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A 22-year-old Asian male developed testicular alpha-fetoprotein (AFP)-secreting germ cell tumor 3 years after treatment of a disseminated intracranial lesion identified as non-secreting germ cell tumor on the basis of clinical data. Magnetic resonance imaging showed a massive lesion with necrosis appearing as hypointense on T1- and hyperintense on T2-weighted imaging, with heterogeneous enhancement. The blood AFP level was as high as 129 ng/ml (previously, as low as 5 ng/ml) and abdominal computed tomography showed para-aortic lymph node swelling. Left orchidectomy was performed and histological examination indicated the presence of AFP-secreting germ cell tumor despite severe necrosis of the tissue. Improved chemoradiotherapy for intracranial germ cell tumor will lead to long-term survival of most patients with germ cell tumor. Patients may subsequently develop germ cell tumors at other sites in the body. Therefore, follow up should monitor for tumor recurrence not only in the brain but also in other locations.

Purpose To investigate the prognostic effect of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model reclassification after targeted therapy administration in metastatic renal cell carcinoma (mRCC). Patients and method A total of 245 mRCC patients treated with targeted therapy are included. The IMDC model reclassification is performed at 1 month after treatment induction of both first-line and second-line targeted therapy. Results Of the 245 patients, 74 (30.2%) are divided into different risk groups by the IMDC model reclassification after first-line targeted therapy, and patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group ( P = 0.018). Of the 119 patients treated with subsequent second-line targeted therapy, 25 (21.0%) are divided into different risk groups by the IMDC model reclassification after second-line targeted therapy, and patients newly classified with poor risk tend to have increased all-cause mortality compared with those remaining in the primary intermediate-risk group ( P = 0.007), whereas patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group ( P = 0.034). Conclusion Approximately a quarter of the mRCC patients are classified into different risk groups of the IMDC model following targeted therapy administration in the first-line and second-line settings. There is a significant difference in overall survival of subgroups after the IMDC model reclassifications.

Accumulating evidence suggests that OCT4 participates in tumorigenicity and malignancy in human cancers. However, the prognostic significance of OCT4 expression in prostate cancer (PCa) or predictive significance of OCT4 in docetaxel sensitivity in castration-resistant prostate cancer (CRPC) remains unclear. The aim of this study was to assess the prognostic value of OCT4 expression in PCa. We retrospectively analyzed the clinical records and evaluated the OCT4 expression in 205 patients with PCa who underwent radical prostatectomy. We examined the change of OCT4 expression in 3 patients with CRPC who underwent transurethral resection for local progression before and after docetaxel chemotherapy. OCT4 expression was significantly associated with higher pathological T stage (P < .001). The 5-year prostate-specific antigen recurrence-free survival rate was 56.8% in patients with higher OCT4 expression and 90.6% in patients with lower OCT4 expression (P < .001). Multivariate analysis revealed that high OCT4 expression was an independent prognostic indicator of prostate-specific antigen recurrence (P < .001). Elevated strong OCT4 expression in residual CRPC cells after docetaxel chemotherapy was observed in all CRPC patients, compared with before chemotherapy in corresponding specimens. Higher OCT4 expression represents a clinically relevant predictor of patient prognosis in PCa and may be a new biomarker that will provide additional prognostic information in CRPC when treated with docetaxel.

Herein we report a case of epithelioid angiomyolipoma of the kidney which is a rare subtype of angiomyolipoma. A 68-year-old man without a history of tuberous sclerosis complex (TSC) was referred to our department with a 40 × 84 mm left renal tumor incidentally detected by computed tomography. Computed tomography demonstrated a left renal heterogeneous mass which was enhanced at the early phase and washed out at the late phase. A tumor thrombus was seen extending into the main renal vein. No metastatic disease was evident. Thus, on the diagnosis of renal cell carcinoma, the patient underwent a left radical nephrectomy. Pathological examination showed that this tumor was composed predominantly of epithelioid cells, with a few blood vessels and adipose tissue and was diagnosed as epithelioid angiomyolipoma. He shows no disease progression for 6 months after the operation.

We report a case of paraneoplastic liver dysfunction associated with a renal cell carcinoma, which disappeared after surgery. A 62-year-old male presented with fatigue and weight loss. The most prominent laboratory abnormality was elevated alkaline phosphatase, C-reactive protein, and interleukin-6 while normal aminotransferases. Computed tomography scan revealed a solid mass in the left kidney. A left radical nephrectomy was performed. After the surgery, biochemical abnormalities returned to normal.

Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT

Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC.

Jay D. Raman*, Carla Caruso, Zhaohai Yang, David DeGraff, Hershey, PA; Shahrokh Shariat, Vienna, Austria; Jose Karam, Christopher Wood, Houston, TX; Alon Weizer, Ann Arbor, MI; Mesut Remzi, Andrea Haitel, Vienna, Austria; Karim Bensalah, Nathalie Rioux-Leclerq, Rennes, France; Christian Bolenz, Mannheim, Germany; Marco Roscigno, Bergamo, Italy; Laura-Maria Krabbe, Payal Kapur, Yair Lotan, Vitaly Margulis, Dallas, TX

Vertebral hemangiomas are common; however, aggressive vertebral hemangiomas with extraosseous extensions causing neurological deficits are rare. The treatment for this subtype of hemangioma remains controversial, since there are few reports on long-term clinical outcomes or tumor recurrence rates. We describe a case of aggressive vertebral hemangioma treated by total en bloc spondylectomy, with a literature review focusing on long-term recurrence. A 52-year-old male with a two-month history of numbness in the bilateral lower extremities was referred to our hospital. Imaging studies showed a tumor originating in the T9 vertebra and extending to the T8 and T10 vertebrae, with extraosseous extension causing spinal-cord compression. Ten months after onset, the patient presented with progressive paraparesis and hypalgesia. Total en bloc spondylectomy was performed, and pathology was consistent with cavernous hemangioma. Motor and sensory deficits improved significantly, and no signs of recurrence are seen at 2.5 years after operation. A review of literature revealed a recurrence rate of 12.7% (10/79 cases). The available evidence indicates satisfactory long-term outcomes for total tumor resection without adjuvant radiotherapy.

It is thought that the export of angiogenic fibroblast growth factors (FGF) from tumors may be involved in the onset of tumor angiogenesis. To create a new active targeting drug that inhibits the tumor angiogenic process without toxicities to normal cells, human basic FGF (h-bFGF) was inserted genetically into the Gly89 position of cross-linked RNase1 (the ribonuclease inhibitor protein [RI] binding site of cross-linked human pancreatic RNase) to prevent stereospecific binding to RI. The resultant insertional-fusion protein (CL-RFN89) was active both as h-bFGF and as RNase1. Furthermore, it acquired an additional ability of evading RI through steric blockade of RI binding caused by the fused h-bFGF domain. In the present study, the effect of the resultant protein, CL-RFN89, on the antitumor response though its antiangiogenic properties was investigated in an in vivo model. Continuous systemic treatment with CL-RFN89 significantly inhibited the growth of human A431 squamous cell carcinomas in vivo. Seven days of treatment with CL-RFN89 resulted in a 58.2% inhibition of tumor growth compared with control mice (P

血液透析歴3年の85歳, 女性. 透析中に吐血, 上部消化管内視鏡検査で出血性胃潰瘍を認め入院となった. 症状は一時改善したが, その後腹部膨満が出現, 腹部CTを施行したところイレウス所見を認めた. 以後, 水様性の下痢便が出現し, 持続した. 4週間後に再度施行した腹部CTで大腸の拡張, 直腸壁の肥厚を認めたため, 下部消化管内視鏡検査を施行, 肉眼的所見より潰瘍性大腸炎と診断された. 治療としてプレドニゾロン40mg/日を点滴静注したが症状の改善はなく, 全身状態は悪化し, 永眠した. 剖検による病理診断では結腸をはじめとする全身性AAアミロイドーシスであったが, 先行する慢性炎症性疾患は認めなかった. 抗生剤に反応しない, 持続する下痢症ではアミロイドーシスを疑うことの重要性が示唆され, また, 透析患者の原因が同定できなかったAAアミロイドーシスの合併例はまれと考えられた.

Purpose The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count. Patients and method A total of 277 patients are included for the analysis. All patients underwent targeted therapies and associated outcome are assessed using multivariate analysis. Results Pretreatment NLR levels are elevated in 30.3% and 23.1% of patients in the first-line and subsequent second-line setting, respectively. Kaplan-Meier curves reveal that elevated pretreatment NLR is significantly associated with poor overall survival (OS) since first-line (P Conclusion Changes in NLR levels could be predictive for prognosis in patients with mRCC treated with first-line and second-line targeted therapy. The addition of NLR significantly improves the predictive accuracy of the IMDC risk model in the first-line and subsequent second-line setting.

