The third national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from complicated urinary tract infection patients.

The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2-64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 µg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum ß-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.

Fibroblast Growth Factor Family in the Progression of Prostate Cancer.

Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) play an important role in the maintenance of tissue homeostasis and the development and differentiation of prostate tissue through epithelial-stromal interactions. Aberrations of this signaling are linked to the development and progression of prostate cancer (PCa). The FGF family includes two subfamilies, paracrine FGFs and endocrine FGFs. Paracrine FGFs directly bind the extracellular domain of FGFRs and act as a growth factor through the activation of tyrosine kinase signaling. Endocrine FGFs have a low affinity of heparin/heparan sulfate and are easy to circulate in serum. Their biological function is exerted as both a growth factor binding FGFRs with co-receptors and as an endocrine molecule. Many studies have demonstrated the significance of these FGFs and FGFRs in the development and progression of PCa. Herein, we discuss the current knowledge regarding the role of FGFs and FGFRs-including paracrine FGFs, endocrine FGFs, and FGFRs-in the development and progression of PCa, focusing on the representative molecules in each subfamily.

A comparison of clinicopathological features and prognosis in prostate cancer between atomic bomb survivors and control patients.

An atomic bomb (A-bomb) was dropped on Hiroshima on 6th August 1945. Although numerous studies have investigated cancer incidence and mortality among A-bomb survivors, only a small number have addressed urological cancer in these survivors. The aim of the present study was to investigate the clinicopathological features of prostate cancer (PCa) in A-bomb survivors. The clinicopathological features and prognosis of PCa were retrospectively reviewed in 212 survivors and 595 control patients between November 1996 and December 2010. The histopathological and clinical outcomes of surgical treatment of PCa were also evaluated in 69 survivors and 162 control patients. Despite the higher age at diagnosis compared with the control group (P=0.0031), survivors were more likely to have been diagnosed with PCa from a health check compared with the control group (P<0.0001). As a consequence, the survivors were found to exhibit metastasis significantly less frequently (199/212, 93.9%) compared with the control patients (521/595, 87.6%; P=0.0076). Prognosis in the two groups was examined, subsequent to a mean length of follow-up of 44 months. Overall survival (OS) and PCa-specific survival (CS) were similar between the two groups (OS, P=0.2196; CS, P=0.1017). A-bomb exposure was not found to be an independent predictor for prognosis by multivariate analysis (OS, P=0.7800; CS, P=0.8688). The clinicopathological features of patients who underwent a prostatectomy were similar except for the diagnosis opportunity between the two groups. Progression-free survival rates were similar between the two groups (P=0.5630). A-bomb exposure was not a significant and independent predictor for worsening of progression-free prognosis by multivariate analysis (P=0.3763). A-bomb exposure does not appear to exert deleterious effects on the biological aggressiveness of PCa and the prognosis of patients with PCa.

Regeneration of rat corpora cavernosa tissue by transplantation of CD133+ cells derived from human bone marrow and placement of biodegradable gel sponge sheet.

The objective is to develop an easier technique for regenerating corpora cavernosa tissue through transplantation of human bone marrow-derived CD133 + cells into a rat corpora cavernosa defect model. We excised 2 mm × 2 mm squares of the right corpora cavernosa of twenty-three 8-week-old male nude rats. Alginate gel sponge sheets supplemented with 1 × 10 4 CD133 + cells were then placed over the excised area of nine rats. Functional and histological evaluations were carried out 8 weeks later. The mean intracavernous pressure/mean arterial pressure ratio for the nine rats (0.34258 ± 0.0831) was significantly higher than that for eight rats with only the excision (0.0580 ± 0.0831, P = 0.0238) and similar to that for five rats for which the penis was exposed, and there was no excision (0.37228 ± 0.1051, P = 0.8266). Immunohistochemical analysis revealed that the nine fully treated rats had venous sinus-like structures and quantitative reverse transcription polymerase chain reaction analysis of extracts from their alginate gel sponge sheets revealed that the amounts of mRNA encoding the nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) were significantly higher than those for rats treated with alginate gel sheets without cell supplementation (NGF: P = 0.0309; VEGF: P < 0.0001). These findings show that transplantation of CD133 + cells accelerates functional and histological recovery in the corpora cavernosa defect model.

