Comparison of Metastatic Patterns Among Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Nonneuroendocrine Carcinomas of Various Primary Organs.

BACKGROUND: Both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) exhibit neuroendocrine differentiation and are classified as neuroendocrine neoplasms (NENs). NECs and nonneuroendocrine neoplasms (non-NENs), such as adenocarcinoma, have similar mutational profiles. The purpose of this study was to identify differences in metastatic patterns and to identify the key factor causing these differences by simultaneously comparing the metastatic patterns of NETs, NECs and non-NENs from various primary organs. METHODS: We retrieved data for 4,223 patients with NENs and 41,637 patients with non-NENs arising at various primary sites from an institutional database and then compared NET, NEC, and non-NEN metastatic patterns. RESULTS: NETs and NECs showed generally similar metastatic patterns. Most NEN patients had a higher liver organotrophic metastasis rate, lower lung organotrophic metastasis rate, and lower pleural/peritoneal organotrophic metastasis rate than non-NEN patients. Some differences were characteristics of specific organs. Some of these site-specific differences were not caused by NENs but by non-NENs, including a higher bone organotrophic metastasis rate for medullary thyroid carcinoma and a lower bone organotrophic metastasis rate for pulmonary NEN. Other differences were probably caused by NENs, including a higher bone organotrophic metastasis rate for colorectal NETs. Uterine cervical NEC showed unique patterns of metastasis compared to NEN from other sites. CONCLUSION: Significant differences between the metastatic patterns of NENs and non-NENs were detected. The multigene program that causes neuroendocrine differentiation might be associated with organotropic metastasis.

Fat Loss in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < -5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07-2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17-2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy.

Recoverability of Diabetic Nephropathy of Donor Kidney After Kidney Transplantation.

Some kidney donors have diabetes, and little of their natural course of diabetic nephropathy (DN) is known. The aim of this study was to analyze the changes in pathologic lesions in the diabetic donor kidney after KT by performing protocol biopsy two weeks and one year after KT. This retrospective study included 103 patients who underwent KT, with kidneys from donors with a history of diabetes mellitus (DM). Among them, data of 34 patients who underwent biopsy two weeks and one year after KT were reviewed. Biopsy specimens were reviewed using light microscopy and electron microscopy. Glomerular basement membrane (GBM) thickness at 2 weeks and 1 year was compared. Biopsy showed that DN occurred in 29 of the 34 patients. Only trivial histological changes were observed in 22 patients (64.7%), including 5 patients who did not show DN. At one year after transplantation, there was no change in the DN histologic class in 26 patients (76.5%), and there was no statistically significant difference in the change in GBM thickness. This pattern was observed regardless of the recipient's DM or glycemic control. With this understanding, clinicians can use kidneys from DM donors with more comfort, thereby reducing the kidney discard rate.

Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.

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.

Diagnostic Performance of Mass Enhancement on Dynamic Contrast-Enhanced MRI for Predicting Clinically Significant Peripheral Zone Prostate Cancer.

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.

Renal involvement and favorable outcome in a child with mastocytosis.

Mastocytosis is a rare myeloproliferative disease in which mast cells abnormally accumulate in the skin, bone marrow, intestine, liver, spleen, and lymph nodes. Characterized by uncontrolled proliferation of aberrant mast cells, the disease can present either cutaneously or systemically. Mast cells facilitate the immune response and inflammation, and mastocytosis with renal involvement has been rarely reported in adults. Here, we describe a pediatric case of renal involvement in a patient with mastocytosis. A 12-year-old female with mastocytosis was admitted for edema, foamy urine, and gross hematuria. Initial laboratory findings showed azotemia, proteinuria, and hematuria. Renal biopsy findings were compatible with diffuse proliferative glomerulonephritis (DPGN). Immunofluorescence analysis of CD117 (c-Kit) staining resulted positive for rare infiltrating cells. These findings are unusual for primary glomerulonephritis (GN), and secondary GN is typically associated with mastocytosis. According to the literature, steroid treatment can be attempted in cases with renal disease associated with systemic mastocytosis. Therefore, the patient was treated with oral prednisolone, and proteinuria and hematuria disappeared after 4 months of treatment. After 5 months, prednisolone treatment was stopped, and the skin lesion improved. The renal function 22 months after prednisolone treatment was normal. This is a unique report of mastocytosis with DPGN in a child. c-Kit staining can be helpful for diagnosis, and the response to steroid treatment is favorable. Further study about the pathological relevance between mastocytosis and GN is necessary.

The concept of nail matrix onychodermis (onychomatricodermis) in the nail unit: Histology and elastin immunohistochemistry.

