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The repair mechanism after ischemic acute kidney injury (AKI) involves complex immunologic processes, which determine long-term renal outcomes. Through investigating two murine ischemia-reperfusion injury (IRI) models: bilateral IRI (BIRI) and unilateral IRI (UIRI), we aimed to determine an appropriate murine model that could simulate the recovery phase of ischemic AKI. Changes in renal function, phenotypes of kidney mononuclear cells, renal fibrosis, and intrarenal cytokine/chemokine expression were serially analyzed up to 12 weeks after IRI. Plasma creatinine and BUN concentrations increased and remained elevated in the BIRI group until 7 days but decreased to comparable levels with the sham control group at 2 weeks after surgery and thereafter, whereas plasma creatinine and BUN concentrations remained unchanged in the UIRI group. Intrarenal total leukocytes, and effector memory and activated phenotypes of CD4 and CD8 T cells markedly increased in the postischemic kidneys in both IRI groups. Expression of proinflammatory cytokines/chemokines and TGF-β1 was enhanced in the postischemic kidneys of both IRI groups with a higher degree in the UIRI group. Importantly, intrarenal immunologic changes of the BIRI group persisted until 6 weeks despite full functional recovery. The postischemic kidneys of the UIRI group showed earlier and more pronounced proinflammatory conditions as well as more severe atrophic and fibrotic changes compared to the BIRI group. These findings support the utility of longer follow-ups of BIRI and UIRI models for investigating the adaptive repair process, which facilitates recovery of ischemic AKI and maladaptive repair process may result in AKI to CKD transition, respectively., Competing Interests: None., (AJTR Copyright © 2022.)

Purpose: We aimed to investigate the risk factors and patterns of locoregional recurrence (LRR) after radical nephrectomy (RN) in patients with locally advanced renal cell carcinoma (RCC)., Materials and Methods: We retrospectively analyzed 245 patients who underwent RN for non-metastatic pT3-4 RCC from January 2006 to January 2016. We analyzed the risk factors associated with poor locoregional control using Cox regression. Anatomical mapping was performed on reference computed tomography scans showing intact kidneys., Results: The median follow-up duration was 56 months (range, 1 to 128 months). Tumor extension to renal vessels or the inferior vena cava (IVC) and Fuhrman's nuclear grade IV were identified as independent risk factors of LRR. The 5-year actuarial LRR rates in groups with no risk factor, one risk factor, and two risk factors were 2.3%, 19.8%, and 30.8%, respectively (p < 0.001). The locations of LRR were distributed as follows: aortocaval area (n=2), paraaortic area (n=4), retrocaval area (n=5), and tumor bed (n=11). No LRR was observed above the celiac axis (CA) or under the inferior mesenteric artery (IMA)., Conclusion: Tumor extension to renal vessels or the IVC and Fuhrman's nuclear grade IV were the independent risk factors associated with LRR after RN for pT3-4 RCC. The locations of LRR after RN for RCC were distributed in the tumor bed and regional lymphatic area from the bifurcation of the CA to that of the IMA.

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of TMPRSS2-ERG gene fusions and PTEN loss, increased percentage of genomic instability, and higher prevalence of germline BRCA2 mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate-ribose) polymerase inhibitors for patients harboring increased genomic instability or BRCA2 mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor.

We investigated the clinical relevance of urinary cytokines/chemokines reflecting intrarenal immunologic micromilieu as prognostic markers and the optimal measurement timing after living donor kidney transplantation (LDKT). This prospective cohort study included 77 LDKT patients who were followed for ≥ 5 years. Patients were divided into control (n = 42) or acute rejection (AR, n = 35) group. Early AR was defined as AR occurring within 3 months. Serum and urine cytokines/chemokines were measured serially as follows: intraoperative, 8/24/72 h, 1 week, 3 months, and 1 year after LDKT. Intrarenal total leukocytes, T cells, and B cells were analyzed with immunohistochemistry followed by tissueFAXS. Urinary MCP-1 and fractalkine were also analyzed in a validation cohort. Urinary MCP-1 after one week was higher in the AR group. Urinary MCP-1, fractalkine, TNF-α, RANTES, and IL-6 after one week were significantly higher in the early AR group. Intrarenal total leukocytes and T cells were elevated in the AR group compared with the control group. Urinary fractalkine, MCP-1, and IL-10 showed positive correlation with intrarenal leukocyte infiltration. Post-KT 1 week urinary MCP-1 showed predictive value in the validation cohort. One-week post-KT urinary MCP-1 may be used as a noninvasive diagnostic marker for predicting AR after LDKT., (© 2021. The Author(s).)

