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Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8

Many types of rare cancers develop in the genitourinary tract. However, guidelines underlying clinical practice have not been established due to the lack of nationwide epidemiological data for many of these cancers. While epidemiological data in Western countries has been revealed by population-based study, it has been attempted to build the data using hospital-based cancer registry(HBCR)in Japan. The data from nationwide designated cancer care hospitals and other core cancer care hospitals includes the patients' demographics, tumor characteristics, and the first course of treatment. Although HBCR data does not reflect the status of clinical practice at all hospitals, it may be a useful tool for understanding the actual practice of rare cancers in Japan. We focused on the current status and prospects of penile and urachal cancer, which are relatively common in daily clinical practice. A standard of care has not been established for penile and urachal cancer patients, and the prognoses of those patients are poor. Recently, genomic analysis using a next-generation sequencer has been actively performed for many types of cancer. It is an important future task to establish a standard of care for patients with rare cancers based on molecular biological characteristics through active genomic analysis.

Radical cystectomy is the gold standard treatment for muscle invasive bladder cancer, but some patients have medically inoperable disease or refuse cystectomy to preserve their bladder function. Bladder preservation therapy with transurethral resection of the bladder tumor and concurrent chemoradiotherapy, known as trimodal treatment, is regarded to be a curative-intent alternative to radical cystectomy for patients with muscle invasive bladder cancer during the past decade. After the development of immune checkpoint inhibitors, a world-changing breakthrough occurred in the field of metastatic urothelial carcinoma and many clinical trials have been conducted against non-muscle invasive bladder cancer. Interestingly, preclinical and clinical studies against other malignancies have shown that immune checkpoint inhibitors interact with the radiation-induced immune reaction. As half of the patients with muscle invasive bladder cancer are elderly, and some have renal dysfunction, not only as comorbidity but also because of hydronephrosis caused by their tumors, immune checkpoint inhibitors are expected to become part of a new therapeutic approach for combination treatment with radiotherapy. Accordingly, clinical trials testing immune checkpoint inhibitors have been initiated to preserve bladder for muscle invasive bladder cancer patients using radiation and immune checkpoint inhibitors with/without chemotherapy. The objective of this review is to summarize the evidence of trimodal therapy for muscle invasive bladder cancer during the past decade and to discuss the future directions of bladder preservation therapy in immuno-oncology era.

Objective Japan’s national database of hospital-based cancer registries is estimated to cover ~67% of all new cancer cases. Using this database, we analyzed the characteristics of the recently diagnosed testicular malignancy. Methods We obtained data for 6510 adult testicular malignancy patients diagnosed in 2012–2015. The distributions of patient ages, histological diagnoses and testicular germ cell tumor hospital care volumes were determined. Results The most common histology was seminoma (60.3% of all testicular malignancies), followed by non-seminoma (24.1%) and diffuse large B-cell lymphoma (13.1%). The median and mean ages of the testicular germ cell tumor patients were high at 38 and 39.8 years, respectively. The age distribution peaked at 30–40 years, followed by 40–50 years. Approximately 18% of testicular germ cell tumor patients were ≥50 years. The ages of the diffuse large B-cell lymphoma patients peaked at 70–80 years (mean 67.7 years). When the analysis was limited to the testicular germ cell tumor patients who received first-course cancer treatment at the participating hospitals, the number of high-volume hospitals with ≥20 testicular germ cell tumor care volume was limited to 61 (10.0% of the 605 hospitals that treated ≥1 testicular germ cell tumor patient). However, when the patients who changed hospitals during treatment or relapsed after treatment completion were analyzed together, the number of high-volume hospitals increased to 104 (17.0% of 612 hospitals). Conclusion The testicular germ cell tumor patients’ mean age was nearly 40 years. The proportions of older testicular germ cell tumor patients and diffuse large B-cell lymphoma patients were higher than previously thought. The reasons for this trend are unknown, but it is important to address the trend identified herein in a country with a super-aging population.

Background: Urological education is as important as surgical training for undergraduates. However, those in undergraduate medical schools have less exposure to surgery and urology as their curriculum focuses more on clinical skills, particularly community-based healthcare for a super-aging society. This study aimed to evaluate whether urologic hands-on training could encourage surgical and urological interest in medical undergraduate students. Methods: A one-day elective program in urologic surgery at the University of Tsukuba, particularly in robotic, laparoscopic, and endoscopic surgeries, was offered to 58 fourth-year medical students in 2018 and 2019, prior to their clinical clerkship. The average age of participants was 22 (range: 21–25) years. We assessed scores (1–5 Likert-type items) in training activity, interest in surgery, and interest in urology before and after the course. Results: Before attending the program, average scores in interest in urology were 3.53 in 2018 and 3.15 in 2019. After training, the total likely scores of this program in 2018 and 2019 were 4.59 and 4.76, respectively. The likely scores in surgery increased after the program; however, this was not significantly different to that prior to the program. However, the average interest scores in urology were significantly increased to 3.91±0.63 (p