The impact of change in serum C-reactive protein level on the prediction of effects of molecular targeted therapy in patients with metastatic renal cell carcinoma.

OBJECTIVES: To investigate the impact of pretreatment serum C-reactive protein (CRP) level and its change after targeted therapy on the anti-tumour effect of targeted agents in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: The serum CRP level in 190 cases of molecular targeted therapy for mRCC was measured before starting the prescription of molecular targeted agents and when computed tomography showed the maximum effect. Patients in which the pretreatment CRP level was ≥0.5 mg/dL were classified into a 'higher-CRP' group and others into a 'lower-CRP' group. The higher-CRP group was further classified into two subgroups, i.e. those whose serum CRP level decreased after molecular targeted therapy ('decreased-CRP' subgroup), and those whose level did not decrease after therapy ('non-decreased-CRP' subgroup). All patients were also classified according to their other clinical details and progression-free survival (PFS) rates of each subgroup were compared. RESULTS: Of the 190 patients, 97 were categorised as lower CRP and 93 as higher CRP, with 50 and 43 patients in the higher-CRP group further categorised as decreased- and non-decreased-CRP subgroups, respectively. For the maximum effects of the targeted therapy, determined based on the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, in the lower-CRP group, significantly more patients had a complete response (CR) and partial response (PR) (P = 0.002) and significantly fewer had progressive disease (PD) (P < 0.001) vs the higher-CRP group. In the higher-CRP group, significantly fewer patients had PD in the decreased-CRP subgroup (P < 0.001) than those in the non-decreased-CRP subgroup. The 2-year PFS rate for the lower-CRP group (39.1%) was significantly better vs the decreased-CRP subgroup (21.2%; P = 0.013) and significantly better vs the non-decreased CRP subgroup (0%; P < 0.001). Multivariate analyses in the higher-CRP group revealed that decreased CRP was an independent predictive factor for PFS (P = 0.002, hazard ratio 2.454, 95% confidence interval 1.404-4.290). CONCLUSION: A decrease of CRP and pretreatment CRP levels show promise as a novel predictive factor for anti-tumour effects in patients treated with molecular targeted therapy.

FGF19 promotes progression of prostate cancer.

BACKGROUND: Fibroblast growth factor (FGF) signaling pathways have been reported to play important roles in prostate cancer (PCa) progression. FGF19 is one of a subfamily of FGFs that circulate in serum and act in an endocrine manner. Our objective was to investigate its role in the progression of PCa. METHODS: The effect of FGF19 on the proliferation and epithelial-mesenchymal transition of LNCaP and PC3 cells was examined using MTT assay and Western blotting. Serum concentration of FGF19 was measured by ELISA in 209 patients with PCa, and the association between clinicopathological features and the presence of FGF19-positive cells in tissues derived from 155 patients who undergone radical prostatectomy was investigated. RESULTS: Under androgen-deprived conditions achieved by incubation in medium with FGF19, the expression of N-cadherin in LNCaP cells was enhanced, that of E-cadherin and caspase 3 was suppressed, and the viability of LNCaP and PC3 cells was significantly enhanced. Significantly higher levels of PSA were recorded in the group determined by immunohistochemistry staining to be FGF19-positive (P = 0.0046). The 5-year biochemical recurrence-free survival rate after radical prostatectomy was 46.4% in the FGF19-positive group and 70.0% in the FGF19-negative group (P = 0.0027). In multivariate analysis, the presence of FGF19-positive tissues was an independent factor for worse prognosis after radical prostatectomy (P = 0.0052). Serum FGF19 levels in high Gleason grade group were higher than that in low Gleason grade group (P = 0.0009). CONCLUSIONS: FGF19 might be associated with biochemical recurrence after radical prostatectomy by promoting cell proliferation and epithelial-mesenchymal transition of PCa.