Objectives: Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT)., Methods: Conventional kidney transplant (KT) recipients ( n  = 20) and CKBMT recipients ( n  = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion., Results: Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non-tolerant group). The CD45RA - FOXP3 ++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non-tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA - FOXP3 ++ Treg cells to CD45RA - FOXP3 + cells indicated good discrimination between the tolerant and non-tolerant groups., Conclusion: Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex-mismatched combined kidney and bone marrow transplantation (CKBMT)., Methods: From December 2011 to May 2017, 8 major histocompatibility complex-mismatched patients received CKBMT. The initial conditioning regimen (protocol 1) consisted of cyclophosphamide (CP), rituximab, rabbit antithymocyte globulin, and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS)., Results: This regimen was complicated by transient acute kidney injury, which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of 2 subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (protocol 2). The final modification was reducing the fludarabine and rabbit antithymocyte globulin doses (protocol 3). Mixed chimerism, detected by the short tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the 3 subjects treated with protocol 2, IS was successfully discontinued for >35 months in one subject, but the other 2 subjects suffered from severe BK virus-associated nephritis. All 3 subjects treated with protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo donor-specific antibody was not detected in any subject during all the follow-up periods., Conclusions: Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT.

OBJECTIVE. Current criteria for positive findings on dynamic contrast-enhanced MRI (DCE-MRI) are unclear. We compared the diagnostic performance of mass enhancement on DCE-MRI versus conventional DCE-MRI criteria for identifying clinically significant prostate cancer (csPCa) in the peripheral zone (PZ). MATERIALS AND METHODS. A total of 173 consecutive patients with MRI- and surgically proven prostate cancer (PCa) were evaluated. Two readers independently interpreted DCE-MRI examinations of the PZ. Criteria denoting a positive DCE-MRI examination included conventional criteria from the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and mass enhancement. The diagnostic performance of and interreader agreement for the two types of enhancement criteria in identifying csPCa in the PZ that met Epstein criteria were investigated. RESULTS. The proportion of csPCa in the PZ was 69.3% (120/173). For both readers, the specificity and positive predictive value of mass enhancement were increased compared with conventional enhancement criteria (specificity, 75.5% vs 5.7% [for reader 1] and 84.9% vs 30.2% [for reader 2], respectively; positive predictive value, 87.1% vs 70.6% [for reader 1] and 91.5% vs 75.3% [for reader 2], respectively). The AUC value of mass enhancement was higher than that of conventional criteria (for reader 1, 0.744 [95% CI, 0.672-0.807] vs 0.528 [95% CI, 0.451-0.605] [ p < 0.001], respectively; for reader 2, 0.783 [95% CI, 0.714-0.842] vs 0.602 [95% CI, 0.497-0.700] [ p < 0.001], respectively). The weighted kappa value for agreement between the two readers was 0.206 for conventional criteria and 0.613 for mass enhancement. CONCLUSION. PZ lesions with mass enhancement on DCE-MRI are more likely to be csPCa. This enhancement pattern may need to be considered as one of the criteria in PI-RADS.

Bone marrow preconditioning using cyclophosphamide (CP) is generally used for bone marrow transplantation (BMT). However, because of CP's hepatotoxicity and nephrotoxicity, additional fludarabine (FDR) administration and a reduced dose of CP are used for reduced-intensity preconditioning. Recently, preclinical studies using non-human primates (NHPs) were performed to induce immune tolerance after solid organ transplantation by conducting BMT simultaneously. However, dose optimization of CP and FDR for BMT preconditioning in cynomolgus monkeys has not been conducted. Therefore, the objective of this study was to evaluate the efficacy and tolerability of induction protocols using different doses of CP and FDR. Our results showed that relatively low-dose CP (30 mg/kg×2) combined with additional high-dose FDR (60 mg/m 2 ×4) was associated with sufficient suppression in periphery as well as in bone marrow compared with high-dose CP (60 mg/kg×2) combined with low-dose FDR (30 mg/m 2 ×4) and did not show hepatic or renal toxicity. CD34 + stem cells were also well suppressed with both doses. Therefore, we concluded that the combination of 60 mg/kg of CP with 240 mg/m 2 of FDR can be used effectively and safely for non-myeloablative preconditioning for BMT in cynomolgus monkeys., Competing Interests: None., (AJTR Copyright © 2019.)

