Prediction of Time to Castration-Resistant Prostate Cancer Using Bone Scan Index in Men with Metastatic Hormone-Sensitive Prostate Cancer.

INTRODUCTION: We evaluated bone scan index (BSI) as a predictive biomarker for time to castration-resistant prostate cancer (CRPC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). MATERIALS AND METHODS: We identified 85 consecutive mHSPC patients treated with first-line androgen deprivation therapy. We analyzed the correlations between time to CRPC and clinicopathological characteristics, including age, prostate-specific antigen (PSA) level, Gleason score, clinical TNM stage, hemoglobin, lactate dehydrogenase, C-reactive protein, and BSI. RESULTS: The median BSI was 2.7%. Progression to CRPC occurred in 55 (64.7%) patients and the median time to CRPC was 12.9 months. In multivariate analysis, 3 significant risk factors for time to CRPC were identified: age (>73 vs. ≤73 years; hazard ratio [HR] 0.53), p = 0.038, PSA level (>270 vs. ≤270 ng/mL; HR 0.53, p = 0.038), and BSI (>2.7 vs. ≤2.7%; HR 2.97, p < 0.001). CONCLUSION: Age, PSA level, and BSI were found to be significant predictive factors for time to CRPC in patients with mHSPC.

Predictors of poor response to secondary alternative antiandrogen therapy with flutamide in metastatic castration-resistant prostate cancer.

OBJECTIVE: In Japan, flutamide had been commonly used as second-line alternative antiandrogen hormonal therapy for metastatic castration-resistant prostate cancer that relapses after initial hormone therapy before new androgen pathway inhibitors became available. In this study, we attempted to identify predictive factors for efficacy of alternative antiandrogen as second-line hormone therapy. METHODS: We identified consecutive 65 patients with metastatic castration-resistant prostate cancer who were treated with alternative antiandrogen as second-line hormonal therapy (bicalutamide to flutamide). All patients were treated with combined androgen blockade initially. We analyzed correlations between progression-free survival of alternative antiandrogen and clinicopathological characteristics, including patients' ages, initial prostate-specific antigen levels, prostate-specific antigen levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease grades on bone scan and previous duration of prostate cancer response to combined androgen blockade. RESULTS: In univariate analysis, T stage, N stage and previous duration of response to combined androgen blockade were correlated with shorter progression-free survival. We found four significant risk factors for shorter progression-free survival in multivariate analysis: initial prostate-specific antigen level, clinical N stage, extent of disease grades and previous duration of response to combined androgen blockade. CONCLUSIONS: Initial prostate-specific antigen, N stage, extent of disease grades on bone scan and previous duration of response to combined androgen blockade were the significant predictors for efficacy of alternative antiandrogen as second-line hormone therapy in patients with metastatic castration-resistant prostate cancer. These findings might support that decision-making of when to start the new androgen receptor pathway inhibitors.

[A Case of Abdominal Wall Desmoid Tumor after Radical Nephrectomy for Renal Cancer].

A 71-year-old man with a right renal tumor underwent nephrectomy. The procedure was converted from laparoscopy to open surgery due to profound bleeding from the renal vein. Pathological diagnosis was clear cell carcinoma G2pT3b v1 ly1 INFα. Three years after surgery, a 5 cm tumor in the abdominal wall was found on computed tomography (CT). A mild uptake was shown on positron emission tomography/CT and as the tumor was located near the surgical wound, recurrence of the renal cell carcinoma was suspected. However, desmoid tumor was suggested by the pathological examination of the tumor biopsy. En-bloc resection of the mass was carried out and the pathological examination showed an array of proliferating and tangling atypical spindle-shaped tumor cells. Immunohistochemical staining of the tumor cells was positive for vimentin, but negative for CD34, c-kit, and s100. Pathological diagnosis was desmoid tumor. There has been no recurrence so far. Desmoid tumor, despite its extremely low incidence, should be considered in a postoperative neoplasm.

[A case of pneumatosis cystoides intestinalis secondary to sunitinib treatment for renal cell carcinoma].

