Unveiling the Genomic Landscape of Intraductal Carcinoma of the Prostate Using Spatial Gene Expression Analysis.

Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.

Standardization of robot-assisted pelvic lymph node dissection-Development of a common understanding of regional anatomy and surgical technique based on cross-disciplinary discussion among colorectal surgery, urology, and gynecology.

BACKGROUND: Pelvic lymph node dissection is a procedure performed in gastroenterological surgery, urology, and gynecology. However, due to discrepancies in the understanding of pelvic anatomy among these departments, cross-disciplinary discussions have not been easy. Recently, with the rapid spread of robotic surgery, the importance of visual information in understanding pelvic anatomy has become even more significant. In this project, we attempted to clarify a shared understanding of pelvic anatomy through cross-disciplinary discussions. METHOD: From May 2020 to November 2021, a total of 11 discussions were held entirely online with 5 colorectal surgery specialists, 4 urologists, and 4 gynecologists. The discussions focused on evidence from each specialty and surgical videos, aiming to create a universally understandable pelvic anatomical illustration. RESULTS: The common area of dissection recognized across the three departments was identified as the obturator lymph nodes. A dynamic illustration of pelvic anatomy was created. In addition to a bird's-eye view of the pelvis, a pelvic half view was developed to enhance understanding of the deeper pelvic anatomy. The following insights were incorporated into the illustration: (1) the cardinal ligament in gynecology partly overlaps with the vesicohypogastric fascia in colorectal surgery; (2) the obturator lymph nodes continue cephalad into the fossa of Marcille in urology; and (3) the deep uterine vein in gynecology corresponds to the inferior vesical vein in colorectal surgery. CONCLUSION: Based on the dynamic illustration of pelvic anatomy from cross-disciplinary discussions, we anticipate advancements in pelvic lymph node dissection aiming for curative and safe outcomes.

Comparison of perioperative outcomes and complications between intracorporeal, extracorporeal, and hybrid ileal conduit urinary diversion during robot-assisted radical cystectomy: a comparative propensity score-matched analysis from nationwide multi-institutional study in Japan.

BACKGROUND: To investigate the impact of different urinary diversion (UD) techniques on the peri- and postoperative complications of robot-assisted radical cystectomy (RARC) with ileal conduit. METHODS: We retrospectively analyzed 373 patients undergoing RARC with ileal conduit at 11 institutions in Japan between April 2018 and December 2021. Propensity score weighting was performed to adjust for confounding factors such as age, sex, body mass index, performance status, American Society of Anesthesiologists score, previous abdominal surgery, neoadjuvant chemotherapy, and preoperative high T stage (≥ cT3) and high N stage (≥ cN1). Perioperative complications were then compared among three groups: extracorporeal, intracorporeal, and hybrid urinary diversion (ECUD, ICUD, and HUD, respectively). RESULTS: A total of 150, 68, and 155 patients received ECUD, HUD, and ICUD, respectively. Bowel reconstruction time and UD time were significantly shorter in the ECUD group (p < 0.001), and console time was significantly longer and blood loss was significantly higher in the ICUD group (p < 0.001). For postoperative complications (Clavien-Dindo Classification grade ≥ 3), surgical site infection (p = 0.004), pelvic abscess (p = 0.013), anastomotic urine leak (p = 0.007), and pelvic organ prolapse (p = 0.011) significantly occurred in the ECUD group. For all grades, ileus was more common in the HUD group, whereas anastomotic stricture was more common in the ECUD group compared with the other groups (p < 0.05). CONCLUSIONS: Severe complications did not increase after HUD and ICUD compared with ECUD; however, console time tended to be longer and blood loss was slightly higher during RARC.

Impact of timing of radium­223 administration on the survival of patients with bone metastatic castration­resistant prostate cancer.

The present study aimed to evaluate the optimal timing of radium-223 chloride (Ra-223) administration among patients with bone metastasis from castration-resistant prostate cancer (BmCRPC). Patients, who were diagnosed with BmCRPC and treated with Ra-223 therapy between October, 2016 and January, 2022, were reviewed. The survival time was calculated from the initiation of Ra-223 administration. The time from the diagnosis of BmCRPC to the initiation of Ra-223 administration was identified as a potential prognostic factor. A total of 51 patients were examined in the present study. Ra-223 was administered as the first- and second-line therapy (earlier Ra-223 administration) in 32 patients and as the third- to fifth-line therapy (later Ra-223 administration) in 19 patients. In the multivariate analysis, which considered the potential prognosis, the difference in survival times between patients who received early and late Ra-223 administration was not significant [hazard ratio (HR), 2.67; 95% confidence interval (CI), 0.79-9.07; P=0.11]. By contrast, an incomplete Ra-223 administration (HR, 128.03; 95% CI, 10.59-1548.42; P<0.01) and higher levels of prostate-specific antigen prior to Ra-223 administration (HR, 7.86; 95% CI, 2.7-27.24; P<0.01) were independent factors, significantly associated with a poorer prognosis. The timing of Ra-223 administration did not significantly affect the survival of patients from the initiation of treatment. Further studies are thus required to determine the optimal timing for Ra-223 administration.

