with poor sleep quality increased from 0 (0%) at baseline to 7 (70%) at the 4th dose and to 6 (60%) patients at the 8th dose. Among 10 patients, 6 (60%) were assigned to the sleep deterioration group and 4 (40%) to the non-deterioration group. Sleep quality was restored to baseline levels in 5 of 6 patients (83%) within 1 month after the last dose in the sleep deterioration group, and the nocturia subscore of the International Prostate Symptom Score was significantly increased only in this group (P=0.03).

Conclusions: This is the first study that confirms intravesical Bacillus Calmette-Guerin-induced sleep quality deterioration based on a questionnaire survey and actigraphy.
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http://dx.doi.org/10.1007/s00520-021-06468-3DOI Listing
January 2022

Comparison of disease-specific quality of life in prostate cancer patients treated with low-dose-rate brachytherapy: A randomized controlled trial of silodosin versus naftopidil.

Int J Urol 2021 Nov 10;28(11):1171-1176. Epub 2021 Aug 10.

Departments of Urology, Nara Medical University, Kashihara, Nara, Japan.

Objectives: To compare the effects of naftopidil and silodosin administration on the quality of life of patients with prostate cancer who underwent low-dose-rate brachytherapy.

Methods: In total, 141 men diagnosed with localized prostate cancer who were treated with low-dose-rate brachytherapy were enrolled. Patients were randomized (1:1) to the naftopidil (75 mg/day, n = 63) or silodosin group (8 mg/day, n = 64). Naftopidil and silodosin were administered 1 day after low-dose-rate brachytherapy, and were continued for at least 3 months. Using the University of California at Los Angeles Prostate Cancer Index and Sexual Health Inventory for Men scores, the mean changes and rates of deterioration from baseline were compared. The deterioration rates in the quality of life of patients at 1 and 3 months after low-dose-rate brachytherapy were evaluated based on the minimal important difference.

Results: The rates of deterioration from baseline to 1 and 3 months after low-dose-rate brachytherapy were not significantly different between the two groups in terms of urinary function, urinary bother, bowel bother, sexual function or Sexual Health Inventory for Men scores. In contrast, there were significant differences in bowel function (naftopidil 1 month, 52%; 3 months, 52%; silodosin 1 month, 28%; 3 months, 34%; 1 month, P < 0.01; 3 months, P = 0.048) and sexual bother (naftopidil 3 months, 11%; silodosin 3 months, 29%; P = 0.01).

Conclusions: Naftopidil and silodosin provide different disease-specific quality of life outcomes in patients undergoing, especially in terms of bowel function and sexual bother. These findings can help in the selection of α-1 adrenoceptor antagonists after low-dose-rate brachytherapy.
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http://dx.doi.org/10.1111/iju.14667DOI Listing
November 2021

Trends in risk classification at diagnosis and choice of primary therapy for prostate cancer: An analysis of 10 839 patients from the Nara Urological Research and Treatment Group registry between 2004 and 2015.

Int J Urol 2021 Nov 5;28(11):1164-1170. Epub 2021 Aug 5.

Department of, Urology, Nara Medical University, Kashihara, Nara, Japan.

Objective: To evaluate trends in risk classification at diagnosis and choice of primary therapy in patients diagnosed with prostate cancer.

Methods: This retrospective study included 10 839 patients who were newly diagnosed with prostate cancer between 2004 and 2015 at 23 Japanese institutions. Risk classification and primary therapies between 2004 and 2015 were evaluated. The trends in risk classification and primary therapy were evaluated using chi-squared tests for trend during four periods (2004-2006; 2007-2009; 2010-2012; and 2013-2015). Binary logistic analysis was used to evaluate the extent to which factors such as age, risk classification, and institution influenced primary therapy choice in the 2013-2015 cohort.

Results: The number of patients with very-low or low-risk classification (P < 0.001) and metastasis (P = 0.04) decreased and the number with intermediate-risk classification (P < 0.001) increased during the four periods. A tendency to choose radical prostatectomy as primary therapy for prostate cancer was not observed during the four periods (P = 0.90). The number of patients who chose radiation therapy (P < 0.001) and active surveillance/watchful waiting (P < 0.001) as primary therapies increased during the four periods and the number of patients who chose androgen deprivation therapy (P < 0.001) decreased. Age, institution, and risk classification significantly influenced primary therapy choice.

