[A Case of Intra-Abdominal Testicular Cancer Occurring from an Overlooked Intra-Abdominal Testis in Undescended Testicular Surgery].

Here, we report an adult case of intra-abdominal testicular cancer after surgical treatment of an undescended testis in infancy. A 36-year-old male patient was accidentally diagnosed with a tumor in the pelvic cavity by ultrasonographic examination. He had hematuria and the human chorionic gonadotropin beta subunit level was slightly elevated. T2-weighedmagnetic resonance imaging revealed a well-defined and highly intense mass. Since these findings suggested intra-abdominal testicular cancer, laparoscopic surgery was performed to remove the mass. Laparoscopy revealed an intra-abdominal tumor accompanied by a looping vas deferens entering the left inguinal canal. The distal part of the looping vas had already been removed from the external inguinal ring. The pathological findings revealed a pT1 seminoma. The patient has been recurrence-free for 12 months. The present case implies the importance of careful investigation and treatment for intra-abdominal testicular cancer, since intra-abdominal testis might have been overlooked at the time of surgery for undescended testis.

Population­based prostate­specific antigen screening for prostate cancer may have an indirect effect on early detection through opportunistic testing in Kusatsu City, Shiga, Japan.

Prostate cancer is the most common genitourinary cancer in men. Population-based serum prostate-specific antigen (PSA) testing is used to screen men for the early detection of asymptomatic prostate cancer. The present study compared the features of patients with prostate cancer in Kusatsu City, the only municipality in Shiga Prefecture of Japan to implement organized PSA screening, with those in other municipalities. The target population for organized PSA screening by mail invitation was men ≥50 years. Patients were pathologically diagnosed via prostate biopsy because of elevated serum PSA. This multicenter observational study was subsequently conducted in 14 hospitals. The following information was extracted from patient records: age, reason for PSA testing, initial PSA level, Gleason score, clinical stage, and place of residence. Risk classification was defined as low, intermediate, high, and advanced. Each patient was stratified according to their city/town. A total of 984 patients diagnosed with prostate cancer in Shiga in 2012 and 2017 were analyzed, of which 955 (97%) were opportunistically tested, with the remaining 29 (3%) assessed by organized screening. In Kusatsu, 93 patients were diagnosed, of whom 26 (28%) were detected by organized screening. By contrast, only three of 891 patients (0.3%) were detected by organized screening in other municipalities. Of patients in Kusatsu, cases identified by opportunistic testing had a higher initial PSA value (P=0.010) than those identified by organized screening. However, patients detected through opportunistic testing in Kusatsu City were younger (P=0.034), had a lower PSA value (P=0.001), and improved risk classification (P<0.001) than those in other municipalities. It was concluded that more patients were diagnosed with early-stage cancer by organized PSA screening. Furthermore, population-based PSA screening in Kusatsu City may have indirectly affected early detection, even by opportunistic testing.

Near-infrared ray catheter and indocyanine green via nephrostomy in delayed robotic reconstruction of injured ureter: A case report.

Delayed surgical reconstruction of iatrogenic ureteral injuries is often a challenging procedure because spreading scar tissue impedes accurate identification and dissection of the injured ureter. We report a novel real-time navigation system using a ureteral near-infrared ray catheter (NIRC) and indocyanine green (ICG) via nephrostomy in delayed robot-assisted ureteral reconstruction. A female patient presented with complete obstruction of the right upper ureter after gynecological surgery with extensive lymphadenectomy. A nephrostomy tube was urgently placed, and surgical repair was performed. A straight NIRC was placed in the right ureter up to the obstruction point. ICG was administered via nephrostomy. Near-infrared light could clearly visualize the ureter and renal pelvis encased in scar tissue. The ureter and renal pelvis were dissected and successfully anastomosed. We found that near-infrared navigation using ureteral NIRC and ICG via nephrostomy was valuable for delayed laparoscopic reconstruction of the injured ureter.

Clinical, pathological, and therapeutic features of newly diagnosed prostate cancer predominantly detected by opportunistic PSA screening: A survey of Shiga Prefecture, Japan.

