Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma.

Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy to block programmed death-1 and cytotoxic T-lymphocyte antigen 4, but the response rate for ICIs is still low and tumor cell heterogeneity is considered to be responsible for resistance to immunotherapy. Tumor-infiltrating lymphocytes (TILs) have an essential role in the anti-tumor effect of cancer immunotherapy; however, the specificity of TILs in renal cell carcinoma (RCC) is elusive. In this study, we analyzed a 58-year-old case with clear cell RCC (ccRCC) with the tumor showing macroscopic and microscopic heterogeneity. The tumor was composed of low-grade and high-grade ccRCC. A tumor cell line (1226 RCC cells) and TILs were isolated from the high-grade ccRCC lesion, and a TIL clone recognized a novel neoantigen peptide (YVVPGSPCL) encoded by a missense mutation of the tensin 1 (TNS1) gene in a human leukocyte antigen-C*03:03-restricted fashion. The TNS1 gene mutation was not detected in the low-grade ccRCC lesion and the TIL clone did not recognized low-grade ccRCC cells. The missense mutation of TNS1 encoding the S1309Y mutation was found to be related to cell migration by gene over-expression. These findings suggest that macroscopically and microscopically heterogenous tumors might show heterogenous gene mutations and reactivity to TILs.

Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies.

Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb. SIGNIFICANCE: FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.

Neuregulin-1-ß1 and γ-secretase play a critical role in sphere-formation and cell survival of urothelial carcinoma cancer stem-like cells.

Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1high) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1high cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-ß1 were preferentially expressed in ALDH1high cells compared with ALDH1low cells; however, siRNA experiments revealed that NRG1-ß1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-ß1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-ß1 remain elusive.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in urological malignancies: a multi-center retrospective study.

INTRODUCTION: We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients. MATERIALS AND METHODS: We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists. RESULTS: Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m2 were significant predictors for ARONJ. CONCLUSION: ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.

Ureteral calculi secondary to a gradually migrated acupuncture needle.

We herein presented a case of calculi secondary to a migrated acupuncture needle. A 74-year-old woman with a history of acupuncture therapy for lumbago was referred to our hospital for treatment of ureteral and renal pelvic calculi. Abdominal multi-detector computed tomography scans showed ipsilateral hydronephrosis and two calculi secondary to a migrated acupuncture needle. First, a percutaneous nephrolithotomy was performed to extract two calculi and fine needle fragments from the pelvis. Subsequently, residual needle fragments and calculi in the ureter were then removed by flexible transurethral lithotripsy using a holmium laser. In the present case, the formation of the calculi was caused by a migrated acupuncture needle. Calculi and needle fragments were removed safely endoscopically because the whole calculi and needle fragments were located in the ureteral lumen.

Does cognitive behavioral therapy using a self-check sheet improve night-time frequency in patients with nocturia? Results of a multicenter randomized controlled trial.

OBJECTIVE: To determine whether cognitive behavioral therapy using a self-check sheet is effective in improving night-time frequency of patients with nocturia. METHODS: We carried out a multicenter, open-labeled, randomized controlled trial in eight institutions. Patients having two or more episodes of nocturia were randomly assigned to either cognitive behavioral therapy with completion of frequency volume charts regularly (cognitive behavioral therapy group) or frequency volume charts regularly alone (frequency volume charts group). The cognitive behavioral therapy checklist was composed of eight items: wake up time/bedtime, mealtime, napping, alcohol/caffeine intake, water intake, salt intake, exercise and taking a bath. A physician explained cognitive behavioral therapy within 5 min using a brief manual. The patients in the cognitive behavioral therapy group filled out the self-check sheet every day. The primary end-point was the difference in night-time frequency based on the International Prostate Symptom Score Q7 at 4 weeks. RESULTS: Of the 100 first-visit patients randomly allocated, 37 in the cognitive behavioral therapy group and 41 in the frequency volume charts group completed the protocol. No difference was observed in the mean ± standard deviation of night-time frequency at 4 weeks between the cognitive behavioral therapy group (2.6 ± 1.0) and the frequency volume charts group (3.1 ± 1.2; P = 0.056). However, when six patients with achievement of cognitive behavioral therapy of <50% were excluded from the analysis, night-time frequency at 4 weeks was significantly lower in the cognitive behavioral therapy group (2.5 ± 1.0) than in the frequency volume charts group (3.1 ± 1.2; P = 0.027). CONCLUSIONS: The efficacy of cognitive behavioral therapy using a self-check sheet for nocturia remains to be shown. However, strictly practicing cognitive behavioral therapy might be beneficial to these patients.