Conclusions: We have shown the trends in risk classification of prostate cancer and primary therapy choices between 2004 and 2015 in Japan. Age, institution, and risk classification significantly influenced the decision on primary therapy for prostate cancer.
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http://dx.doi.org/10.1111/iju.14666DOI Listing
November 2021

Diffuse large B-cell lymphoma (DLBCL) with significant intravascular invasion. Close resemblance of its clinicopathological features to intravascular large B-cell lymphoma, but not to DLBCL-not otherwise specified.

J Clin Exp Hematop 2021 Sep 30;61(3):152-161. Epub 2021 Jun 30.

Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan.

Intravascular large B-cell lymphoma (IVLBCL) is defined by the World Health Organization (WHO) Classification as one type of extranodal large B-cell lymphoma and it is characterized by the selective growth of lymphoma cells within blood vessels with minimal extravascular invasion. According to the criteria, however, several reported cases of IVLBCL with significant extravascular invasion cannot be classified as IVLBCL. The purpose of the present study was to assess the clinicopathological significance of the WHO criteria for IVLBCL. We characterized clinical, histopathological, and immunohistochemical features of 11 patients with extranodal diffuse large B-cell lymphoma (DLBCL) with significant intravascular invasion (DLBCL-IV), and statistically compared their features with those of 11 patients with IVLBCL and 15 patients with extranodal DLBCL with virtually no intravascular invasion (DLBCL-noIV). When compared with the DLBCL-noIV group, the DLBCL-IV group was characterized by significantly higher rates of splenomegaly, hemophagocytosis, advanced stage disease, and CD5 expression; higher average platelet count, serum lactate dehydrogenase level, and serum ferritin level. Progression-free survival was significantly shorter in the DLBCL-IV group than the DLBCL-noIV group. In contrast, there were no significant differences in clinicopathological features between the DLBCL-IV and the IVLBCL groups. Our study suggests that DLBCL-IV should be regarded as IVLBCL-related.
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http://dx.doi.org/10.3960/jslrt.20066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519243PMC
September 2021

Intravesical Bacillus Calmette-Guérin Treatment for T1 High-Grade Non-Muscle Invasive Bladder Cancer with Divergent Differentiation or Variant Morphologies.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette-Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000-2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG.
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http://dx.doi.org/10.3390/cancers13112615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198171PMC
May 2021

The sustaining of fluorescence in photodynamic diagnosis after the administration of 5-aminolevulinic acid in carcinogen-induced bladder cancer orthotopic rat model and urothelial cancer cell lines.

Photodiagnosis Photodyn Ther 2021 Jun 24;34:102309. Epub 2021 Apr 24.

Department of Urology, Nara Medical University, Kashihara, Nara, Japan. Electronic address:

Background: The administration of 5-aminolevulic acid hydrochloride (5-ALA·HCl) 3 h (range: 2-4 h) before photodynamic diagnosis (PDD) is recommended for detecting bladder tumors. However, there is insufficient evidence on the time duration for the fluorescence of PDD after oral administration of 5-ALA. We investigated the sustainability of the photodynamic effect and protoporphyrinⅨ (PpⅨ) after 5-ALA administration in a carcinogen-induced bladder tumor rat model and bladder cancer cell lines.

Methods: The carcinogen-induced bladder tumor orthotopic rat model was established by the administration of N-butyl-N-(4-hydroxybutyl) nitrosamine.

Results: Red fluorescence was visible 2-8 h after the oral administration of 5-ALA in the carcinogen-induced bladder tumor rat model. Plasma and intratissue PpⅨ (nM) progressed to a higher level at 2 h and remained almost constant 2-8 h after oral administration of 5-ALA. The peak fluorescence intensity of PpⅨ was observed 3-4 h after the administration of 5-ALA in bladder cancer cell lines. The accumulated PpⅨ remained for 4 h after the removal of 5-ALA in UMUC3 cells. It was not clearly visible 3 h after the removal of 5-ALA in MGHU3 and T24 cells. The expression level of ferrochelatase was significantly lower in UMUC3 cells than in other cells. Our findings suggest that 5-ALA-assisted PDD (ALA-PDD) can aid in detecting non-muscle-invasive bladder cancer 2-8 h after 5-ALA administration.

