Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer.

Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2 /M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.

Trp53 Mutation in Keratin 5 (Krt5)-Expressing Basal Cells Facilitates the Development of Basal Squamous-Like Invasive Bladder Cancer in the Chemical Carcinogenesis of Mouse Bladder.

The biological processes of urothelial carcinogenesis are not fully understood, particularly regarding the relationship between specific genetic events, cell of origin, and molecular subtypes of subsequent tumors. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced mouse bladder cancer is widely accepted as a useful model that recapitulates the pathway of human bladder tumorigenesis from dysplasia to invasive cancer via carcinoma in situ. However, the long and variable time of tumorigenesis often hinders efficient preclinical or translational research. We hypothesized that Trp53 mutation in specific types of urothelial cells facilitates efficient development of clinically relevant bladder cancer. Using lineage tracing, we showed that Trp53 mutation in Krt5-expressing cells resulted in more efficient tumorigenesis of mouse muscle-invasive bladder cancer (MIBC) with squamous differentiation compared with Trp53 mutation in Upk2-expressing cells, or wild-type or hemizygous Trp53 in the entire urothelium. Mouse MIBC that developed at 24 weeks of BBN treatment showed morphologic and genetic similarities to the basal squamous subtypes of human MIBC, irrespective of pre-induction of Trp53 mutation or whether the cell of origin was Krt5- or Upk2-expressing cells. Our findings suggest that intermediate cells as well as basal cells also can give rise to basal-like MIBC, with pre-induction of Trp53 mutation accelerating MIBC. Thus, in BBN chemical carcinogenesis, pre-induction of Trp53 mutation in basal cells facilitates efficient modeling of the basal squamous subtype of human MIBC.

Faithful preclinical mouse models for better translation to bedside in the field of immuno-oncology.

The success of immunotherapy using immune checkpoint inhibitors has changed the practice of cancer treatment tremendously. However, there are still many clinical challenges, such as drug resistance, predictive biomarker development, exploration of combination therapies, and prediction of immune-related adverse events in preclinical settings. To overcome these problems, it is essential to establish faithful preclinical mouse models that recapitulate the clinical features, molecular genetics, biological heterogeneity, and immune microenvironment of human cancers. Here we review the advantages and disadvantages of current preclinical mouse models, including syngeneic murine tumor cell lines, autochthonous tumor models, cancer cell line-derived xenografts, patient-derived-xenografts, and various kinds of immunologically humanized mice. We discuss how these models should be characterized and applied in preclinical settings, and how we should prepare preclinical studies for successful translation from bench to bedside.

Systematic chemical screening identifies disulfiram as a repurposed drug that enhances sensitivity to cisplatin in bladder cancer: a summary of preclinical studies.

BACKGROUND: Since the standard gemcitabine and cisplatin (GC) chemotherapy for advanced bladder cancer yields limited therapeutic effect due to chemoresistance, it is a clinical challenge to enhance sensitivity to GC. METHODS: We performed high-throughput screening by using a library of known chemicals and repositionable drugs. A total of 2098 compounds were administered alone or with GC to human bladder cancer cells, and chemicals that enhanced GC effects were screened. RESULTS: Disulfiram (DSF), an anti-alcoholism drug, was identified as a candidate showing synergistic effects with cisplatin but not with gemcitabine in multiple cell lines. Co-administration of DSF with GC affected cellular localisation of a cisplatin efflux transporter ATP7A, increased DNA-platinum adducts and promoted apoptosis. Micellar DSF nanoparticles (DSF-NP) that stabilised DSF in vivo, enhanced the inhibitory effect of cisplatin in patient-derived and cell-based xenograft models without severe adverse effects. A drug susceptibility evaluation system by using cancer tissue-originated spheroid culture showed promise in identifying cases who would benefit from DSF with cisplatin. CONCLUSIONS: The present study highlighted the advantage of drug repurposing to enhance the efficacy of anticancer chemotherapy. Repurposing of DSF to a chemotherapy sensitiser may provide additional efficacy with less expense by using an available drug with a well-characterised safety profile.

