Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab.

PURPOSE: Radiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. METHODS: We performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. RESULTS: Patients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. CONCLUSION: Radiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

6p21 translocation renal cell carcinoma: A case report.

6p21 translocation renal cell carcinoma (RCC) was newly classified in the WHO 2016 classification as a subtype of microphthalmia-associated transcription factor (MIT) family translocation RCC.A 42-year-old man was referred to our hospital with an asymptomatic solid mass in the right kidney identified during routine medical checkup. Computed tomography (CT) revealed a 14-mm buried-type solid mass accompanied by punctate calcification. CT-guided biopsy suggested clear-cell carcinoma. He underwent robotic-assisted partial nephrectomy. Pathological findings revealed 6p21 translocation RCC based on diffuse nuclear immunoreactivity for TFEB and TFEB gene rearrangement in tumor cells by FISH analysis.

Usefulness of picosecond pulse alexandrite laser treatment for nevus of Ota.

BACKGROUND AND AIMS: Recently, novel picosecond pulse duration lasers (ps-lasers) have been developed for the treatment of multicolored and recalcitrant tattoos, and safety and efficacy have been reported. We therefore hypothesized that ps-lasers could be an alternative treatment for dermal pigmented lesions. We performed a retrospective review to evaluate the efficacy and safety of the ps-laser for nevus of Ota. SUBJECTS AND METHODS: A retrospective photographic review of 15 patients with nevus of Ota was performed (ages from 10 months to 65 yr). The patients were treated in the Ohshiro Clinic with a picosecond-domain 755 nm alexandrite laser (ps-Alex laser) from June 2015 to August 2017. Improvement was evaluated as the percentage of pigmentation clearance comparing the baseline findings with those at 3 months after the final treatment using a four category grading scale: Poor, 0-24%; Fair, 25-49%; Good, 50-74%; and Excellent 75-100% improvement. Adverse events were also assessed. RESULTS: All patients obtained clinical improvement ranging from fair to excellent. All 5 patients whose primary treatment was the ps-Alex laser obtained excellent in 2-3 treatment sessions (average 2.5 sessions), and the average total treatment span was 10.0 months. Treatment with the ps-Alex laser caused transient hyperpigmentation followed by improvement to complete resolution at 3 months of follow-up. CONCLUSIONS: Our results suggest that 755 nm ps laser treatment is efficacious for the treatment of nevus of Ota with minimum adverse events.

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.

Diagnostic Ureteroscopy for Cases Clinically Suspected of Carcinoma in Situ of the Upper Urinary Tract.

　We elucidate the fate of cases clinically suspected of carcinoma in situ (Cis) of the upper tract with serial ureteroscopy. Of 143 patients who underwent ureteroscopy for suspected upper tract urothelial carcinoma (UTUC) between January 2008 and February 2016, 12 cases with consistently positive urine cytology and poorly detectable upper-tract malignancies by imaging were reviewed. In these 12 patients, 19 ureteroscopy procedures (25 renal units) were performed. Vesical random biopsy was performed before the 1st ureteroscopy to exclude malignancy of the bladder in all 12 cases. Median follow-up was 42 (13-67) months. Positive biopsy results at the 1st ureteroscopy were obtained in 3 (25%) patients and all were diagnosed wth Cis of the upper tract. Two (17%) of 9 patients who were negative or inconclusive at the 1st ureteroscopy were finally diagnosed as UTUC, but plural ureteroscopy procedures were needed for the diagnoses in both. Carcinoma of the bladder appeared in 5 (42%) patients during follow-up, despite the earlier ruling out of vesical malignancy. Four (33%) of those 5 patients never developed upper-tract urothelial carcinoma during follow-up. Caution is required before undertaking radical surgery for cases clinically suspected of Cis of the upper tract. In our experience, only 42% of such patients developed UTUC; another 33% eventually developed carcinoma of the bladder without UTUC.

A Combination Therapy of Partial Nephrectomy and Cryoablation Achieved Good Cancer Control and Renal Function in Bilateral Synchronous Renal Cell Carcinoma.

We report the case of a 58-year-old Japanese man with bilateral synchronous renal cell carcinoma (RCC). The diameters of the right and left tumors were 56 and 69 mm, respectively. Both tumors were endophytic. Cryoablation with prophylactic embolization was performed for the left tumor, and 1 month later, a right open partial nephrectomy was performed. No recurrence was observed during a 16-month follow-up, and the serum creatinine level has been stable. The prognosis of bilateral synchronous RCC is better than that of dialysis patients. The novel approach of combining cryoablation and partial nephrectomy can achieve good cancer control and renal function in bilateral RCC.