Conclusion: Urologists might not be required to make excess effort to start ALA-PDD-assisted transurethral resection of bladder tumor after the administration of 5-ALA.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102309DOI Listing
June 2021

Clinical outcomes after intravesical bacillus Calmette-Guérin for the highest-risk non-muscle-invasive bladder cancer newly defined in the Japanese Urological Association Guidelines 2019.

Int J Urol 2021 Jul 18;28(7):720-726. Epub 2021 Mar 18.

Departments of, Department of, Urology and, Nara Medical University, Kashihara, Nara, Japan.

Objective: To assess the clinical outcomes of highest-risk non-muscle-invasive bladder cancer patients treated with intravesical bacillus Calmette-Guérin.

Methods: The medical charts of patients with non-muscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin between 2000 and 2018 at a single institution were retrospectively reviewed. Patients were stratified into three groups (intermediate-, high- and highest-risk groups) according to the risk classification of the updated Japanese Urological Association guidelines 2019. Among the three groups, the intravesical recurrence-free survival and progression-free survival were estimated and compared, respectively. Furthermore, the different types of risk factors in the highest-risk group were analyzed.

Results: Of the 165 patients, 49 (30%) patients had intravesical recurrence and 23 (14%) patients showed progression to muscle-invasive disease during a median follow-up period of 53 months. Significant differences were not noted in the recurrence-free survival and progression-free survival among the three groups. Multivariable survival analysis of 74 patients in the highest-risk group showed that carcinoma in situ in the prostatic urethra was a significant predictor associated with recurrence (hazard ratio 3.20, P = 0.026) and progression (hazard ratio 4.36, P = 0.013).

Conclusions: Intravesical bacillus Calmette-Guérin can control highest-risk non-muscle-invasive bladder cancer in most patients. Our findings might aid in decision-making regarding the treatment of this subset of patients who require intensive treatment, such as intravesical therapy with bacillus Calmette-Guérin and radical cystectomy.
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http://dx.doi.org/10.1111/iju.14545DOI Listing
July 2021

Effect of Prolonged Duration of Transrectal Ultrasound-Guided Biopsy of the Prostate and Pre-Procedure Anxiety on Pain in Patients without Anesthesia.

Res Rep Urol 2021 4;13:111-120. Epub 2021 Mar 4.

Department of Urology, Nara Medical University, Nara, Japan.

Objective: To evaluate factors correlated with pain during prostate biopsy and willingness to undergo transrectal ultrasound-guided prostate biopsy (TR-PBx) again without anesthesia in patients undergoing TR-PBx without anesthesia.

Methods: This retrospective, single-center study evaluated 624 patients who underwent TR-PBx without anesthesia. Based on a nomogram using patient age and prostate volume, 6-12 core biopsy samples were allocated. Anxiety was evaluated using the Faces Anxiety Scale before the TR-PBx. Pain was evaluated using the Faces Pain Scale at each puncture and immediately after confirmation of cessation of bleeding from the rectum after the transrectal probe was pulled out. The question "If this operation must be repeated, would you agree to undergo it again under same conditions?" was asked after the procedure was completed. The change in pain at each puncture and factors correlated with post-procedural pain were calculated using multiple regression analysis, and factors predicting an answer of "yes" to the question using binary logistic analysis were evaluated.

Results: Scores on the Faces Pain Scale significantly increased from the first core sample to last as the number of samples increased. However, the number of samples did not show significant correlation with pain evaluated after the procedure was complete. Time during the biopsy and the anxiety score had a significant correlation with the pain scale score for the completed procedure. Short duration of TR-biopsy and a low anxiety score predicted a reply of "Yes" to the question.

Conclusion: A long operative time during the TR-PBx procedure and strong pre-procedure anxiety can increase pain for patients undergoing the procedure without anesthesia and cause patients to be unwilling to undergo TR-PBx again without anesthesia.
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http://dx.doi.org/10.2147/RRU.S297703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939514PMC
March 2021

TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma.

Hum Pathol 2021 05 2;111:59-66. Epub 2021 Mar 2.

Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan.