We conducted the present phase I/IIa positron emission tomography (PET) imaging study with 89Zr conjugated with desferroxamine-IAB2M (89Zr-Df-IAB2M), an anti-prostate-specific membrane-antigen minibody, to assess its safety and feasibility in patients with urological cancer. 89Zr-Df-IAB2M was synthetized by IBA Molecular (Somerset, NJ, USA) and transported by air to Tsukuba Molecular Imaging Center (Tsukuba, Ibaraki, Japan).17 patients received 74 MBq (2 mCi) of 89Zr-Df-IAB2M at total mass doses of 10 mg. Whole-body and plasma clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated. We also preliminarily tested the performance of 89Zr-immuno-PET imaging for 13 patients with prostate cancer and 4 patients with other urological cancer. The administration of 89Zr-Df-IAB2M was well-tolerated, and no infusion-related reactions were observed in any patient. No adverse events were noted in the laboratory parameters, vital signs, or other parameters. The plasma clearance was biphasic, with an initial rapid phase (t 1/2 fast: 10.1 ± 3.4 h) followed by a slow phase (t 1/2 slow: 49.0 ± 22.7 h). The half-life of radioactivity in the whole body (WB t1/2) was 237 ± 9 h. The highest absorbed radiation dose was 1.67 mGy/MBq, observed in the liver and kidney. The effective dose was 0.68 ± 0.08 mSv/MBq. The radiation dose rate at 0.5 m distance from the patient was 8.67 µSv/h on day 1, and decreased to 2.26 µSv/h at 5 days after injection. Both bone and lymph node metastases were detected with 89Zr-Df-IAB2M by 24 or 48 h imaging. Administration of 89Zr-Df-IAB2M was well-tolerated and safe in terms of adverse events and radiation exposure and protection. 89Zr-Df-IAB2M is feasible for usage by long-distance transportation. Further studies are warranted for analysis of its use for tumor lesion detection (UMIN000015356).

To elucidate the clinicopathological features, hospital-based care volume and prognoses associated with primary retroperitoneal sarcoma (PRS). Clinical data on PRS cases, diagnosed from 2008 to 2009 (cohort A) and from 2012 to 2015 (cohort B), were obtained from the national hospital-based cancer registry in Japan. Since data on survival, 5 years after PRS diagnosis, were available only for cohort A, patient prognoses were analyzed in this group alone. The numbers of participating hospitals were 154 in cohort A and 537 in cohort B. In total, 380 and 2011 patients with PRS were identified in cohorts A and B, respectively. The incidence of PRS among all the registered urogenital malignancies was 0.52% (2391/462,866). Liposarcoma was the most commonly observed PRS subtype (55.8%), followed by leiomyosarcoma (19.0%). In cohort A, the 5-year overall survival (OS) was 40.4%. The 5-year OS associated with stage I (n = 107), stages II and III (n = 61), and stage IV (n = 59) disease were 59%, 39%, and 6%, respectively. Only two institutions treated over ten patients per year in each cohort. When institutions were divided by hospital care volume (8 hospitals with ≥ = 3 cases and 149 with

Objectives To identify the prognosis of pure non-urothelial carcinoma (non-UC) of bladder and to compare them with those of pure urothelial carcinoma (UC). Methods We used Japan’s nationwide hospital-based cancer registry data to extract histologically confirmed pure non-UC and UC cases of bladder diagnosed in 2008–2009. We estimated the 5-year overall survival (OS) by a Kaplan–Meier analysis. Results A total of 8094 patients with confirmed histological subtypes of bladder cancer were identified. The most common pure non-UC was squamous cell carcinoma (SQ, n = 192, 2.4%) followed by adenocarcinoma (AC, n = 138, 1.7%) and small cell neuroendocrine carcinoma (SmC, n = 54, 0.7%). The proportion of female patients (48%) was significantly higher in the SQ group compared with the pure UC group (P Conclusion The prognosis of pure non-UC was worse than that of pure UC, especially in the stage I and III non-UC patients. To improve these patients’ oncologic outcomes, a more aggressive surgical approach may be necessary in stage I patients with non-UC, especially in pure SQ.

