Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation.

Bladder cancer is an often widely disseminated and deadly cancer. To block the malignant outgrowth of bladder cancer, we must elucidate the molecular-level characteristics of not only bladder cancer cells but also their surrounding milieu. As part of this effort, we have long been studying extracellular S100A8/A9, which is elevated by the inflammation associated with certain cancers. Extracellularly enriched S100A8/A9 can hasten a shift to metastatic transition in multiple types of cancer cells. Intriguingly, high-level S100A8/A9 has been detected in the urine of bladder-cancer patients, and the level increases with the stage of malignancy. Nonetheless, S100A8/A9 has been investigated mainly as a potential biomarker of bladder cancers, and there have been no investigations of its role in bladder-cancer growth and metastasis. We herein report that extracellular S100A8/A9 induces upregulation of growth, migration and invasion in bladder cancer cells through its binding with cell-surface Toll-like receptor 4 (TLR4). Our molecular analysis revealed the TLR4 downstream signal that accelerates such cancer cell events. Tumor progression locus 2 (TPL2) was a key factor facilitating the aggressiveness of cancer cells. Upon binding of S100A8/A9 with TLR4, TPL2 activation was enhanced by an action with a TLR4 adaptor molecule, TIR domain-containing adaptor protein (TIRAP), which in turn led to activation of the mitogen-activated protein kinase (MAPK) cascade of TPL2. Finally, we showed that sustained inhibition of TLR4 in cancer cells effectively dampened cancer survival in vivo. Collectively, our results indicate that the S100A8/A9-TLR4-TPL2 axis influences the growth, survival, and invasive motility of bladder cancer cells.

Long-term ureteroscopic management of upper tract urothelial carcinoma: 28-year single-centre experience.

BACKGROUND: Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period. METHODS: We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan-Meier methodology. RESULTS: A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3-20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached. CONCLUSIONS: Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients.

Photodynamic diagnostic ureteroscopy using the VISERA ELITE video system for diagnosis of upper-urinary tract urothelial carcinoma: a prospective cohort pilot study.

BACKGROUND: The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system. METHODS: We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated. RESULTS: A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS). CONCLUSIONS: Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system. TRIAL REGISTRATION: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803-002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205).

Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment.

CASE PRESENTATION: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection. CONCLUSION: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial.

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.

Robotic Renal Autotransplantation: A Feasibility Study in a Porcine Model.

We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci® robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort® and irrigated on ice with Ringer's solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery.

Combined Laparoscopic and CT Monitoring of the Ice-Ball Margin during Cryoablation for Renal Cell Carcinoma Associated with von Hippel-Lindau Disease: First Case.

We report a 47-year-old Japanese female with 10 previous treatments for multiple bilateral renal cell carcinoma (RCC) associated with von Hippel-Lindau disease. The 14-mm right lower pole renal tumor was in contact with the right ureter. Laparoscopic cryoablation was performed to protect the ureter wrapped with gauze. Computed tomography (CT) monitoring was used to confirm the precise ≥ 6 mm ice-ball margin. There was no local progression at 6-months post-surgery. The serum creatinine has been stable. This is apparently the first report of combined laparoscopic and CT monitoring of an ice-ball formation and its margin during cryoablation for RCC.

Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection.

OBJECTIVES: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

Loss of psoas major muscle volume during systemic chemotherapy is related to worse prognosis in testicular cancer.

OBJECTIVE: In several cancers, the loss of skeletal muscle is well associated with oncological outcome. However, its effect is unknown in testicular cancer. This study evaluated the prognostic impact of psoas major muscle volume loss during systemic chemotherapy. METHODS: This was a retrospective study of patients who underwent chemotherapy from 2008 to 2017. Psoas major muscle volume was calculated by volume analyzer software, and its loss was calculated during systemic chemotherapy. The patients were divided according to muscle volume loss: Group 1 (<20%) and Group 2 (≥20%). The losses were compared with Kaplan-Meier curves, and a Cox proportional hazard model was applied to test predictors of poor prognosis. RESULTS: Fifty patients were included. Seventeen were classified into Group 1, and 33 into Group 2. The Kaplan-Meier curves revealed that the progression-free and the overall survival of Group 1 were significantly better than those of Group 2 (P = 0.002, P = 0.03, respectively). A multivariate analysis identified psoas major muscle volume loss as a significant and independent predictor of poor prognosis. CONCLUSIONS: Patients with psoas major muscle volume loss during chemotherapy had a significantly worse prognosis than those without loss.