Prognostic significance of C-reactive protein in patients with intermediate-risk metastatic renal cell carcinoma treated with molecular targeted therapy.

The present study aimed to investigate the impact of pre-treatment C-reactive protein (CRP) levels on the prediction of prognosis in patients with metastatic renal cell carcinoma (mRCC), who were classified as intermediate-risk patients using the Memorial Sloan Kettering Cancer Center (MSKCC) risk classification and who received molecular targeted therapy. The oncological outcome of 140 patients with mRCC who underwent molecular targeted therapy was analyzed. Patients were divided into favorable-, intermediate- and poor-risk groups (groups F, I and P, respectively) based on the MSKCC risk classification. The patients in group I were then further classified into two groups based on pre-treatment serum CRP levels. The overall survival (OS) rates of the patients in these groups were then assessed. The OS rate of the patients in group I with normal pre-treatment CRP levels was found to be significantly increased compared with that of patients with high pre-treatment CRP levels (P<0.0001), while there was no significant difference in the OS rate in the patients with normal pre-treatment CRP levels in group I compared with those in group F. Multivariate analyses revealed that high pre-treatment CRP levels were an independent prognostic factor for OS in the patients in group I (P<0.0001; hazard ratio, 3.898). Thus, pre-treatment CRP levels may be a candidate predictor for OS in patients with intermediate-risk mRCC.

Prostate cancer detection by prostate-specific antigen-based screening in the Japanese Hiroshima area shows early stage, low-grade, and low rate of cancer-specific death compared with clinical detection.

INTRODUCTION: We investigate the effectiveness of prostate-specific antigen (PSA) screening for prostate cancer. We compare the characteristics of 2 sets of patients: (1) those in whom prostate cancer was detected via PSA screening (the PS group) and (2) those in whom prostate cancer was detected at the outpatient office (the non-PS group). METHODS: Between 2002 and 2010, prostate cancer was detected in 315 patients by PSA screening. Their age, initial PSA level, pathological findings in biopsy specimens, clinical stage, and prognosis were compared with those of 497 prostate cancer patients diagnosed at the outpatient office of the Department of Urology, Hiroshima University, in the same period. RESULTS: The rates of patients with initial PSA higher than 50 ng/mL, with a Gleason score of 8 or higher, and with clinical stage D were significantly lower in the PS group than those in the non-PS group. The 5-year overall survival and cancer-specific survival in the PS group was 91.3% and 98.2%, respectively; these results were significantly better than those in the non-PS group (86.4%, p = 0.0178, and 94.9%, p = 0.0112, respectively). A Cox hazard analysis showed that PSA screening was an independent predictive factor for cancer-specific survival. CONCLUSIONS: Although our study is limited by its retrospective nature and small size, the present data indicate that prostate cancer detected in the PS group showed earlier stage, lower grade, and better prognosis than in the non-PS group.

Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells.