BACKGROUND: In all the prefectures of Japan, with the exception of Shiga Prefecture, more than half of local governments have an organized prostate-specific antigen (PSA) screening system in place. However, in the Shiga Prefecture, only a single city performed PSA screening over the time period of this survey. The purpose of the present study was to determine the clinical, pathological, and therapeutic features of newly diagnosed prostate cancer in localities where a formally organized screening system was almost entirely absent. METHODS: A multicenter observational study was conducted in the Shiga Prefecture, which has the lowest rate of population-based PSA-screening in Japan. Patients' age, initial PSA, reasons for PSA testing, Gleason score, clinical stage, and primary treatments were surveyed. We stratified patients according to the reasons for PSA measurement, and compared the differences between groups subject to organized versus opportunistic screening. RESULTS: In the 2 years 2012 and 2017, 984 newly diagnosed prostate cancer patients were analyzed. Of these, 954 (97%) were opportunistically tested (i.e., not as part of an organized screening system), with the remaining 29 (3%) measured as part of an organized screening program. Patients in the former group exhibited a higher initial PSA value than in the organized screening group (median: 11.49 vs. 5.67 ng/ml). They also had worse clinical features, including higher Gleason score and TNM stage. More patients in the organized screening group were treated curatively than in the nonorganized screening group in terms of the primary treatment. The results were similar in a subanalysis of the patients of age 50-69 years. CONCLUSIONS: Organized PSA screening contributes to increasing the number of patients diagnosed with early-stage cancer who can be treated curatively.

[COST ANALYSIS OF ANDROGEN DEPRIVATION THERAPY AND DRUGS FOR CASTRATION-RESISTANT PROSTATE CANCER].

(Purpose) Recently, new effective drugs for the treatment of castration-resistant prostate cancer (CRPC) have been developed. Although they are expected to prolong the survival time of patients with advanced prostate cancer, they may result in an economic burden. In this study, we determined the treatment results and the cost of CRPC drugs. (Methods) From 2014 to 2017, patients who were unfit for curative therapy were enrolled in this study. First, they received androgen deprivation therapy (ADT) by surgical or chemical castration. Once castration-sensitive cancer progressed to castration-resistant cancer, CRPC drugs, such as docetaxel, cabazitaxel, abiraterone and enzalutamide, were administered sequentially. In elderly or fragile patients, drug doses were often reduced to minimize their toxicity. The total costs of drugs for castration-sensitive and castration-resistant cancers were calculated, and the results were evaluated. (Results) Prostate biopsies detected prostate cancer in 257 patients. Eighty-one patients were treated with ADT, and 56 of the cancers were metastatic or showed a high prostate specific antigen level (>100 ng/ml). Thirty patients out of the 56 with advanced cancers developed CRPC, and the median time to CRPC was 10 months (range, 3-39). Drugs targeting CRPC were administered in 25 patients for a median duration of 20 months (range, 3-50). During the median observation period of 48 months (range, 13-75), 15 patients died of prostate cancer. The median annual cost of drugs for castration-sensitive cancer was 234,000 Japanese yen (2,187 US dollars) [range, 50,000-315,000 yen (467-2,943 US dollars) ]. In contrast, the median annual cost of drugs for CRPC was 2,041,000 yen (19,075 US dollars) [range, 346,000-5,017,000 yen (3,230-46,886 US dollars) ]. (Conclusions) Advanced prostate cancer tended to rapidly progress to CRPC, which required a sequence of expensive drugs for treatment. Early diagnosis preventing the development of advanced prostate cancer is desirable to reduce the economic burden for the health insurance system.

Underweight body mass index is a risk factor of mortality in outpatients with nocturia in Japan.

BACKGROUND: Although nocturia has been reported to increase mortality in elderly individuals, the particular risk factors that are associated with this event are unclear. Therefore, we evaluated risk factors for death in outpatients with nocturia. METHODS: Between October 2002 and December 2009, 250 consecutive patients with nocturia were enrolled in two general hospitals in Japan. Among them, 193 patients were able to be followed for at least 1 year and up to 9 years (median 4.8 years) if the patients did not die. Mortality rates and risk factors were evaluated in the nocturic outpatients. RESULTS: Two- and 5-year survival of the nocturic outpatients was 94.6% [95% confidence interval (CI) = 92.2-97.1] and 82.6% (95% CI = 75.4-87.8), respectively. Higher Charlson Comorbidity Score, lower body mass index (BMI) and lower Physical Component Summary of Short Form-36 item scores were significantly correlated with mortality (p < 0.0001, p < 0.005 and p < 0.05, respectively) in multivariate analysis. The International Prostate Symptom Score, Pittsburgh Sleep Quality Index, Mental or Role/Social Component Summary of Short Form-36 item scores and Nocturnal Polyuria index were not significantly correlated with mortality. The mortality rate was significantly higher in subjects with an underweight BMI (<18.50) compared with a normal range (18.50-24.99) or overweight (≥25.00) BMI [p < 0.00005, hazard ratio (HR) = 5.84, 95% CI = 2.03-16.8; p < 0.0005, HR = 5.92, 95% CI = 1.94-18.0]. CONCLUSIONS: Additional attention is required for nocturic outpatients with not only a high Charlson Comorbidity Score but also an underweight BMI because of their high mortality. Large prospective studies are warranted to validate this finding and extend more.