[Percutaneous Fibrin Glue Injection for Persistent Urinary Leakage after Partial Nephrectomy : A Case Report].

A 69-year-old man with left atrophic kidney was referred to our hospital because of a 5.7 cm solid mass in the lower pole of right kidney revealed by computed tomography for evaluation of aortic aneurysm. An open transperitoneal partial nephrectomy was performed, and final pathological diagnosis was clear cell carcinoma, grade 2, pT1b, pNx. One month postoperatively, a computed tomography revealed 16 cm retroperitoneal fluid collection which was diagnosed as urinoma due to urinary leakage from partial nephrectomy scar of the right lower calyx. Following percutaneous drainage of a 6 Fr Pigtail catheter, 6 Fr double-J ureteral stent and urethral catheter were placed, but the discharge through the percutaneous drain continued to be 700 to 1,000 ml/day. Forty-one days after drainage, two open-end catheters (5 Fr) were directed into the urinary fistula lumen through the percutaneous tract and 6 ml of fibrin glue was injected under fluoroscopic guidance. Four days later, another 2 ml of fibrin glue was injected because of a small amount of residual urinary leakage and percutaneous drainage catheter was removed. Thereafter, urinary leakage was completely cured and ureteral stent and urethral catheter were removed.

[Risk Factors for Mortalityin Patients with Urosepsis].

Urosepsis is not uncommon and sometimes causes a critical condition including death. We retrospectivelyanaly zed the risk factors for mortalityin urosepsis. We treated 80 patients as urosepsis from 2010 to 2014 in our hospital. Five patients (6%) died within 30 days of hospitalization. The median age of the patients who died of urosepsis was 92 years (range, 83-95 years). The main causes of urosepsis were complicated pyelonephritis in 4 patients and emphysematous pyelonephritis in one. In the subgroup analysis of elderly patients over 75 years old, bad performance status and lower serum albumin were significantlyrelated to mortality(p ＝0.033, 0.046). The elderlypatients, especiallywith bad performance status and lower serum albumin, are more likelyto die.

[A Crossover Comparison Study on Lower Urinary Tract Symptoms with Overactive Bladder Secondary to Benign Prostatic Hyperplasia: Naftopidil versus Tamsulosin with Solifenacin].

We compared the efficacy of naftopidil monotherapy with combination therapy using tamsulosin hydrochloride and solifenacin succinate in the treatment of lower urinary tract symptoms (LUTS) with overactive bladder (OAB) secondary to benign prostatic hyperplasia (BPH). Thirty one patients were enrolled in a randomized crossover study. Fourteen patients were initially prescribed naftopidil 75 mg (N) for 8 weeks, followed by tamsulosin 0.2 mg and solifenacin 5 mg (TS) for 8 weeks (group N) ; another 17 were initially prescribed TS, followed by N (group TS). The efficacy variables were the changes in international prostate symptom score (I-PSS), quality of life (QOL) score, overative bladder symptom score (OABSS), and post-void residual (PVR) urine volume. After the study, a questionnaire survey was carried out about the choice of treatment. After treatment with each agent, total I-PSS, storage symptom score, QOL score and OABSS except for the daytime frequency were significantly improved from baseline. PVR was significantly increased after TS treatment. There were no significant differences between the two treatments except for PVR. As a result of the questionnaire survey, 13 patients chose N and 17 chose TS. In conclusion, N monotherapy can be expected to have an equal effect in the treatment of LUTS with OAB secondary to BPH in comparison with TS combination therapy.

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.

[THE IMPACT OF LOWER URINARY TRACT SYMPTOMS ON GENERIC HEALTH-RELATED QUALITY OF LIFE IN MALE PATIENTS WITHOUT CO-MORBIDITY].