A 78-year-old man was diagnosed as having right renal cell carcinoma (RCC) with metastasis to the right lung. He received sunitinib and the treatment reduced the size of both RCC and lung metastasis. Then he received right radical nephrectomy. The pathological diagnosis was clear cell RCC. After the initial surgery, he was diagnosed with polymyalgia rheumatic and steroid therapy was started. During follow-up, local recurrence was discovered and sunitinib was then started at a dose of 25 mg/day. Two months after the treatment, abdominal computed tomography (CT) revealed colonic pneumatosis cystoides intestinalis. Administration of sunitinib was stopped and the patient was observed carefully without pursuing surgical intervention. A follow-up CT demonstrated resolution of the colonic pnumatosis.

Localized amyloidosis of the ureter: a case report.

BACKGROUND: Amyloidosis is a collection of disorders characterized by the extracellular deposition of amyloid, a specialized fibrous protein, in diverse tissues, leading to functional impairments. CASE PRESENTATION: A 70-year old Asian-Japanese female was referred to our department for further examination of her left hydronephrosis come from lower ureteral obstruction. Contrast enhanced CT and retrograde pyelo-nephrography revealed left ureteral tumor. Though ureteroscropic biopsy did not show malignant pathological findings, ureteroscopic image suspected malignant disease, thus nephroureterectomy was performed. Pathological findings revealed localized ureteral amyloidosis. Whole body examination including gastro endoscopy and cardio ultrasonography could not reveal amyloidosis except ureter. She was free from recurrence 9 months postoperatively. CONCLUSION: We herein report a rare case of localized ureteral amyloidosis.

Prognosis of patients with T1 bladder cancer after en bloc transurethral resection of bladder tumor stratified by invasion to the level of the muscularis mucosa.

PURPOSE: To evaluate the prognosis of patients with pT1 bladder cancer who underwent en bloc resection of bladder tumors (ERBTs), stratified by invasion to the muscularis mucosa (MM) level. METHODS: Among 64 specimens obtained by ERBT with bipolar energy from patients with pT1 bladder cancer, MM was detected in 61 specimens. Thus, 61 specimens were included in this retrospective study. Patients were stratified by invasion to the MM level (pT1a, invasion above the MM level; pT1b, invasion within the MM level; and pT1c, invasion beyond the MM level). In specimens with discontinuous MM, invasion to the MM level was predicted from the dispersed MM in the specimen. The primary endpoints were progression-free survival (PFS) and cancer-specific survival (CSS). RESULTS: Progression occurred in 2/39 patients with pT1a (5.1%), 1/6 patients with pT1b (16.7%), and 6/16 patients with pT1c cancer (37.5%). Cancer death occurred in 1/39 patients with pT1a (2.6%), 0/7 patients with pT1b, and 3/16 patients with pT1c cancer (18.8%). Patients with pT1a or pT1b cancer had a significantly better prognosis than those with pT1c cancer. On univariate analysis, tumor size ≥ 3 cm and pT1c were significantly associated with shorter PFS. On multivariate analysis, only pT1c was independently associated with shorter PFS. CONCLUSION: This is the first study evaluating the prognosis by T1 substaging based on invasion to the MM level using ERBT specimens. ERBT provided high-quality specimens for diagnosing the MM and showed poor prognosis in pT1c bladder cancer. ERBT could be an appropriate surgical approach for an accurate diagnosis and prognosis of the T1 bladder cancer substage.

[Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy for hormone-refractory prostate cancer].

The objective of this study was to evaluate the efficacy and safety of low-dose docetaxel, estramustine and dexamethasone combination chemotherapy in patients with hormone-refractory prostate cancer (HRPC). Sixty-nine patients with HRPC were enrolled. Docetaxel was given at a dose of 25 mg/m(2) on days 1 and 8 every 3 weeks, oral estramustine 280 mg twice daily on days 1 to 3 and 8 to 10, and oral dexamethasone 1 mg daily throughout the course. Cycles were repeated every 21 days. Treatment was continued until disease progression or excessive toxicity. Patients were evaluated for response and toxicity. Patients received a median of eleven cycles (range : 1-25). Prostatic-specific antigen (PSA) was decreased greater than 50% in 53 (77%) out of 69 patients and median duration of PSA response was 10.2 months. Median time to progression and overall survival 10.2 and 24 months, respectively. Grade 1-2 fatigue was the most common toxicity observed in 10 (15%) patients. Grade 3-4 toxicities were observed in five (7%) patients (2 thrombosis, 2 bilirubin elevation, and 1 aspartate transaminase/alanine transaminase elevation). Low-dose docetaxel, estramustine and dexamethasone combination chemotherapy is an effective and well tolerated treatment for Japanese HRPC patients.