[LAPAROSCOPIC ADRENALECTOMY: COMPARISON OF TRANSPERITONEAL AND RETROPERITONEAL APPROACHES].

OBJECTIVE: Laparoscopic adrenalectomy is generally performed by either a transperitoneal approach (TA) or a retroperitoneal approach (RA). However, the optimal selection criteria for each approach are unclear. We investigated the factors affecting the safety of laparoscopic adrenalectomy to evaluate the optimal criteria for each approach. PATIENTS AND METHODS: In total, 149 patients who underwent laparoscopic adrenalectomy from February 1994 to July 2013 were retrospectively analyzed. We performed TA for 75 tumors in 73 patients and RA for 78 tumors in 76 patients. Patient characteristics and operative outcomes were compared between the two groups. Furthermore, operative outcomes in patients with some surgical risks were specifically compared between the two approaches. RESULTS: Patient characteristics were similar between the two groups, although the patients in the RA group were significantly older than those in the TA group. Four patients with a large pheochromocytoma in the TA group had excessive blood loss and one of them was given blood transfusion. However, there was no difference in intraoperative blood loss (p = 0.091). The other serious adverse events were not observed. CONCLUSIONS: The present findings suggest that both RA and TA can be effective surgical strategies, with close attention to large pheochromocytoma to avoid excessive hemorrhage.

[A case of primary mucosa-associated lymphoid tissue-type lymphoma of the urinary bladder that progressed after antibiotic therapy].

We report a case of primary mucosa-associated lymphoid tissue (MALT)-type lymphoma of the urinary bladder, which temporarily regressed after antibiotic therapy and progressed 1 year after the treatment. The patient was a 72-year-old female with a history of recurrent cystitis. She was referred to our hospital for microscopic hematuria. Urinalysis also showed microscopic pyuria and cystoscopy revealed an erythematous and edematous submucosal lesion in the right side wall of the bladder. She was diagnosed with acute cystitis and treated with antibiotics. Cystoscopy after 2 months was normal. However, she presented with macroscopic hematuria and fever 1 year after the treatment. Computed tomography (CT) scan showed a solitary mass measuring 25×40 mm above the right ureteric orifice and right hydronephrosis. Transurethral resection was performed, and the histopathological findings were consistent with MALT-type lymphoma. No evidence of lymphoma was found on positron emission tomography-CT scan and bone marrow biopsy, and she was diagnosed with primary MALT-type lymphoma of the bladder. She was successfully treated with a combination of rituximab and radiotherapy. Since MALT-type lymphoma of the bladder sometimes regresses temporarily after antibiotic therapy, it should be followed carefully.

Urinary retention in a female patient caused by a urethral venous thrombus with massive edema.

Female urinary retention is rarely caused by an unknown condition. In such a case, common causes including neurogenic, anatomical, traumatic and iatrogenic voiding dysfunction are excluded. Both the radiological and histological findings specific to the condition remain unclear. We herein report a 75-year-old woman in whom a large venous mass and massive edema at the proximal urethra caused urinary outlet obstruction based on magnetic resonance images and histological findings. Ultrasonography and cystoscopy showed a urethral mass lesion protruding into the bladder neck. Fat-suppressed T2-weighted and gadolinium-enhanced T1-weighted magnetic resonance images suggested thrombosed veins with massive edema under the urethral mucosa. Transurethral resection of the mass lesion was carried out, and histopathological analysis proved the presence of thrombosed large veins. The patient regained normal urination, and the mass lesion did not recur. Thrombosed venous mass with edema at the proximal urethra might be an important cause of atypical urinary retention in women.