Adenomatoid tumors (ATs) are benign mesothelial tumors with a good prognosis and usually occur in female and male genital tracts, including in the uterus. ATs are genetically defined by tumor necrosis factor receptor-associated factor (TRAF) 7 mutations, and a high number of AT cases show immunosuppression. On the other hand, malignant mesotheliomas (MMs) are malignant mesothelial tumors with a very poor prognosis. Genetic alterations in TRAF, methylthioadenosine phosphorylase(MTAP), and BRCA-associated nuclear protein 1 (BAP1) in ATs derived from the uterus and MMs of pleural or peritoneal origin were compared by gene sequence analysis or immunohistochemical approaches. Formalin-fixed paraffin-embedded tissues derived from patients were used for immunohistochemical staining of L1 cell adhesion molecule (L1CAM), BAP1, MTAP, and sialylated protein HEG homolog 1 (HEG1) in 51 uterine AT cases and 34 pleural or peritoneal MM cases and for next-generation sequencing of the TRAF7 gene in 44 AT cases and 21 MM cases. ATs had a significantly higher rate of L1CAM expression than MMs, whereas MMs had a significantly higher rate of loss of MTAP and BAP1 expression than ATs. There was no difference in the rate of HEG1 expression between the tumor types. Most of the ATs (37/44; 84%) had somatic mutations in TRAF7, but none of the MMs had somatic mutations in TRAF7 (0/21; 0%). In addition, a low number of AT cases were associated with a history of immunosuppression (9/51; 17.6%). TRAF7 mutation is one of the major factors distinguishing the development of AT from MM, and immunosuppression might not be associated with most AT cases.
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http://dx.doi.org/10.1016/j.humpath.2021.02.007DOI Listing
May 2021

Hexylaminolevulinate-mediated fluorescent urine cytology with a novel automated detection technology for screening and surveillance of bladder cancer.

BJU Int 2021 08 16;128(2):244-253. Epub 2021 Apr 16.

Department of Urology, Nara Medical University, Kashihara, Nara, Japan.

Objectives: To evaluate the diagnostic performance of fluorescent voided urine cytology (FVUC) using a novel automated detection technology to screen for primary bladder cancer and for surveillance of recurrent bladder tumour.

Patients And Methods: We created a rapid, objective, automated, and high-throughput detection device for hexylaminolevulinate-mediated FVUC, named the cellular fluorescence analysis unit-II (CFAU-II). Two different cohorts were used in this study: (i) screening test for primary bladder cancer (165 patients with bladder cancer and 52 controls), and (ii) surveillance test for detecting intravesical recurrent tumour (192 patients with treated non-muscle-invasive bladder cancer and 15 with post-nephroureterectomy upper urinary tract cancer). Voided urine samples were subjected to urine analysis, conventional VUC (cVUC), and FVUC. Diagnostic performance was compared between cVUC, FVUC, and a combination of the two.

Results: A total of 614 urine samples were successfully collected, processed, and analysed. Comparative analysis of the screening test cohort demonstrated that the overall sensitivity of FVUC (63%, P < 0.001) and combination testing (72%, P < 0.001) was significantly higher than that of cVUC (29%). FVUC was found to be superior in most of the subgroups, especially in low-grade, Ta, and small tumours. Analysis of the surveillance test cohort showed that combination testing achieved a sensitivity of 82% and a negative predictive value of 98%, whereas those of cVUC were 39% and 96%, respectively. According to the pathological finding of recurrent tumours presenting false-negative result in the FVUC, the majority of the overlooked recurrent diseases were Ta low-grade tumours. Logistic regression analysis suggested an association between the risk of false-positive results and high density of urine white blood cells and alkaluria.

Conclusion: The present findings clearly demonstrate that FVUC using the newly developed automation technology has superior sensitivity to cVUC for both screening for primary bladder cancer and recurrent tumour detection. It is essential to confirm the clinical usefulness of this method via further large-scale studies, in addition to ensuring its affordability and availability.
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http://dx.doi.org/10.1111/bju.15368DOI Listing
August 2021

Fluorescent cystoscopy-assisted en bloc transurethral resection versus conventional transurethral resection in patients with non-muscle invasive bladder cancer: study protocol of a prospective, open-label, randomized control trial (the FLEBER study).

Trials 2021 Feb 12;22(1):136. Epub 2021 Feb 12.

Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Background: Transurethral resection of bladder tumor (TURBT) is an essential procedure both for the treatment and staging of bladder cancer, particularly non-muscle invasive bladder cancer (NMIBC). The dissemination of cancer cells during resection and the consequent seeding into the bladder mucosa is the main cause of post-TURBT intravesical recurrence. Although the tumor dissemination is inevitable during conventional TURBT (cTURBT), this drawback can be overcome by tumor resection in one piece with intact surrounding normal tissues, referred to as en bloc resection. We previously described the photodynamic diagnosis (PDD)-assisted en bloc TURBT (EBTUR) technique and its favorable outcomes. Based on our preliminary studies, this randomized controlled trial was designed to evaluate the superiority of PDD-EBTUR to PDD-cTURBT.

Methods: The FLEBER study is a single-center randomized controlled trial in NMIBC patients who require TURBT. The longest diameter of the tumor must be between 6 and 30 mm. A total of 160 eligible patients will be enrolled after screening and randomly allocated to the PDD-EBTUR (experimental) and PDD-cTURBT (control) groups in a 1:1 ratio (80 cases to 80 cases). All patients will be treated using a single, immediate postoperative intravesical chemotherapy with epirubicin. The primary endpoint of this trial is the 2-year recurrence-free survival after surgery in pathologically proven low- or intermediate-risk NMIBC. All patients will be monitored by cystoscopy and urine cytology every 3 months for 2 years. Patient data including adverse events and complications, and data from frequency volume charts, pain scales, and health-related QOL questionnaires will be collected before and after the TURBT at indicated visits.

Discussion: The goal of this trial is to determine the potential benefits of PDD-cTURBT and PDD-EBTUR followed by a single immediate postoperative intravesical chemotherapy in patients with low- or intermediate-risk NMIBC who undergo TURBT. Ultimately, our findings will lead to the development of better interventions and potentially change the standard of care.

Trial Registration: This clinical trial was prospectively registered with the UMIN Clinical Trials Registry on 1 August 2020. The reference number is UMIN000041273 , and the Ethics Committee of Nara Medical University Approval ID is 2702.
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http://dx.doi.org/10.1186/s13063-021-05094-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881486PMC
February 2021

Photodynamic Diagnosis-Assisted Transurethral Resection Using Oral 5-Aminolevulinic Acid Decreases the Risk of Repeated Recurrence in Non-Muscle-Invasive Bladder Cancer: A Cumulative Incidence Analysis by the Person-Time Method.

Diagnostics (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.

Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome ( = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16-0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact = 0.011; incidence rate ratio 0.37, Clopper-Pearson confidence interval 0.15-0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT.
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http://dx.doi.org/10.3390/diagnostics11020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911613PMC
January 2021

Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma.

Cancers (Basel) 2020 Oct 27;12(11). Epub 2020 Oct 27.

Department of Urology, Nara Medical University, Nara 634-8522, Japan.

Over the past decade, an "immunotherapy tsunami", more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.
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http://dx.doi.org/10.3390/cancers12113153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692684PMC
October 2020

The prognostic significance of whole-body and spleen MTV (metabolic tumor volume) scanning for patients with diffuse large B cell lymphoma.

Int J Clin Oncol 2021 Jan 23;26(1):225-232. Epub 2020 Oct 23.

Cancer Center, Ehime University Hospital, Toon, Ehime, Japan.

Background: Positron Emission Tomography-Computed Tomography (PET-CT) has been changing diagnostic and therapeutic strategies for patients with cancers, and several PET-CT-related prognostic factors have been reported. We have focused on metabolic tumor volumes (MTVs) over the whole body and in specific organs using 18F-PET-CT imaging, and have compared clinical data to know the prognosis of patients with diffuse large B cell lymphoma (DLBCL).

Patients And Methods: From January 2006 to December 2016, patients who were newly diagnosed for de novo DLBCL and who received 18F-FDG PET-CT scans for disease staging at Ehime University Hospital were reviewed.

Results: A total of forty out of 108 patients with DLBCL were analyzed. The median and the average follow-up were 3.9 years and 3.6 years. Both MTV50 and MTV60 whole-body searching indicated effective prognostic values for patients with DLBCL statistically (P = 0.027). However, analysis of MTVs in the spleen and in bone marrow did not provide any prognostic value. Receiver operating characteristic (ROC) analysis indicated that the cutoff level 25.8 in MTV60 is the most effective prognostic value (P = 0.022) which predicts patient survival after treatment with R-CHOP chemotherapy.

