A prospective study of the relationship between CRPC patient's quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS.

BACKGROUND: Enzalutamide (ENZ) is used in the treatment of patients with castration-resistant prostate cancer (CRPC). The quality of life (QoL) of CRPC patients during ENZ treatment is very important, but predictive markers of QoL have not been identified. We investigated the relationship between the serum testosterone (T) level before ENZ treatment and QoL changes in CRPC patients. PATIENTS AND METHODS: This prospective study was conducted between 2014 and 2018 at Gunma University Hospital and related facilities. We analyzed 95 patients in whom QoL could be evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire at baseline, and after 4 and 12 weeks of ENZ treatment. Serum T levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The study population of 95 patients had a median age of 72 years and median prostate-specific antigen level of 21.6 ng/mL. The median overall survival from the commencement of ENZ treatment was 26.8 months. The median serum T level before ENZ treatment was 50.0 pg/mL. The mean total FACT-P scores at baseline, and after 4 and 12 weeks of ENZ treatment, were 95.8, 91.7, and 90.1, respectively. Differences in FACT-P scores between the high T level (High-T) group and low T level (Low-T) group (distinguished based on median split of the T level) were examined. The mean FACT-P scores were significantly higher in the High-T than Low-T group after both 4 and 12 weeks of ENZ treatment (98.5 vs. 84.6 and 96.4 vs. 82.2, respectively, both p < 0.05). The mean FACT-P score was significantly lower in the Low-T group after 12 weeks than before ENZ treatment (p < 0.05). CONCLUSION: The serum T level before treatment may be useful for predicting QoL changes after ENZ treatment in CRPC patients.

Enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment in Japan (Japanese research for patients with non-metastatic castration-resistant prostate cancer-enzalutamide: JCASTRE-zero)-a prospective single-arm interventional study.

BACKGROUND: The effect of enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade, which represents a patient profile similar to real-world clinical practice in Japan, remains unknown. Therefore, we investigate the efficacy and safety of enzalutamide after combined androgen blockade for recurrence following radical treatment in Japanese patients with non-metastatic castration-resistant prostate cancer. METHODS: We analyzed 66 patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical prostatectomy or radiation therapy who were prospectively enrolled from October 2015 to March 2018. They received enzalutamide 160 mg orally once daily until the protocol treatment discontinuation criteria were met. The primary endpoint was prostate-specific antigen-progression-free survival, defined as the time from enrollment to prostate-specific antigen-based progression or death from any cause. The secondary endpoints included overall survival, progression-free survival, metastasis-free survival, time to prostate-specific antigen progression, prostate-specific antigen response rate, chemotherapy-free survival, and safety assessment. RESULTS: The median observation period was 27.3 months. The median prostate-specific antigen-progression-free survival was 35.0 months (95% confidence interval, 17.5 to not reached). The median overall survival, median progression-free survival, median metastasis-free survival, and chemotherapy-free survival were not reached, with the corresponding 2-year rates being 91.6%, 67.1%, 72.4%, and 85.8%, respectively. The 50% prostate-specific antigen response rate was 88.9%, with the median time being 2.8 months. In total, 42.2% of the patients experienced adverse events, with malaise being the most common. CONCLUSIONS: Enzalutamide effectively manages non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment. TRIAL REGISTRATION:  UMIN000018964, CRB6180007.

Oncological outcomes for patients with locally advanced prostate cancer treated with neoadjuvant endocrine and external-beam radiation therapy followed by adjuvant continuous/intermittent endocrine therapy in an open-label, randomized, phase 3 trial.

BACKGROUND: To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). METHODS: A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. RESULTS: The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). CONCLUSIONS: Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression.

BACKGROUND: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA velocity (PSAV) while monitoring oncologic outcomes and survival in Japanese patients. METHODS: We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients' median age was 75 ± 7.9 years (range, 53-93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA-progression-free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595). RESULTS: We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA-PFS, and OS were significantly higher compared with post docetaxel (PSA-PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1-2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA-progression (P < .05). CONCLUSIONS: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.

A rare case of a testicular lesion related to hand, foot, and mouth disease.

Introduction: Hand, foot, and mouth disease generally occurs in children. In rare cases, hand, foot, and mouth disease affects the testicles. Case presentation: A 29-year-old man presented to our emergency department with testicular pain for several days after the onset of hand, foot, and mouth disease. Ultrasonography revealed hypoechoic mass-like areas in the right testis. A mild inflammatory response was noted, tumor markers and urinary data were normal, and tests for infection were all negative. Antibiotics were initiated and ultrasonography was performed in every subsequent examination. Testicular pain disappeared 6 months later. Conclusion: We encountered a rare case of a testicular lesion related to hand, foot, and mouth disease that was successfully treated. The careful selection of treatment for testicular pain and scrotal enlargement in young adult males, such as surgery and symptomatic treatment, based on their medical history and laboratory findings, is important.