Clinical impact of abdominal fat distribution measured by 3-D computed tomography volumetry on post-transplant renal function in recipients after living kidney transplantation: a retrospective study.

BACKGROUND: Excessive visceral fat may decrease renal function because of metabolic derangements. The aim of this study was to evaluate the impact of abdominal fat distribution on renal function of recipients after kidney transplantation using the visceral adipose tissue (VAT)/subcutaneous adipose tissue (SAT) ratio. METHODS: Seventy-nine patients underwent living kidney transplantation from 2009 to 2017. Patients without a correct measurement of VAT and SAT, follow-up of < 6 months, or with kidney transplant rejection or a virus infection were excluded. VAT and SAT were calculated automatically by 3-D volume analyzer software in recipients prior to living kidney transplantation. Our primary aim was to identify abdominal fat distribution measured by CT associated with renal dysfunction (estimate glomerular filtration rate; eGFR < 45) at 6 month post renal transplantation in recipient. RESULTS: Fifty-eight living kidney recipients were included in this retrospective study: 30 for the high VAT/SAT ratio group; 28 for the VAT/SAT low group. Multiple logistic regression analysis showed the VAT/SAT ratio and pre-donor eGFR were associated with eGFR < 45 ml/min/1.73 m2. An increase in VAT/SAT ratio was associated independently with the incidence of decreased renal function. CONCLUSION: This finding indicates that adipose tissue distribution is an important predictor of the outcome of living kidney transplantation in recipients.

Use of single-dose perioperative antimicrobial therapy is acceptable in recipients of living-donor renal transplants in the rituximab era.

OBJECTIVE: The aim of this study was to evaluate the efficacy of single-dose perioperative antimicrobial therapy as infection prophylaxis in recipients of living-donor renal transplants in the rituximab era. PATIENTS AND METHODS: Between 2009 and 2017, 84 recipients underwent living-donor renal transplantation (LDRT) at Okayama University Hospital; 3 with vascular/urinary complications requiring additional surgery were excluded from this analysis. Data including recipient characteristics, antimicrobial prophylaxis and administration of rituximab were retrospectively examined for an association with perioperative infections. Prophylactic antimicrobial agents, selected according to the Results of preoperative urine cultures, were administered just before incision. Perioperative infections, which consisted of surgical site infections, remote infections, and urinary tract infections, were defined as a positive culture indicating required administration of additional antimicrobial agents. RESULTS: Among the 81 recipients, prophylactic cefazolin, ampicillin/sulbactam, and others were administered to 66 (82%), 13 (16%), and 2 (3%) recipients, respectively. Twenty-one (26%) received single-dose antimicrobial prophylaxis, while 60 (74%) received multiple doses up to 7 days. Rituximab was used in 59 (72.8%) recipients. The incidence of urinary tract infection, surgical site infection and remote infection was 13 (16%), 1 (1%), and 0, respectively. Univariate analysis could not demonstrate any significant risk factors for postoperative urinary tract infections, including a single dose vs multiple doses of antimicrobial therapy (P = 0.069) and administration of rituximab (P = 0.717). CONCLUSIONS: Our data suggest that the use of single-dose perioperative antimicrobial therapy is acceptable for prophylaxis of infections in patients undergoing LDRT, even in the rituximab era.

Contrast-enhanced Computed Tomography-Guided Percutaneous Cryoablation of Renal Cell Carcinoma in a Renal Allograft: First Case in Asia.