PURPOSE: We investigated the impact of lower urinary tract symptoms (LUTS) on generic health-related quality of life (HRQOL) in male patients without co-morbidity. PATIENTS AND METHOD: From 2003 to 2011, a total 567 men who presented out urological department completed the questionnaires including International Prostate Symptom Score (IPSS), incontinence-frequency score (IFS) from the UCLA prostate cancer index, MOS 36-Item Short-Form Health Survey (SF-36). Among 230 patients with no coexisting morbidity, the relations between each LUTS score of IPSS indices and IFS and 8 domain scores of SF-36 were analyzed by Pearson's product-moment correlation and stepwise multiple regression analysis. RESULT: Univariate analysis showed that the IFS had a significant correlation with all of 8 domain scores of SF-36, and also the IPSS item scores of urgency, nocturia and straining correlated significantly with multiple domain scores of SF-36. In multiple regression analysis, the proportionate contributions of LUTS to each SF-36 domain scores were low (R2 was 10% or less). Incontinence was considered as the most influential factor that had a negative impact on HRQOL in 7 SF-36 domains of physical functioning, role-physical, bodily pain, general health perception, vitality, social functioning and mental health. Additionally, nocturia, straining and urgency were significantly associated with deficit of HRQOL in 4 SF-36 domains (role-physical, general health perception, role-emotional, mental health), 2 domains (bodily pain, social functioning) and 1 domain (role-emotional) of SF-36, respectively. CONCLUSION; Among LUTS, incontinence, nocturia and straining were the most important symptoms in association with the negative impact on generic HRQOL measured by SF-36.

[Rechallenge of everolimus for metastatic renal cell carcinoma after recovery from grade 3 interstitial lung disease: a case report].

We report a case of the rechallenge of everolimus for metastatic renal cell carcinoma (RCC) after successful recovery from grade 3 interstitial lung disease (ILD). A 76-year-old man with metastatic RCC developed grade 3 ILD one month after the initiation of everolimus therapy (10 mg/day). ILD subsided in 4 months after the withdrawal of everolimus and treatment with corticosteroids. Half dose (5 mg/day) of everolimus was rechallenged for 9 months until another grade 3 ILD developed. Everolimus kept the disease under control for 13 months including the discontinuation period.

[Observational study on urinary status following HoLEP].

We assessed the safety, and postoperative urinary status of holmium laser enucleation of the prostate (HoLEP) for the treatment of benign prostatic hyperplasia (BPH). Of the initial 117 patients who underwent HoLEP from November 2004 to March 2011, 49 were followed up for two yearsor longer. These 49 patients were evaluated once preoperatively, and at the 3rd, 6th, 12th, 24th, 48th, and 60th month postoperatively using International Prostate Symptom Scores (I-PSS) total and sub-score, quality of life score (QOL), maximum flow rate (Qmax), and post-voiding residual urine volume (PVR). The median estimated transition zone and enucleated volume were 45. 1 and 47. 9 g, respectively. Evaluation scores showed significant improvementsthroughout the follow-up. I-PSS total scoresimproved from 21 points(before surgery) to 6 points(12 monthsafter surgery), QOL scoresimproved from 5 pointsto 2 points, Qmax improved from 6.8 ml/s to 17.4 ml/s, and PVR improved from 101 ml to 26 ml, respectively. Transient urinary incontinence was noted in 14 patients (28.5%). One case showed a Clavien grade 3 complication of postoperative bleeding. No blood transfusion or re-surgery for BPH was required. In conclusion, HoLEP proved to be a safe and effective therapy, with potential to become a new gold standard for treating BPH.

[Risk factors for recurrence in pT3aN0M0 renal cell carcinoma according to 2009 TNM classification].