Teratomas show diverse biologic behaviour and prognosis as well as variable histological features. Importantly, post-pubertal testicular teratomas composed of mature components have a potential for malignant behaviour, in contrast to ovarian dermoid cysts and pre-pubertal testicular teratomas which are considered almost always benign. On the other hand, the biological behaviour and histogenesis of extragonadal teratomas are still not fully elucidated. In this study of mediastinal mature teratoma (MT), we investigated clinicopathological features and chromosome 12 short arm (12p) status which constitutes a major genetic aberration in the germ cell tumours (GCT) and is indicative of malignant potential. A total of 123 cases of primary mediastinal MT were included, and clinical data were retrieved regarding demographic information, adjuvant treatment, post-operative clinical course, and level of serum tumour markers. Histopathological features were evaluated in 123 cases and 12p status was studied by FISH in 25 cases. Female predilection was identified in the post-pubertal group (38 males vs 77 females), and paediatric teratoma cases had longer follow-up (mean 62.2 months vs 26.5 months). All patients had excellent prognosis with no tumour-associated death, regardless of age and sex. None of the MT cases had cytological atypia and all 21 cases finally evaluated by fluorescence in situ hybridisation were negative for 12p over-representation. Our results support the benign nature of mediastinal MT and suggest the possibility that it may share a common histogenesis with pre-pubertal type GCTs., (Copyright © 2018. Published by Elsevier B.V.)

Background: Recent studies suggest that FGFR3 is a potential therapeutic target in urothelial carcinoma (UC). The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in patients with muscle-invasive UC who received radical resection., Methods: We analyzed surgical tumor samples from 74 UC patients who had received radical cystectomy (n = 40) or ureteronephrectomy (n = 34). Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations., Results: Fifty-four patients (73%) had high-grade tumors, and 62% had lymph node involvement. Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n = 13): Y373C (n = 3), N532D (n = 3), R248C (n = 2), S249C (n = 1), G370C (n = 1), S657S (n = 1), A797P (n = 1), and 746&#95;747insG (n = 1). Three additional patients had a FGFR3-TACC3 rearrangement. The frequency of FGFR3 aberrations was higher in bladder UC (25%) than in UC of the renal pelvis and ureter (18%) but the difference was not statistically significant (P = 0.444). Genes that were co-aberrant with FGFR3 included APC (88%), PDGFRA (81%), RET (69%), and TP53 (69%)., Conclusions: We report the frequency and types of FGFR3 aberrations in Korean patients with UC. Patients with FGFR3 mutations or FGFR3-TACC3 fusion may constitute potential candidates for a novel FGFR-targeted therapy in the perioperative setting.

Epithelial-mesenchymal transition (EMT) is a process which epithelial cells gain mesenchymal phenotype such as motility and invasiveness. We investigated the role of EMT in upper urinary tract urothelial carcinoma (UTUC). The patient cohort included 93 cases of UTUC treated with radical nephroureterectomy. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemical staining was performed for E-cadherin, vimentin, and smooth muscle actin to evaluate the EMT status. Interpretation criteria were defined for the staining results and EMT phenotypes were assigned as wild type, incomplete type (loss of E-cadherin and negative for vimentin), and complete type (loss of E-cadherin and positive for vimentin). The loss of E-cadherin and vimentin-expression was observed in 76 (81.7%) and 10 (10.8%) cases, respectively, yielding EMT phenotypes comprised of 17 cases (18.3%) of wild type, 66 cases (71.0%) of incomplete type, and 10 cases (10.8%) of complete types. In survival analyses, wild type showed statistically significant association with longer extra-bladder recurrence free survival (p < .001) and overall survival (p < .001). In multivariate analyses, complete type was an independent prognostic factor for extra-bladder recurrence free survival and overall survival. EMT phenotype based on the combination of EMT-related markers may provide a useful prognostic marker for UTUC patients., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