Spatial Gene Expression Analysis Reveals Characteristic Gene Expression Patterns of De Novo Neuroendocrine Prostate Cancer Coexisting with Androgen Receptor Pathway Prostate Cancer.

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.

Radical prostatectomy trends between 2010 and 2020 in Ehime, Japan, identified using data from the Medical Investigation Cancer Network (MICAN) study.

OBJECTIVES: The use of radical prostatectomy is increasing with the rising incidence of prostate cancer. We assessed the surgical trends related to radical prostatectomy using data from a multi-center, retrospective cohort study, the MICAN (Medical Investigation Cancer Network) study, which was conducted in all the urology-related medical facilities in Ehime Prefecture, Japan. METHODS: We compared data from the MICAN study with prostate biopsy registry data collected in Ehime between 2010 and 2020 and recorded the surgical trends. RESULTS: There was a significant increase in the mean age of patients with positive biopsies, and the positivity rate increased from 46.3% in 2010 to 60.5% in 2020, while the number of biopsies obtained decreased. The number of radical prostatectomies performed increased over the years, with robot-assisted radical prostatectomy becoming the predominant procedure. In 2020, robot-assisted radical prostatectomies accounted for 96.0% of the surgeries performed. The age at surgery also gradually increased. Of the registered patients aged ≤75 years, 40.5% underwent surgery in 2010, compared with 83.1% in 2020. The prevalence of surgery also increased from 4.6% to 29.8% in patients aged >75 years. There was a gradual increase in the proportion of high-risk cases, from 29.3% to 44.0%, but a decrease in that of low-risk cases, from 23.8% in 2010 to 11.4% in 2020. CONCLUSIONS: We have shown that the number of radical prostatectomies performed in Ehime is increasing in patients aged both ≤75 and >75 years. The proportion of low-risk cases has decreased, while that of high-risk cases has increased.

Summary of the Clinical Practice Guidelines for Penile Cancer 2021 by the Japanese Urological Association.

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

CD21lo B Cells Could Be a Potential Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitor (ICI) therapy increases the risk of immune-related adverse events (irAEs). In particular, combination checkpoint blockade (CCB) targeting inhibitory CTLA-4 and PD-1 receptors could lead to irAEs at a higher rate than ICI monotherapy. Management of irAEs is important while using ICIs. However, there are no reliable biomarkers for predicting irAEs. The aim of this study was to elucidate early B cell changes after CCB therapy in patients with renal cell carcinoma (RCC) and verify whether B cells can be a predictor of irAEs. This prospective cohort study was conducted with 23 Japanese patients with metastatic RCC. An increase in the proportion of CD21lo B cells and CD21lo memory B cells was confirmed following CCB therapy. Although there were no differences in clinical outcomes between irAE and no-irAE groups, the proportion of CD21lo B cells at baseline was lower in the irAE group, with a significant increase after the first cycle of CCB therapy. Further analysis revealed a moderate correlation between irAEs and CD21lo B cell levels at baseline (area under the curve: 0.83, cut-off: 3.13%, sensitivity: 92.3, specificity: 70.0). This finding indicates that patients with low baseline CD21lo B cell levels warrant closer monitoring for irAEs. The clinical registration number by the Certified Review Board of Ehime University is No. 1902011.

Uhrf1 governs the proliferation and differentiation of muscle satellite cells.

DNA methylation is an essential form of epigenetic regulation responsible for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are tightly regulated during differentiation. However, it is unclear how these DNA methylation patterns affect the function of satellite cells. We demonstrate that a key epigenetic regulator, ubiquitin like with PHD and RING finger domains 1 (Uhrf1), is activated in proliferating myogenic cells but not expressed in quiescent satellite cells or differentiated myogenic cells in mice. Ablation of Uhrf1 in mouse satellite cells impairs their proliferation and differentiation, leading to failed muscle regeneration. Uhrf1-deficient myogenic cells exhibited aberrant upregulation of transcripts, including Sox9, with the reduction of DNA methylation level of their promoter and enhancer region. These findings show that Uhrf1 is a critical epigenetic regulator of proliferation and differentiation in satellite cells, by controlling cell-type-specific gene expression via maintenance of DNA methylation.