The TNM classification of renal cell carcinoma was updated in 2009. In this new classification system, T3a consists of tumors with renal vein involvement and tumors with fat invasion. To assess risk factors for recurrence, we retrospectively reviewed 89 patients with pT3aN0M0 renal cell carcinoma who underwent radical or partial nephrectomy between 1992 and 2011. Analyzed risk factors for recurrence were age, gender, tumor size, grade, v factor, infiltrative growth (INF), adjuvant interferon, surgical technic (radical or partial), clinical T classification, renal vein thrombus, and pathological fat invasion. The median follow-up was 52.2 months. Five-year recurrence-free survival rate was 69.0%. Within the pT3a subcategory, the five-year recurrence-free survival was 76.7% in patients with fat invasion only, 42.9% in patients with renal vein thrombus only, and 28.6% in patients with the two concomitant features. On univariate analysis, tumor size, grade, INF, clinical T classification, and renal vein thrombus were significantly associated with recurrence. On multivariate analysis, INF (p = 0.023, HR 3.927) was an independent risk factor for recurrence. In pT3aN0M0 renal cell carcinoma, INF significantly affects recurrence, and patients with both fat invasion and renal vein thrombus have worst prognosis.

[Perioperative agranulocytosis induced by immunosuppressants in a renal graft recipient : a case report].

A 20-year-old man with end-stage renal disease was scheduled to have an ABO-incompatible living kidney transplantation donated by his mother. His complete blood count including differential white blood cell count was normal before preoperative immunosuppressive therapy including mycophenolate mofetil (MMF), tacrolimus (FK506), and prednisolone was started 3 weeks before the operation. The dosage of MMF was initially 2,000 mg/day, but was reduced to 500 mg/day due to diarrhea 10 days before the operation. He received rituximab 13 days before the operation. The neutrophil (Neu) count was 3,100/µl a day before the operation. Transplant surgery was finished without any complications. The Neu count was found to be 300/µl on the day and 80/µl the next day. Granulocyte colony-stimulating factor was administered daily. Then the Neu count increased to 9,100/µl on postoperative day (POD) 2, and was maintained within the normal range. MMF was re-started on POD 12. The dosage was 500 mg, and was increased to 1,000 mg on POD 21. On POD 30 the 12-hr blood concentration of MMF was 117.2 mg× hr/l, which was almost double the adequate target dose. Then the dosage was reduced to 500 mg. In this case MMF is the most suspected drug for drug-induced agranulocytosis. Although MMF-induced neutropenia is frequently observed in transplant recipients, it usually happens three months after transplantation or later. The present case is a rare case as it occurred on the day of transplantation. The pharmacokinetics of MMF varies with the individual. Although routine monitoring of blood concentration of MMF is not recommended, specific attention to prevent overdosage should be given particularly in a patient presenting possible adverse effects including diarrhea and depilation.

[The safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) for treatment of metastatic renal cell carcinoma].

We prospectively investigated the safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) in 24 patients (22 males, 2 females ; age range 39-86 years, median 64 years) with metastatic renal cell carcinoma (RCC). During the observation period (3-62 weeks, median 21 weeks), thrombocytopenia was seen in 13 (54.2%), leukopenia in 11 (45.8%), hand-foot syndrome in 5 (20.8%), hypertension in 4 (16.7%), and hypothyroidism in 3 (12.5%) patients, while grade 3 or higher adverse events were found in 4 (16.7%), 1 (4.2%), 1 (4.2%), 2 (8.3%), and 0 patients, respectively. Of the 21 patients evaluable for response, 5 (23. 8%) showed partial response, 8 (38.1%) stable disease, and 8 (38.1%) progressive disease. This new modified regimen may lead to a reduction in adverse events for treatment of patients with metastatic RCC as a substitute for the standard dosing regimen of sunitinib.

A case of renal cell carcinoma with antiphospholipid syndrome treated by robot-assisted partial nephrectomy.

