Effectiveness of Synthetic Polymer-coated Peripherally Inserted Central Catheter in Patients With Advanced Cancer.

BACKGROUND/AIM: A peripherally inserted central catheter (PICC) is recommended for the safe administration of anticancer agents. The effectiveness of synthetic polymer-coated and non-coated PICCs was compared. PATIENTS AND METHODS: Patients with advanced cancers who had indwelling PICCs were reviewed using their medical records. Three types of PICCs were compared in terms of complications and catheter failure. RESULTS: A total of 90 patients were retrospectively analyzed, including 31 with Groshong PICCs, 30 with Argyle PICC kit, and 29 with Argyle PICC kit II. The incidence of catheter failure for Groshong PICC, Argyle PICC kit, and Argyle PICC kit II per 1,000 PICC days was 4.4614, 5.6617, and 0.8658, respectively. Catheter failure-free survival in the Argyle PICC kit II group was significantly better than that in the Argyle PICC kit group (p=0.0339). CONCLUSION: Argyle PICC kit II, a synthetic polymer-coated PICC, may render longer patency and prevention of catheter failure than non-coated PICCs.

CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells.

Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel-resistant and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145-TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145-TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel.

Evaluating urinary incontinence before and after radical prostatectomy using the international consultation on incontinence questionnaire-short form.

AIMS: To evaluate urinary incontinence using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), daily pad use, and 24-h pad weight test before and after radical prostatectomy (RP) chronologically, and the correlation between them. METHODS: ICIQ-SF and questions on daily pad use provided subjective, and 24-h pad weight test for objective evaluation. RESULTS: In total, 258 cases were recruited. The continence rate at 12 months after RP was 67% for no pad use, 87% for security 1 pad/day, and 94% for 1 pad/day. The median ICIQ-SF total score before and at 1, 3, 6, and 12 months after RP was 0, 10, 7, 5, and 4, respectively. Incontinence patterns differed when comparing ICIQ-SF results pre- and post-RP. Significant correlation existed between the ICIQ-SF total score, 24-h pad weight test, and daily pad use; however, point distribution on each scatter plot varied widely. Comparing results before and at 12 months after RP revealed complete recovery for 35% of patients from the ICIQ-SF total score, 67% from daily pad use, and 64% from the 24-h pad weight test. A combination of all 3 showed a recovery of preoperative levels in 29% of patients. CONCLUSIONS: ICIQ-SF was effective and convenient for evaluating UI, including the pattern of UI, after RP. Significant correlation, but wide variations, among ICIQ-SF, daily pad use, and the 24-h pad weight test existed. The best evaluation method would be the one that can compare UI status pre- and post-RP using the ICIQ-SF and 24-h pad weight test.

Establishment and characterization of two cabazitaxel-resistant prostate cancer cell lines.

Once castration-resistant prostate cancer (CRPC) become resistant for cabazitaxel treatment, the patients are obliged to best supportive care. Therefore, the elucidation of the mechanism of the cabazitaxel-resistance and the conquest are important themes to improve the prognosis of the patients. Then we tried to establish cabazitaxel-resistant CRPC cell lines and characterized them. We established two cabazitaxel-resistant cell lines, PC-3-TxR/CxR and DU145-TxR/CxR from PC-3-TxR and DU145-TxR cell lines previously we established. PC-3-TxR/CxR and DU145-TxR/CxR cells became resistant for cabazitaxel by 11.8-fold and 4.4-fold, respectively. The TxR/CxR cells showed cabazitaxel-resistant using SCID mice in vivo. Although expression of multi-drug resistance gene 1 (MDR1) was up-regulated in DU145-TxR compared with DU145 cells, it was not up-regulated in DU145-TxR/CxR cells any more. In contrast, expression of MDR1 gene was up-regulated in PC-3-TxR compared with PC-3 cells and it was further up-regulated in PC-3-TxR/CxR compared with PC-3-TxR cells. Comparison of cDNA microarray between PC-3-TxR and PC-3-TxR/CxR cells or between DU145-TxR and DU145-TxR/CxR cells revealed that many genes were up-regulated or down-regulated. Finally, knockdown of MDR1 recovered the sensitivity to cabazitaxel not only in PC-3-TxR/CxR cells but also DU145-TxR/CxR cells. Together, regulation of MDR1 gene is important for conquest of the cabazitaxel-resistance.