E7386, a Selective Inhibitor of the Interaction between ß-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

Non-bacterial cystitis with increased expression of programmed death-ligand 1 in the urothelium: An unusual immune-related adverse event during treatment with pembrolizumab for lung adenocarcinoma.

INTRODUCTION: Immune checkpoint inhibitors are now a standard therapeutic option for lung adenocarcinoma. However, Immune checkpoint inhibitors often induce various immune-related adverse events. CASE PRESENTATION: The patient was a 78-year-old woman with lung adenocarcinoma who had a partial response to pembrolizumab. During treatment, she complained of pollakiuria and nocturia with painful micturition. Histological analysis revealed infiltration of CD8-positive and/or TIA-1 cytotoxic granule-associated RNA binding protein-positive lymphocytes and programmed death-ligand 1 expression in the urothelium. A diagnosis of immune-related adverse event cystitis was made based on these clinical and pathological findings. The patient's subjective symptoms and findings on cystoscopy improved dramatically after treatment with prednisolone. CONCLUSION: Immune checkpoint inhibitors-induced cystitis is extremely rare. This report is the first to include an immunohistochemical analysis of the urothelial epithelium in immune-related adverse event cystitis and describes an instructive case.

The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: a multi-institutional retrospective study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. METHODS: The data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5-33.2). RESULTS: The median duration of nivolumab therapy was 7.1 months (IQR 2.9-24.4). The objective response rate was 25% and the 1- and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.1) and 3.3 (IQR 2.4-5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020). CONCLUSIONS: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

Incidence and risk factors of postoperative delirium in elderly patients undergoing urological surgery: A multi-institutional prospective study.

OBJECTIVES: To investigate the incidence and risk factors of postoperative delirium among patients aged ≥65 years undergoing elective urological surgery. METHODS: From April 2015 through December 2016, 1023 consecutive patients aged ≥65 years who received transurethral, laparoscopic (with or without robot assistance) or open surgery in eight institutions were enrolled in this prospective observational study. Their preoperative cognitive status was assessed with the Hasegawa Dementia Scale-Revised score. The treating physician or nurse assessed delirium using the Intensive Care Delirium Screening Checklist. Multivariate logistic regression analysis was used to determine predictive factors for postoperative delirium. RESULTS: We analyzed 946 patients whose median age was 74 years (range 65-95 years). Postoperative delirium was observed in 32 patients (3.4%). Multivariate analysis showed that a history of cerebrovascular disease (odds ratio 5.24, 95% confidence interval 2.05-13.40), low Hasegawa Dementia Scale-Revised score <20 points (odds ratio 3.50, 95% confidence interval 1.36-9.02), low serum albumin level <3.5 g/dL (odds ratio 3.12, 95% confidence interval 1.25-7.83) and long surgery duration >4 h (odds ratio 4.94, 95% confidence interval 2.20-11.10) were independent risk factors for the development of postoperative delirium. CONCLUSIONS: The preoperative medical history, cognitive status, low serum albumin level and operative duration were associated with the development of postoperative delirium, although the incidence was just 3.4% in elective urological surgery. The present results suggest that the Hasegawa Dementia Scale-Revised is a useful tool for assessment of the risk for delirium.

[PD-L1-Mediated Immune Escape Mechanism of Cancer Stem-Like Cells].

Immune checkpoint inhibitors(ICIs)have provided great success in cancer treatment field, and immunotherapies using ICIs have become standard therapy for several cancers. Cancer stem-like cells(CSCs)are defined by their higher tumorigenicity and resistance to chemotherapy and radiotherapy, thus they are supposed to be responsible for recurrence and distant metastasis. Therefore, control of CSCs is a key factor to improve patients' prognosis. In this review article, we summarize the expression of PD-L1, a molecular target of ICIs, in CSCs, and discuss the possibility of CSC-targeting immunotherapy using ICIs.

Antitumor and Antiangiogenic Activities of Lenvatinib in Mouse Xenograft Models of Vascular Endothelial Growth Factor-Induced Hypervascular Human Hepatocellular Carcinoma.

High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.

Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8+ T cells secreting interferon (IFN)-γ+ and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8+ T cells, among CD45+ cells and increased IFN-γ+ and GzmB+ CD8+ T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.

[Necrotizing Fasciitis and Frostbite of the Male External Genitalia : A Case Repor].

We report a case diagnosed as both necrotizing fasciitis and frostbite of the male external genetalia. The patient was a 58-year-old man with diabetes mellitus. He was referred to our hospital with swelling of his penis and icing there for 3 weeks. We diagnosed his condition as necrotizing fasciitis of the external genitalia and decided to perform an emergency operation. Although we consulted plastic surgeons about debridement of a large area, they considered that there was no necessity for it because the scrotum, perineum and abdominal wall were frostbitten. The final clinical diagnosis was necrotizing fasciitis of the penile region and frostbite around the perineal region. We performed partial penectomy without debridement. Through collaboration with another medical department it was thus possible to avoid unnecessary invasive treatment.

Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models.

Unresectable hepatocellular carcinoma (uHCC) is one of the most lethal and prevalent cancers worldwide, and current systemic therapeutic options for uHCC are limited. Lenvatinib, a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs), recently demonstrated a treatment effect on overall survival by statistical confirmation of noninferiority to sorafenib in a phase 3 study of uHCC. Here, we investigated mechanisms underlying the antitumor activity of lenvatinib in preclinical HCC models. In vitro proliferation assay of nine human HCC cell lines showed that lenvatinib selectively inhibited proliferation of FGF signal-activated HCC cells including FGF19-expressing Hep3B2.1-7. Lenvatinib suppressed phosphorylation of FRS2, a substrate of FGFR1-4, in these cells in a concentration-dependent manner. Lenvatinib inhibited in vivo tumor growth in Hep3B2.1-7 and SNU-398 xenografts and decreased phosphorylation of FRS2 and Erk1/2 within the tumor tissues. Lenvatinib also exerted antitumor activity and potently reduced tumor microvessel density in PLC/PRF/5 xenograft model and two HCC patient-derived xenograft models. These results suggest that lenvatinib has antitumor activity consistently across diverse HCC models, and that targeting of tumor FGF signaling pathways and anti-angiogenic activity underlies its antitumor activity against HCC tumors.

[LONGITUDINAL CHANGES OF FREE TESTOSTERONE LEVELS AND SEXUAL FUNCTION IN JAPANESE MEN EVALUATING TWO CROSS-SECTIONAL COMMUNITY-BASED STUDIES].

(Purpose) We conducted cross-sectional studies two times, in 1992 and 2007 and investigated the longitudinal changes of fT levels and sexual function by comparing the results. (Methods) In 1992 and 2007, we conducted cross-sectional surveys about lower urinary tract symptoms and sexual function in male inhabitants aged 40 to 79 years in Shimakaki village, Hokkaido. Comparing the results of these surveys, we analyzed longitudinal changes in fT levels and sexual function. FT levels were measured by radioimmunoassay and sexual function was evaluated using a validated questionnaire. (Results) A total of 123 inhabitants participated in the both surveys. The average age at the initial survey was 57.2 years.Complications causing sexual dysfunction were observed in 43 participants (35%) and 75 participants (61%) in the first and second surveys, respectively. Average fT levels were 12.9 pg/ml and 4.4 pg/ml in the first and second surveys, respectively. Linear approximations of fT (Y) using age (X) were Y = -0.12 X+19.6 and Y = -0.10 X+11.6, for the first and second surveys, respectively. Although decreased fT levels with aging were comparable in both surveys, fT levels were lower in the second survey than in the first survey. There was no significant association between fT levels and sexual function. (Conclusions) The fT levels at the time of the second surey were lower than those in the first survey. The fT level has no significant association with sexual function.

GRIK2 has a role in the maintenance of urothelial carcinoma stem-like cells, and its expression is associated with poorer prognosis.