To investigate the appropriate cut-off level of PSA or other clinical parameters at aged ≤ 50 years. The rate of detection of PCa in young men will continue to rise associated with the advancement of the current and evolving practices of screening and detection. In this study, we determined whether to investigate the appropriate cut-off level of PSA or other clinical parameters at aged ≤ 50 years. The study population included 106 patients aged ≤ 50 years who had prostate biopsy at our institute. The differences of clinical variables including various PSA related parameters between the patients with significant PCa and insignificant PCa were analyzed. Receiver operating characteristics (ROC) curves and the corresponding areas under the ROC curves (AUC) were calculated. There were no significant differences between no-PCa and PCa patients regarding PSA value, prostate volume (P vol), PSA density (PSAD), transition zone volume (TZ vol), PSATZ density (PSATZD). When the patients meeting the following criteria, Gleason score was ≤ 6 with less than 2 positive biopsy cores, were classified as having insignificant prostate cancer, PSAD could become a useful predictor of significant PCa in men. The AUC was significantly greater in PSAD (0.801) than for the other parameters. The sensitivity and specificity of a PSAD threshold of 0.32 were 85.7% and 77.8%, respectively. In conclusion, PSAD can be a useful and very effective predictor in a man aged ≤ 50 and we can counsel patients with discretion regarding the likelihood of significant PCa.

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Case report and review of the literature. Myxopapillary ependymoma (MPE) is a relatively rare glioma that develops from the spinal part of the filum terminale, usually in adulthood. While it is generally benign, MPE can disseminate intraspinally, and this malignant behavior requires a multidisciplinary response with surgery and radiotherapy. We report here a case of MPE occurring in the lumbosacral spine area of an 8-year-old boy. Japan, Tokyo. We report here a case of MPE, treated with subtotal surgical resection followed by craniospinal irradiation (CSI), in an 8-year-old boy. The patient was referred to our hospital with a 6-month history of severe pain in the lower back and legs, paralysis of the legs and dysuria. Magnetic resonance imaging images showed a large tumor that filled the entire spinal canal below L1. After subtotal resection of the tumor, the pathological findings established a diagnosis of MPE. Since the tumor had perforated its capsule, increasing the risk of intraspinal dissemination, the patient underwent radiotherapy and CSI after surgery. Magnetic resonance images obtained 3 years after the surgery did not show any recurrence of MPE. Although tumor resection followed by CSI can be considered an effective strategy for treating a child with MPE, long-term follow-up is necessary to ensure early detection of any local recurrence or dissemination of the tumor, or of post-radiotherapy scoliosis.

A 53-year-old man was referred for further examination of left hydronephrosis. He had undergone high anterior resection for sigmoid colon cancer about 2 years previously. Retrograde pyelography demonstrated a filling defect in the middle portion of the left ureter. Brushing cytology of the lesion was class IV. Left nephroureterectomy was performed. Histology indicated metastatic adenocarcinoma from colon cancer.

association between gain of 8q and age (p1⁄40.23), sex (p1⁄40.42), and CCI (p1⁄40.59) was seen. Gain of chromosome 8q was associated with a 6.56 (95% CI, 3.06-14.05, p

INTRODUCTION AND OBJECTIVES: There are few molecular markers which are known to predict a poor prognosis in upper tract urothelial carcinomas (UTUC). Axl, which is in the TAM family of receptor tyrosine kinases, has been shown to be associated with tumor progression and cancer metastasis in some types of cancer, although the association with UTUC is still not clear. We therefore investigated the biological significance of Axl on UTUC outcome. METHODS: The protein expression of Axl by immunohistochemistry and its correlation with clinicopathologic features were investigated in surgical specimens obtained from 167 patients who had been surgically treated for UTUC at our institution. The mean follow-up period was 81.8 (1-291) months. The immunoreactivity for Axl was assessed independently by a single uropathologist. RESULTS: Axl labeling was strong in 85 of 167 (55%) cases and was weak in 82 of 167 (45%) cases. Overall strong positivity of Axl expression was statistically significantly associated with high grade tumors (p1⁄40.004), positive lymphovascular invasion (LVI) (p1⁄40.001), and occurrence of postoperative metastasis (p