Objectives To identify the clinicopathological features of malignant urachal tumor in Japan, and analyze the 5-year overall survival of malignant urachal tumor patients. Methods We used the hospital-based cancer registry data to extract malignant urachal tumor cases that were diagnosed in 2008-2009 and 2012-2015, histologically confirmed, and received the first course of treatment. We analyzed the 5-year overall survival using the 2008-2009 cohort's data. Results We identified 456 patients, and malignant urachal tumor accounted for 0.4% of all malignant bladder cancers. The median age was 61 years (range 2-97), and 66% were men. The most common histology was adenocarcinoma (80%), followed by urothelial carcinoma (11%) and squamous cell carcinoma (3%). The proportions of patients were: 19% Ta/Tis/T1N0M0, 55% T2-3N0M0, 13% T4/N+ and 13% M+. Regarding the initial treatment, the proportions of surgery alone were 79% and 33% in cases of T3 or less N0M0 and T4/N+, respectively. The proportion of combination therapy including surgery and chemotherapy were 13% and 44% in T2-3N0M0 and T4/N+, respectively. Radiation therapy was not common at any stage. In the 2008-2009 cohort, the 5-year overall survival rate in Ta/Tis/T1N0M0, T2-3N0M0, T4/N+ and M+ were 60%, 64%, 63% and 12%, respectively. Conclusions Malignant urachal tumors are quite rare in Japan, and most of those without metastasis are likely to be treated by surgery alone, even at advanced stages. A standard of care must be established for malignant urachal tumor patients at advanced stages or with metastasis, as the prognosis of these patients can be poor.

OBJECTIVES We aimed to compare the diffusion capacity of carbon monoxide (DLCO), which was adjusted using the two equations the Cotes method and the Dinakara method, to assess bleomycin-induced lung injury in testicular cancer patients preparing for post-chemotherapy surgery. METHODS Between November 1990 and October 2018, 89 patients with advanced testicular cancer were recruited into the study. All patients received chemotherapy and underwent DLCO measurements using the single-breath technique prior to surgery for residual tumor removal. RESULTS The mean DLCO adjusted for hemoglobin using the Cotes and Dinakara methods was 69.5% and 86.0%, respectively (P < 0.001). According to the Cotes method, adjusted DLCO was severely diminished to below 65% in 40 patients (45%), whereas this proportion was only 16% according to the Dinakara method. We observed a significant correlation between hemoglobin levels and DLCO adjusted using the Cotes method (P < 0.001), but not using the Dinakara method. Four patients received a clinical diagnosis of bleomycin-induced pneumonitis (BIP), and all patients recovered after oral steroid therapy or observation. The DLCO adjusted by either methods was not well correlated with the development of BIP. No patients had major postoperative respiratory complications. CONCLUSIONS We found that Cotes-adjusted DLCO may be influenced by anemia. We recommend the addition of Dinakara-adjusted DLCO, along with chest computed tomography, for preoperative risk assessment.

A 78-year-old man was referred to Tsukuba University Hospital for right hydronephrosis. He had undergone ureteroscopy and ureteral stenting in another hospital, but no tumor was revealed in renal pelvis and ureter. The urinary cytology was negative. Computed tomography (CT) revealed remarkable thickening of right renal pelvis and ureter wall. CT also showed para-aortic, iliac, supraclavicular and mediastinal lymph node (LN) swelling. 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) revealed high uptake at thickened right renal pelvis and ureter wall and enlarged LNs. The soluble interleukin-2 receptor was elevated to 1,110 U/ml (normal range: 613 U/ml). Those findings suggested that the malignant lymphoma originated from the renal pelvis and ureter rather than urothelial cancer. Therefore we performed open biopsy of iliac LN and periureteral tissue. The pathological diagnosis was mucosa associated lymphoid tissue (MALT) lymphoma. The patient was trasferred to the department of hematology, and treated with rituximab and bendamustine. After 6 courses of chemotherapy, swelling of renal pelvis, ureter and LN was markedly reduced. The ureteral sent could be removed. MALT lymphoma of the upper urinary tract is extremely rare and pretreatment diagnosis is difficult. In 8 of 11 reported cases, the diagnosis was made by nephroureterectomy. In our cases, open biopsy could avoid nephroureterectomy.

A 78-year-old man presented with swelling of para-aortic and left iliac lymph nodes (LNs). He had undergone left high orchiectomy 10 years ago. He was diagnosed with stage I seminoma, and was managed with active surveillance. Eight years later, the follow-up computed tomography (CT) revealed para-aortic LN swelling, but the patient refused further treatment. He complained of left lower extremity edema 10 years after orchiectomy. CT showed enlargement of both LNs, especially, diameter of left iliac lymph nodes was up to 9 cm. He was referred to our hospital. LDH was slightly increased to 261 IU/1, but α-fetoprotein, and total and free beta human chorionic gonadotropin were within normal limits. Results of pathological review of the testicular tumor was also seminoma. The treatment with etoposide and cisplatin (EP) was started under the diagnosis of late relapse of seminoma. However, CT after 1 course of EP showed no shrinkage of LN metastases. At this time, soluble interleukin-2 receptor (sIL-2R) was elevated up to 5,090 U/ml (normal range: 613 U/ml). Needle biopsy from pelvic LN was performed on suspicion of metachronous malignant lymphoma. The pathological diagnosis was mantle cell lymphoma. The patient was transferred to the department of hematology, and treated successfully with rituximab and bendamustine. When LN swelling is seen after long-term active surveillance, there is a possibility of late relapse. However, metachronous malignant lymphoma also should be considered in an elderly patient.