Pembrolizumab-Induced Severe Neuropathy in a Patient with Metastatic Urothelial Carcinoma after Achieving Complete Response: Guillain-Barré Syndrome-Like Onset.

An 85-year-old female was admitted to our hospital for left ureteral cancer and para-aortic lymph node metastasis. To control hematuria, a laparoscopic retroperitoneal nephroureterectomy was performed, and papillary urothelial carcinoma (pT3b) was found. To treat para-aortic lymph node metastasis, she received chemotherapy with gemcitabine and nedaplatin. After 2 cycles, a computed tomography scan revealed its disappearance; however, bilateral lung metastases appeared. The patient was administered second-line therapy with pembrolizumab every 3 weeks. After 3 courses, lung metastases disappeared and she achieved a complete response. After the fifth administration of pembrolizumab, she was readmitted with right upper limb pain and weakness in both lower extremities. She was diagnosed with pembrolizumab-induced grade 3 peripheral neuropathy with Guillain-Barré syndrome-like onset. High-dose monocorticotherapy was initiated for treatment. Three weeks later, the pain and weakness of the limbs improved. After discharge, the dose of prednisolone was tapered and there was no relapse of adverse events. Pembrolizumab was discontinued at the onset of neuropathy, but she maintained a complete response.

Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas.

AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. METHODS: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. RESULTS: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. CONCLUSIONS: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

[Histopathological characteristics of radical prostatectomy specimen and long-term PSA changes in men with PSA levels of 4.0 ng/ml or less].

Out of 132 prostate cancer (Pca) patients who underwent radical prostatectomy 31 (mean age 65 +/- 5 years) had prostate specific antigen (PSA) levels of 4.0 ng/ml or less (low PSA group). The average PSA level was 3.3 +/- 0.5 ng/ml in the low PSA group and 8.5 +/- 5.5 ng/ml in patients with a higher PSA (high PSA group). The pT2 ratio of the radical prostatectomy specimens was 74% (23/31) in the low PSA group and 55% (55/101) in the high PSA group, pT3a was 16% (5/31) and 31% (31/101), pT3b was 10% (3/31) and 10% (10/101), pN1 was 0% and 5% (5/101), respectively. The digital rectal examination (DRE) gave a positive result significantly (p = 0.026) less frequently in the low PSA group (6/31 : 20%), than in the high PSA group (44/101 : 44%). However all three pT3b patients with a low PSA were positive in DRE. This suggests the importance of DRE to detect significant Pca with PSA < or = 4.0. PSA was measured at least three times for more than one year in 19 of the 31 patients with a low PSA level before diagnosis. In 14 of these 19 cases (74%), PSA velocity was more than 0.5 ng/ml/ year and PSA doubling time was less than 4 years. Some patients with significant Pca can not be detected with a PSA cutoff level at 4.0 ng/ml. We recommend that individuals have their own PSA levels, and that long-term changes of PSA are sometimes very important to detect cases of Pca with lower PSA.

Fluorescent Light-Guided Cystoscopy with 5-ALA Aids in Accurate Surgical Margin Detection for TURBO: A Case Report.

Recent studies have revealed that transurethral resection in one piece (TURBO) has several benefits over standard transurethral resection of bladder tumor (TUR-Bt), including a higher rate of containing the bladder muscle tissue and single-block resection. Five-aminolevulinic acid (5-ALA) was approved for the detection of bladder tumor treated with TUR-Bt. A 71-year-old male patient who received right nephroureterectomy developed bladder tumor recurrence on routine cystoscopy follow-up. We planned TURBO using fluorescent light-guided cystoscopy with 5-ALA. We herein report a case of bladder tumor successfully treated with TURBO using fluorescent light-guided cystoscopy with 5-ALA to detect the tumor surgical margin.

Time-dependent change in relapse sites of renal cell carcinoma after curative surgery.