Matrix metalloproteinase levels in peritoneal effluents were increased in a patient with appendicitis undergoing continuous ambulatory peritoneal dialysis.

A differential diagnosis of common bacterial peritonitis and appendicitis is difficult in continuous ambulatory peritoneal dialysis (CAPD) patients, and thus the definite diagnosis of appendicitis is often delayed. In this case, a 60-year-old man undergoing CAPD was at first diagnosed with bacterial peritonitis but not appendicitis, and antibiotics were administered. The number of leukocytes in the peritoneal effluent decreased mildly, but the level of C-reactive protein continued to be high and the pain aggravated. When the catheter was removed, suppurative appendicitis was confirmed for the first time. Levels of matrix metalloproteinase (MMP)-2 and -9 in peritoneal effluents were markedly high. Appendicitis should be diagnosed as early as possible because MMPs directly injure the peritoneum via degradation of extracellular matrix proteins. Future studies in a greater numbers of cases of appendicitis are required.

A Prospective Study of the Relationship Between Clinical Outcomes After Enzalutamide and Serum Androgen Levels Measured via Liquid Chromatography-tandem Mass Spectrometry in Patients with Castration-resistant Prostate Cancer.

BACKGROUND: Enzalutamide (ENZ) is used to treat patients with castration-resistant prostate cancer (CRPC). However, the kinetics of serum androgens before and after ENZ treatment are unknown. OBJECTIVE: To elucidate the kinetics of serum androgens and explore the possibility of identifying a useful marker for predicting the effects of ENZ. DESIGN SETTING AND PARTICIPANTS: We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. Data were analyzed for 104 patients with CRPC treated with ENZ. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured serum androgen levels using liquid chromatography-tandem mass spectrometry. Relationships with outcomes were assessed using multivariable Cox regression and log-rank analyses. RESULTS AND LIMITATIONS: The median age of the patients was 73 yr. Median serum testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. We performed multivariate analysis using Cox regression to predict prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS). Hemoglobin level (≥12.5 vs <12.5 g/dl), docetaxel treatment history (no vs yes), and DHT level (≥5.9 vs <5.9 pg/ml) were significant predictors of PSA-PFS (p < 0.05). Eastern Cooperative Oncology Group performance status (0 vs. 1-2), hemoglobin level (≥12.5 vs <12.5 g/dl), presence of visceral metastasis (no vs yes), amount of bone metastasis (extent of disease 0-2 vs 3-4), and docetaxel treatment history (no vs yes) were significant predictors of OS (p < 0.05). Binomial logistic analysis of the predictors of any grade of anorexia, malaise, and fatigue showed that the presence of visceral metastasis and a low DHT level (<5.9 pg/ml) were significant. CONCLUSIONS: Our results suggest that serum androgen levels before ENZ treatment may be useful for predicting efficacy, prognosis, and the incidence of adverse events. PATIENT SUMMARY: We measured blood levels of testosterone and other male hormones before treatment with enzalutamide among men with prostate cancer resistant to castration. We found that the levels of these hormones may be useful for predicting the efficacy of enzalutamide treatment, prognosis, and the occurrence of adverse side effects.

Patient-reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial.

BACKGROUND: We evaluated patient-reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca). METHODS: A multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT-P questionnaires and EPIC urinary, bowel, and sexual bother subscales. RESULTS: The FACT-P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well-being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05). CONCLUSION: The PRO was significantly favorable in IADT on FACT-P total score at 20 M and 38 M, PWB and functional scores at 38 M.

The effects of PSA kinetics on the outcome of hypofractionated salvage radiotherapy for biochemical recurrence of prostate cancer after prostatectomy.

The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53-74) years, 0.28 (0.20-0.79) ng/ml and 7.7 (2.3-38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30-100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule.

Carbon-ion Radiotherapy for Prostate Cancer: Analysis of Morbidities and Change in Health-related Quality of Life.