Objective We conducted the present study to elucidate the clinical presentation, treatment outcomes and risk factors for the development of metachronous brain metastasis at a single progressive disease site, the so-called isolated brain metastasis, in patients with testicular germ cell tumors. Methods To identify metachronous brain metastasis in a timely manner, brain imaging was performed when the re-elevation of tumor markers was observed during chemotherapy, even in patients who were free from central nervous system symptoms. The medical records of 147 patients with metastatic germ cell tumors who were treated between 1991 and 2015 were retrospectively reviewed. Results Eight (5.4%) of the 147 patients presented synchronous brain metastasis. Of these, five patients suffered from metachronous brain metastasis relapse. An additional nine patients developed metachronous brain metastasis during or after chemotherapy. Ten of the 14 patients with metachronous brain metastasis did not have central nervous system symptoms. Eight (57%) patients had isolated brain metastasis. Ten patients underwent multimodal treatments, predominantly chemotherapy and radiotherapy. The 3-year overall survival of all 14 patients was 34.6%, but that of the patients with isolated brain metastasis was high as 66.7%. The development of metachronous brain metastasis was associated with a choriocarcinoma element at the primary site and an human chorionic gonadotropin level of >50 000 IU/L and brain metastasis at the initial diagnosis. Conclusions In our series, we identified isolated brain metastasis in 57% of the metachronous brain metastasis patients. The monitoring of tumor markers and appropriate brain imaging are mandatory for the diagnosis of isolated brain relapse, which is associated with a higher rate of long-term survival.

Objective DNA methyltransferase 3-like plays an important role in germ cell development. The aim of this study was to analyse the DNA methyltransferase 3-like protein expression in testicular germ cell tumors. Methods The immunohistochemical expression of DNA methyltransferase 3-like was examined in 86 testicular germ cell tumor specimens in various clinical settings. The association between DNA methyltransferase 3-like expression and disease stage was analyzed. Results DNA methyltransferase 3-like was strongly expressed in seven of the eight pure embryonal carcinomas (87.5%). Partial DNA methyltransferase 3-like expression was observed in 6 of 23 (26.1%) pure seminomas. Various degrees of DNA methyltransferase 3-like expression was observed in all four pure yolk sac tumors, of which three were prepubertal yolk sac tumors. In mixed germ cell tumors, DNA methyltransferase 3-like protein was expressed in various degrees in elements of the embryonal carcinoma (14/18, 77.8%), seminoma (4/11, 36.4%), teratoma (4/7, 57.1%) and choriocarcinoma (3/3, 100%) but not in the yolk sac tumors (0/4). When DNA methyltransferase 3-like expression was analyzed according to disease stages, it was significantly correlated with advanced seminoma rather than Stage I seminoma (46.2 vs. 0%, P = 0.019), whereas there was no significant difference in the DNA methyltransferase 3-like-positive proportion between Stage I and advanced disease in the mixed germ cell tumors. Conclusions Our findings suggest that DNA methyltransferase 3-like protein may play roles not only in the development of embryonal carcinoma but also in the development of advanced pure seminoma and pure yolk sac tumor.

Background We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC). Methods We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated. Results PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9–4.4), 2.1 months (1.2–5.5), and 3.0 months (2.0–4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7–30.9), 30.9 months (11.8–47.4), and 10.2 months (8.6–20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin

Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.

p16INK4a (p16) is a key molecule in bladder tumor (BT) development. We previously reported that a p16 antitumor peptide inhibited the growth of subcutaneous BT grafts in mice through restoration of p16 function using a Wr-T peptide transporter system. In the present study, the efficacy of mouse p16 peptide administration in a mouse lung metastasis model for BT and also the toxicity of peptides by cardiac peptide injection were evaluated. Mouse lung metastases were developed by tail vein injection of a p16-deficient MBT-2 cell line. Six-week-old C3H/He female mice were divided into three groups: A control group (n=12) receiving no treatment; a group treated once on the 3rd experimental day (n=12); and a group treated three times on the 3rd, 5th and 7th experimental days (n=10) with an injection of a mixture of 80 nmol mouse p16 peptide and 50 nmol Wr-T into the tail vein. At the 14th experimental day, the lung metastases were histologically evaluated. Lung metastases were observed in 100% (12/12), 41.7% (5/12) and 30% (3/10) of the aforementioned three groups, respectively. The number and area of metastatic lung tumors were significantly different between control and treatment groups (control vs. triple treatment group for the number and area, P=0.0029 and P=0.0296, respectively). Immunohistochemistry demonstrated that phosphorylated retinoblastoma (Rb) protein was decreased in lung tumors of the treatment groups, compared with the control group. The toxicity of p16 peptide transduction was evaluated by using low-dose treatment (three dosages) and high-dose treatment (two dosages) on three male and three female C3H/He mice in early and late experimental phases. In low and high dose groups, no notable change was determined in body weight or blood analyses in early or late phases following mouse p16 peptide administration. In addition, no notable change was observed histologically in bone marrow of treatment groups. To conclude, systemic p16 peptide administration decreased lung tumor development in a mouse metastatic BT model without severe adverse events, as assessed by blood analyses and histological evaluation.