Fibroblast growth factor receptor 2 (FGFR2) is thought to mediate an important signaling pathway between prostate epithelial cells and stromal cells for maintenance of homeostasis in normal prostate tissue. Abnormalities of FGFR2 have been shown in advanced prostate cancer or prostate cancer cell lines, and we previously demonstrated the tumor-suppressive effects of the restoration of FGFR2IIIb in prostate cancer cells. The aim of the present study was to determine whether FGFR2IIIb plays a role in the chemosensitivity of castration-resistant prostate cancer cells. A clonal line of PC-3 cells expressing FGFR2IIIb (PC-3R2IIIb) was established by transfection with an IRESneo2-expressing vector bearing FGFR2IIIb cDNA. The effects of chemotherapeutic agents (docetaxel, cisplatin, 5-fluorouracil and zoledronic acid) on cell viability and apoptosis were examined by MTT assay and western blot analysis, respectively. Expression levels of molecules that were markers of epithelial-to-mesenchymal transition and chemosensitivity-related proteins were assessed by western blot analysis. Viability of the PC-3R2IIIb cells was significantly lower than that of the control PC-3 cells transfected with the vector alone (PC-3neo), and viability was further suppressed by treatment with chemotherapeutic agents, particularly docetaxel. Induced expression of caspase-3 was evident in the PC-3R2IIIb cells and was further enhanced by treatment with docetaxel. Expression of N-cadherin, vimentin, survivin and XIAP was lower in the PC-3R2IIIb cells than that in the PC-3neo cells. In contrast, expression of p21 was higher in the PC-3R2IIIb cells than that in the control PC-3neo cells. These data indicate that restoration of FGFR2IIIb in castration-resistant prostate cancer cells may reverse some of the epithelial-to-mesenchymal cell properties characteristic of tumor cells and induce in part mesenchymal-to-epithelial transition properties. This together with enhancement of apoptotic pathways involving caspase-3 may enhance chemosensitivity particularly to docetaxel which is widely used in the treatment of castration-resistant prostate cancer.

Accumulation of FGF9 in prostate cancer correlates with epithelial-to-mesenchymal transition and induction of VEGF-A expression.

AIM: The aim of the present study was to investigate the molecular mechanism of fibroblast growth factor (FGF)-9 in prostate cancer cells. MATERIALS AND METHODS: Expression of vascular endothelial growth factor (VEGF)s and cadherins in LNCaP cells by incubation with FGF9 was assessed by western blot analysis. Tissues obtained during a radical prostatectomy in 88 patients were immunohistochemically-stained using anti-FGF9, anti-cadherin, and anti-VEGF antibodies. RESULTS: Expression of N-cadherin and VEGF-A were induced in LNCaP cells incubated in FGF9-containing medium. The biochemical relapse-free survival rate in cases with FGF9, N-cadherin and VEGF-A-positive cells was significantly lower than the rate in cases where positive cells were not detectable. The prevalence of both VEGF-A- and N-cadherin-positive cells in the sample with FGF9-positive cells were significantly higher in comparison to FGF9-negative cases. CONCLUSION: FGF9 can be associated with epithelial-to-mesenchymal transition and invasion by inducing VEGF-A expression in prostate cancer cells.

Restoration of IGFBP-rP1 increases radiosensitivity and chemosensitivity in hormone-refractory human prostate cancer.

We previously reported the tumor-suppressive activity of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) through induction of apoptosis in human prostate cancer cells. The aim of this study was to investigate the effects of IGFBP-rP1 for radiosensitivity and chemosensitivity in hormone-refractory human prostate PC-3 cancer cells. Five assays were performed using PC-3 cells transfected with IGFBP-rP1 (PC-3rP1) and control cells transfected with an empty vector (PC-3N): PC-3rP1 and PC-3N were compared by clonogenic survival assay, cell cycle analysis and apoptotic assay for radiosensitivity. The number of colonies of PC-3rP1 cells significantly decreased after 4 and 8 Gy of irradiation, compared with those of PC-3N in the clonogenic survival assay. After 16 hr irradiation at 8 Gy, the percentage of apoptotic cells significantly increased in PC-3rP1 compared with PC-3N. Growth of PC-3rP1 was significantly lower than that of PC-3N after docetaxel treatment both in vitro and in vivo. These results indicate that restoration of IGFBP-rP1 to PC-3 cells increases both their radiosensitivity and chemosensitivity.

Impact of pre-implant lower urinary tract symptoms on postoperative urinary morbidity after permanent prostate brachytherapy.