Background: We previously demonstrated the presence of onychodermis, a specialized mesenchymal cell population beneath the nail matrix and proximal nail bed demonstrating CD10 expression. We hypothesize that the onychodermis could be the nail analog of the follicular dermal papilla, which is known to express CD13. We compare CD13 expression patterns between specialized mesenchymes of nail and hair, and compare these findings with CD10 expression patterns., Methods: CD10 and CD13 immunohistochemistry was performed on polydactyly and adult cadaveric nail units, and on hair follicles in scalp nevus sebaceus excision specimens., Results: CD10 and CD13 were expressed in the mesenchyme below the nail matrix and nail bed. Stronger CD13 expression was observed in the mesenchyme containing onychofibroblasts below the nail matrix compared with that below the nail bed. CD10 was expressed in the dermal sheath of terminal hair follicles, but it was expressed in the dermal sheath and follicular dermal papilla of primitive hair follicles within nevus sebaceus lesions. CD13 was expressed in the dermal sheath and dermal papilla of terminal and primitive hair follicles., Conclusion: CD13 may be a marker for onychofibroblasts within nail matrix onychodermis. We demonstrate CD13 expression in the specialized mesenchymes of both nail and hair., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu., (Copyright © 2017 the American Physiological Society.)

Prostate cancer is one of the major health care problems, but the molecular pathogenesis has been relatively insufficiently elucidated. Recently, whole exome sequencing of prostate cancer identified recurrent mutations involving MED12 in Caucasian patients, which finding was not reproduced in one subsequent study by Sanger sequencing. Thus, we investigated mutation status of MED12 in exons 2 and 26 by Sanger sequencing in 102 radical prostatectomy cases from Korean patients. The analysis found the mutation in none of the cases. Therefore, MED12 mutation does not appear to represent a significant molecular alteration in this cohort of patients according to the analysis by the traditional "gold standard."

Aims: TMPRSS2/E26 transformation-specific (ETS) family gene fusion in prostate carcinoma (PCa) can be detected by several methods including immunohistochemistry (IHC) for ETS-related gene (ERG), the diagnostic utility of which has not been clearly defined., Methods: We explored TMPRSS2-ERG gene rearrangement status in 132 patients with PCa with four detection methods including fluorescence in situ hybridisation for TMPRSS2-ERG fusion, real-time reverse transcription PCR (RT-qPCR) for ERG and TMPRSS-ERG fusion transcript mRNA and IHC for ERG., Results: Concordant results were found in 126 cases for the four detection methods and the remaining six cases showed discrepancy in one method: two cases in IHC, three cases in RT-qPCR for ERG and one case in RT-qPCR for fusion transcript. In discordant cases, the majority results were determined as final fusion status. Analysis of discrepancy cases for ERG IHC showed that weak immunoreactivity for ERG should be regarded as equivocal and that even strong immunoreactivity can be false positive. The overall incidence of TMPRSS-ERG gene fusion was 24%., Conclusions: ERG IHC is a useful surrogate test for the detection of TMPRSS2-ERG gene fusion, but it needs to be interpreted with caution and definite judgement should not be based on IHC alone. A relatively low incidence of TMPRSS2-ERG gene fusion was demonstrated in this Korean cohort., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-α and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required., (Copyright © 2016 the American Physiological Society.)