Sequential immune-targeted surgical therapy resulted in disease-free survival in a case with advanced renal cell carcinoma.

BACKGROUND: Currently, immunotherapy is indicated for patients with metastatic RCC or unresectable RCC, but there is no indication for immunotherapy in the neoadjuvant setting. We report a case in which the combined use of nivolumab and ipilimumab and sequential TKI therapy enabled surgical treatment. CASE PRESENTATION: A 71-year-old female was diagnosed with a metastatic clear-cell renal cell carcinoma with a level IV tumor thrombus. She was started on nivolumab-ipilimumab therapy, and was switched to pazopanib monotherapy because the tumor thrombus progressed within the right atrium. The tumor shrank to resectable status with sequential therapy. She then underwent right nephrectomy and thrombectomy. Pathological analysis showed 10-20% residual tumor in the primary tumor, but no viable cells in tumor thrombus. She remains clinically disease-free 1 year after surgery. CONCLUSION: This case suggests the utility of sequential immune-targeted therapy as neoadjuvant therapy in advanced renal cell carcinoma.

Extended robot-assisted laparoscopic prostatectomy and extended pelvic lymph node dissection as a monotherapy in patients with very high-risk prostate cancer Patients.

BACKGROUND: Patients with very-high-risk prostate cancer (VHRPCa) have earlier biochemical recurrences (BCRs) and higher mortality rates. It remains unknown whether extended robot-assisted laparoscopic prostatectomy (eRALP) without neoadjuvant or adjuvant therapy can improve the outcomes of VHRPCa patients. We aimed to determine the feasibility and efficacy of eRALP as a form of monotherapy for VHRPCa. METHODS: Data from 76 men who were treated with eRALP without neoadjuvant/adjuvant therapy were analyzed. eRALP was performed using an extrafascial approach. Extended pelvic lymph node (LN) dissection (ePLND) included nodes above the external iliac axis, in the obturator fossa, and around the internal iliac artery up to the ureter. The outcome measures were BCR, treatment failure (defined as when the prostate-specific antigen level did not decrease to <0.1 ng/ml postoperatively), and urinary continence (UC). Kaplan-Meier, logistic regression, and Cox proportional-hazards model were used to analyze the data. RESULTS: The median operative time was 246 min, and median blood loss was 50 ml. Twenty-one patients experienced postoperative complications. Median follow-up was 25.2 months; 19.7% of patients had treatment failure. Three-year, BCR-free survival rate was 62.0%. Castration-resistant prostate cancer-free survival rate was 86.1%. Overall survival was 100%. In 55 patients who had complete postoperative UC data, 47 patients (85.5%) recovered from their UC within 12 months. Clinical stage cT3b was an independent preoperative treatment failure predictor (p = 0.035), and node positivity was an independent BCR predictor (p = 0.037). The small sample size and retrospective nature limited the study. CONCLUSIONS: This approach was safe and produced acceptable UC-recovery rates. Preoperative seminal vesicle invasion is associated with treatment failure, and pathological LN metastases are associated with BCR. Therefore, our results may help informed decisions about neoadjuvant or adjuvant therapies in VHRPCa cases. PRECIS: Extended robot-assisted laparoscopic prostatectomy and extended pelvic lymph node dissection without adjuvant therapy is safe and effective for some patients with very-high-risk prostate cancer. The clinical stage and node positivity status predicted monotherapy failure, which may indicate good adjuvant therapy candidate.

PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear. METHODS: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived CM using a tube formation assay that mimics angiogenesis. RESULTS: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP-derived CM containing PSMA-positive membranes, such as microvesicles transformed HUVECs "PSMA-negative" into "PSMA-positive." Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP-derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner. CONCLUSIONS: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.

Predictors of Hypotension after Adrenalectomy for Pheochromocytoma.