AIM: To prospectively evaluate the feasibility of carbon-ion radiotherapy (C-ion RT) for prostate cancer using a new compact-sized accelerator. PATIENTS AND METHODS: Seventy-six patients underwent C-ion RT at our center using a recommended dose fractionation of 57.6 GyE in 16 fractions established at the National Institute of Radiological Sciences. Health-related Quality of Life (HRQOL) assessment was also performed using the Medical Outcome Study 8-items Short Form Health Survey (SF-8) questionnaire. RESULTS: The median follow-up time was 51 months (range=8-58 months). Grade 2 gastrointestinal and genitourinary complications developed in 1 (1.3%) and 5 (6.6%) patients, respectively. Recurrences occurred in 4 patients, and the 4-year biochemical relapse-free rate was 94.6%. The HRQOL scores after C-ion RT were objectively well-maintained. CONCLUSION: Irrespective of the small number of patients of the study, C-ion RT for prostate cancer using the first commercial-based accelerator reproduced the toxicity outcomes at the NIRS.

Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels.

BACKGROUND: Angiogenesis plays important roles in pathogenesis in human cancer. We assessed the relationship between clinical features of renal cell cancer (RCC) and PlGF levels in relation to VEGF. MATERIALS AND METHODS: Plasma PlGF and VEGF levels were measured in patients with renal cell cancer. The levels of these angiogenetic factors were analyzed in relation to clinical parameters. RESULTS: PlGF and VEGF levels in patients with RCC were significantly higher than those in non-cancer controls. PlGF levels were significantly associated with histological grade and total tumor vascularity (TTV), and VEGF levels were significantly associated with T, M stage, histological grade, venous invasion and TTV. Multivariate analysis showed plasma PlGF was an independent prognostic factor. CONCLUSION: These findings suggested that plasma PlGF levels were significantly associated with the clinical features of RCC, especially prognostic significance.

[Surgical statistics of the Department of Urology, Isesaki Municipal Hospital during a five-year period (June 1998-May 2003)].

We reviewed the surgical statistics of the Department of Urology, Isesaki Municipal Hospital between June 1998 and May 2003. A total of 1940 surgeries were performed. These consisted of 399 surgeries on the kidney, adrenal, and pelvis, 212 on the ureter, 433 on the bladder, 256 on the prostate, 149 on the urethra and the penis, 192 on the scrotum, 255 on the arteriovenous fistula and CAPD. In September 2003, a screening program for prostate cancer was started, and the number of prostate biopsies and total prostatectomies increased. As the adaptation of many procedures to laparoscopy expanded, the number of laparoscopic surgeries increased.

[PSA-related parameters in prostate cancer relapsed after endocrine therapy].

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.

Risk factors for rectal bleeding associated with I-125 brachytherapy for prostate cancer.

The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4-5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50-200% of the prescribed dose (RV50-200) and the minimal doses received by 1-30% of the rectal volume (RD1-30). The median follow-up time was 42 months (ranging 18-73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100-150 and RD1-10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm(3) was 36%, whereas that with an RV100 ≤ 1.0 cm(3) was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm(3), especially in additional dose-escalated brachytherapy.

Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer.

BACKGROUND: Prostate cancer frequently metastasizes to bone. The skeletal metastases of prostate cancer origin are osteoblastic rather than osteolytic. Recently, the expression of bone morphogenetic proteins (BMPs) in prostate cancer cell lines was detected. The present study indicated the existence of BMP-7 in normal prostate tissue, but its function has not been clarified. The mechanism by which prostate cancer causes osteoblastic metastasis is not clear. We investigated the expression of BMP-7 and -6 in normal and metastatic bone tissues to clarify the biological relationship between the expression of BMPs and bone metastasis in prostatic cancer. METHODS: Six samples of normal bone tissue and nine samples of bone metastasis tissue were collected during the autopsies of six patients with prostate cancer. Total RNA was extracted from these samples. After reverse transcription (RT) of the RNA samples, the expression of BMP-6 and -7 in each sample was measured by the real-time quantitative polymerase chain reaction (PCR). Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as an internal standard. RESULTS: Although the expression of BMP-7 was detected in five out of seven (71%) metastatic bone lesions of prostate cancer, it was not detected in normal bone tissues. The expression level of BMP-7 was significantly higher in metastatic bone lesions than in normal bone (P < 0.05). There was no significant difference between the level of expression of BMP-6 in metastatic bone lesions from prostate cancer and the level in normal bone tissue (P = 0.81). CONCLUSIONS: These results suggest that high expression of BMP-7 in metastatic bone lesions of prostate cancer is related to osteoblastic metastasis. BMP-7 in the bone metastasis tissue indicates that the cells expressing BMP-7 probably originated from the prostate, because we have detected high expression of BMP-7 in the prostate. Prostate 54: 268-274, 2003.