BACKGROUNDS: We previously demonstrated the presence of onychodermis below nail matrix and nail bed. Because nail matrix is a producer of nail plate, we hypothesized that onychodermis below nail matrix could be the nail counterpart of follicular dermal papilla. In this study, we sought to further characterize histologic, histochemical, and immunohistochemical features of nail matrix onychodermis. METHODS AND RESULTS: Hematoxylin and eosin slides of 10 polydactyly nail units and 10 nail matrix biopsies from children and adults were reviewed. In polydactyly nail units, the onychodermis beneath nail matrix was characterized by onychofibroblasts showing abundant cytoplasm, and this area was slightly separated from the undersurface of the nail matrix. Nail matrix biopsy specimens also showed similar histology in the nail matrix onychodermis. Alcian blue stain demonstrated mucin deposition in onychofibroblasts within the nail matrix onychodermis. Immunohistochemically, elastin was rarely expressed in the nail matrix onychodermis while it was strongly expressed in the dermis of other areas of polydactyly nail units. Elastin was not expressed in follicular dermal papilla of terminal hair follicles of the scalp. CONCLUSION: Our findings demonstrate the presence and localization of nail matrix onychodermis (onychomatricodermis). Our study also demonstrates similar elastin expression patterns in the onychomatricodermis and follicular dermal papilla.

First-year GFR slope and long-term renal outcome in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most frequent primary glomerular disease and the leading cause of end-stage renal disease. We investigated clinicopathologic predictors of renal survival in patients with IgAN with a focus on glomerular filtration rate (GFR) decline slope. MATERIALS AND METHODS: We screened all patients with primary IgAN between 1995 and 2012. Renal progression was defined as doubling of serum creatinine. Using serial serum creatinine levels during the first-year, we calculated the GFR decline slopes. Further, we defined patients in the steepest GFR slope quartile as rapid decliners and those in the second steepest GFR slope quartile as slow decliners. Others were defined as nondecliners. RESULTS: Of 214 participants, baseline GFR was 81 (62, 100) mL/min/1.73 m2 , which was not different among the 3 groups. Rapid decliners and slow decliners had higher levels of urinary protein/creatinine ratio (0.88, 0.89 and 0.58 g/gCr, respectively, P < .001). Five-year renal survival was 76% in rapid decliners, 91% in slow decliners and 100% in nondecliners (P < .001, rapid or slow decliners vs nondecliners). After adjustment for clinicopathologic variables, slow decliners were associated with an 8.8-fold higher risk of progression (P = .011), and rapid decliners were associated with a 10.2-fold increased risk of progression (P = .007) compared with nondecliners. CONCLUSIONS: First-year GFR slope was associated with increased risk of renal progression, independent of proteinuria and histologic findings. Further studies are needed to investigate whether early GFR change can identify high-risk patients who benefit from immunosuppressive treatment in IgAN.

Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma.

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_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.

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation.

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.

CD13 is a marker for onychofibroblasts within nail matrix onychodermis: Comparison of its expression patterns in the nail unit and in the hair follicle.

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.

Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice.

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.

Scattered atypical melanocytes with hyperchromatic nuclei in the nail matrix: diagnostic clue for early subungual melanoma in situ.

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.

Microsteatosis may not interact with macrosteatosis in living donor liver transplantation.

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.

CCAR1 promotes chromatin loading of androgen receptor (AR) transcription complex by stabilizing the association between AR and GATA2.

Androgen receptor (AR), a ligand-dependent transcription factor, plays a critical role in prostate cancer onset and progression, and its transcriptional function is mediated largely by distinct nuclear receptor co-regulators. Here, we show that cell cycle and apoptosis regulator 1 (CCAR1) functions as an AR co-activator. CCAR1 interacted with and enhanced the transcriptional activity of AR. Depletion of CCAR1 caused reduction in androgen-dependent expression of a subset of AR target genes. We further showed that CCAR1 is required for recruitment of AR, MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen-induced long-range prostate specific antigen enhancer-promoter interaction. The molecular mechanism underlying CCAR1 function in AR-mediated transcription involves CCAR1-mediated enhanced recruitment of GATA2, a pioneer factor for AR, to AR-binding sites. CCAR1 stabilized the interaction between AR and GATA2 by interacting directly with both proteins, thereby facilitating AR and GATA2 occupancy on the enhancers. Furthermore, CCAR1 depletion inhibited the growth, migration, invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo. Our results firmly established CCAR1 as an AR co-activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis.

Megalocytic interstitial nephritis following acute pyelonephritis with Escherichia coli bacteremia: a case report.

Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid.

Expression of Peroxisome Proliferator Activated Receptor gamma in Prostatic Adenocarcinoma.

Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer.

Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice.

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.

Reassessment of prognostic heterogeneity of pT3 renal pelvic urothelial carcinoma: analysis in terms of proposed pT3 subclassification systems.

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.

Comparison of apparent diffusion coefficient calculation between two-point and multipoint B value analyses in prostate cancer and benign prostate tissue at 3 T: preliminary experience.

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.