Pregnancy and delivery after myelomeningocele repair, ventriculoperitoneal shunt implantation, and augmentation cystoplasty.

INTRODUCTION: Management of pregnancy and delivery of a patient with a history of myelomeningocele requires a multidisciplinary team approach. CASE REPORT: We report a case of pregnancy and delivery by a patient who had a history of myelomeningocele surgical repair, ventriculoperitoneal (VP) shunt, and bladder augmentation enterocystoplasty. Regarding types of delivery style, anesthesiologists recommended a Cesarean section under general anesthesia. However, urologists recommended a vaginal delivery because they were concerned that she would require a nephrostomy because of severe adhesion between her uterus and the neobladder if she had a Cesarean section. DISCUSSION: In a pregnant myelomeningocele patient with a VP shunt, neurosurgeons are expected to manage the VP shunt during pregnancy and delivery. The possible types of delivery style and the best options based on the neurological deficit should be discussed together with a medical team.

Picosecond pulse duration laser treatment for dermal melanocytosis in Asians : A retrospective review.

Background and aims: Recently novel picosecond duration lasers (ps-lasers) have been developed for the treatment of multicolored and recalcitrant tattoos, and safety and efficacy have been reported. We therefore hypothesized that the ps-laser could be an alternative treatment for dermal pigmented lesions and performed a retrospective review to evaluate the efficacy and safety of the ps-laser. Subjects and methods: A retrospective photographic review of 10 patients with dermal pigmented lesions was performed (ages from 4 months to 52 yr), 6 nevus of Ota, 3 ectopic Mongolian spots and 1 Mongolian spots. The patients were treated in the Ohshiro Clinic with picosecond 755 nm alexandrite laser (ps-Alex laser) and picosecond 1064 nm Nd:YAG laser (ps-Nd:YAG laser) from April 2014 to December 2015 (ps-Alex laser, 7 patients; ps-Nd:YAG laser, 3 patients, 1 to 3 treatment sessions). Improvement was evaluated as percentage of pigmentation clearance comparing the baseline findings with those at 3 months after the final treatment using a five category grading scale: Poor, 0-24%; Fair, 25-49%; Good, 50-74%; Excellent, 75-94%; and Complete, 95-100% improvement. Adverse events were also assessed. Results: All ten patients obtained clinical improvement ranging from fair to excellent. Treatment with the ps-Alex laser caused transient hyperpigmentation followed by improvement to complete resolution at 3 months follow-up. The ps-Nd:YAG laser caused severe transient erythema and swelling but no post-inflammatory hyperpigmentation. Conclusions: Our results suggest that the 755 nm and 1064 nm ps-lasers are efficacious for the treatment of dermal pigment lesions, with minimum adverse events.

A Case of Metastatic Urachal Cancer Including a Neuroendocrine Component Treated with Gemcitabine, Cisplatin and Paclitaxel Combination Chemotherapy.

The present case report describes a case of recurrent and advanced urachal carcinoma including neuroendocrine features with iliac bone metastasis after partial cystectomy and adjuvant chemotherapy consisting of irinotecan and cisplatin in a 32-year-old man. He received gemcitabine/cisplatin/ paclitaxel (GCP) combination chemotherapy, consisting of gemcitabin (1,000mg/m2) on day 1, 8, cisplatin (70mg/m2) on day 1, and paclitaxel (80mg/m2) on day 1 and 8. After three cycles of chemotherapy, PET-CT showed complete regression of the disease. So the patient underwent total cystourethrectomy, and histological examination showed an almost complete pathological response. External beam radiation therapy was also given to the ileac bone metastasis regions. However, PET-CT taken 17 months after the external beam radiation showed multiple lung metastases. He received GCP chemotherapy again, which resulted in a complete response again after three cycles of chemotherapy. This is the first report on GCP chemotherapy used not only as a salvage chemotherapy but also as a rechallenge regimen for metastatic urachal cancer including a neuroendocrine component.

Factors Predicting Adhesion between Renal Capsule and Perinephric Adipose Tissue in Partial Nephrectomy.

