Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma.

BACKGROUND: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. METHODS: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. RESULTS: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. CONCLUSION: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39-) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39- T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

Negative impact of neoadjuvant hormonal therapy on detecting biochemical recurrence after radical prostatectomy.

BACKGROUND: Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. METHODS: We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. RESULTS: The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p < 0.001) and between 1 and 2 years (p = 0.005) were significant between non-NHT and NHT patients. CONCLUSION: Patients who received NHT had a higher risk of a rapid PSA increase when they experienced BCR, especially within 2 years after RP. In order to not miss the optimal timing of salvage treatment for BCR, intensive PSA follow-up is necessary.

Long-term follow-up comparing salvage radiation therapy and androgen-deprivation therapy for biochemical recurrence after radical prostatectomy.

BACKGROUND: The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). METHODS: We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). RESULTS: During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time < 6 months (10-year CRPC-free survival 73.4 vs. 40.3%, p = 0.040). CONCLUSION: This study revealed that salvage RT increases the CRPC-free survival rate compared with salvage ADT in high-risk patients with Grade Group ≥ 4 and PSA-doubling time < 6 months.

Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma.

CONTEXT: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P < .001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P < .001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P < .001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. CONCLUSION: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy.

PURPOSE: To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. METHODS: The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death. RESULTS: During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0-4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR. CONCLUSIONS: Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

External validation of the "optimal PSA follow-up schedule after radical prostatectomy" in a new cohort.

BACKGROUND: Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the "optimal PSA follow-up schedule after RP". The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. METHODS: We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the "optimal PSA follow-up schedule" at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2-0.4 ng/ml. RESULTS: During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). CONCLUSION: This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

Correction to: Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration.

The original article can be found online.

Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration.

BACKGROUND: Our specific aim was to investigate the prognostic value of effective duration of first androgen deprivation therapy (ADT) and to evaluate the clinical impact on early docetaxel administration with oncological outcomes in castration-resistant prostate cancer (CRPC) patients treated with docetaxel. METHODS: We identified 148 mCRPC patients who were treated with 75 mg/m2 docetaxel. We defined 16 months as the threshold for the effective duration of ADT, and defined 12 months as the cut-off time for starting docetaxel from the onset of CRPC. Univariate and multivariate analyses were conducted to investigate the prognostic indicators that influenced the survival outcomes. RESULTS: Overall, 81 (54.7%) patients died. The median 1st ADT response was 22.2 months and the median time interval from CRPC onset to docetaxel treatment was 11.7 months. Multivariate analysis indicated that visceral metastasis, bone metastasis extent of disease (EOD) ≥ 2, and effective duration of ADT < 16 months were the independent prognostic indicators for progression-free survival (PFS). Referring to cancer-specific survival (CSS), besides visceral metastasis and effective duration of ADT < 16 months, late docetaxel treatment ≥ 12 months became as the predictors for poor prognosis. Among the ADT poor-responder group (ADT < 16 months), Kaplan-Meier method showed that 1-year and 2-year CSS rates were 96.0% and 80.0% in the patients who introduced docetaxel in early setting (< 12 months), which were significantly higher than those who introduced in late settings (93.6% and 30.8%, respectively, p < 0.001). CONCLUSION: CRPC patients who had poor response during 1st ADT would obtain survival benefit by introducing docetaxel treatment in early stage.

Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients.

BACKGROUND: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. METHODS: We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). RESULTS: Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4-17.5) and 29.4 (95% CI 25.5-33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4-4.2, p = 0.001). CONCLUSIONS: The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel.

The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9-21.2), respectively. Waterfall plot analysis revealed that a prostate-specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil-lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects.

Incidence and timing of inadvertent nephrostomy catheter displacement in patients with ureteral obstruction
.

INTRODUCTION: To evaluate nephrostomy catheter displacement, we assessed the cumulative nephrostomy catheter displacement rate in patients with percutaneous nephrostomy and compared the nephrostomy displacement rates between pigtail and balloon catheters. MATERIALS AND METHODS: Between 2003 and 2011, 87 patients who underwent percutaneous nephrostomy catheter placement and more than one subsequent catheter replacement were retrospectively identified. We evaluated their inadvertent nephrostomy catheter displacement. RESULTS: 20 patients (23.0%) experienced incidental nephrostomy catheter displacement during the follow-up period. Kaplan-Meier analysis revealed that the 1-year nephrostomy catheter displacement-free survival rate was 62 ± 9%. No significant independent risk factors for predicting nephrostomy catheter displacement were identified, including the type of catheter. The median time from initial placement to displacement of pigtail catheters was shorter than that of balloon catheters. CONCLUSION: There were no significant differences in the nephrostomy catheter displacement-free survival rates between the two types of catheters. Regardless of the type of catheter, our results indicated that careful handling and guiding during catheter placement are important for all patients because of the high risk of inadvertent events.
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Baseline risk stratification or duration of prior therapy predicts prognosis in patients with metastatic renal cell carcinoma treated with axitinib.