INTRODUCTION AND OBJECTIVES: Many transcriptional programs governing somatic cell reprogramming and cancer progression have similarities. Cancer cells show heterogeneity in terms of drug resistance and cancer stemness is predicted to show enhanced drug resistance. We aimed to apply the knowledge of the similarity of transcriptional program between cancer progression and somatic cell reprogramming to identify a new clinically available drug to overcome the docetaxel-resistant prostate cancer (PCa), focusing on gene network of cancer stemness. METHODS: We retrospectively analyzed the clinical records and evaluated the OCT4 expression by immunohistochemistry in 164 patients with PCa who underwent radical prostatectomy. We enriched DU145 and LNCaP cells by using a vector system with endogenous OCT4 promoter activity, used in human induced pluripotent stem cells purification. The vector contains GFP and the puromycin resistance gene driven by the OCT4 enhancer. To find a new drug, we focused transciptome signature through Connectivity Map. We screened the drugs which converted the signature genes expression. RESULTS: Strong nuclear OCT4 staining in high stage tumors was observed. OCT4 expression was significantly associated with higher pathological T stage (p

Of 86 patients with spinal meningioma who were treated by surgical resection at our hospital between 1983 and 2008, four patients were found to have a tumor that invaded the vertebral body from outside, or from both sides, of the dura mater. These four patients, all males, were enrolled in this study. The patients were 37–65 years of age (mean 54.5) at the time of the first surgery. The surgeries were performed via a posterior approach. After tumor resection (including the affected dura mater) and duraplasty, the invading tumor was removed from the vertebral body and bone was grafted in. The mean postoperative follow-up period was 10.3 years. We analyzed initial symptoms, duration of illness (the interval from the initial symptom to surgery), the spinal level affected, tumor location, histopathological features (histologic type and MIB-1 staining index), whether the tumor could be removed entirely, whether the tumor recurred, and outcome for each of the subjects.

Heparan sulfate proteoglycans play important biological roles in cell‐cell and cell‐matrix adhesion, and are closely associated with growth factor actions. Loss of syndecan‐1, a cell surface‐bound heparan sulfate proteoglycan, has been reported for advanced head and neck carcinomas, and expression of endoglycosidic heparanase, which cleaves heparan sulfate glycosaminoglycans (HS‐GAGs), is associated with invasion and metastatic potential of malignant tumors. Paraffin sections of 103 primary esophageal squamous cell carcinomas were immunohistochemically examined for the expression of syndecan‐1 core protein, HS‐GAGs and heparanase protein, and the results were compared with various clinicopathological parameters, such as invasion depth. For 16 cases, fresh tumor samples were quantitatively analyzed for heparanase and syndecan‐1 mRNA expression by real‐time RT‐PCR in addition to the immunohistochemical studies. Syndecan‐1 core protein and HS‐GAGs expression was significantly decreased in pT2 and pT3 cases compared with their pTis and pTl counterparts. Decreased expression of core protein and HS‐GAGs was correlated with the incidence of lymphatic invasion, and venous involvement. Furthermore, decreased expression of HS‐GAGs was correlated positively with the incidence of nodal metastasis and distant organ metastasis, and negatively with the grade of tumor cell differentiation. The percentage of cytoplas‐mic heparanase protein‐positive cases increased significantly in pT2 and pT3 cases compared to that in pTis and pTl cases, and this was associated with lymphatic invasion, and venous and lymph nodal involvement. The level of heparanase mRNA was inversely correlated with the degree of HS‐GAGs expression rather than core protein. In conclusion, loss of syndecan‐1 and heparanase overexpression in esophageal squamous cell carcinomas are closely associated with malignant potential. Regarding the mechanism of loss of HS‐GAGs, heparanase upregulation appears to play an important role.

Tumor necrosis factor-α (TNF-α) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-α and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-α and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-α in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-α and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-α and CD44 expression, and co-upregulation of TNF-α and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-α enhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-α also up-regulated the expression of TNF-α itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-α plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment.