Background: The lack of highly specific clinical and histopathological criteria has contributed to the delay in diagnosis of subungual melanoma in situ in its early stages., Methods: Eighteen cases of subungual melanoma in situ, the largest series reported to date, were analyzed to characterize the clinical and histopathological findings of early stages of subungual melanoma in situ along with five cases of nail matrix nevus and five cases of subungual lentigo serving as histologic control., Results: Clinically, longitudinal melanonychia was present in all 18 cases of subungual melanoma in situ, consisting of irregular dark brown to black streaks within a brown background with (11 cases) or without Hutchinson's sign. Histopathologically, variable shaped and sized, hyperchromatic nuclei surrounded by retraction artifact were present in all cases. Nine cases showed a significant increase in the number of atypical melanocytes with marked nuclear atypia, while the rest of the cases showed less noticeable changes in nail matrix including lower density of melanocytes and/or mild nuclear atypia. In 15 cases, the nuclear enlargement in some of the melanocytes was greater than two times that of the neighboring matrix cells. In the remaining three cases, the nuclei were enlarged to a much lesser degree. All cases displayed areas of haphazard and uneven distribution of solitary melanocytes and, although not observed in all cases, some degree of pagetoid spread was present in majority of the cases. In contrast, nail matrix nevi showed well-formed nests consisting of relatively monomorphous melanocytes with abundant cytoplasm and subungual lentigos consisted of subtle increase in the number of dendritic melanocytes in solitary units within the lower layers of the nail matrix., Conclusion: Increase in the number of scattered atypical melanocytes with large hyperchromatic nuclei in a partial nail matrix may provide a diagnostic clue to subungual melanoma in situ in concert with its clinical suspicion., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: The insignificance of pure microsteatosis (MiS) was reported in living donor liver transplantation (LDLT). However, since steatosis is mostly found in a mixed form of microsteatosis (MiS) and macrosteatosis (MaS), we aimed to determine the importance of MiS mixed with MaS in LDLT., Methods: Donor matching and recipient matching were independently performed with unfixed matching ratios. In donor matching, 51 donors with high (⩾30%) MiS mixed with MaS (H-MiS) were matched with 160 donors with low (⩽10%) MiS mixed with MaS (L-MiS), based on MaS degree, remnant liver volume, and others. In recipient matching, 50 recipients who received H-MiS grafts were matched with 176 recipients who received L-MiS grafts, based on MaS degree, graft volume, MELD score, and others., Results: The median MiS degree was 10% (range 0%-10%) vs. 35% (range 30%-80%) in L-MiS livers vs. H-MiS livers after both matching. L-MiS and H-MiS donors were not significantly different regarding postoperative biochemical liver function (e.g. peak AST 232 vs. 246 IU/L, p=0.931). L-MiS and H-MiS recipients were not significantly different regarding 2-week graft regeneration (51% for both) and 5-year survival (HR 0.87, 95% CI 0.43-1.76, p=0.699). Post-transplant donor/recipient complication rates were not significantly different, either., Conclusions: There were no evidences of a significant impact of MiS mixed with MaS on post-LDLT outcomes. The results suggest less importance of MiS, and further indicate that there is no interaction between MiS and MaS. Thus, the risk of steatosis may be determined by the relative composition of MiS and MaS, rather than the total quantitative degree., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) have been studied in several models of immune-mediated disease because of their unique immunomodulatory properties. We hypothesized that HUCB-MSCs could suppress the inflammatory response in postischemic kidneys and attenuate early renal injury. In 8- to 10-wk-old male C57BL/6 mice, bilateral ischemia-reperfusion injury (IRI) surgery was performed, and 1 × 10(6) HUCB-MSCs were injected intraperitoneally 24 h before surgery and during reperfusion. Renal functional and histological changes, HUCB-MSC trafficking, leukocyte infiltration, and cytokine expression were analyzed. Renal functional decline and tubular injury after IRI were attenuated by HUCB-MSC treatment. PKH-26-labeled HUCB-MSCs trafficked into the postischemic kidney. Although numbers of CD45-positive leukocytes in the postischemic kidney were comparable between groups, the expression of interferon-γ in the postischemic kidney was suppressed by HUCB-MSC treatment. The rapid decrease in intrarenal VEGF after IRI was markedly mitigated by HUCB-MSC treatment. In inflammatory conditions simulated in a cell culture experiment, VEGF secretion from HUCB-MSCs was substantially enhanced. VEGF inhibitor abolished the renoprotective effect of HUCB-MSCs after IRI. Flow cytometry analysis revealed the decreased infiltration of natural killer T cells and increased number of regulatory T cells in postischemic kidneys. In addition, these effects of HUCB-MSCs on kidney infiltrating mononuclear cells after IRI were attenuated by VEGF inhibitor. HUCB-MSCs attenuated renal injury in mice in the early injury phase after IRI, mainly by humoral effects and secretion of VEGF. Our results suggest a promising role for HUCB-MSCs in the treatment of renal IRI., (Copyright © 2014 the American Physiological Society.)