Crosstalk Between Androgen-sensitive and Androgen-insensitive Prostate Cancer Cells.

AIM: To investigate how androgen-sensitive LNCaP cells crosstalk with androgen-insensitive DU145 or PC-3 cells. MATERIALS AND METHODS: The numbers of LNCaP cells were counted when co-cultured with DU145 or PC-3 cells and vise versa. Androgen receptor (AR) activity in LNCaP cells was examined by luciferase reporter assay after transfection with a luciferase reporter driven by PSA promoter in the presence of DU145 or PC-3 cells. Concentration of androgens in the medium was measured by liquid chromatography-mass spectrometry (LC-MS/MS). The ability of migration and invasion of PC-3 and DU145 cells was investigated using a 2-layer chamber, in the presence of LNCaP cells. RESULTS: Co-culture of LNCaP cells with DU145 cells resulted in the conversion of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT), which stimulated cell proliferation and PSA promoter activity in LNCaP cells. The increased cell proliferation rate and AR activity, induced in LNCaP cells after DHT treatment, was further enhanced by co-culture with DU145 cells. LNCaP cells also stimulated the proliferation of DU145 and PC-3 cells, via secreting soluble factors. Finally, LNCaP cells promoted migration and invasion of PC-3 cells, in a co-culture system; however inhibited migration and invasion of DU145 cells. CONCLUSION: Crosstalk between androgen-sensitive PCa cells and androgen-insensitive PCa cells might develop the progression of PCa.

Changes in penile length after radical prostatectomy: investigation of the underlying anatomical mechanism.

OBJECTIVE: To measure changes in penile length (PL) over time before and after radical prostatectomy (RP), and to investigate the underlying mechanisms for these changes. PATIENTS AND METHODS: The stretched PL (SPL) of 102 patients was measured before, 10 days after, and at 1, 3, 6, 9, 12, 18 and 24 months after RP. The perpendicular distance from the distal end of the membranous urethra to the midline of the pelvic outlet was measured on mid-sagittal magnetic resonance imaging (MRI) slice at three time points: preoperatively; 10 days after RP; and 12 months after RP. Pre- and postoperative SPLs were compared using paired Student's t-test. Predictors of PL shortening at 10 days and at 12 months after RP were evaluated on univariate and multivariate analyses. RESULTS: The SPL was shortest 10 days after RP (mean PL shortening from preoperative level: 19.9 mm), and gradually recovered thereafter. SPL at 12 months after RP was not significantly different from preoperative SPL. On MRI examination, the distal end of membranous urethra was found to have moved proximally (mean proximal displacement: 3.9 mm) at 10 days after RP, and to have returned to the preoperative position at 12 months after RP. On univariate analysis, only the volume of the removed prostate was a predictor of SPL change at 10 days after surgery; on multivariate analysis, the association was not statistically significant. No predictor of SPL change was found at 12 months after RP. CONCLUSION: The SPL was shortest at 10 days after RP and gradually recovered thereafter in the present study. Anatomically, the glans and corpus spongiosum surrounding the urethra are an integral structure, and the proximal urethra is drawn into the pelvis during urethrovesical anastomosis. This is the first report showing that slight vertical repositioning of the membranous urethra after RP causes changes in SPL over time. These results can help inform patients about changes in penile appearance after RP.

Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis.

Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.

Efficacy of tegafur-uracil in advanced urothelial cancer patients after the treatment failure of platinum-based chemotherapy.