Nephron-sparing treatment should be offered whenever possible to avoid dialysis in allograph cases. Cryoablation is a new treatment option for treating small-sized renal cell cancer (RCCs). We report a case of RCC arising in a kidney allograft treated by cryoablation. To our knowledge, this is the first case in Asia of RCC in a renal allograft treated using cryoablation. Contrast-enhanced CT-guided percutaneous renal needle biopsy and cryoablation were used to identify the RCC, which could not be identified by other techniques. The postoperative course was uneventful. Contrast-enhanced CT also showed no recurrence or metastases at the 6-month follow-up.

Comparison of the predictive value among inflammation-based scoring systems for bleomycin pulmonary toxicity in patients with germ cell tumors.

OBJECTIVE: To compare the predictive value of pretreatment inflammation-based scoring systems in patients with germ cell tumors receiving first-line bleomycin-based chemotherapy. METHODS: Retrospectively, we evaluated 57 patients with germ cell tumors. Bleomycin pulmonary toxicity was defined as the presence of asymptomatic decline in pulmonary function tests, pulmonary symptoms or interstitial pneumonia on computed tomography in the absence of infection. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, albumin-to-globulin ratio, Prognostic Nutritional Index, Glasgow Prognostic Score and C-reactive protein were measured in all patients. To assess the predictive ability of each scoring system, the area under the receiver operating characteristic curve was calculated, and multivariate analysis was carried out to identify the predictive scores associated with bleomycin pulmonary toxicity. RESULTS: Of the 57 patients, 15 patients developed bleomycin pulmonary toxicity. The neutrophil-to-lymphocyte ratio had the highest area under the curve value (0.763) of all inflammation-based scoring systems, followed by the Prognostic Nutritional Index (0.749). In multivariate analysis, the neutrophil-to-lymphocyte ratio (odds ratio 11.5; P = 0.009) and Prognostic Nutritional Index (odds ratio 9.07; P = 0.013) were independently associated with development of bleomycin pulmonary toxicity. As these two independent markers were combined, the area under the curve achieved the highest value (0.822). CONCLUSIONS: The present study shows that the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index are independent risk factors for development of bleomycin pulmonary toxicity. The combination of the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index seems to have superior predictive value compared with other inflammation-based scoring systems.

The assessment of renal cortex and parenchymal volume using automated CT volumetry for predicting renal function after donor nephrectomy.

BACKGROUND: Contrast-enhanced CT is necessary before donor nephrectomy and is usually combined with a Tc-99m-mercapto-acetyltriglycine (MAG3) scan to check split renal function (SRF). However, all transplant programs do not use MAG3 because of its high cost and exposure to radiation. We examined whether CT volumetry of the kidney can be a new tool for evaluating SRF. METHODS: Sixty-three patients underwent live donor nephrectomy. Patients without a 1.0 mm slice CT or follow-up for <12 months were excluded leaving 34 patients' data being analyzed. SRF was measured by MAG3. Split renal volume (SRV) was calculated automatically using volume analyzer software. The correlation between SRF and SRV was examined. The association between the donor's postoperative estimated glomerular filtration rate (eGFR) and predicted eGFR calculated by MAG3 or CT volumetry was analyzed at 1, 3, and 12 months post nephrectomy. RESULTS: Strong correlations were observed preoperatively in a Bland-Altman plot between SRF measured by MAG3 and either CT cortex or parenchymal volumetry. In addition, eGFR after donation correlated with SRF measured by MAG3 or CT volumetry. The correlation coefficients (R) for eGFR Mag3 split were 0.755, 0.615, and 0.763 at 1, 3 and 12 months, respectively. The corresponding R values for cortex volume split were 0.679, 0.638, and 0.747. Those for parenchymal volume split were 0.806, 0.592, and 0.764. CONCLUSION: Measuring kidney by CT volumetry is a cost-effective alternative to MAG3 for evaluating SRF and predicting postoperative donor renal function. Both cortex and parenchymal volumetry were similarly effective.