Purpose: We determined whether the 3 pT3 subclassification systems reported by the Asan, Cornell and Nagoya groups provide an accurate estimation of patient prognosis. We also determined which subclassification is most predictive of the heterogeneous oncological outcomes of pT3 renal pelvic urothelial carcinoma., Materials and Methods: Using a Korea-Japan multi-institutional, retrospective database 250 pT3 renal pelvic urothelial carcinomas treated with radical nephroureterectomy were assigned to the 3 pT3 subcategories by tumor location and depth of parenchymal invasion after pathological reevaluation. Recurrence-free and cancer specific survival was assessed according to the 3 pT3 subclassifications. Predictive accuracy for survival in 4 models (baseline and each of the 3 pT3 subclassifications) was quantified and predictive accuracy increments for each model were compared., Results: In the baseline multivariate Cox regression model nodal metastasis and high grade were significant for survival. On multivariate analysis including the pT3 subclassifications the 3 subclassifications remained significantly associated with survival rates. Of the 3 pT3 subclassification systems the Cornell subclassification had the highest predictive accuracy for discriminating the heterogeneous prognosis of pT3 renal pelvic urothelial carcinoma, followed by the Nagoya subclassification. Compared with the baseline model adding the Cornell subclassification significantly increased predictive accuracy for recurrence-free survival from 0.687 to 0.742 (p = 0.029) and for cancer specific survival from 0.713 to 0.758 (p = 0.047)., Conclusions: The criteria of microscopic vs macroscopic parenchymal invasion and/or peripelvic fat invasion provide the most accurate differential classification of the prognostic heterogeneity of pT3 renal pelvic urothelial carcinoma. Further studies should be performed to determine the need to modify the current pT3 renal pelvic urothelial carcinoma staging system., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to prospectively evaluate the reliability and variability of apparent diffusion coefficient (ADC) calculations between two-point and multipoint b value analyses in prostate cancer and benign prostate tissue., Subjects and Methods: Forty-eight consecutive patients with suspected prostate cancer underwent diffusion-weighted MRI (DWI) at 3 T followed by surgery. DWI was examined under different b values. ADC maps were generated by two different methods: two-point b values (0 and 1000 s/mm(2)) and multipoint b values (0, 100, 300, 700, and 1000 s/mm(2)). Two independent readers measured ADC in the cancers, benign peripheral zone and transition zone, and obturator internus muscle. Statistical analyses were performed using the intraclass correlation coefficient (ICC), correlation of variation (CV), Bland-Altman test, and paired Student t test., Results: The intermethod ADC calculation revealed excellent reliability for all tissues in both readers: cancer (ICC = 0.979-0.981), transition zone (0.989-0.993), peripheral zone (0.990-0.994), and obturator internus muscle (0.967-0.975). In both readers, the variability of the intermethod ADC calculation was 2.90-3.09% CV in cancer, 1.16-1.48% CV in the transition zone, 1.03-1.29% CV in the peripheral zone, and 2.44-2.62% CV in the obturator internus muscle. For interreader variability, the CVs of ADC calculation for two-point versus multipoint b value analyses in all tissues were 7.21-9.65% versus 7.18-9.01%., Conclusion: For estimating ADC values on 3-T DWI of the prostate, two-point b value analysis seems to present excellent correlation with multipoint b value analysis, with little error in accuracy.

Objective: The purpose of this study was to retrospectively investigate the value of adding diffusion-weighted imaging (DWI) to T2-weighted imaging for the prediction of extracapsular extension (ECE) in patients with prostate cancer, as well as to compare apparent diffusion coefficients (ADCs) between patients with and without ECE., Materials and Methods: Seventy-six patients with suspected prostate cancer underwent T2-weighted imaging and DWI at 3 T using a phased-array coil, followed by radical prostatectomy. For prediction of ECE, the prostate was divided into six sectors. Two experienced radiologists analyzed T2-weighted images alone and in combination with DWI in consensus and rated the likelihood of ECE on a five-point scale. Tumor ADC values were measured, and the results were compared between patients with and without ECE., Results: Of the 456 sectors studied, 74 (16%) were positive for ECE in 31 patients. For prediction of ECE, the specificity and accuracy of combined T2-weighted imaging and DWI were 94.5% and 91.7%, respectively, superior to those of T2-weighted imaging alone (87.2% and 81.2%, respectively) (p < 0.001). On receiver operating characteristic analysis, the area under the curve (Az) of combined T2-weighted imaging and DWI (Az = 0.900) was significantly greater than that of T2-weighted imaging alone (Az = 0.828) (p < 0.001). The mean tumor ADC values were significantly lower in patients with ECE than patients without ECE (p < 0.001)., Conclusion: DWI at 3 T in addition to T2-weighted imaging improves the ability to predict ECE in patients with prostate cancer. Furthermore, tumor ADC values in patients with and without ECE are significantly different.

