PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China / 亚洲男科学杂志(英文版)

Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN <17 weeks (42.83 vs 21.50 weeks, P < 0.001). The time to PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was <17 weeks. We found several factors to be associated with OS, including TTN (hazard ratio [HR]: 3.937, 95% confidence interval [CI]: 1.502-10.309, P = 0.005), PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [<0 response] compared to Class 2 [0-50% response], HR: 3.978, 95% CI: 1.278-12.387, P = 0.017). In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

Preconditioning with L-alanyl-glutamine upon cerebral edema and hypocampus red neurons counting in rats subjected to brain ischemia /reperfusion injury

PURPOSE: To evaluate the effects of the dipeptide L-alanyl-glutamine (L-Ala-Gln) as a preconditioning agent to potentially promote reduction in the intensity of lesion or induction of resilience in rats subjected to global cerebral ischemia/reperfusion (I/R) injury. METHODS: Thirty-six male Wistar rats weighing 280-300g were randomly assigned to six groups (n=6). Groups Sham 1h and 24h were treated with saline and spared of further interventions. The remaining groups were submitted to clamping of the common carotid arteries for 30 minutes (ischemia) and treated with saline (SS) or L-Ala-Gln. Brain reperfusion was allowed for 1or 24 h. L-Ala-Gln was administered intravenously (0.75g/kg) 30 minutes before sham procedure or induction of global brain I/R injury. Brain edema and red neuron counting were determined. Results were expressed as Mean±SD for normal results and Median±Percentile for non parametric data. Significance was established at p<0.05. RESULTS: Global I/R injury promoted an increase in brain edema at 24 h after reperfusion, whereas preconditioning with L-Ala-Gln induced no change in edema. On the other hand, L-Ala-Gln preconditioning decreased significantly red neurons counting both at 1h and 24h post reperfusion (p<0.05). CONCLUSION: There was a significant preconditioning effect with L-Ala-Gln decreasing cell death (red neurons counting) at early (1h) and late reperfusion (24h) in the cerebral tissue. .

Multiple cores of high grade prostatic intraepithelial neoplasia and any core of atypia on first biopsy are significant predictor for cancer detection at a repeat biopsy

PURPOSE: To investigate the differences in the cancer detection rate and pathological findings on a second prostate biopsy according to benign diagnosis, high-grade prostatic intraepithelial neoplasia (HGPIN), and atypical small acinar proliferation (ASAP) on first biopsy. MATERIALS AND METHODS: We retrospectively reviewed the records of 1,323 patients who underwent a second prostate biopsy between March 1995 and November 2012. We divided the patients into three groups according to the pathologic findings on the first biopsy (benign diagnosis, HGPIN, and ASAP). We compared the cancer detection rate and Gleason scores on second biopsy and the unfavorable disease rate after radical prostatectomy among the three groups. RESULTS: A total of 214 patients (16.2%) were diagnosed with prostate cancer on a second biopsy. The rate of cancer detection was 14.6% in the benign diagnosis group, 22.1% in the HGPIN group, and 32.1% in the ASAP group, respectively (p<0.001). When patients were divided into subgroups according to the number of positive cores, the rate of cancer detection was 16.7%, 30.5%, 31.0%, and 36.4% in patients with a single core of HGPIN, more than one core of HGPIN, a single core of ASAP, and more than one core of ASAP, respectively. There were no significant differences in Gleason scores on second biopsy (p=0.324) or in the unfavorable disease rate after radical prostatectomy among the three groups (benign diagnosis vs. HGPIN, p=0.857, and benign diagnosis vs. ASAP, p=0.957, respectively). CONCLUSIONS: Patients with multiple cores of HGPIN or any core number of ASAP on a first biopsy had a significantly higher cancer detection rate on a second biopsy. Repeat biopsy should be considered and not be delayed in those patients.