OBJECTIVES: To assess the impact of baseline lower urinary tract symptoms on postoperative urinary morbidity in patients being treated for prostate cancer with 125-I permanent prostate brachytherapy. METHODS: A total of 104 prostate cancer patients were enrolled in this study. Their urinary morbidity was followed up using the International Prostate Symptom Score and Expanded Prostate Cancer Index Composite for 12 months or more after permanent prostate brachytherapy. Patients were classified into two groups based on their baseline International Prostate Symptom Score: the low International Prostate Symptom Score group (score ≤ 7) and the high International Prostate Symptom Score group (score ≥ 8). Urinary morbidity was estimated in each group based on the results of the International Prostate Symptom Score and Expanded Prostate Cancer Index Composite measured before permanent prostate brachytherapy, and at 1, 3, 6, 9 and 12 months after the end of all radiation therapy. RESULTS: The overall mean total International Prostate Symptom Score, International Prostate Symptom Score quality of life score, and urinary-related scores for Expanded Prostate Cancer Index Composite were significantly worse at 1 month after the end of treatment, but they improved gradually after the treatment and recovered to the baseline level within 12 months. Even in the high-International Prostate Symptom Score group, the International Prostate Symptom Score and International Prostate Symptom Score Quality of Life score were significantly worse at 1-3 months after permanent prostate brachytherapy, and then recovered to the baseline level without prolongation. Although the urination-related Expanded Prostate Cancer Index Composite score in the high-International Prostate Symptom Score group was significantly worse at 1 month after permanent prostate brachytherapy in comparison with that in the low-International Prostate Symptom Score group, it recovered to the baseline level without prolongation. CONCLUSIONS: The present findings suggest that the presence of lower urinary tract symptoms before implantation does not prolong urinary morbidity after permanent prostate brachytherapy.

Impact of laparoscopic experience on the proficiency gain of urologic surgeons in robot-assisted surgery.

PURPOSE: The aim of our study is to assess the impact of skill in laparoscopic surgery on the learning of robot-assisted surgery by urologic surgeons using the Mimic dV-trainer (MdVT). MATERIALS AND METHODS: Twenty-three urologic surgeons using the MdVT were assessed. Ten of them were laparoscopic surgeons certified by the Japanese Society of Endourology. Each of the subjects completed four trials of a program consisting of four EndoWrist modules and two needle-driving modules. The performances of all subjects were recorded using a built-in scoring algorithm. RESULTS: In only one of the needle-driving tasks, Suture Sponge (that all subjects felt was the most difficult task), the scores of the certified laparoscopic surgeons became significantly better than those of the other subjects at the 2nd and the 3rd trials (p=0.0236 and p=0.0043 at the 2nd and 3rd trials, respectively). At the 4th trial there was no significant difference between the two groups with regard to the overall scores of any tasks. CONCLUSIONS: Our data indicate that familiarity with laparoscopic surgery is not associated with any advantage in learning the most fundamental techniques of robot-assisted surgery.

Six-year experience of permanent prostate brachytherapy for clinically localized prostate cancer.

This report presents the outcome of prostate permanent brachytherapy (PPB). One hundred and seventy-two patients with clinically localized prostate cancer were treated with permanent brachytherapy using iodine-125 seeds (125-I) at Hiroshima University Hospital from July 2004 to June 2010. This study evaluated the efficacy of PPB in these patients. The median patient age was 69 years (range 53 to 82 years), the median prostate-specific antigen (PSA) value before biopsy was 6.75 ng/ml (range 3.5 to 47.9 ng/ml), and the median prostate volume was 23.1 ml (range 10.1 to 57 ml). The median follow-up was 37 months (range 1 to 72 months). The serum PSA levels decreased continuously after PPB throughout the entire follow-up period in 97% of patients without neoadjuvant hormonal therapy. No relapse occurred during the follow-up period in patients at low risk. Our 6-year experience suggests that PPB is effective for localized prostate cancer. Patients with prostate cancer that does not require combined external beam radiation therapy (EBRT) have the best chance of responding to treatment.