Thioredoxin-interacting protein suppresses bladder carcinogenesis.

Thioredoxin-interacting protein (TXNIP), which has a tumor-suppressive function, is underexpressed in some human cancers. The function of TXNIP in vivo in carcinogenesis is not fully understood. Here, we show TXNIP to be downregulated in human bladder cancer according to grade and stage and also that loss of TXNIP expression facilitates bladder carcinogenesis using a mouse bladder cancer model. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer was found in 100% of Txnip knockout (KO) mice at week 8 of 0.025% BBN administration but in only 22% of wild-type (WT) mice at the same point. Among growth stimulators, phospho-extracellular signal-regulated kinase (pERK) expression was stronger during bladder carcinogenesis in Txnip-KO mice than in WT mice. We then evaluated TXNIP's effects on ERK activation through various growth stimulators and their receptors. Overexpression of TXNIP in human bladder cancer cells attenuated pERK expression upon stimulation with stromal cell-derived factor-1 (SDF-1) but not with epidermal growth factor or insulin-like growth factor-1. In Txnip-KO mice, immunohistochemical analysis showed enhanced expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor of SDF-1, and of pERK in urothelial cells during BBN-induced bladder carcinogenesis. Finally, subcutaneous injection of CXCR4 antagonist, TF14016, attenuated pERK in urothelial cells and suppressed bladder carcinogenesis. These data indicate that TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1-CXCR4-induced ERK activation. This signal transduction pathway can be a potent target in preventing or treating bladder cancer.

Overexpression of Eg5 predicts unfavorable prognosis in non-muscle invasive bladder urothelial carcinoma.

OBJECTIVE: To investigate the relationship between Eg5 expression and prognosis of patients with non-muscle invasive bladder urothelial carcinoma. METHODS: Eg5 expression was examined by immunohistochemistry in non-muscle invasive urothelial carcinoma specimens (grade: G1, 32 cases; G2, 92 cases; and G3, 39 cases. Stage: pTa, 49 cases and pT1, 114 cases). The correlation between clinicopathological characteristics and Eg5 expression was evaluated. The prognostic significance of Eg5 immunoreactivity was analyzed through survival analysis in 163 non-muscle invasive cases that were treated with transurethral resection and adjuvant intravesical instillations. RESULTS: The expression of Eg5 was significantly associated with tumor grade (P = 0.006), with a trend towards significant association with stage (P = 0.057). The 163 patients with non-muscle invasive tumors were regularly followed with the mean of 32.52 (from 6 to 72) months. Univariate analysis showed Eg5 overexpression exhibited a significant unfavorable influence on intravesical recurrence (P = 0.012) while having only a marginal correlation with disease progression (P = 0.070). Subsequent Cox hazard multivariate analysis showed that both grade (P = 0.045) and Eg5 expression (P = 0.029) were independent predictors for early intravesical recurrence. CONCLUSIONS: Overexpression of Eg5 correlates with poor differentiation of bladder cancer, and it represents an independent prognostic factor in predicting early intravesical recurrence in non-muscle invasive bladder carcinoma patients.

A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor.

Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-L-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer.

A potent chemotherapeutic strategy for bladder cancer: (S)-methoxy-trityl-L-cystein, a novel Eg5 inhibitor.

PURPOSE: Eg5, which has an essential role in the formation and maintenance of a bipolar mitotic spindle, was recently identified as an attractive target in cancer chemotherapy. We examined the anticancer activity of a novel Eg5 inhibitor for bladder cancer with particular reference to metastatic disease. MATERIALS AND METHODS: We examined bladder cancer cell lines and clinical tissue samples for Eg5 expression and analyzed the antiproliferative activity of 5 Eg5 inhibitors in cell lines by cell viability assay. The anticancer efficacy of the most potent Eg5 inhibitor was investigated in vitro by apoptosis assay with Hoechst nuclear staining and flow cytometry. Immunofluorescence and immunostaining were used to elucidate the inhibitory mechanism. We evaluated the inhibitory effect in vivo in subcutaneous xenograft and metastatic cancer models. RESULTS: Eg5 expression was increased in bladder cancer samples vs that in normal bladder epithelium samples. (S)-methoxy-trityl-L-cystein showed the strongest antiproliferative activity of the 5 Eg5 inhibitors and induced cell death after mitotic arrest via the caspase dependent apoptotic pathway. In vivo (S)-methoxy-trityl-L-cystein effectively suppressed tumor growth in subcutaneous and metastatic xenograft models. Survival time in (S)-methoxy-trityl-L-cystein treated nude mice was significantly longer than in untreated mice (p <0.001). CONCLUSIONS: (S)-methoxy-trityl-L-cystein is a promising, novel anticancer agent for bladder cancer. Our data indicates its potential as effective therapy for metastatic bladder cancer.