Clinical effect of abiraterone acetate in Korean patients with metastatic castration-resistant prostate cancer according to duration of androgen deprivation therapy

PURPOSE: Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT. MATERIALS AND METHODS: We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria. RESULTS: The mean age and PSA value of the entire cohort were 76.0+/-7.2 years and 158.8+/-237.9 ng/mL, respectively. The median follow-up duration was 13.4+/-6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration or =35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration or =35 months. CONCLUSIONS: Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.

Two-dimensional neovascular complexity is significantly higher in nontumor prostate tissue than in low-risk prostate cancer

PURPOSE: Prostate cancer is the most frequent cancer in men in Europe. A major focus in urology is the identification of new biomarkers with improved accuracy in patients with low-risk prostate cancer. Here, we evaluated two-dimensional neovascular complexity in prostate tumor and nontumor biopsy cores by use of a computer-aided image analysis system and assessed the correlations between the results and selected clinical and pathological parameters of prostate carcinoma. MATERIALS AND METHODS: A total of 280 prostate biopsy sections from a homogeneous series of 70 patients with low-risk prostate cancer (Gleason score 3+3, prostate-specific antigen [PSA]<10 ng/mL, and clinical stage T1c) who underwent systematic biopsy sampling and subsequent radical prostatectomy were analyzed. For each biopsy, 2-microm sections were treated with CD34 antibodies and were digitized by using an image analysis system that automatically estimates the surface fractal dimension. RESULTS: Our results showed that biopsy sections without cancer were significantly more vascularized than were tumors. No correlations were found between the vascular surface fractal dimension and patient's age, PSA and free-to-total PSA ratios, pathological stage, Gleason score, tumor volume, vascular invasion, capsular penetration, surgical margins, and biochemical recurrence. CONCLUSIONS: The value of angiogenesis in prostate cancer is still controversial. Our findings suggest that low-risk prostate cancer tissues are less vascularized than are nontumor tissues. Further studies are necessary to understand whether angiogenesis is a hallmark of intermediate- and high-risk prostate cancer.

Pathologic Outcomes in Men with Low-risk Prostate Cancer Who Are Potential Candidates for Contemporary, Active Surveillance Protocols

The purpose of this study was to determine whether contemporary active surveillance (AS) protocols could sufficiently discriminate significant from indolent tumors in men with low-risk prostate cancer. We retrospectively analyzed 312 patients with low-risk prostate cancer treated with radical prostatectomy. After exclusion of patients with fewer than 10 cores taken at biopsy and those who received neo-adjuvant treatment, 205 subjects satisfied the final inclusion criteria. Five widely accepted AS protocols were employed in this study. A total of 82.0% of the patients met the inclusion criteria of at least one protocol, and 18% did not meet any criteria of published AS protocols. A significant proportion of patients had non-organ-confined disease (8.6% to 10.6%) or a Gleason score of 7 or greater (18.6% to 23.9%) between the different AS criteria. Among patients who did not meet any AS criteria, 32.4% of patients had a pathologically insignificant cancer. Our results indicated a significant adverse pathology in patients who met the contemporary AS protocols. On the other hand, some patients in whom expectant management would be appropriate did not meet any criteria of published AS protocols. None of the clinical or histological criteria reported to date is able to sufficiently discriminate aggressive tumors from indolent ones.

Lower Levels of Human MOB3B Are Associated with Prostate Cancer Susceptibility and Aggressive Clinicopathological Characteristics

Mps one binder (MOB) proteins are integral components of signaling pathways that control important cellular processes, such as mitotic exit, centrosome duplication, apoptosis, and cell proliferation. However, the biochemical and cellular functions of the human MOB (hMOB) protein family remain largely unknown. The present study investigated the association between hMOB3B expression and clinicopathological characteristics of prostate cancer (PCa).Study subjects included 137 PCa patients and 137 age-matched benign prostatic hyperplasia (BPH) patients. hMOB3B expression was estimated using real-time PCR and compared with clinicopathological parameters of PCa. hMOB3B mRNA expression was significantly lower in PCa tissues than in BPH control tissues (P or =10 ng/mL), a Gleason score> or =8, and metastatic disease (any T, N+/M+) than in those with low PSA levels, a low Gleason score, and non-metastatic disease (each P<0.05). In conclusion, low levels of hMOB3B are closely associated with aggressive clinicopathologic features in patients with PCa. Our results suggest that hMOB3B may act as a tumor suppressor in human PCa.