Objective: The purpose of this article is to retrospectively evaluate the utility of diffusion-tensor imaging (DTI) at 3 T in differentiating central gland prostate cancer from benign prostatic hyperplasia (BPH)., Materials and Methods: Eighty consecutive patients (57 with central gland cancer and 23 without central gland cancer) were included in this study. All patients underwent T2-weighted imaging and DTI at 3 T, followed by surgery. For predicting central gland cancer, experienced and less-experienced radiologists independently analyzed T2-weighted imaging and combined T2-weighted imaging and DTI, respectively. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured for central gland cancers and BPH foci of stromal and glandular hyperplasia. Statistical analyses were performed using McNemar test, linear mixed model, receiver operating characteristic (ROC), and kappa statistics., Results: For predicting central gland cancers, the area under the curve (Az) of combined T2-weighted imaging and DTI for the experienced (0.915) and less-experienced reader (0.753) was superior to that of T2-weighted imaging (0.723 vs 0.664; p<0.001). The mean ADC and FA values were 0.77×10(-3) mm2/s and 0.35, respectively, for central gland cancers, 1.22×10(-3) mm2/s and 0.26, respectively, for stromal hyperplasia foci, and 1.59×10(-3) mm2/s and 0.21, respectively, for glandular hyperplasia foci, and the values differed significantly. For differentiating central gland cancer from stromal hyperplasia foci and glandular hyperplasia foci, Az values of ADC versus FA were 0.989 and 1.0 versus 0.818 and 0.916, respectively, and the difference was statistically different., Conclusion: DTI at 3 T is useful for distinguishing central gland cancers from BPH foci, with significantly different ADC and FA values. Furthermore, ADC showed greater diagnostic accuracy than FA in differentiating central gland cancers from stromal and glandular hyperplasia foci.

We encountered an undescribed histologic feature of papillary urothelial neoplasms: "urothelial eddy", which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis.

Familial juvenile hyperuricemic nephropathy (FJHN; OMIM 162000) is an autosomal dominant disorder characterized by hyperuricemia and gouty arthritis due to reduced kidney excretion of uric acid and progressive renal failure. Gradual progressive interstitial renal disease, with basement membrane thickening and glomerulosclerosis resulting from fibrosis, starts in early life. In most cases of FJHN, uromodulin gene (UMOD) is responsible for the disease; however, there has been only one report of a genetically confirmed FJHN family in Korea. Here we report another Korean family with FJHN, in which three male members. a father and 2 sons.developed gout and progressive renal insufficiency. The clinical, laboratory, and radiological findings were consistent with FJHN, and renal biopsy showed chronic parenchymal damage, which can be found in FJHN but is not specific to this disease. In order to confirm the diagnosis, sequence analysis of the UMOD was performed, and a novel heterozygous missense variant (c.187T>C; p.Cys63Arg) in exon 3 was identified. We assume that this variant is likely to be the causative mutation in this family, as the variant segregated with the disease. In addition, approximately two-thirds of the known mutations lead to a cysteine amino acid change in uromodulin, and all such variants have been shown to cause UMOD-associated kidney disease. In summary, we report a Korean FJHN family with three affected members by genetic analysis of the UMOD, and provide the first report of a novel heterozygous missense mutation.