The management of blood pressure is a significant concern for surgeons and anesthesiologists performing adrenalectomy for pheochromocytoma. We evaluated clinical factors in pheochromocytoma patients to identify the predictors of postoperative hypotension. The medical records of patients who underwent adrenalectomy for pheochromocytoma between 2001 and 2017 were retrospectively reviewed and clinical and biochemical data were evaluated. Of 29 patients, 13 patients needed catecholamine support in the perisurgical period while 16 patients did not. There were significant differences in median age, tumor size, and blood pressure drop (maxmin) between the 2 groups (68 vs 53 years old, p=0.045; 50 vs 32 mm diameter, p=0.022; 110 vs 71 mmHg, p=0.015 respectively). In univariate logistic analysis, age > 65.5 years, tumor size > 34.5 mm, urine metanephrine > 0.205 mg/day and urine normetanephrine > 0.665 mg/day were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urine metanephrine and urine normetanephrine levels were correlated with postoperative hypotension. These predictors may help in the safe perioperative management of pheochromocytoma patients treated with adrenalectomy.

Venous reconstruction using a Y-shaped saphenous vein in kidney transplantation: A report of three cases.

INTRODUCTION: Transplantation, especially, of the right kidney may be difficult to properly choose the main drainage vein due to abundance of renal veins with the thin wall and the small diameter. Therefore, we report three cases, wherein anastomosis-related complications may be avoided by using a reconstructed Y-shaped major saphenous vein graft. CASE PRESENTATION: The first case was a case of congestion when anastomosed with a trifurcated renal vein which ligated branch. The second case was a case of donated kidney with three renal veins, which were all short, small, and thin-walled. The third case was a case of donated kidney with four renal veins. Two of them were unused, though the other two veins were short and thin-walled with equal diameters. In all of three cases, renal veins were anastomosed with Y-shaped saphenous vein graft. CONCLUSION: Y-shaped saphenous vein graft is possibly effective for such reconstructions as it may prevent anastomosis-related complications.

Prognostic value of the preoperative albumin-globulin ratio in patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration.

OBJECTIVE: To assess the value of preoperative albumin to globulin ratio for predicting pathologic and oncological outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy in a large multi-institutional cohort. MATERIALS AND METHODS: Preoperative albumin to globulin ratio was assessed in a multi-institutional cohort of 2492 patients. Logistic regression analyses were performed to assess the association of the albumin to globulin ratio with pathologic features. Cox proportional hazards regression models were performed for survival endpoints. RESULTS: The optimal cut-off value was determined to be 1.4 according to a receiver operating curve analysis. Lower albumin to globulin ratios were observed in 797 patients (33.6%) compared with other patients. In a preoperative model, low preoperative albumin to globulin ratio was independently associated with nonorgan-confined diseases (odds ratio 1.32, P = 0.002). Patients with low albumin to globulin ratios had worse recurrence-free survival (P < 0.001), cancer-specific survival (P = 0.001) and overall survival (P = 0.020) in univariable and multivariable analyses after adjusting for the effect of standard preoperative prognostic factors (recurrence-free survival: hazard ratio (HR) 1.31, P = 0.001; cancer-specific survival: HR 1.31, P = 0.002 and overall survival: HR 1.18, P = 0.024). CONCLUSIONS: Lower preoperative albumin to globulin ratio is associated with locally advanced disease and worse clinical outcomes in patients treated with radical nephroureterectomy for upper tract urothelial carcinoma. As it is difficult to stage disease entity, low preoperative serum albumin to globulin ratio may help identify those most likely to benefit from intensified care, such as perioperative systemic therapy, and the extent and type of surgery.

A low RENAL Nephrometry Score can avoid the need for the intraoperative insertion of a ureteral catheter in robot-assisted partial nephrectomy.

BACKGROUND: Intraoperative urinary collecting system entry (CSE) in robot-assisted partial nephrectomy (RAPN) may cause postoperative urinary leakage and extend the hospitalization. Therefore, identifying and firmly closing the entry sites are important for preventing postoperative urine leakage. In RAPN cases expected to require CSE, we insert a ureteral catheter and inject dye into the renal pelvis to identify the entry sites. We retrospectively analyzed the factors associated with intraoperative CSE in RAPN and explored the indications of intraoperative ureteral catheter indwelling in RAPN. METHODS: Of 104 Japanese patients who underwent RAPN at our institution from August 2016 to March 2020, 101 were analyzed. The patients were classified into CSE and non-CSE groups. The patients' background characteristics, RENAL Nephrometry Score (RNS), and surgical outcomes were analyzed. RESULTS: Intraoperative CSE was observed in 41 patients (41%). The CSE group had a significantly longer operative time, console time, ischemic time, and hospital stay than the non-CSE group. In a multivariable analysis, the N-score (odds ratio [OR] = 3.9, P < 0.05) and RNS total score excluding the L-score (OR = 3.1, P < 0.05) were associated with CSE. In a logistic regression analysis, CSE showed a moderate correlation with the RNS total score excluding the L-score (AUC 0.848, cut-off 5, sensitivity 0.83, specificity 0.73). CONCLUSION: A ureteral catheter should not be placed in patients with an RNS total score (excluding the L-score) of ≤ 4.