We conducted the present phase I/IIa positron emission tomography (PET) imaging study withThe administration ofAdministration of

A 70-year-old man was admitted with complaint of gross hematuria. Cystoscopy and computed tomography (CT) revealed a 2.5 cm nodular tumor in the urinary bladder. Pathological diagnosis after the transurethral resection of bladder tumor (TURBT) was invasive urothelial cancer with trophoblastic differentiation of pT1. The tumor was positively stained with human chorionic gonadotropin (HCG). The serum HCG level was 12.8 IU/l in the fourth week after TURBT, and it increased to 35.7 IU/l in the 20th week after TURBT. However, radiological examination at this point did not reveal tumor recurrence or metastases. Three months later, the patient coughed up bloody sputum. Lung metastases (up to 2.4 cm) were identified, and they were surgically removed. The pathological specimen consisted of syncytiotrophoblastic giant cells with hemorrhage and necrosis, but no urothelial cancer element. Because the lung and lymph node metastases developed soon after surgery, chemotherapy was planned. Because the patient had impaired renal function with a creatinine clearance of 33.7 ml/min, we selected combination chemotherapy with gemcitabine and oxaliplatin (GEMOX) rather than cisplatin -based chemotherapy. CT after two courses of GEMOX showed stable disease, but HCG levels markedly decreased from 1,240 IU/l to 7.9 IU/l. This marker of response continued through six courses of GEMOX. Then, the chemotherapy was discontinued due to grade 2 neuropathy. He died of cancer 12 months after development of metastases. Autopsy revealed only tumor cells with trophoblastic differentiation, but no urothelial carcinoma in multiple metastatic sites.

A 68-year-old Japanese man was referred to Tsukuba University Hospital for bladder cancer treatment. He had undergone a transurethral resection of a bladder tumor (TURBT) at a local hospital, but the pathological specimen did not contain muscle layer. Abdominal computed tomography (CT) and magnetic resonance imaging revealed a 3 cm non-papillary bladder tumor with muscle invasion, but there was no apparent calcification. The patient underwent re-TURBT at our hospital for diagnosis and staging. A non-papillary pedunculated tumor was identified in the bladder dome, and it contained a small papillary part. The non-papillary part was stony hard and difficult to cut with electrocautery, whereas the small papillary part was easily cut. Histologically, the non-papillary part was composed of sarcomatous elements including osteosarcoma, chondrosarcoma, and spindle cell sarcoma. The papillary part was composed of high-grade urothelial carcinoma and spindle cell sarcoma. Muscularis propria was not present in the specimen. Since the staging study with CT was negative for metastases, we performed a total cystectomy with an ileal conduit under the clinical diagnosis of muscle-invasive sarcomatoid urothelial carcinoma. The pathological findings were identical to those of the re-TURBT specimens, and our diagnosis was pTxN0 sarcomatoid urothelial carcinoma. The patient received adjuvant chemotherapy with two courses of gemcitabine and cisplatin. There was neither recurrence nor metastases during the 20-month follow-up. Reports of sarcomatoid urothelial carcinoma of the bladder with an osteosarcoma element are rare, and only eight other cases hane been reported in the Japanese literature.

A 54-year-old woman presented withtransient back pain. She was diagnosed withleiomyosarcoma of the inferior vena cava (IVC) by computed tomography (CT) and was referred to our hospital. Contrastenhanced CT revealed a mass (38×42 mm) located in the retroperitoneal space along the course of the right ovarian vein. The mass compressed the IVC into a crescent shape. A tumor thrombus was also found in the IVC. 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) revealed high uptake at the caudal side of the tumor. These radiological findings strongly suggested the diagnosis of leiomyosarcoma arising from the right ovarian vein. She underwent tumor resection with right nephrectomy, IVC resection, and IVC patch reconstruction without any notable events after surgery. Histopathological diagnosis was leiomyosarcoma arising from the ovarian vein, not from the IVC. Two months after the surgery, CT revealed multiple pulmonary metastases and a single liver metastasis. The patient was referred to another hospital for further treatment. She was treated with chemotherapy and was alive with disease at 14 months after the surgery.