Introduction: Antiphospholipid syndrome is an autoimmune disease that presents with thrombus hyperplasia. Although very rare, this disease is reported to become severe after the surgical invasion and other interventions. To our knowledge, there are no reports of partial nephrectomy in patients with antiphospholipid. Case presentation: A 45-year-old man visited our hospital for treatment of left renal cell carcinoma. He had a history of antiphospholipid syndrome and took two antithrombotic agents. We performed a robot-assisted partial nephrectomy. We selectively ligated only the feeding branch during the procedure. Postoperatively, there were no complications, and the patient was discharged on postoperative day 10. One year after surgery, there was no worsening of antiphospholipid syndrome. Conclusion: We reported the first case of robot-assisted partial nephrectomy for an antiphospholipid syndrome patient. Selective ligation of the renal artery might not have contributed to the severe antiphospholipid syndrome.

[Gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) in patients with metastatic urothelial cancer].

Twenty-four patients with metastatic urothelial carcinoma of bladder (11) and upper urinary tract (13) received gemcitabine 1,000 mg/m2 on days 1, 8, and 15, and cisplatin 70 mg/m2 (GC) or carboplatin area under the serum concentration-time curve (AUC) 5 (GCarbo) on day 2, every 28 days. One to 13 chemotherapy cycles (median number, 4) per patient were administered. Three patients (12.5%) achieved a complete response (CR) and 9 (37.5%) a partial response (PR). Six patients (25%) experienced no change (NC) and six patients (25%) progressive disease (PD). The overall response rate (CR＋PR) of GC (57.9%) was greater than that of GCarbo (20%), but the difference was not statistically significant (p＝0.13). At a median follow-up of 14.7 months, the median time to progression was 4.6 months (range, 0.9-34.7), and the median overall survival 12.3 months (range, 2.1-46.4). Grade 3 and 4 leukocytopenia occurred in 15 patients (53.6%) and grade 3 and 4 thrombocytopenia in 16 (57.1%). Gemcitabine could be administrated on both day 8 and day 15 only in 43 (34.7%) of the total 114 courses because of hematological toxicity. Gemcitabine chemotherapy combined with cisplatin or carboplatin is effective in the management of metastatic urothelial cancer. High hematological toxicity was observed and caused high omission rates of gemcitabine on day 8 and/or day 15.

[Granulocyte-colony-stimulating factor (G-CSF)-producing carcinoma of collecting ducts of Bellini: a case report].

We report a case of granulocyte-colony-stimulating factor (G-CSF)-producing carcinoma of collecting ducts of Bellini. A 62-year-old male was admitted to our hospital with the chief complaint of high grade fever,right flank pain and general malaise. The white blood cell count and serum G-CSF concentration were elevated to 20,100/ µ l and 140 pg/ml,respectively. Enhanced thoracoabdominal computed tomography (CT) showed a right renal malignant tumor without capsule,para-aortic lymph node metastases and lung metastases. CT-guided right renal biopsy was performed. The histological diagnosis was GCSF- producing carcinoma of collecting ducts of Bellini. The chemotherapy (gemcitabine and cisplatin) and the molecular target therapy (sunitinib) were administerd but the primary lesion and metastases was progressive and serum G-CSF concentration was elevated to 229 pg/ml. He died 3 months after diagnosis.

Modification of Platinum-based Systemic Chemotherapy for Advanced Urothelial Carcinoma in Patients With Suboptimal Renal Function.