DNA maintenance methylation enzyme Dnmt1 in satellite cells is essential for muscle regeneration.

Epigenetic transcriptional regulation is essential for the differentiation of various types of cells, including skeletal muscle cells. DNA methyltransferase 1 (Dnmt1) is responsible for maintenance of DNA methylation patterns via cell division. Here, we investigated the relationship between Dnmt1 and skeletal muscle regeneration. We found that Dnmt1 is upregulated in muscles during regeneration. To assess the role of Dnmt1 in satellite cells during regeneration, we performed conditional knockout (cKO) of Dnmt1 specifically in skeletal muscle satellite cells using Pax7CreERT2 mice and Dnmt1 flox mice. Muscle weight and the cross-sectional area after injury were significantly lower in Dnmt1 cKO mice than in control mice. RNA sequencing analysis revealed upregulation of genes involved in cell adhesion and apoptosis in satellite cells from cKO mice. Moreover, satellite cells cultured from cKO mice exhibited a reduced number of cells. These results suggest that Dnmt1 is an essential factor for muscle regeneration and is involved in positive regulation of satellite cell number.

The Prognostic Impact of Intraductal Carcinoma of the Prostate: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review and meta-analysis aimed to assess the prognostic impact of intraductal carcinoma of the prostate in patients with prostate cancer. MATERIALS AND METHODS: A systematic search was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. We searched PubMed®, Web of Science™, the Cochrane Library and Scopus® up to October 2019. The end points were biochemical recurrence-free, cancer specific and overall survival. RESULTS: We identified 32 studies with 179,766 patients. A total of 31 studies containing 179,721 patients with localized and advanced prostate cancer were eligible for meta-analysis. In localized prostate cancer intraductal disease was associated with adverse outcomes including lower biochemical recurrence-free survival (pooled HR 2.09, 95% CI 1.75-2.50) and cancer specific survival (pooled HR 2.93, 95% CI 2.25-3.81). In advanced prostate cancer overall survival was lower in patients with vs without intraductal disease (pooled HR 1.75, 95% CI 1.43-2.14). Subgroup analysis by specimen type revealed that intraductal carcinoma of the prostate is a significant negative prognostic factor in both biopsies and prostatectomy specimens. Moreover, subgroup analyses based on the histopathological definitions of intraductal carcinoma of the prostate indicated that intraductal disease was significantly associated with lower biochemical recurrence-free, cancer specific and overall survival for almost all definitions. CONCLUSIONS: Intraductal disease is a histopathological feature of biologically and clinically aggressive prostate cancer. It confers worse oncologic outcomes in both localized and advanced prostate cancer, whether assessed in biopsy or prostatectomy specimen. The pathologist should assess for and report on the presence of intraductal disease in all prostate specimens. The urologist and radiation oncologist should consider this adverse feature in their clinical decision making.

Prognostic value of testosterone for the castration-resistant prostate cancer patients: a systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to assess the prognostic value of testosterone in patients with castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: PubMed, Web of Science, and Scopus databases were systematically searched until December 2019, according to the Preferred Reporting Items for Systemic Review and Meta-analysis statement. The endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 11 articles with 4206 patients for systematic review and nine articles with 4136 patients for meta-analysis. Higher testosterone levels were significantly associated with better OS (pooled HR 0.74, 95% CI 0.58-0.95) and better PFS (pooled HR 0.51, 95% CI 0.30-0.87). Subgroup analyses based on the treatment type revealed that higher testosterone levels were significantly associated with better OS in CRPC patients treated with androgen receptor-targeted agents (ARTAs) (pooled HR 0.64, 95% CI 0.55-0.75), but not in those treated with chemotherapy (pooled HR 0.78, 95% CI 0.53-1.14). CONCLUSION: This meta-analysis demonstrated that the PFS and OS were significantly greater in patients with CRPC in those with higher testosterone levels than that of those with lower testosterone levels. In the subgroup analyses, lower testosterone levels were a consistently poor prognostic factor for OS in patients treated with ARTAs, but not in those treated with chemotherapy. Therefore, higher testosterone levels could be a useful biomarker to identify patient subgroups in which ARTAs should be preferentially recommended in the CRPC setting.