Dicoumarol enhances doxorubicin-induced cytotoxicity in p53 wild-type urothelial cancer cells through p38 activation.

OBJECTIVE: To investigate the effectiveness of a combined treatment of 3-30-methylene-bis[4-hydroxycoumarin] (dicoumarol) with doxorubicin for the treatment of urothelial cancer, as doxorubicin is a common chemotherapeutic agent but its therapeutic efficacy is limited. MATERIALS AND METHODS: The synergistic effect of dicoumarol with chemotherapeutic agents such as cisplatin, doxorubicin and paclitaxel was evaluated in RT112 urothelial cancer cells. Then, dicoumarol-mediated enhancement of doxorubicin-induced cytotoxicity was screened in urothelial cancer cell lines with different p53 statuses or RT112 stable transfectants with a dominant-negative mutant of p53 (p53DN). To clarify the importance of the modification of p53 function by dicoumarol to enhance doxorubicin toxicity, the change in the p53-p21 pathway and mitogen-activated protein kinase (MAPK)-mitochondria pathway by the combined treatment were elucidated by Western blot analysis. Finally, the effect of p21 knockdown in the susceptibility to doxorubicin was examined with RT112 stable transfectants with short hairpin RNA (shRNA) of p21. RESULTS: Dicoumarol significantly increased the susceptibility of RT112 cells to cisplatin and doxorubicin, but not to paclitaxel in RT112 cells. Dicoumarol (100 microm) also enhanced the cytotoxicity of doxorubicin in other bladder cancer cell lines with wild-type p53 (wt-p53; three times in 253J and 13 times in KK47), but not in those with mutant-type p53 (TCCsup, J82 and EJ) or in RT112 p53DN. The combined treatment with dicoumarol suppressed p53/p21 induction by doxorubicin and resulted in sequential p38 MAPK activation, myeloid cell leukaemia 1 suppression and caspase cleavage. The synergistic effect of doxorubicin/dicoumarol was suppressed by the p38 MAPK inhibitor SB202190 and, furthermore, p21 knockdown with shRNA transfection made RT112 cells six times more susceptible to doxorubicin with p38 MAPK activation. CONCLUSION: These results suggest that concomitant use of dicoumarol could enhance the cytotoxicity of doxorubicin in urothelial cancer cells with wt-p53 through the p53/p21/p38 MAPK pathways. This combined treatment may provide a new therapeutic option to overcome chemoresistance in bladder cancer.

Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.

We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.

Oral bisphosphonate prevents bone loss in androgen deprivation therapy for nonmetastatic prostate cancer.

We studied the short-term efficacy of alendronate, an oral bisphosphonates, on bone mineral density (BMD) during androgen deprivation therapy (ADT) in 45 nonmetastatic prostate cancer patients at the beginning of ADT (treatment group). All received alendronate five mg daily from the initiation of ADT. Lumber BMD was evaluated by dual energy X-ray absorptiometry, at baseline and after six months of treatment. Historical data on 24 patients with prostate cancer who received ADT without bisphosphonate administration were studied as controls (control group). BMD decreased in 13.9 and 45.8% of the patients in the treatment and control groups, respectively. Mean BMD changes in the lumber spine were +1.6 +/- 3.0% in the treatment group and -1.1 +/- 2.7% in the control group (p = 0.006). No pathological fractures occurred during the study period. No severe adverse effects were observed, but three patients could not continue alendronate treatment because of adverse events. Despite the short-term of this evaluation, our results showed that oral alendronate is an effective and safe treatment for preventing bone loss and increasing BMD in patients receiving ADT for prostate cancer.

Results of treatment of renal calculi with lower-pole fluoroscopically guided percutaneous nephrolithotomy.