BACKGROUND/AIM: Standard chemotherapy for advanced urothelial carcinoma (UC) patients with moderate renal dysfunction has not yet been established. PATIENTS AND METHODS: We retrospectively assessed outcomes of patients with advanced UC who underwent first-line chemotherapy with full-/reduced-dose gemcitabine plus cisplatin (GC-f/GC-r) or full-/reduced-dose gemcitabine plus carboplatin (G-Car-f/G-Car-r) according to renal function. RESULTS: Seventy-eight patients were included in this study. The objective response rate was 42%, 30%, 42%, and 27% for the GC-f, GC-r, G-Car-f, and G-Car-r groups, respectively. For the GC-r and G-Car-f groups, the median progression-free survival and the median overall survival was 4.5 vs. 7.0 months (p=0.07) and 7.5 months vs. 12.0 months (p=0.124), respectively. Grade 3/4 thrombocytopenia occurred more frequently in the GC-r group than the G-Car-f group (80% vs. 38%, p=0.021). CONCLUSION: G-Car-f could be more beneficial than GC-r for patients with advanced UC who have moderate renal dysfunction.

Enhancement of transduction efficiency using Adeno-associated viral vectors by chemical pretreatment to mice bladder urothelium.

Adeno-associated virus (AAV) vectors have been recognized as promising tools for gene delivery. The bladder is a seemingly ideal organ for virus transfer, with easy access through the urethra enabling organ-specific delivery. However, achieving adequate transduction efficiency in the urothelium has been a major challenge because of the barrier function of the glycosaminoglycan (GAG) layer. We investigated optimal pretreatments of the bladder urothelium to maximize transduction efficiency by AAV vectors in vivo. Murine bladders were pretreated with five different chemical agents followed by transurethral instillation with an AAV2 vector encoding a tdTOMATO reporter. After 7 days, transduction efficiency of the urothelium was evaluated. Bladder urothelia pretreated with HCl showed clear evidence of AAV infection and gene delivery. Mice treated with 0.1 N HCl for 4 min showed significantly higher survival rates (nearly 80 %) compared with mice receiving other pretreatment regimens. AAV vector transduction in the urothelium was observed in seven of 20 mice (35 %), and the mean transduction efficiency in these mice was 14.5 %. Thus, HCl pretreatment enhanced transduction efficiency of the mice bladder urothelium by an AAV vector in vivo. Pretreatment with 0.1 N HCl for 4 min was the optimal condition to maximize survival and transduction efficiency of the urothelium.

Efficacy of Immediate Postoperative Instillation of Chemotherapy for Primary Non-Muscle-Invasive Bladder Cancer in Real-World Clinical Practice.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) can be treated using transurethral resection (TUR), but high incidence of intravesical recurrence remains a clinical challenge. Single immediate postoperative instillation of chemotherapy (IPIOC) is controversial for NMIBC patients with intermediate recurrence risk. The aim of the present study was to report the efficacy and toxicity of IPIOC, particularly in intermediate-risk NMIBC patients, in the real-world setting. PATIENTS AND METHODS: We retrospectively analyzed 363 consecutive patients with primary NMIBC who underwent radical TUR at Kyoto University Hospital between 2007 and 2016. RESULTS: In low-risk patients, recurrence-free survival (RFS) was significantly better for IPIOC than non-IPIOC (2-year RFS: 89.3% vs. 59.4%; P = .001). In intermediate-risk patients, IPIOC was associated with significantly longer RFS compared with non-IPIOC (2-year RFS: 85.5% vs. 58.2%; P = .011). IPIOC and bacillus Calmette-Guérin (BCG) were independent predictors for post-TUR recurrence (non-IPIOC vs. IPIOC: hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.14-4.88; P = .02; non-BCG vs. BCG: HR, 2.22; P = .045, 95% CI, 1.02-5.30). In the high-risk group, only BCG was an independent prognostic factor of recurrence in a multivariate Cox proportional hazards model (HR, 2.55; P = .006, 95% CI, 1.32-4.87). There were no significant differences between the BCG-only group and the IPIOC with BCG group in Grade 3 or more local (16 patients [21%] vs. 21 patients [24%]; P = .61) or systemic (3 patients [4%] vs. 6 patients [7%]; P = .40) toxicity rates. CONCLUSION: Our study showed the efficacy of IPIOC for the prevention of intravesical recurrence in primary intermediate-risk NMIBC patients regardless of BCG therapy.