Abstract Recent reports demonstrated the expression of inducible-type NO synthase in the heart of viral myocarditis. Since NO has multiple biological actions, a substantial amount of NO produced in the diseased heart may act either as a cytotoxic or as a cytoprotective molecule in the process of myocarditis. In the present study, we examined the effect of inhibition of NO synthesis on the mortality and the extent of myocardial injury in a murine model of coxsackievirus B3–induced myocarditis. We fed the infected mice drinking water containing a relatively low concentration (0.37 mmol/L) of N ω -nitro- l -arginine methyl ester (L-NAME) for 14 days after virus inoculation. This dose of L-NAME did not change virus titers in the heart. However, L-NAME–fed mice showed a significant reduction in mortality compared with those fed normal drinking water (nontreated mice). On the contrary, mice given a higher concentration of L-NAME (3.7 mmol/L) exhibited increased mortality. In addition, mice fed a low concentration of L-NAME showed reductions in the severity of heart failure and in the area of myocardial necrosis. Although systemic blood pressure was reduced in nontreated mice, in mice fed a low concentration of L-NAME, it was maintained at a level similar to that in uninfected control mice. L-NAME–treated mice also exhibited a reduction in the degree of inflammatory cell infiltration associated with decreased production of tissue prostaglandin E 2 levels in the heart compared with nontreated mice. Therefore, NO is likely to be involved in the pathogenic mechanisms of myocardial injury and resultant cardiac dysfunction in a murine model of coxsackievirus B3–induced viral myocarditis.

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796CT (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.

Renal cell carcinoma (RCC) represents over 80 % of kidney cancer, and about 30 % of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs.

To evaluate the suitability of preoperative multiparametric magnetic resonance imaging (MRI) positivity as a predictor of biochemical recurrence after radical prostatectomy (RP).We reviewed the clinical records of patients who underwent either standard RP or laparoscopic RP between January 2005 and December 2009 at our institution. Patients who received radiotherapy or androgen deprivation therapy before surgery were excluded. A total of 314 patients met the study inclusion criteria. Cox proportional hazard regression models were used for analyses. In accordance with the criteria in the established guidelines, a radiologist scored the probability of the presence of prostate cancer using a five-point scale of diagnostic confidence level. The highest confidence level of any pulse sequence was considered as the evaluation result.MRI positivity was significantly associated with a high clinical stage (cT ≥ 2; P = 0.039), a high positive biopsy core rate (≥0.2; P0.001), a high biopsy Gleason score ([GS] ≥8; P0.001) and a high pathological GS (≥8; P = 0.005). Univariate analysis and multivariate analysis showed that MRI positivity was a prognostic indicator in the analysis that included only preoperative variables and also in the analysis including preoperative and pathological variables.Multiparametric MRI positivity can independently predict biochemical recurrence after RP.

elevated pre-CRP level and not receiving adjuvant chemotherapy, post-CRP normalization was observed in 62 (64.6%) after RNU. The 5-year cancer-specific survival rates were 73.4% in patients in the normalized post-CRP group and 47.7% in their counterparts (p 0.011). Multivariate analysis demonstrated that post-CRP normalization was an independent predictor for cancer-specific mortality (HR 2.20), in addition to pT stage. CONCLUSIONS: Serum CRP could provide useful information on cancer-specific mortality in UTUC patients treated with RNU. In the elevated pre-CRP group, post-CRP normalization was an independent predictor for better outcome. We propose that serum CRP may become a useful biomarker in UTUC patients, due to its low cost and easy accessibility.

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial–mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients., Acquisition of mesenchymal properties by cancer cells is a critical event for the development of malignancy. Here, the authors show that in renal cancer cells, lysosphosphatidic acid does not utilize the RhoA pathway but specifically activates the Arf6 mesenchymal pathway via its GPCRs and EFA6 to promote invasion, metastasis and drug resistance.

597 Background: With its excellent resolution of adipose tissue, CT presents precise quantitative assessment of visceral obesity. We assessed the impact of visceral obesity on progression free and overall survival in patients treated with systemic therapy for metastatic renal cell carcinoma. Methods: This retrospective cohort study included 114 patients treated with systemic therapy for metastatic renal cell carcinoma between 2007 and 2015 at Keio university hospital in Japan. The visceral fat area was measured at the level of umbilicus using CT. A visceral fat area ≥100cm2 was used as the definition of visceral obesity. Progression free and overall survival was compared according to visceral obesity. Results: In the whole cohort, the median progression free survival in first line treatment was 12.0 month. The median overall survival was 42.5 month. According to Memorial Sloan-Kettering Cancer Center classification, 31 patients were favorable risk, 61 were intermediate risk, and 22 were poor risk; median overall survival for these groups were 76.9, 40.8, and 23.7 months, respectively (P