OBJECTIVE: To prospectively assess the clinical efficacy and safety of lower-pole fluoroscopically guided percutaneous nephrolithotomy (PNL). METHODS: A total of 90 renal units in 87 patients underwent lower-pole fluoroscopically guided PNL for renal calculi. The average patient age was 56.0 years. Staghorn calculi were present in 41 renal units. There were 22 were upper pole, 54 middle pole, 76 lower pole, 70 pelvic and 18 ureteropelvic junction calculi. Patients without significant residual fragments greater than 3mm on postoperative day 2 were defined as primarily successful. Significant residual fragments were treated with shock wave lithotripsy (SWL) every other day from postoperative day 3. RESULTS: Mean operative time was 129.5 min (SD, 49.0). Blood transfusion was required in four patients. Septic shock developed in three patients. Sixty-three percent of the patients (57 of 90 procedures) were primarily successful after PNL: 83.7% of non-staghorn patients (41 of 49 procedures) and 39.0% of staghorn patients (16 of 41 procedures). Of the 33 patients with significant residual fragments, 13 staghorn and six non-staghorn patients had residual fragments in their middle calyces. Of the preoperative variables, staghorn calculus and calculus in the middle calyx were significant predictors of significant residual fragments after PNL. After adjunctive SWL, the overall success rate was 94.5%. CONCLUSIONS: Our study suggests that lower-pole fluoroscopically guided PNL is a safe and effective therapy for patients with staghorn or non-staghorn calculi. In patients with staghorn calculi or calculi in the middle calyx, adjunctive treatment is sometimes required to treat significant residual fragments.

Secreted CXCL1 is a potential mediator and marker of the tumor invasion of bladder cancer.

PURPOSE: The purpose of this study was to identify proteins that are potentially involved in the tumor invasion of bladder cancer. EXPERIMENTAL DESIGN: We searched for the candidate proteins by comparing the profiles of secreted proteins among the poorly invasive human bladder carcinoma cell line RT112 and the highly invasive cell line T24. The proteins isolated from cell culture supernatants were identified by shotgun proteomics. We found that CXCL1 is related to the tumor invasion of bladder cancer cells. We also evaluated whether the amount of the chemokine CXCL1 in the urine would be a potential marker for predicting the existence of invasive bladder tumors. RESULTS: Higher amount of CXCL1 was secreted from highly invasive bladder carcinoma cell lines and this chemokine modulated the invasive ability of those cells in vitro. It was revealed that CXCL1 regulated the expression of matrix metalloproteinase-13 in vitro and higher expression of CXCL1 was associated with higher pathologic stages in bladder cancer in vivo. We also showed that urinary CXCL1 levels were significantly higher in patients with invasive bladder cancer (pT1-4) than those with noninvasive pTa tumors (P = 0.0028) and normal control (P < 0.0001). Finally, it was shown that CXCL1 was an independent factor for predicting the bladder cancer with invasive phenotype. CONCLUSIONS: Our results suggest that CXCL1 modulates the invasive abilities of bladder cancer cells and this chemokine may be a potential candidate of urinary biomarker for invasive bladder cancer and a possible therapeutic target for preventing tumor invasion.

Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways.

Wnts are secreted glycoproteins that control diverse biological processes, such as proliferation, differentiation, and apoptosis. We here found that Wnt5a inhibited apoptosis induced by serum deprivation in primary-cultured human dermal fibroblasts. Anti-apoptotic activity of Wnt5a was not inhibited by a dickkopf-1 (DKK), which blocks the canonical Wnt pathway. On the other hand, loss of function of protein kinase A (PKA), induced by treatment with PKA inhibitors, siRNA-mediated knocking down of endogenous PKA catalytic subunits, or enforced expression of dominant-negative PKA inhibited the Wnt5a anti-apoptotic activity, indicating the involvement of PKA in the Wnt5a anti-apoptotic activity. In agreement, phosphorylation levels of a cAMP response element binding protein (CREB), a representative downstream effector of PKA, the activation of which is known to lead to the pro-survival effects, was elevated by Wnt5a. In addition, Wnt5a increased the nuclear beta-catenin level and treatment with imatinib or ionomycin, either of which blocks the beta-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the beta-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at serine 9 that caused inactivation of GSK-3beta and subsequently resulted in activation of the beta-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3beta and subsequent activation of the beta-catenin pathway.