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are small sub-population of cancer cells that are endowed with higher tumor-initiating ability, self-renewal ability and differentiation ability. CSCs/CICs could be isolated as high aldehyde dehydrogenase 1 activity cells (ALDH1high) from various cancer samples. In this study, we isolated urothelial carcinoma CSCs/CICs as ALDHhigh cells and investigated the molecular aspects. ALDH1high cells showed greater sphere-forming ability and higher tumor-initiating ability in immune-deficient mice than those of ALDH1low cells, indicating that CSCs/CICs were enriched in ALDH1high cells. cDNA microarray analysis revealed that an ionotropic glutamate receptor glutamate receptor, ionotropic, kainate 2 (GRIK2) was expressed in ALDH1high cells at a higher level than that in ALDH1low cells. GRIK2 gene knockdown by siRNAs decreased the sphere-forming ability and invasion ability, whereas GRIK2 overexpression increased the sphere-forming ability, invasion ability and tumorigenicity, indicating that GRIK2 has a role in the maintenance of CSCs/CICs. Immunohistochemical staining revealed that higher levels of GRIK2 and ALDH1 expression were related to poorer prognosis in urinary tract carcinoma cases. The findings indicate that GRIK2 has a role in the maintenance of urothelial CSCs/CICs and that GRIK2 and ALDH1 can be prognosis prediction markers for urinary tract carcinomas.

The discrepancy between serum creatinine and cystatin C can predict renal function after treatment for postrenal acute kidney injury: multicenter study and pooled data analysis.

BACKGROUND: Although serum cystatin C and creatinine are used as practical markers of renal function, the discrepancy between them in postrenal acute kidney injury (AKI) cases was reported. The aim of this study was to determine whether the preoperative serum cystatin C (pre-CysC) level could predict clinical outcomes after treatment in patients with postrenal AKI. METHODS: Patients who underwent urological interventions with postrenal AKI were enrolled in this prospective observational study. Associations among preoperative serum creatinine (pre-sCr), pre-CysC, and nadir postoperative serum creatinine (post-sCr) were evaluated. In addition, based on our results in combination with detailed data from the literature, a predictive equation for postoperative serum creatinine (post-sCr) was developed by simple regression analysis and validated using Bland-Altman plots. RESULTS: Finally, 19 patients were eligible for analysis in this study. The value calculated by subtracting pre-CysC (mg/L) from pre-sCr (mg/dl) had a strong correlation to the decrement of serum creatinine (r = 0.9508, p < 0.0001). We added the data of 16 patients obtained from the literature to our series, which were totally randomized into 2 groups, training set and validation set in a 2:1 ratio (n = 23 and 12, respectively) to develop and validate a predictive equation for post-sCr. The mean difference between the predictive and actual post-sCr, -0.68 mg/dl (95% CI -1.62 to 0.26) in the validation set was within the limits of agreement. CONCLUSION: We showed that the discrepancy between pre-sCr and pre-CysC could predict improvement of renal function after intervention in patients with postrenal AKI.

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus.

The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin (mTOR) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase II clinical study of metastatic renal cell carcinoma (RCC). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human RCC xenograft mouse models (A-498, Caki-1, and Caki-2). In particular, the combination led to tumor regression in the A-498 and Caki-1 models. In the A-498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti-angiogenic effects. The anti-angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki-1 xenografts, in which fibroblast growth factor (FGF)-driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor (VEGF)-activated, and synergistic activity against FGF-activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed mTOR-S6K-S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP-1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF and FGF signaling pathways by the combination underlies its superior anti-angiogenic activity in human RCC xenograft models.

Changes of sexual function and perception in Japanese men: A 15-year cross-sectional community-based study.

OBJECTIVES: To investigate the longitudinal changes of sexual function of Japanese men. METHODS: From 1992 to 1993, we carried out a cross-sectional community-based study on sexual function in Japanese men aged 40-79 years. After 15 years, a follow-up study was carried out to determine longitudinal changes of their sexual function. Of the 319 participants in the initial study, 135 participated again in the follow-up study. Sexual function was assessed using the same validated questionnaire in the two studies. RESULTS: Erectile rigidity declined in men of each age decade at baseline (40s, 50s, 60s and 70s) of the initial study (P < 0.01, <0.01, <0.01 and <0.05). The frequency of sexual drive was significantly decreased in men aged in their 40s, 50s and 60s (P < 0.05, <0.01 and <0.01). Men aged in their 40s were dissatisfied with their decreased sexual function (P < 0.05). In contrast, men aged in their 70s were satisfied with their sexual life (P < 0.01). CONCLUSIONS: Over a 15-year period, the sexual function of Japanese men declined in each age decade. However, the perception of this decline differed among different age group. Most elderly Japanese men did not worry about their impaired sexual function.