BACKGROUND: Platinum-based chemotherapy is the first-line treatment for advanced urinary tract urothelial cancers. However, the optimal second-line treatment is unclear. Although tegafur-uracil is sometimes used for advanced urothelial cancer patients after the treatment failure of platinum-based chemotherapy, there is little evidence regarding its use as a second-line treatment. PATIENTS AND METHODS: Advanced urothelial cancer patients previously treated with platinum-based chemotherapy were retrospectively analyzed. Overall survival (OS) was compared between patients with and without tegafur-uracil treatment. RESULTS: Thirty-one patients (27 and 4 patients with and without tegafur-uracil treatment, respectively) were analyzed. OS from the last day of the final chemotherapy course was better in patients with tegafur-uracil treatment than in those without (p<0.001, 358 and 66.5 days of the median survival time, respectively). CONCLUSION: Tegafur-uracil may be a candidate for the secondary treatment of advanced urothelial cancer patients after the treatment failure of platinum-based chemotherapy.

The relationship between prostate-specific antigen and TNM classification or Gleason score in prostate cancer patients with low prostate-specific antigen levels.

BACKGROUND: Prostate-specific antigen (PSA) is a useful biomarker for risk classification in patients with prostate cancer. However, it is unclear whether a correlation exists between low PSA levels (<10 ng/ml) at diagnosis and prognosis. METHODS: Of the 642 Japanese patients who underwent prostate biopsy and were diagnosed with prostate cancer at Kanazawa University Hospital from 2000 to 2010, 406 patients with a PSA level <20 ng/ml were retrospectively reviewed. RESULTS: PSA levels in 275 (68%) patients were <10 ng/ml. Although the percentage of Gleason score 8-10 in patients with a PSA level of <3.5 ng/ml was higher than that in patients with a PSA level between 3.5 and 10 ng/ml, it was not statistically significant. On the other hand, the percentage of higher stage (T3 and T4) patients with a PSA level <3.5 ng/ml was significantly greater than that in patients with a PSA level between 3.5 and 10 ng/ml (P < 0.0001). The percentage of metastases (N1 and M1) in patients with a PSA level <3.5 ng/ml was also significantly higher than that in patients with a PSA level between 3.5 and 10 ng/ml (P = 0.0112). CONCLUSIONS: Patients with prostate cancer with a PSA level <3.5 ng/ml at diagnosis had a more advanced stage of cancer compared with those with a PSA level between 3.5 and 10 ng/ml. Therefore, risk classification using PSA levels at diagnosis may need to take into consideration this specific PSA range in order to better predict survival.

[Treatment with recombinant thrombomodulin on disseminated intravascular coagulation caused by urinary tract infections; a retrospective comparative study with control cases].

We examined the efficacy of recombinant thrombomodulin (rTM) for treatment of patients with disseminated intravascular coagulation (DIC) caused by urinary tract infections. Thirteen DIC patients treated with rTM (rTM group) and 11 not receiving rTM (non-rTM group) were enrolled in this study. Blood data including coagulation markers collected before and after the treatment,a hospitalized term,and period of antibiotic treatment were compared. There were no significant differences in baseline characteristics between the two groups. Both groups showed significant improvement in all parameters such as blood biochemical data,coagulation markers,and DIC score 5-7 days after treatment. However, changes in platelet and DIC score from baseline to early phase (day 1-3) were significantly greater in the rTM group than in the non-rTM group (p＜0.05). In addition,changes in FDP value showed slight but not significant improvement in rTM group compared to the non-rTM group in the early treatment phase (p＝ 0.084). The period of antibiotic usage was significantly shorter in the rTM group,whereas the hospitalized term showed no significant difference between the groups. Definite adverse effects were not present in the rTM group. In conclusion,administration of rTM may have a beneficial effect in patients with DIC induced by urinary tract infections,compared with conventional treatment.

Active estrogen synthesis and its function in prostate cancer-derived stromal cells.

BACKGROUND: It remains unclear whether estrogen is produced in prostate cancer (PCa) and how it functions in PCa. MATERIALS AND METHODS: To examine the production of estrogen in PCa cells, the concentration of estrogen in the medium in which LNCaP cells and PCa-derived stromal cells (PCaSC) were co-cultured, was measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), while aromatase (CYP19) mRNA expression was confirmed by real-time polymerase chain reaction (RT-PCR) methods. To verify whether estrogen is synthesized from testosterone in PCaSC functions, PCaSC were co-cultured with breast cancer MCF-7-E10 cells, which were stably-transfected with ERE-GFP, in the presence of testosterone. GFP expression was detected when PCaSCs could synthesize estrogen. The proliferation of PC-3 cells in the presence of PCaSC was determined by cell count. RESULTS: PCaSC metabolized excessive testosterone to estrogen, which activated estrogen receptor in breast cancer cells. Moreover, estrogen synthesized from testosterone in PCaSC regulated the proliferation of PC-3 cell via repression of some unknown growth factors that were secreted from PCaSC. CONCLUSION: A chimeric co-culture method between breast cancer cells and PCaSC revealed the production of active estrogen in PCaSC. High-dose testosterone therapy might introduce a new potential strategy to treat CRPC.