402 Background: Programmed cell death protein (PD-1) expressed on active T cells, and its ligand PD-L1 expressed on the surface of cancer cells, complementarily down-regulate T cell activation and are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the role of PD-1 expression on clinical outcome has not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 100 patients who had been surgically treated for UTUC. At a magnification of 200x, PD-1 protein expression was estimated and the positive cells were graded as no (negative), moderate (1-10 cells), and strong ( > 10 cells). Results: Twenty-four patients (24.0%) had strong PD-1 staining, 32 patients (32.0%) had moderate PD-1 staining, and 44 patients (44.0%) had no PD-1 staining. PD-1 staining was associated with pathological T stage (p = 0.023), tumor grade (p = 0.005), and lymphovascular invasion (p = 0.033). Lymphovascular invasion (p < 0.001) and PD-1 staining (p = 0.02) were independent factors for predicting disease metastasis. The 5-year matastatic free survival rate in patients with strong PD-1 staining was 57.3 %, which was significantly lower than that with no PD-1 staining (87.3%, p=0.001) and that with moderate PD-1 staining (74.3%, p = 0.05). In a sub-group analysis of patients with ≥pT2 (N = 59), a significant difference in disease metastasis was observed between patients with strong PD-1 staining and no PD-1 staining (p = 0.018), but was not observed between strong and moderate PD-1 staining (p = 0.146). Conclusions: PD-1 expression may be a useful indicator for a worse prognosis in UTUC patients who undergo radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC.

388 Background: The variant isoforms of CD44 (CD44v), which are some of the new cell surface markers for cancer stem cells, have been associated with tumor growth, treatment resistance, and cancer death in several cancers. We investigated the role of CD44v8-10, which is a CD44v, on the clinical outcome of patients with advanced upper tract urothelial cancer (UTUC). Methods: The protein expression of CD44v8-10 was immunohistochemically evaluated using CD44v9 antibody, which detects immunogen of CD44v8-10, and investigated the association with clinical characteristics and outcome in surgical specimens obtained from 110 patients who had been treated with radical nephroureterectomy for ≥pT2 UTUC. The mean percentage of positive cancer cells stained with CD44v9 antibody in each tumor was estimated. Results: The median percentage of CD44v9 positivity was 5.50±7.74%. Patients were subsequently stratified into a CD44v9-positive group (n = 82) and a CD44v9-negative group (n = 28) based on a cut-off level of 5%. During the mean follow-up of 4.8 years, disease recurrence was observed in 49 patients (59.8%) in the CD44v9-positive group and in 8 patients (28.6%) in the CD44v9-negative group. The 5-year recurrence-free survival rates were 47.6% in the CD44v9-positive group and 66.6% in the CD44v9-negative group (p= 0.038). Multivariate analysis showed that tumor grade G3 (p= 0.005, HR = 3.77), the presence of lymphovascular invasion (p= 0.041, HR = 1.84), and CD44v8-10 expression (p= 0.028, HR = 2.33) were independent risk factors for disease recurrence. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. The 5-year cancer-specific survival rates were 57.8% in the CD44v9-positive group and 80.4% in the CD44v9-negative group (p= 0.032). The CD44v9 expression (p= 0.040, HR = 2.67) in addition to tumor grade G3 (p= 0.003, HR = 8.35) were independently associated with cancer death. Conclusions: The expression ofCD44v8-10 may be a new biomarker of malignant potential in locally advanced UTUC and could provide additional prognostic information in patients with UTUC.