Objective: To elucidate the prognostic utility of several biomarkers including ROR2/Wnt5a in stage 1 pure seminoma, which is a highly curable tumor in need of prognostic markers to avoid unnecessary treatment., Study Design: A total of 47 patients of stage 1 seminoma who underwent radical orchiectomy were included in the study. Tissue microarray-based immunohistochemical analysis of placental alkaline phosphatase, D2-40, c-Kit, Oct-3/4, ROR2, Wnt5a, beta-catenin, CD30, vimentin, pancytokeratin, beta-hCG and p53 was conducted, and relevant clinicopathologic features were assessed., Results: ROR2 protein revealed strong diffuse membranous immunoreactivity (IR) in 12.8% and partial weak IR in 40.4%, respectively. Cytoplasimc Wnt5a IR was observed in 27.7%. ROR2 IR was correlated with Wnt5a IR (p = 0.029) and Oct3/4 IR (p = 0.035). c-Kit IR was correlated with Wnt5a IR (p = 0.034). No significant differences were found between ROR2/Wnt5a protein expression and the prognostically relevant features such as lymphatic invasion or pathologic T stage. Pathologic T stage was not correlated with rete invasion (p= 0.23). The expression or loss of other aforementioned antibodies was not associated with the prognostic clinicopathologic characteristics., Conclusion: Our results do not support the relevance of ROR2/Wnt5a as biomarkers in stage 1 pure seminomas. The utility of the explored biomarkers as prognostic or differentiation indicators remains to be clarified.

Purpose: To evaluate the feasibility and complications of ultrasound (US)-guided biopsy of small renal masses (SRMs) and to determine factors that contribute to nondiagnostic biopsy specimens., Materials and Methods: Between June 2004 and May 2011, 58 consecutive patients underwent US-guided core biopsy of a SRM (>1 cm and ≤4 cm) using an 18-gauge core biopsy device. The diagnostic rate, histologic diagnosis, and complications of US-guided core biopsy were assessed. Mann-Whitney U and Fisher exact tests were used to compare diagnostic and nondiagnostic biopsy specimens. Univariate analysis was performed to determine the predictive factors for nondiagnostic biopsy specimens., Results: There were 59 biopsies of SRMs performed, and the diagnostic rate was 81% (48 of 59). The mass size of diagnostic and nondiagnostic biopsy specimens ranged from 1.2-3.9 cm (2.4 cm±0.7) for diagnostic specimens and from 1.1-3.5 cm (1.9 cm±0.7) for nondiagnostic specimens (P = .024). Of the diagnostic biopsy specimens, 77% (37 of 48) were malignant, and 23% (11 of 48) were benign. Minor complications developed in 20.3% (12 of 59) of biopsies. The lesion size or core number threshold for decreasing diagnostic rate was 2 cm or three cores. A cystic mass, fewer cores (three or fewer cores), an upper pole mass, and a small mass (≤2 cm) significantly predicted a nondiagnostic biopsy specimen (P = .007-.046)., Conclusions: US-guided core biopsy is a feasible and safe procedure for histologic diagnosis of a SRM. However, nondiagnostic rates may increase when a cystic mass is biopsied, a mass is located in an upper pole mass, a mass is 2 cm or less, and three cores or fewer are sampled., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Aim of the study was to determine protective effect of triphala on radiation-induced rectal mucosal damage. Male Sprague Dawley rats (30) were divided into 5 groups. Rats in group A were sham irradiated and rats in group B underwent only irradiation. Rats in group C were administered triphala 1 g/kg/day orally for 5 consecutive days before irradiation. Rats in group D and E were administered triphala 1 and 1.5 g/kg/day orally for 10 consecutive days, respectively. Rectal mucosal damage was induced by a single fraction of 12.5Gy gamma irradiation (Ir-192) on 5th day. All the rats were autopsied on 11th day and histological changes in surface epithelium, glands, and lamina propria were assessed. Proctitis showed significant improvement in surface epithelium (P < 0.024), glands (P < 0.000) and lamina propria (P < 0.002) in group E compared to group B. Rats in group E showed significantly less change in glands (P < 0.000) compared to rats in group D, All histological variables (surface epithelium, P < 0.001; glands, P < 0.000; lamina propria, P < 0.003) compared to rats in group C. In a Tukey-b test, group E had a significantly recovered grade for glands (P < 0.000) compared to groups B, C and D. Results of the present study showed that high-dose triphala improved radiation-induced damage of glands.