Deep vein thrombus (DVT) in a patient awaiting surgery is a considerable source of pulmonary embolisms (PEs) during the surgical period, but screening for DVTs has not been emphasized. This retrospective study was conducted to identify factors associated with a positive D-dimer result and DVT diagnosis in order to evaluate the usefulness of DVT screening for patients awaiting surgery. A total of 1,061 patients (872 males, 189 females) underwent D-dimer testing prior to urological surgery at Tsukuba University Hospital between April 2013 and March 2016. Factors associated with a positive D-dimer result and DVT diagnosis were determined by a univariate analysis. Among the 75 patients with a positive Ddimer result, venousultras onography of the lower extremitieswasperformed in 69 patientsand DVT was diagnosed in 14 patients. The overall true-positive rate of D-dimer was 20. 3% (14/69), and it was significantly higher in the females (males11.3% vsfemales50% ; p＝0.0021). Age, body mass index and Ddimer value were not associated with the true-positive D-dimer result. Among the 1,061 patients, DVT was significantly more likely to be diagnosed in elderly patients (median age 73.5 vs 67 yrs, p＝0.0087) and females(males0. 69% vsfemales4. 23% ; p＝0. 0010). Among the three patientswith an acute-phase thrombus, two postponed surgery and required anti-thrombus therapy, and the other patient underwent the implantation of an inferior vena cava filter in order to undergo surgery on schedule. No PE occurred during the surgical period. These results indicate that DVT screening for patients awaiting surgery is useful and should be considered as part of the prevention of PEs during the surgical period.

Histologically pure seminoma with elevated alpha-fetoprotein (AFP), so-called AFP-positive seminoma, is rare. It is recommended that patients with AFP-positive seminoma be managed as non-seminoma, but the clinical features and prognosis of this disease are not fully understood. In this study, we retrospectively analyzed 6 cases of metastatic AFP-positive seminoma at Tsukuba University Hospital (TUH). AFP was elevated before induction chemotherapy in 4 patients with an average of 1,372 ng/ml. In the remaining 2 patients, AFP became elevated during or after induction chemotherapy. In all 4 patients examined, AFPL3% was abnormally increased. As induction chemotherapy, all patients received bleomycin, etoposide and cisplatin (BEP), which was then followed by etoposide, ifosfamide and cisplatin (VIP) in 3 patients. After or during induction chemotherapy, 3 patients suffered from disease progression accompanied by AFP elevation. All 3 were treated by salvage chemotherapy and surgery. Four patients underwent retroperitoneal lymph node dissection (RPLND) after induction chemotherapy ; the pathological findings were necrosis in 3 patients, and viable nonseminomatous cancer in 1 patient. Furthermore, RPLND was performed as salvage surgery in 3 patients ; the pathological findings were necrosis, viable nonseminomatous cancer and teratoma with malignant transformation, respectively. The 5-year progression-free survival rate of the 6 patients was 50%, which is somewhat inferior to that of poor-prognosis non-seminoma patients treated at TUH. One patient ultimately died of cancer, and the remaining 5 are in remission with a median follow-up of 58 months. The present study demonstrates that AFP-positive seminoma patients have a higher risk of relapse compared to non-seminoma patients.

432 Background: Activation of FGFR signals in bladder cancer is frequently observed. Previous study reported that infiltration of tumor immune cells is suppressed in FGFR3 mutated bladder cancer. In this study, we elucidate the relationship between molecular mechanism of FGFR activation and tumor immune environment in bladder cancer. Methods: We analyzed 103 tissues of bladder cancer patients. Detection of somatic mutations were performed by target sequencing and gene expressions were analyzed by RNA-seq. Immunohistochemical staining of CD8 was performed for evaluating tumor-infiltrating lymphocytes. We compared the relationship between molecular mechanism of FGFR activation and tumor immune environment. Results: FGFR3 activated mutation or fusion was found in 37 cases (36%). FGFR1 overexpression was found in 10 cases (10%). FGFR3 activated mutation or fusion and FGFR1 overexpression were mutually exclusive. Tumors harboring FGFR3 mutation showed less infiltration of CD8 positive cells ( p = 0.01) and low PD-L1 expression ( p = 0.08) compared to those without. On the other hand, tumors with FGFR1 overexpression showed more infiltration of CD8 positive cells ( p = 0.06) and high PD-L1 expression ( p = 0.02). Conclusions: Clinicopathological features and intratumor immune environment of bladder cancer is different depending on the molecular mechanism of FGFR activation. These results suggest a possible association between molecular mechanism of FGFR activation and sensitivity of immunotherapy.