We investigated time-dependent changes in the relapse features of renal cell carcinoma (RCC) after curative surgery. Between 1985 and 2015, 1398 patients with RCC (1226 clear cell RCC, 89 papillary RCC, and 53 chromophobe RCC) underwent curative surgery at Yokohama City University Hospital and its affiliated hospitals. We retrospectively reviewed the clinicopathologic factors of patients with relapse after surgery. Median follow-up was 56.3 months. Recurrence occurred in 245 patients (217 clear cell RCC, 12 papillary RCC, and 3 chromophobe RCC). Papillary RCC and chromophobe RCC had no recurrence beyond 5 years after surgery, but 20 cases of clear cell carcinoma had recurrence beyond 10 years after surgery. The typical recurrence sites of clear cell RCC were lung (46.6%), bone (17.9%), liver (7.6%), and lymph nodes (6.5%). The proportion of recurrences at these typical sites was 83.9% for recurrences within 5 years, 76.3% between 5 and 10 years, and 40.0% beyond 10 years. In contrast, the proportion of retroperitoneal organ recurrence, including contralateral kidney, pancreas, and adrenal glands, increased with increasing time after surgery. Interestingly, the hazard ratio of typical site relapse decreased whereas that of retroperitoneal organ relapse increased in a time-dependent manner. In summary, clear cell RCC showed potential to relapse beyond 10 years after surgery. Recurrence at typical sites decreased whereas retroperitoneal organ recurrence increased in a time-dependent manner. Clinicians should check for recurrence at various sites beyond 10 years, especially in clear cell RCC.

[Neoadjuvant and adjuvant chemotherapy with methotrexate, cisplatin and bleomycin for advanced penile cancer: a case report].

A 58-year-old male consulted our hospital because of penile swelling and pain with bilateral inguinal lymphadenopathy. Pathological examination of the penile tumor and right superficial inguinal lymph node biopsy demonstrated moderately differentiated squamous cell carcinoma with lymph node metastasis. We diagnosed the tumor inoperable radically and adjuvant chemotherapy with methotrexate, cisplatin and bleomycin was administered, followed by partial penectomy and left superficial lymphadenectomy. The surgical specimens showed few viable tumor cells. This combination chemotherapy is suggested to be effective for the treatment of advanced penile cancer.

Prognostic Value of Automated Bone Scan Index in Men With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide or Abiraterone Acetate.

PURPOSE: Bone scan index (BSI) is an objective tool for quantifying bone metastasis load. We assessed its prognostic usefulness in patients with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide (ENZ) or abiraterone acetate (AA). MATERIALS AND METHODS: We analyzed 40 patients who received ENZ or AA treatment (ENZ/AA) for metastatic CRPC. The Cox proportional hazards model and a C-index were used to investigate associations between overall survival (OS) and BSI, and patient age, prostate-specific antigen, time to CRPC, previous docetaxel use, and pain. RESULTS: Median OS after ENZ/AA was 17.8 months. All patient deaths (n = 19; 47.5%) were from prostate cancer. In multivariate analysis, decreased BSI was an independent predictor for longer OS (hazard ratio, 8.97; P = .011). Inclusion of BSI improved the C-index from 0.721 to 0.792 in predicting OS after ENZ/AA. CONCLUSIONS: Decreased BSI after ENZ/AA independently predicts longer OS.

[Prostate cancer development after transurethral resection of the prostate--histopathological studies of radical prostatectomy specimens].