Decreasing trend in prostate cancer with high serum prostate-specific antigen levels detected at first prostate-specific antigen-based population screening in Japan.

To clarify the recent trends in prostate-specific antigen (PSA) distribution in men in Japan, we analyzed the PSA distributions of men undergoing PSA-based population screening. We summarized the annual individual data of PSA-based population screening in Kanazawa, Japan, from 2000 to 2011, and analyzed baseline serum PSA values of the participants at the first population screening. Serum PSA distributions were estimated in all participants and those excluding prostate cancer patients according to age. From 2000 to 2011, 19 620 men participated aged 54-69 years old in this screening program. Mean baseline serum PSA level of all participants at the first screening was 2.64 ng ml⁻¹ in 2000, and gradually decreased to approximately 1.30 ng ml⁻¹ in 2006. That of participants excluding prostate cancer patients was 1.46 ng ml⁻¹ in 2000, and there was no remarkable change during the study period. The 95 th percentiles in the participants excluding prostate cancer patients detected at the first population screening of men aged 54-59, 60-64, and 65-69 years old were 2.90, 3.60, and 4.50 ng ml⁻¹, respectively. After the commencement of population screening, the proportion of prostate cancer patients with high serum PSA levels decreased. However, there were no changes in serum PSA levels in men without prostate cancer. Age-specific PSA reference level of men without prostate cancer in Japan was similar to that in China and Korea.

Inflammatory myofibroblastic tumor of the urinary bladder with benign pelvic lymph node enlargement: a case report.

Inflammatory myofibroblastic tumors (IMTs) rarely occur in the urinary bladder. It is apparently difficult to distinguish these tumors from other malignant spindle cell proliferations. Herein, we report a case of IMT of the urinary bladder with enlarged pelvic lymph nodes. The definitive pathological diagnosis could not be established by biopsy. Instead, the diagnosis of IMT of the urinary bladder was determined by a positive reaction to anaplastic lymphoma kinase by immunohistochemistry after radical cystectomy. No malignant findings were observed on histopathological evaluations of the enlarged lymph nodes.

Cardiovascular and respiratory effects of the degree of head-down angle during robot-assisted laparoscopic radical prostatectomy.

BACKGROUND: Robot-assisted laparoscopic radical prostatectomy (RALP) requires a steep Trendelenburg position and CO2 pneumoperitoneum for several hours to secure the surgical visual field. The present study was performed to investigate the influence of each angle of Trendelenburg position during RALP on cardiovascular and respiratory homeostasis. METHODS: Forty-seven ASA physical status 1 and 2 patients underwent open retropubic radical prostatectomy (RRP) or RALP. Patients receiving RALP were randomized to undergo the operation in the 20°, 25° or 30° Trendelenburg position. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), end-tidal CO2 pressure (PetCO2 ), tidal volume (Vt), peak inspiratory pressure (PIP) and dynamic compliance (Cdyn) were recorded during the operation. RESULTS: Angle of head-down tilt was significantly correlated with MAP, PIP and Cdyn, but not with HR, RR or PetCO2 . MAP decreased gradually over time in each group in the Trendelenburg position with pneumoperitoneum. As the angle of head-down tilt became stronger, MAP, RR, PetCO2 and PIP tended to increase and Cdyn tended to decrease. CONCLUSIONS: This study demonstrated that the degree of the head-down angle at RALP affected the cardiovascular and respiratory parameters. Pneumoperitoneum with head-down position in RALP influenced the cardiovascular and respiratory system to a greater extent than RRP, and these effects were stronger with deeper head-down angle.