Burned-out Prostate Cancer ? Primary Metastatic Cancer Not Detected on Repeat Biopsy.

Metastatic prostate cancer (PCa) cases that cannot be detected on repeat prostate biopsy are extremely rare. Our patient was a 51-year-old Japanese man diagnosed as metastatic PCa by histopathological examination of lesions obtained bone biopsy and lymph node dissection. The primary tumor was not detected after repeated prostate biopsy. Metastatic PCa was diagnosed based on immunohistochemical staining: PSA, AR, P504S, and NKX3.1 of bone and lymph node with metastasis. We speculate that the primary PCa was "burned-out," demonstrating remote metastases with no apparent primary tumor in the prostate. Burned-out PCa may be difficult to diagnose and treat due to its rarity.

Ureterolithotripsy for a Ureteral Calculus at the Ureteroureterostomy of a Renal-transplant Recipient.

We describe a 40-year-old living-donor renal-transplant recipient who underwent successful ureterolithotripsy. He had been on hemodialysis for >15 years pre-transplant and underwent ureteroureterostomy along with the surgery. One year post-transplant, ultrasound examination demonstrated hydronephrosis, and CT showed a 6-mm ureteral calculus at the ureteroureterostomy site. No pain and no elevated serum creatinine were present. As the ureter was easily accessed, we performed a ureterolithotripsy, which would confirm whether a suture caused the calculus. Despite ureteral tortuosity, laser stone fragmentation succeeded. The calculus was completely removed with an antegrade guidewire. Mild postoperative ureteral stenosis resolved with a temporary ureteral stent without balloon dilation. Ureterolithotripsy is effective even in renal transplant recipients with ureteroureterostomy.

Robotic Renal Autotransplantation: First Case Outside of North America.

A 38-year-old woman with a 2.7-cm left ureteral stenosis requiring chronic ureteral stent exchange elected to undergo robotic renal autotransplantation. Left ureteropelvic junction obstruction (UPJO) was also suspected. Robotic donor nephrectomy contributed to the fine dissection for desmoplastic changes. The kidney was removed through a Gelport and examined on ice. UPJO was not seen. An end-to-side robotic anastomosis was created between the renal and external iliac vessels. The console time was 507 min, and the warm ischemia time was 4 min 5 sec. She became stent-free. Robotic renal autotransplantation is a new, minimally invasive approach to renal preservation.

The Efficacy of Rituximab in High-risk Renal Transplant Recipients.

Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

Common glycoproteins expressing polylactosamine-type glycans on matched patient primary and metastatic melanoma cells show different glycan profiles.

Recently, we reported comparative analysis of glycoproteins which express cancer-specific N-glycans on various cancer cells and identified 24 glycoproteins having polylactosamine (polyLacNAc)-type N-glycans that are abundantly present in malignant cells [ Mitsui et al., J. Pharm. Biomed. Anal. 2012 , 70 , 718 - 726 ]. In the present study, we applied the technique to comparative studies on common glycoproteins present in the matched patient primary and metastatic melanoma cell lines. Metastatic melanoma cells (WM266-4) contained a large amount of polyLacNAc-type N-glycans in comparison with primary melanoma cells (WM115). To identify the glycoproteins expressing these N-glycans, glycopeptides having polyLacNAc-type N-glycans were captured by a Datura stramonium agglutinin (DSA)-immobilized agarose column. The captured glycopeptides were analyzed by LC/MS after removing N-glycans, and some glycoproteins such as basigin, lysosome-associated membrane protein-1 (LAMP-1), and chondroitin sulfate proteoglycan 4 (CSPG4) were identified in both WM115 and WM266-4 cells. The expression level of polyLacNAc of CSPG4 in WM266-4 cells was significantly higher than that in WM115 cells. In addition, sulfation patterns of chondroitin sulfate (CS) chains in CSPG4 showed dramatic changes between these cell lines. These data show that characteristic glycans attached to common proteins observed in different stages of cancer cells will be useful markers for determining degree of malignancies of tumor cells.