579 Background: Accurate staging in patients with urothelial carcinoma (UC) of the bladder (UCB) or the upper urinary tract (UTUC) is essential for planning the appropriate treatment strategy. Although an underestimation of the pathological stage may result in missing the opportunity to perform preoperative treatment, the actual rate of the discrepancy between the clinical and pathological stages in UC is not known. Methods: We used Hospital-Based Cancer Registry (HBCR) data in Japan to extract 3,747 cases of UCB and 6,831 cases of UTUC with cT1-4N0M0 that were diagnosed in 2012–2015, histologically confirmed, and treated with radical surgery. We excluded patients who received chemotherapy or radiotherapy and those with an unknown clinical or pathological stage. Results: The proportion of UCB patients whose pathological stage was up-staged was 25%, and that of the UTUC patients was 30%. Among the patients with cT1 at each tumor location, up-staging to muscle-invasive cancer occurred in 30.9% (UCB, n=1132: pT2, 21.6%; pT3, 7.9%; pT4, 1.5%) and 37.5% (UTUC, n=2526: pT2, 16.9%; pT3, 20.2%; pT4, 0.4%), respectively. In particular, in the group of UTUC patients with cT1, the proportion of up-staging for pT3 was higher than that in the group of UCB patients with cT1. In the cases with cTis, up-staging to muscle-invasive cancer occurred in 10.5% (UCB, n=391: pT2, 6.9%; pT3, 1.8%; pT4, 1.8%) and 18.5% (UTUC, n=872: pT2, 9.7%; pT3, 8.7%). In contrast, the proportion of down-staging to non-muscle-invasive cancer in cases with cT2 or higher was 12% in the UCB group (n=2291) and 15% in the UTUC group (n=504). Conclusions: Among UC patients, up-staging from non-muscle-invasive cancer to muscle-invasive cancer is relatively common, and the frequency of this discrepancy in clinical and pathological stages tends to be especially higher in UTUC patients. More accurate diagnostic imaging techniques and biomarkers are urgently needed for the identification of the appropriate UC candidates for preoperative treatment.

ObjectiveTP53, a well-known tumor-suppressor gene in bladder carcinogenesis, has a functional single-nucleotide polymorphism on codon 72. The aim of this study was to elucidate the association between TP53 codon 72 polymorphism and somatic mutations in bladder cancer.Material and methodsGermline TP53 codon 72 polymorphism and somatic mutations of 50 cancer-associated genes were analyzed in 103 bladder cancer patients (59 non-muscle-invasive and 44 muscle-invasive), using Taqman genotyping assay and target sequencing, respectively. The expression of FGF-FGFR signaling pathway genes was analyzed by RNA sequencing of frozen tissue.ResultsThe allele frequency of TP53 codon 72 in our cohort was 37, 42, and 21% for Arg/Arg, Arg/Pro, and Pro/Pro, respectively. Interestingly, the prevalence of FGFR3 mutation was higher in patients with the Arg allele, whereas that of the RAS mutation was higher in patients without the Arg allele. The same association was seen in non-muscle-invasive bladder cancer (NMIBC) patients and no differences were observed in muscle-invasive bladder cancer patients. In NMIBC, FGFR1 expression was higher in patients without the Arg allele and FGFR3 expression was higher in patients with the Arg allele.ConclusionThe germline TP53 codon 72 polymorphism was associated with mutations of FGFR3 or RAS and expression of FGFR1 and FGFR3 in NMIBC. These findings provide new insight into the molecular mechanisms underlying the influence of the genetic background on carcinogenesis in bladder cancer.

421 Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.

Chronic kidney disease (CKD) is a major long-term morbidity of testicular cancer (TC) survivors cured by cisplatin-based chemotherapy. We conducted the present study to elucidate the usefulness of cystatin-based estimated glomerular filtration rates (eGFRcys) for diagnosis of CKD compared to creatinine-based eGFR (eGFRcreat) in those patients. eGFRcys and eGFRcreat were measured in 53 TC survivors. The 24-h creatinine clearance (CrCl) was measured in 12 TC survivors and 17 CKD patients with medical disease; all of them had eGFRcreat

Bladder metastasis of renal cell carcinoma (RCC) is relatively rare, and only 43 cases have been reported in the Japanese literature. In most cases, the histology of the primary site was clear cell type. Here, we report a case of bladder metastasis of chromophobe RCC. A 74-year-old man presented with asymptomatic gross hematuria. He had a history of chromophobe RCC treated with radical nephrectomy 11 years previously. Since cystoscopy revealed a papillary pedunculated tumor, he underwent transurethral resection of the bladder tumor (TUR-Bt). The pathological diagnosis was chromophobe RCC because the histological findings were similar to those of nephrectomized specimens. Four years after TUR-Bt, the patient received bacillus Calmette-Guérin (BCG) therapy under the diagnosis of carcinoma in situ of urothelial cancer of the bladder but not chromophobe RCC. There was no recurrence of chromophobe RCC within 5 years follow-up after TUR-Bt. To the best of our knowledge, there has been only one other case report of bladder metastasis of chromophobe RCC in the Japanese literature.