BACKGROUND: To elucidate the clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with axitinib. METHODS: A total of 58 patients were retrospectively analyzed. All patients received axitinib treatment for mRCC at Keio University hospital in Japan. Baseline clinical factors and on treatment adverse events were assessed to predict survival. RESULTS: The median progression free survival (PFS) for axitinib treatment was 10.9 months (95% CI 5.8-13.5), and the median overall survival (OS) from the start of axitinib treatment was 39.8 months (95% CI 25.9-NR), respectively. The PFS (P < 0.0001) and OS (P = 0.0022) were significantly correlated with the International mRCC Database Consortium (IMDC) classification, respectively. The PFS and OS were significantly longer in patients who received longer prior treatment (P = 0.0424 and 0.0067, respectively). On-treatment hypertension, hand foot syndrome and hypothyroidism were associated with longer PFS (P = 0.0002, 0.0055 and 0.0290, respectively). On-treatment hypertension, diarrhea, and hand foot syndrome were associated with longer OS (P = 0.0004, 0.0036 and 0.0115, respectively). CONCLUSIONS: Baseline and on treatment factors are identified as prognostic markers in mRCC patients treated with axitinib. Our findings might be helpful for clinicians to select the best treatment to individual patients.

High Absolute Monocyte Count Predicts Poor Clinical Outcome in Patients with Castration-Resistant Prostate Cancer Treated with Docetaxel Chemotherapy.

BACKGROUND: The association of peripheral monocyte count and prostate cancer progression is not well characterized. OBJECTIVE: Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated with docetaxel chemotherapy. METHODS: We retrospectively reviewed the medical records of 214 CRPC patients who received docetaxel therapy and were used as the training and validation set. Docetaxel at a dose of 75 mg/m2 was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). RESULTS: In the training set, the median age was 73.0 years, and the median prostate-specific antigen (PSA) value was 31.7 ng/ml at initial treatment. The median OS and PFS were 23.0 months (range 1.20-84.0) and 11.2 months (range 3.6-78.0), respectively. According to multivariable Cox regression analysis, AMC ≥400/uL, PSA level ≥20 ng/ml, and Hb <10 mg/dL were associated with increased risk of PSA progression [hazard ratio (HR) 2.06, p = 0.005; HR 2.39, p = 0.002; and HR 2.38, p = 0.024, respectively]. Moreover, multivariate analysis for OS indicated that AMC ≥400/uL, pretreatment PSA level ≥20 ng/ml, presence of visceral metastasis, and alkaline phosphatase ≥284 U/L were independent prognostic factors for shortened OS (HR 2.07, p = 0.004; HR 2.18, p = 0.007; HR 2.11, p = 0.011; and HR 1.67, p = 0.048, respectively). According to the validation set, high AMC remained an independent prognostic factor for PFS and OS (HR 2.26, p = 0.001; and HR 3.10, p < 0.001, respectively). CONCLUSIONS: Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with CRPC treated with docetaxel chemotherapy.

Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer.

BACKGROUND: No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. METHODS: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. RESULTS: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. CONCLUSION: There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.

[CLINICAL BACKGROUND ANALYSIS ABOUT TRANSURETHRAL ELECTROCOAGULATION].