In minimally invasive partial nephrectomy (MIPN), it is important to preoperatively predict the degree of difficulty of tumor resection. When severe adhesions occur between the renal capsule and perinephric adipose tissue, detachment can be difficult. Preoperative prediction of adhesion is thought to be useful in the selection of surgical procedure. Subjects were 63 patients of a single surgeon who had received MIPN between April 2008 and August 2013 at Okayama University Hospital. Of these patients, this study followed 47 in whom the presence or absence of adhesions between the renal capsule and perinephric adipose tissue was confirmed using intraoperative videos. Data collected included: sex, BMI, CT finding (presence of fi broids in perinephric adipose tissue), comorbidities and lifestyle. Adhesion was observed in 7 patients (14.9%). The mean operative time was 291.6 min in the adhesion group, and 226.3 min in the group without. The increased time in the adhesions group was significant (p＜0.05). Predictive factors were a positive CT finding for fibroid structure and comorbidity of hypertension (p＜0.05). In MIPN, difficulty of surgery can be affected by the presence of adhesion of the perinephric adipose tissue. Predicting such adhesion from preoperative CT is thus important.

Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy.

In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 × 10(10) , 1.0 × 10(11) , and 1.0 × 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 × 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199).

Ad-REIC Gene Therapy: Promising Results in a Patient with Metastatic CRPC Following Chemotherapy.

A 63-year-old man with metastatic castration-resistant prostate cancer (CRPC) was successfully treated for two years with in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), following chemotherapy. Ad-REIC mediates simultaneous induction of cancer-selective apoptosis and augmentation of antitumor immunity, and a Phase I/IIa clinical study on Ad-REIC has been conducted at Okayama University Hospital since January 2011. At the time of enrollment in December 2012, the patient presented with rapid progression of lymph node (LN) metastases. Two scheduled Ad-REIC injections and 10 additional Ad-REIC injections into metastatic pelvic and para-aortic LNs under CT guidance, with an average four weeks' interval, exhibited the potent direct and indirect effects of Ad-REIC as a therapeutic cancer vaccine. During the next 12 months, three additional injections into para-aortic LNs showing regrowth achieved adequate control of all metastatic LNs with prostate-specific antigen (PSA) decline, without any particular adverse events.

Correct calibration procedure for the Q-switched ruby laser and checking the treatment irradiation pattern.

BACKGROUND AND AIMS: There are many Q-switched lasers. The Q-switched ruby laser is the one most popularly used in dermatology, aesthetic surgery and plastic surgery, to remove pigmented lesions or tattoos. Correct and regular calibration of such a system is essential. However, some clinics fail to perform this with the excuse of having no measuring instrument (MI) in their offices or treatment rooms in some of their hospitals or clinics, or even the case of well-known medical universities in Japan. The present article explains the precise calibration procedure and beam pattern checking for the Q-switched ruby systems in the first author's clinic. RATIONALE: In the case of treatment with a medical laser, the calibration and the irradiated pattern (IP) check of the laser being used for treatment are the most important factors for treatment efficacy and safety. If these factors change, the treatment result could be different from that expected. Such kind of data are not acceptable as scientific information for a presentation or published paper. With such unreliable results and incorrect beam pattern, replicating such a study would be impossible Regular calibration check: In our clinic, we have 2 Q-switched ruby laser systems. On a daily basis, the beam patterns, both the optical axis of the beam and its treatment footprint, are checked on dedicated printed sheets and footprint paper, respectively, at the beginning of the day and after the last procedure. Every two weeks we calibrate our systems in-house using a precise MI. Every six months we calibrate the systems in-house with the MI, and then we send the systems back to the manufacturers for calibration. Once every year, we have our MI calibrated by an accredited facility in Japan. In this way, we are not only ensuring accurate and safe treatment for our patients, but we are also producing accurate system and treatment data which can be replicated by others, the basis of evidence-based medicine.

Ureteroscopic management of chronic unilateral hematuria: a single-center experience over 22 years.

OBJECTIVE: To analyze the short and long term safety and efficacy of ureteroscopic evaluation and management of chronic unilateral hematuria. METHODS: We retrospectively reviewed patients with chronic unilateral hematuria from 1987 to 2008. The distal to middle ureter was evaluated with a semi-rigid ureteroscope without a guidewire. Subsequently, the flexible ureteroscope was advanced into the upper ureter to the renal pelvis using a low-pressure automated irrigant system (Uromat™). Lesions identified ureteroscopically were treated with diathermy fulguration. RESULTS: One hundred and four (56 male, 48 female) patients were identified, with a median age of 37 (14-80) years and median follow-up of 139 (34-277) months. The median preoperative duration of gross hematuria was 5 (1-144) months. Endoscopic findings included 61 (56%) minute venous rupture (MVR; a venous bleeding without clear abnormalities), 21 (20%) hemangioma (vascular tumor-like structure), 3 (3%) varix (tortuous vein), 1 (1%) calculus and 18 (17%) no lesions. The incidence of "no lesions" was less in the recent 12 years (9%) than the first 10 years (27%), while the incidence of MVR increased from 40 to 66% (p<0.05). All patients were treated endoscopically. Immediate success rate was 96% (100% in the recent 12 years). Long-term recurrent gross hematuria rate was 7%. Six resolved spontaneously and only 1 required ureteroscopy, revealing a different bleeding site. CONCLUSION: Ureteroscopy and diathermy fulguration is highly useful for evaluation and treatment of chronic unilateral hematuria. Sophisticated technique and improved instrumentation contributes to a better outcome.