PURPOSE: We investigated prostate cancer (ca.) development after transurethral resection of the prostate (TURP). PATIENTS AND METHODS: From 1995 to 2003, 430 patients (pts.) received TURP at Toshiba Rinkan Hospital. Of them, 23 pts. (5.3%) had incidental carcinoma (Stage A), which developed into clinically significant ca. after 1 to 5 years in 5 (22% of Stage A, 1.2% of TURP). In 13 (3.2%) of 407 Non-Stage A pts. (who had no ca. initially), prostate ca. developed after 1 to 7 yrs. A total of 21 pts. (including 3 Stage A pts. diagnosed before 1994) underwent radical prostatectomy. Stage A pts. received regular needle biopsy of prostate (Pbx). Non-Stage A pts. were followed by yearly PSA measurement and digital rectal examination (DRE). Detailed histopathological studies were done on 21 radical prostatectomy specimens. RESULTS: Clinically significant ca. developed in 8 Stage A pts. (all A2) after 1 to 14 yrs. Long term (5 or 10 years) MAB therapy changed moderately-differentiated adenocarcinoma (AC) to poorly-differentiated AC in 2 pts. during follow-up. When ca. developed PSA increased in only 3 of them, DRE was positive just in 1 pt. Tumor invasion was observed mainly in transition zone (TZ), especially anterior to urethra. In spite of no capsular penetration, surgical margin was positive in 2 pts. PSA failure occurred in another 2 pts. Thirteen Non-Stage A pts. showed aggressive ca. (6 moderately-differentiated AC, 6 poorly-differentiated AC, and 1 ductal carcinoma which showed metastasis later), most of which invaded widely in peripheral zone (PZ). Pbx before TURP was done to reveal that there was no cancer in 11 pts. Capsular penetration was seen in 4 pts. Surgical margin was positive in 4 pts. PSA (8.6 +/- 4.0 ng/ml) decreased after TURP but was kept in high level (4.8 +/- 2.2 ng/ml) after 1 year and increased (8.7 +/- 4.5) when cancer was diagnosed in all 13 pts. DRE was positive in 38% of them. Interval between TURP and diagnosis was short in pts. who had cancer of high Gleason Score (GS) or large prostate. CONCLUSIONS: As significant cancer developed in 22% of Stage A pts. (1.2% of TURP) in long term follow-up, regular Pbx (to get TZ tissue) is mandatory regardless of PSA value or DRE. Aggressive cancer developed in 3.2% of Non-Stage A pts. (3.0% of TURP). Pts. with high PSA or abnormal DRE after TURP must receive needle biopsy actively. Considering that more than 4% of TURP pts. eventually require radical prostatectomy, relatively younger pts. who received TURP have to be carefully followed for a long period.

[Usefulness of extension of disease as a prognostic factor in relapsed prostate cancer patients of stage D].

OBJECTIVE: The prognosis of prostate cancer has been evaluated by clinical stage or pathological grade. PSA parameters including PSA density and PSA doubling time have not always precisely reflected the prognosis of prostate cancer. The aim of this study was to evaluate PSA parameters and extension of disease (EOD) grade as prognostic factors for relapsed prostate cancer. METHODS: The relationship between PSA parameters or EOD grade, and survival of 29 stage D patients with relapsed prostate cancer after initial hormone therapy was examined. RESULTS: Only EOD grade was an independent prognostic factor, even for cause-specific survival period and survival period after relapse. CONCLUSION: EOD grade was a significant prognostic factor, and in particular, very useful as a prognostic factor for patients with bone metastasis. PSA value was not always associated with tumor volume, and therefore it is not an independent prognostic factor.

Dissolving microneedles to obtain rapid local anesthetic effect of lidocaine at skin tissue.

Dissolving microneedles (DMs) were applied to lidocaine for local anesthesia of the skin. Three DM array chips were prepared where lidocaine was localized at the acral portion of DMs (type 1), loaded in whole DMs (type 2), and lidocaine was loaded both in whole DMs and the chip (type 3). DM chips were 15-mm diameter with 225 DMs, each 500-µm long with a 300-µm diameter base. The lidocaine contents were (type 1) 0.08 ± 0.01 mg, (type 2) 0.22 ± 0.01 mg and (type 3) 8.52 ± 0.49 mg. Lidocaine was released from type 1 and 2 DM array chips within 10 min. Pharmacological activity of DMs were compared to lidocaine cream by the suppression of idiospasm of hair-removed rat skin. Type 1, 2 and 3 DMs showed faster onset time, 5 min, than lidocaine cream. Type 2 and 3 DMs showed stronger anti-idioplasmic activity than type 1 DMs. Pharmacokinetic study showed that tissue lidocaine levels, 62.8 ± 3.6 (type 1), 89.1 ± 9.9 (type 2) and 131.2 ± 10.2(type 3) µg/g wet weight at 5 min after the removal of DM were obtained higher than lidocaine cream, 26.2 ± 12.5 µg/g wet weight. Those results suggest the usefulness of type 2 DMs to obtain fast onset time for the local anesthesia in the skin.