Background: The membranous structure of vestibular schwannoma is an important factor in its surgical treatment. Herein, we report intraoperative and microscopic findings relating to an outermost dura-like membrane in cases of vestibular schwannoma and the importance of these findings. Methods: Intraoperative findings of 16 cases of vestibular schwannoma treated with an initial surgery were studied with an aim to determine if the cases had a dura-like membrane. Then we studied microscopic findings of the dura-like membrane using hematoxylin and eosin, Masson trichrome, and immunohistochemical staining in 2 cases. Results: The dura-like membrane was observed in 8 out of 16 cases. The average tumor size of the cases that had a dura-like membrane was 30 ± 8.1 mm, and Koos grading 4 was in 7 out of 8 cases, and one was grade 3. In cases without a dura-like membrane, these values were significantly smaller, with an average tumor size of 12.8 ± 5.2 mm, and Koos grading 4 was only in 1 of 8 cases, grade 3 was in 2 cases, and other 5 cases were grade 2. The outermost dura-like membrane enveloped the vestibular schwannoma around the internal acoustic meatus and was continuous with the dura mater. Reactive angiogenesis was observed in the dura mater. Microscopic findings proved its continuity with the dura mater. In one case, the facial nerve was damaged before it was identified during subcapsular dissection. In that case, the dura-like membrane negatively affected our ability to identify the facial nerve. Conclusions: A dura-like membrane sometimes envelops vestibular schwannoma around the internal acoustic meatus. Recognition of this membranous structure is important for the surgical preservation of facial and acoustic nerves.

To evaluate the MRI findings of renal cell carcinoma (RCC), including findings on diffusion-weighted images (DWIs) and chemical shift images (CSIs), in patients with acquired cystic disease of the kidney (ACDK) in relation to the histopathologic findings.Two radiologists retrospectively reviewed the MRI findings of 10 RCCs in seven consecutive patients with ACDK. They evaluated the signal intensities (SIs) and signal homogeneity of the lesions on T2-weighted images, DWIs, and T1-weighted images. Thereafter, they evaluated the cytoplasmic fat in the lesions by CSIs. After image analyses, the MRI findings were correlated with the histopathologic findings.The RCCs tended to show heterogeneous high SIs on T2-weighted images and DWIs. The high SIs on DWIs were mainly attributable to the viable parts, and the heterogeneity was due to the various SIs arising from the intratumoral degenerative components. Unlike the reported findings for hemorrhagic cysts, the RCCs did not show homogeneous high SIs or fluid-iron levels on T1-weighted images. The four lesions, in which the presence of cytoplasmic fat was suggested on CSIs, were clear cell RCCs.The MRI findings, including findings on DWIs and CSIs, well reflected the histopathologic findings of RCC in patients with ACDK.

To review the imaging findings of renal epithelioid angiomyolipomas.Eight patients treated at two institutions were pathologically diagnosed as having epithelioid angiomyolipoma. All of them underwent computed tomography, and four underwent magnetic resonance imaging. The tumor size, existence of fat, heterogeneity, computed tomography attenuation, degree of enhancement, enhancement pattern and magnetic resonance imaging signal intensity were evaluated.Intratumoral fat was not detected in any of the cases. On unenhanced computed tomography, the intratumoral attenuation was hyperattenuating in six of the seven patients who were examined using this modality. On T2-weighted images, the signal intensity of the solid component, cyst wall or septum was low in three of the four cases. Four of the eight cases were heterogeneous solid-type accompanied by hemorrhage, necrosis or hyalinization. One homogeneous solid-type lesion was large in size and was pathologically accompanied by neither hemorrhage nor necrosis. All three multilocular cystic types were pathologically accompanied by massive hemorrhage in the cystic component. One was accompanied by spontaneous perirenal hematoma.The radiological appearance of most epithelioid angiomyolipomas has a tendency to be hyperattenuating on unenhanced computed tomography images, with low intensities on T2-weighted images. They can be heterogeneously solid, homogeneously solid or a multilocular cystic lesion with massive hemorrhage.

Background The clinical course of pT3 upper tract urothelial carcinoma (UTUC) is highly variable. Objectives The aim of the current study was to validate the clinical and prognostic importance of pT3 subclassification in the renal pelvicalyceal system in a large international cohort of patients. Design, setting, and participants From a multi-institutional international database, 858 renal pelvicalyceal tumors treated with radical nephroureterectomy (RNU) were systematically reevaluated by genitourinary pathologists. Category pT3 pelvic tumors were categorized as pT3a (infiltration of the renal parenchyma on a microscopic level only) versus pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue). Intervention RNU. Measurements Associations of pT3 subclassifications with clinicopathologic features were assessed with the chi-square test. Prognostic impact was assessed with the log-rank test and multivariable Cox regression analyses. Results and limitations Of 858 patients with renal pelvicalyceal tumors, 266 (31%) had pT3 disease. Of these, 146 (54.9%) were classified as pT3a and 120 (45.1%) as pT3b. Compared with pT3a, pT3b cancers were associated with higher tumor grade, nodal disease, and tumor necrosis. Ten-year recurrence-free (pT3a 58% vs pT3b 38%; p 0.001) and cancer-specific (pT3a 60% vs pT3b 39%; p = 0.002) survival rates were lower for patients with pT3b disease. In multivariable analyses, classification pT3b was an independent predictor of both disease recurrence (hazard ratio [HR]: 1.8, p = 0.003) and cancer-specific mortality (HR: 1.7; p = 0.02). The major limitation is the retrospective character of the study. Conclusions Subclassification of pT3 renal pelvicalyceal UTUC helps identify patients who are at increased risk of disease progression and cancer-related death. Further research may help assess the value of subclassification and its inclusion in future editions of the American Joint Committee on Cancer–International Union Against Cancer TNM classification system.