Conclusion: MTV60 using whole-body scanning appears to be an effective indicator in DLBCL and indicates the patient prognosis.
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http://dx.doi.org/10.1007/s10147-020-01807-6DOI Listing
January 2021

A case of a rare non-invasive lung adenocarcinoma.

Int J Surg Case Rep 2020 12;76:386-389. Epub 2020 Oct 12.

Department of Diagnostic Pathology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.

Background: According to the WHO classification, adenocarcinoma in situ (AIS) is a localised small (≤3 cm) adenocarcinoma whose growth is restricted to neoplastic cells along pre-existing alveolar structures, lacking stromal, lymphovascular, or pleural invasion. There is no evidence to define AIS as having a tumour size of ≤3 cm. It is extremely rare for adenocarcinomas with pure lepidic growth lacking invasion to be >3.0 cm. The biological characteristics of these large AISs should be revealed.

Presentation Of Case: The patient was an 82-year-old asymptomatic woman. Chest computed tomography showed a 6-cm-diameter pure ground-glass opacity in the left lower lung. The patient underwent lobectomy. On histologic examination, the tumour was restricted to neoplastic cells along pre-existing alveolar structures, lacking stromal, vascular, alveolar space, and pleural invasion. Papillary patterns were absent. Initially, the histopathological diagnosis was AIS, but the total tumour diameter exceeded 3 cm. The final pathological diagnosis was lepidic adenocarcinoma lacking an invasive component and harbouring an EGFR exon 20 insertion V774_C775insHV mutation using next-generation sequencing (NGS).

Conclusion: We report a rare case of lepidic adenocarcinoma with a total tumour diameter of 6 cm and without an invasive component. Although EGFR mutations are oncogenic driver mutations, AISs have fewer EGFR mutations than invasive adenocarcinomas do. An adenocarcinoma that progresses to AIS, not stepwise progression, might have uncommon mutations and might be another type of adenocarcinoma. NGS could be useful for detecting uncommon genes that reveal the biological characteristics of AIS, and may contribute to the validation of next TNM classification.
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http://dx.doi.org/10.1016/j.ijscr.2020.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575649PMC
October 2020

Gastritis cystica profunda is associated with aberrant p53 and Epstein-Barr virus in gastric cancer: A clinicopathological, immunohistochemical and in situ hybridization study.

Pathol Int 2021 Jan 20;71(1):42-50. Epub 2020 Oct 20.

Department of Diagnostic Pathology, Nara Medical University, Nara, Japan.

Gastritis cystica profunda (GCP) is a lesion characterized by cystic gastric glands within the submucosa. Some studies have reported that GCP is a precancerous lesion. Here, we investigated the association between GCP and gastric cancer. Gastric cancer specimens were taken from 1432 patients undergoing surgery or endoscopic submucosal resection and were classified as GCP or non-GCP. The clinicopathological features, immunohistochemistry and in situ hybridization expression of p53, Ki-67, KCNE2, Epstein-Barr virus (EBV) and programmed death ligand 1 (PD-L1) were compared between the two groups, as well as between GCPs and normal pyloric glands. One hundred and eighty patients (12.6%) had GCPs. In the GCP group, no cancerous lesions were found within the GCPs, but 13% were linked to GCPs and 60.2% were located above or near GCPs. Aberrant p53 expression, EBV-positive cancer cells and PD-L1 scores were significantly higher in the GCP group. The p53 score and Ki-67 labelling index were significantly higher and the KCNE2 score was significantly lower in GCPs than in pyloric glands. Although we suggest GCP is paracancerous, GCP has high proliferation activity and gastric cancer with GCP is associated with aberrant p53 and EBV. GCP is associated with aberrant p53 expression and EBV.
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http://dx.doi.org/10.1111/pin.13039DOI Listing
January 2021

A case of pericytic neoplasm in the shoulder with a novel DERA-GLI1 gene fusion.

Histopathology 2021 02;78(3):466-469

Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara, Japan.

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http://dx.doi.org/10.1111/his.14280DOI Listing
February 2021
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