461 Background: Intravesical instillation of live bacillus Calmette-Guérin (BCG) is an established immunotherapy for non-muscle invasive bladder cancer. However, development of non-infectious agents has been expected, because there are several problems due to instillation of live bacteria. BCG cell wall skeleton is known to stimulate host immune system, but the mechanism is still unknown. Mycolic acid (MA), which consist of three subclasses (α, keto, methoxy), is the most abundant lipid component of BCG cell wall and is expected to be one of essential active components. Objective: In order to identify active component from BCG cell wall and develop non-infectious BCG-derived immunotherapy, anti-tumor activities of cationic liposomes incorporating each subclass of MA were assessed using mouse syngeneic graft model. Methods: Heat killed packed cells of M. bovis BCG Tokyo 172 were fully hydrolyzed and MA was obtained. MA was separated to three subclasses by thin layer chromatography. Cationic and hydrophilic liposomes incorporating each subclass of MA were prepared. C57BL/6 mice were subcutaneously inoculated with a mixture of MB49 cells and PBS or liposome with/without MA followed by additional injection of PBS or liposome. Tumor growth was monitored. Infiltration of CD4/8 lymphocytes was examined by immunostaining. Results: Cationic liposomes were internalized into cytoplasm of MB49 cells, a mouse bladder cancer cell line. Cell proliferation was not affected by liposome incorporating MA. Tumor growth was significantly suppressed in mice treated with keto MA-liposome (vs PBS, p = 0.007), but not in mice treated withα-or methoxy-MA liposomes. Number of infiltrating CD8 lymphocytes was higher in tumor treated with keto MA-liposome than control. Antitumor effect of keto MA-liposome disappeared in nude mouse, while the effect existed in beige mouse with NK activity deficiency (vs PBS, p = 0.045). Conclusions: Keto MA-liposome showed the strongest antitumor effects in mouse model among three subclasses. T cell immunity may contribute to those effects.

A 40-year-old man was referred to our hospital for treatment of metastatic testicular cancer. Computerized tomography revealed multiple lung, liver, and retroperitoneal lymph node metastases. In addition, magnetic resonance imaging revealed multiple brain metastases. Induction chemotherapy with bleomycin, etoposide, and cisplatin was started the day after a high orchiectomy. The pathological diagnosis of the surgical specimen was yolk sac carcinoma. The serum human chorionic gonadotropin (hCG) was markedly increased to 630,000 mIU/ml, which suggested the presence of a choriocarcinoma element at metastatic sites. The patient subsequently suffered respiratory failure due to pulmonary hemorrhage. Intensive supportive care prevented a fatal outcome. Physicians who treat advanced testicular tumors should be aware of the potential complication of acute pulmonary hemorrhage, called choriocarcinoma syndrome, in cases with a high hCG level, which indicates a rapidly progressive and high-volume choriocarcinoma.

555 Background: Urothelial carcinoma (UC) is the most common histology of genitourinary (GU) tract cancer. Non-UC tumors in the GU tract appear to be more aggressive than UC at that location, but the clinicopathological features and their impacts on the prognoses of the non-UC patients are not known due to the low numbers of these patients. Methods: We used Hospital-Based Cancer Registry (HBCR) data in Japan to extract non-UC cases, i.e., patients with adenocarcinoma (AC), squamous cell carcinoma (SCC), or small cell carcinoma (SmCC) of the GU tract who were diagnosed in 2008–2009 with histological confirmation and had received first course of treatment. We retrospectively analyzed the clinicopathological features of these patients, stratified by the bladder and the upper urinary tract (UUT) as tumor locations. We used a Cox proportional hazards regression to identify prognostic factors associated with the overall survival (OS). Results: Of the 8,095 cases at the bladder and 2,580 cases at the UUT, 384 (4.7%) and 131 (5.1%) non-UC cases were identified, respectively. The proportions of histologic subtypes in the bladder were 1.7% AC, 2.4% SCC, and 0.7% SmCC. In the UUT group, these proportions were 1.3%, 3.4%, and 0.4%, respectively. At both tumor locations, the distribution of ages was similar across all subtypes, with the age peak in the 70s. More patients with non-UC were diagnosed at an advanced clinical stage compared to the patients with UC at either location. The 5-yr OS rates of the non-UC patients with a tumor in the bladder and at the UUT were 40% and 26%, whereas the corresponding 5-yr OS rates among the UC patients were 61% and 52%, respectively. A multivariate analysis revealed that the presence of non-UC was significantly associated with increased mortality (hazard ratio 1.66, 95% confidence interval 1.48–1.87) regardless of the tumor location. Conclusions: The clinicopathological features of the non-UC patients were similar between both tumor locations. The presence of non-UC was associated with poor prognosis regardless of the tumor location. A standard of care must be established for non-UC patients, since the prognoses of these patients are not satisfactory.