Laparoscopic-assisted tension-free vaginal mesh: an innovative approach to placing synthetic mesh: transvaginally for surgical correction of pelvic organ prolapse.

Polypropylene mesh implants for the correction of pelvic organ prolapse (POP) are now available in Japan. We developed an innovative approach for correcting POP by placing polypropylene mesh transvaginally with laparoscopic assistance. From June 2007 through March 2010, sixteen consecutive patients with symptomatic stage 2 or 3 pelvic organ prolapse underwent the laparoscopic-assisted tension-free vaginal mesh procedure at Okayama University Hospital. All patients were evaluated before and at 1, 3, 6, and 12 months after surgery. Female sexual function was also evaluated with the Female Sexual Function Index (FSFI). The procedure was performed successfully without significant complications. Fifteen of 16 patients were considered anatomically cured (93.8%) at 12 months postoperatively. One patient with a recurrent stage 3 vaginal vault prolapse required sacral colpopexy six months postoperatively. Total FSFI scores improved significantly from 10.3 ± 1.3 at baseline to 18.0 ± 1.2 at 12 months after surgery. The laparoscopic-assisted trans-vaginal mesh is a safe, effective, and simple procedure for POP repairs. The procedure not only restores anatomic relationships but also improves sexual function.

Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence.

OCT-4, which is also known as POU5f1, is a key regulator of self-renewal in embryonic stem cells. The new cancer stem cell concept proposes that the expression of such genes is potentially correlated with tumorigenesis and can affect some aspects of the cancer behavior, such as recurrence or metastasis. This study investigated the association between OCT-4 expression in cancer tissues obtained by transurethral surgery and the clinical data to clarify the involvement of OCT-4 in human bladder malignancy. Immunohistochemical analysis demonstrated that a positive rate of OCT-4 expression was significantly associated with the higher-grade cancer (G2 and G3) in comparison with that of the lower grade (G1). In addition, positive OCT-4 expression was significantly associated with the intra-bladder tumor recurrence after the operation. The staining intensity of OCT-4 expression was also correlated with tumor recurrence. These data indicate that positive OCT-4 expression may be involved in the development of high-grade bladder cancer and with the bladder cancer recurrence. This is the first study showing a correlation between the expression of OCT-4 and bladder cancer recurrence. OCT-4 may be a valuable clinical marker for the progression of bladder cancer and may be an attractive therapeutic target for the development of new medicines for the treatment of malignancy.

Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging.

The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissue-specific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an ~6- and ~17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adeno-associated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0±1.0- and 15.9±0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

Naftopidil and propiverine hydrochloride for treatment of male lower urinary tract symptoms suggestive of benign prostatic hyperplasia and concomitant overactive bladder: a prospective randomized controlled study.

OBJECTIVE: To assess the efficacy and safety of propiverine hydrochloride (antimuscarinic), naftopidil (alpha(1)-adrenoceptor antagonist) or both in patients with male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia and concomitant overactive bladder (OAB). MATERIAL AND METHODS: Men aged at least 50 years who had a total International Prostate Symptom Score (IPSS) of 8 or higher and bladder dairy documenting micturition frequency (more than eight micturitions/24 h) and urgency (more than one episode/24 h), with or without urgency urinary incontinence were randomized into three groups: group N, naftopidil (50 mg once daily) only; group P, propiverine hydrochloride (20 mg once daily); and group NP, naftopidil (50 mg once daily) plus propiverine hydrochloride (20 mg once daily) for a 4-week treatment regimen. RESULTS: A total of 66 men, including 20 in group N, 23 in group P and 23 in group NP, were treated and 58 (87.9%) completed the 4 weeks of treatment. IPSS improved significantly in groups N and NP. Urinary frequency improved significantly in groups P and NP. Postvoid residual urine volume increased significantly in groups P and NP. Significant improvements in urgency episodes were noted in each group. One patient in group P required catheterization owing to acute urinary retention and another stopped medication because of difficulty in voiding. CONCLUSION: These results suggest that each treatment showed effectiveness for male LUTS with OAB. However, there are some possibilities of adverse effects with propiverine hydrochloride monotherapy.