Objective: A reliable prognostic indicator in patients with pathologic T1a renal cell carcinoma has not yet been fully elucidated. The aim of this study was to investigate the prognosis of pathologic T1a renal cell carcinoma cases with a special focus on pathological factors. Methods: The study population consisted of 338 patients diagnosed with solitary renal cell carcinoma at our hospital between 1996 and 2009. The relationship between disease progression and clinicopathologic features was analyzed retrospectively to determine if it affected recurrence and distant metastasis. Results: The Fuhrman nuclear grade distribution between the tumors was 1, 2, 3 and 4 in 68 (20.1%), 242 (71.6%), 21 (6.2%) and 7 cases (2.1%), respectively. A total of 11 subjects were identified as having recurrent tumors (3.3%), 9 of whom had metastatic lesions. Multivariate analysis showed that the appearance of tumor Grade 3 and 4 (hazard ratio: 13.0, 95% confidence interval: 3.90‐43.0, P , 0.001) was an independent risk factor for tumor recurrence, while no significant correlation was found between tumor recurrence and age, gender, tumor side, tumor size, surgical methods, histology, microvascular invasion or surgical margin status. The 5-year recurrence-free survival rate was 67.8% in patients with a high nuclear grade tumor, and 96.8% in their counterparts. Conclusions: High nuclear grade is possibly one of the most important prognostic factors for predicting tumor recurrence and metastasis after surgery in pathologic T1a renal cell carcinoma. Thus, careful follow-up may be required in patients with pathologic T1a renal cell carcinoma of a high nuclear grade.

Multilocular cystic renal cell carcinoma (MCRCC) accounts for approximately 1 to 2% of all renal tumors. This tumor is currently classified as a subtype of clear cell RCC. Clinically, the majority of these tumors are incidentally found. Macroscopically, the tumor is well demarcated and consists of various-sized cysts. The fibrous septa are generally thin and there is no discernible expansile nodule. Microscopically, the cyst walls are lined with tumor cells with clear to occasionally slightly eosinophilic cytoplasm. The Fuhrman nuclear grade is generally low and usually corresponds to grade 1. The deletion of chromosome 3p was identified in most tumors using FISH analysis and VHL gene mutation was identified in 25% of MCRCC. As MCRCC generally exhibits a low stage of TNM classification, the great majority of these tumors have a favorable clinical course. To date, there are no reports of metastasis, vascular invasion or sarcomatoid change in MCRCC. Accordingly, nephron sparing surgery is first recommended as a therapeutic strategy.

Oligoastrocytoma preferentially arises in the cerebral hemisphere, and a cerebellar location is unusual. We report the case of a 35-year-old woman with an aggressive cerebellar tumor histopathologically diagnosed as oligoastrocytoma World Health Organization (WHO) grade II. After partial removal of the tumor, she underwent concomitant temozolomide (TMZ) therapy with local irradiation followed by additional TMZ monotherapy. However, her symptoms gradually worsened, and chronological magnetic resonance imaging showed remarkable tumor enlargement. In accordance with the aggressive clinical course, unfavorable genetic characteristics such as the gain of the entire chromosome 7, loss of 9p, absence of 1p/19q codeletion, absence of methylation of the O6-methylguanine-deoxyribonucleic acid methyltransferase promoter, and absence of the isocitrate dehydrogenase-1 mutation were observed. The present case illustrates that these molecular characteristics represent the biological features of gliomas more closely than the histopathological diagnosis and may also suggest that infratentorial gliomas arise through a distinct tumorigenic pathway from their supratentorial counterparts.