Factors Influencing the Acceptance of Transrectal Ultrasound-Guided Prostate Biopsies

PURPOSE: This study aimed to improve prostate biopsy compliance by analyzing the factors that influence the acceptance of prostate biopsy by patients to whom transrectal ultrasound (TRUS)-guided prostate biopsy is recommended for suspected prostate cancer. MATERIALS AND METHODS: The subjects of this study were 268 patients to whom TRUS-guided prostate biopsy was recommended from January to June 2011 and who completed a questionnaire. Patients who showed a prostate-specific antigen (PSA) increase to more than 4.0 ng/mL or abnormal findings on a digital rectal examination and TRUS were recommended to undergo prostate biopsy. The questionnaire consisted of 9 questions about the subjects' demographic characteristics and 15 questions that assessed their knowledge of prostate disease. Fisher exact probability test was conducted to assess the influence of the demographic characteristics and levels of knowledge of prostate disease on acceptance of prostate biopsy. RESULTS: The mean age of the subjects was 66.2 years (range, 43-83 years). Of the cohort, 188 patients (70.7%) agreed to the prostate biopsy and 78 patients (29.3%) refused. In terms of demographic characteristics, the patients' acceptance of prostate biopsy was associated only with education level. Patients with relatively lower education levels had a higher acceptance rate for prostate biopsy (80.0% vs. 65.9%, p=0.018). Other demographic factors, as well as the degree of knowledge of prostate disease, had no significant effect on the acceptance rate. CONCLUSIONS: The patients' acceptance of prostate biopsy can be influenced by demographic characteristics, especially education level. Therefore, when prostate biopsy is recommended to patients, their demographic characteristics should be taken into consideration.

Is There an Association Between Serum Prostate-Specific Antigen Values and Serum Testosterone Levels in Healthy Men?

PURPOSE: To evaluate the relationship between levels of total testosterone and total prostate-specific antigen (PSA) in healthy men with PSA or =50 years. RESULTS: In all patients, the mean values for serum PSA and total testosterone were 1.27+/-0.88 ng/mL and 404.04+/-158.86 ng/mL, respectively. No correlation was detected between serum PSA and testosterone levels in either subgroup (group I, r=0.072, p=0.363; group II, r=0.031, p=0.900) or in patients aged or =50 years and in patients aged <50 years were 417.01+/-163.35 and 344.16+/-120.21 ng/dL, respectively (p=0.02). CONCLUSIONS: No impact of testosterone was found on the PSA level in healthy men with PSA <4 ng/mL. Therefore, a high serum testosterone level may not mandate adjustment of PSA values. This serum sex hormone showed a significant increment after the age of 50 years. Further studies including a larger number of patients should be carried out to confirm these findings.

Effect of Histological Inflammation on Total and Free Serum Prostate-Specific Antigen Values in Patients Without Clinically Detectable Prostate Cancer

PURPOSE: We are often confronted with patients in the "gray zone" (prostate-specific antigen [PSA]0.010). A correlation existed between inflammation type and fPSA (r=-0.31, p=0.001) and f/tPSA (r=-0.43, p<0.001) in that the fPSA and f/tPSA were lower in the group with more acute inflammation. CONCLUSIONS: Subclinical inflammation has a significant influence on fPSA in patients with tPSA<10 ng/mL but without PC or clinical prostatitis. Subclinical inflammation is not characterized by elevated tPSA alone but also by a decreased fPSA, a tendency similar to that in PC.