PURPOSE: Transurethral electrocoagulation (TUC) is a rare event but occurs in a constant manner with various causes or disorders and reduces patient quality of life. So far there have been no reports focusing on the details of TUC. We focused on the clinical background and related causes in cases of TUC in our institution. PATIENTS AND METHODS: We identified 76 cases (65 patients) who underwent TUC at Keio University Hospital between April 2001 and March 2011. We focused on patient background, especially with respect to the primary disease, treatment modality, use of antiplatelet or anticoagulant agent, timing of TUC, type of electrosurgical device, and the incidence of transfusion. RESULTS: The primary disease for TUC included bladder tumor (BT) in 31 cases, benign prostate hyperplasia (BPH) in 13, prostate cancer (PCa) in 13, idiopathic bladder bleeding in 4, periarteritis nodosa in 3, uterine cervical cancer in 3, and others in 9. TUC after transurethral resection (TUR) was found in 38 cases, including transurethral resection of bladder tumor (TURBT) in 26 of 31 BT cases and transurethral resection of prostate (TURP) in 12 of 13 BPH cases. After TURBT, TUC was performed before removal of a urethral catheter in 7 cases, and after removal of a urethral catheter in 19 cases. With regard to TUC associated with TURP, the average estimated prostate volume in TUC cases before removal of the urethral catheter was 66.2 ml, which was significantly larger than that in TUC cases after removal of the urethral catheter (46.1 ml, p = 0.045). TUC after the radiation therapy was observed in 21 cases, and the average time from the radiation therapy to TUC was 3.4 years (7 months-10 years). CONCLUSION: TUC was caused by multiple causes or disorders, and 75% of our TUC was associated with BT, BPH or PCa. TUC associated with TURBT frequently occurred within 1 week after TURBT but was still observed after 1 month following the operation. All TUC associated with TURP occurred within 3 weeks after operation. The average period from radiation therapy to TUC was 3.4 years (7 months-10 years) and TUC associated with radiation cystitis could occur beyond 5 years after radiation.

Development of a novel interferon-α2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro.

BACKGROUND: Despite the advent of targeted therapies, interferon-alpha (IFN-α) remains a therapeutic option for advanced renal cell carcinoma (RCC), especially in Japan, with a treatment response rate of 15-20 %. To improve the efficacy of IFN-α-based therapies, we evaluated a novel treatment strategy for RCC using an IFN-α2b gene construct with a repetitive hypoxia-inducible factor binding site. METHODS: We constructed an expression plasmid designated 5HREp-IFN-α2b containing the coding region of the IFN-α2b gene. Five copies of the hypoxia-response element (HRE) sequences were inserted upstream of the IFN-α2b gene, and the construct was transfected into human RCC cell lines ACHN, 786-O and KU19-20. The concentrations of IFN-α2b in the conditioned media were measured by enzyme-linked immunosorbent assay. Cell viabilities were determined by MTS assays. RESULTS: Construct-induced IFN-α secretion was confirmed in all three cell lines. IFN-α production was significantly enhanced by the hypoxia-mimicking agent deferoxamine mesylate in cell lines expressing the wild-type von Hippel-Lindau (VHL) gene (KU19-20 and ACHN) compared with cells expressing the mutant VHL gene (786-O). The construct exerted significant suppressive effects on the viabilities of all RCC cell lines. CONCLUSION: This is the first study to report on the construction of a cytokine gene with a repetitive hypoxia-inducible factor binding site and its application in the suppression of human cancer cells. Gene therapy using this IFN-α2b gene construct with HREs may represent a novel treatment modality for advanced RCC.

A case of testicular cancer in a long-term hydranencephaly survivor with undescended testes.

Introduction: The development of malignant tumors in patients with hydranencephaly is extremely rare. We describe the first case of testicular cancer that developed in the undescended testes of a long-term survivor of hydranencephaly. Case presentation: A 32-year-old man with severe cerebral palsy due to hydranencephaly was referred to our department for the evaluation of a subcutaneous lump in the lower right abdomen. He was a long-term survivor of hydranencephaly. After confirming the diagnosis of right testicular cancer originating in his undescended testes, surgical resection was performed. Pathological examination revealed a mixed-type germ cell tumor. Conclusion: The decision-making process for treating malignant tumors, like testicular cancer, in adults with severe cerebral palsy can be challenging. Clinical ethics consultation could be helpful in avoiding treatment delays.

Recurrent urethral tumor with neuroendocrine differentiation in a female patient after radical cystectomy for bladder cancer.

Introduction: Urethral recurrence after radical cystectomy in female patients with bladder cancer is relatively uncommon. Recurrent bladder tumors with neuroendocrine differentiation are extremely rare. Case presentation: A 71-year-old female patient who underwent radical cystectomy for bladder cancer presented with vaginal bleeding 19 months postoperatively. She was diagnosed with bladder cancer urethral recurrence. Urethral tumor en-bloc resection with the anterior vaginal wall was performed by combining abdominal and vaginal approaches. Pathological examination revealed a recurrent tumor of urothelial bladder cancer containing small-cell carcinoma components. Conclusion: This case is the first report of a recurrent tumor with small-cell carcinoma in the female urethra after radical cystectomy for pure urothelial carcinoma.