Significance of Neoadjuvant Hormonal Therapy in Radical Retropubic Prostatectomy: A Retrospective Single-Surgeon Study

PURPOSE: The purpose of this study was to evaluate whether neo-adjuvant hormonal therapy (NHT) prior to radical retropubic prostatectomy (RRP) for prostate cancer (PCa) is beneficial in terms of surgical outcomes and for preventing or delaying biochemical recurrence via single-surgeon case series study. MATERIALS AND METHODS: Fifty-three men underwent RRP by a single surgeon. The patients were divided into two groups according to whether or not NHT was performed prior to RRP. The study was analyzed retrospectively. We evaluated clinical parameters, surgical parameters, and biochemical recurrence rate. Group 1 (n=34) was treated with RRP only, while Group 2 (n=19) underwent RRP along with NHT. RESULTS: There were no significant differences in clinical, operation-related and pathological factors between the two groups (p>0.05). There was also no significant difference in biochemical recurrence rate between the two groups at the last follow-up, although Group 2 tended to have a lower PCa recurrence rate than Group 1 and the initial prostate-specific antigen (PSA) level was significantly higher in Group 2 than Group 1 (p=0.0496). CONCLUSION: The present single-surgeon case series study revealed a trend toward a lower rate of PCa recurrence in NHT+RRP treated patients compared to those treated with RRP alone, but this did not reach statistical significance, despite the fact that NHT+RRP patients exhibited higher serum PSA levels preoperatively. Prospective studies with a longer duration of observation and a greater number of patients would be helpful in evaluating NHT more definitively.

Native plasma kallikrein is cleared at similar rates by mammalian and avian livers

Rat plasma kallikrein (RPK) is a serine protease that circulates as an inactive precursor, prokallikrein, and once activated is efficiently cleared by the liver by a carbohydrate-dependent, Ca2+ - independent mecanism. Seven hepatic lectin systems have been described for mammals but not all of these animal lectins are expressed in the avian liver. Using a liver perfusion system we compared the plasmakallikrein clearance of rats (N=10) and pigeons (N+4). Our results show that the lectin responsible for the hepatic clearance of plasma kallikrein is also present in pigeon liver and that this organ clears the enzyme with an efficiency (11.4 ñ 1.3 pmol/g,20 min) similar to that of the rat liver (10.0 ñ 0.7 pmolg, 20 min)_

Chronic administration of ethamol does not alter plasma kallikrein hepatic clearance

1. The clearance of plasma kallikrein bu the isolated and perfused liver of rats chronically intoxicated with ethanol was studied. Alcohol was added to the diet as 36% of total calories, and the animals were kept on this diet for 5-7 weeks. 2. The hepatic clearance of plasma kallikrein by these rats (uptake half-life, 15 ñ 2 min; N = 3) was similar to that observed in the control groups (normal diet, iptake half-life, 14 ñ 2 min; N = 5, or normal diet with sucrose added as 36% of total calories, uptake half-life, 16 ñ 3 min; N = 4). 3. These results provided indirect evidence that the endocystosis mechanism of plasma kallikrein by the liver differs from that descrived for glycoproteins which use the galactosyl receptor, since liver endocystosis via this latter system is reduced by chronic alcohol intoxication

Plasma kallikrein clearance by the liver in food-restricted rats

We measured the cleaance rate of plasma kallikrein by the liver in three groups of rats: one recently weaned, and two seven weeks old (control and food-restricted groups). The clearance rates were similar in the three groups when expressed as units/g liver. The livers of the recently weaned and food-restricted rats were, however, smaller than those of the controls and consequently their livers cleared plasma kallikrein less efficiently

Purification and preliminary characterization of Torresea cearensis trypsin inhibitor

An inhibitor against serine proteinases was purified from Torresea cearensis by affinity chromatography on trypsin-Sepharose. The protein is a single polypeptide of molecular weight 13,600 after reduction and has a high content of cysteine residues. Both trypsin (Ki = 0.34 nM) and chymotrypsin (Ki = 0.15 micronM) are inhibited by Torresea cearensis inhibitor. Blood clotting factor XII is also inhibited (Ki = 24 micronM), but not plasma kallikrein, tissue kallikrein or thrombin. The stoichiometry of the inhibitorproteinase complex with trypsin is 1:1