There are concerns whether megestrol acetate (MA) stimulates the growth of prostate cancer in castration-resistant prostate cancer (CRPC). We evaluated the effect of cumulative doses of MA on the disease-specific survival (DSS) in patients with CRPC who were receiving Docetaxel-based chemotherapy. From July 2003 through June 2009, we identified 109 consecutive patients with CRPC and who had received docetaxel-based chemotherapy. Of these patients, 68 (62.4%) have not received MA, whereas 21 patients (19.3%) and 20 patients (18.3%) had received low dose MA (total ≤ 18,400 mg) and high dose MA (total > 18,400 mg), respectively. We assessed the effect of several variables on DSS. None of the clinicopathological variables differed among the three groups. When comparing DSS using Kaplan-Meier analysis, there was no statistically significant survival differences among the three groups (P = 0.546). Using multivariate Cox proportional analyses with backward elimination, the number of docetaxel cycles was only significant factor predicting DSS (HR: 0.578, 95% CI: 0.318-0.923, P = 0.016). Cumulative doses of MA as adjuvant treatment for patients with CRPC and who are receiving docetaxel-based chemotherapy, did not affect their DSS. Therefore, MA can be safely administered in cachexic patients with CRPC.
Cachexia; Castration-Resistant Prostate Cancer; Docetaxel; Megestrol Acetate; Survival
There are limited data on the role of limited pelvic lymph node dissection (PLND) in patients with prostate cancer in Korea. The objective of this study was to demonstrate our clinical experience with limited PLND and the difference in its yield between open retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer patients in Korea.
Materials and Methods
We retrospectively analyzed 601 consecutive patients undergoing radical prostatectomy and bilateral limited PLND by either RRP (n=247) or RALP (n=354) in Asan Medical Center. All patients were divided into three groups according to the D'Amico's risk stratification method. Clinicopathologic data, including the yield of lymph nodes, were thoroughly reviewed and compared among the three risk groups or between the RRP and RALP subjects.
The mean patient age was 64.9 years and the mean preoperative prostate-specific antigen was 9.8 ng/ml. The median number of removed lymph nodes per patient was 5 (range, 0 to 20). The numbers of patients of each risk group were 167, 199, and 238, and the numbers of patients with tumor-positive lymph nodes were 1 (0.6%), 4 (2.0%), and 17 (7.1%) in the low-, intermediate-, and high-risk groups, respectively. In the high-risk group, the lymph node-positive ratio was higher in RRP (14.9%) than in RALP subjects (2.4%).
We speculate that limited PLND may help in prostate cancer staging in intermediate- and high-risk prostate cancer groups. RRP is a more effective surgical modality for PLND than is RALP, especially in high-risk prostate cancer groups.
Lymph node excision; Prostatectomy; Prostatic neoplasms
To investigate whether tumor aggressiveness in patients with prostate cancer has changed in Korea since the introduction of prostate-specific antigen (PSA) testing.
Materials and Methods
The data from 2,508 patients with pathologically confirmed prostate cancer who underwent radical prostatectomy at Asan Medical Center between 2000 and 2011 were reviewed. The patients were divided into four 3-year time series, and the changes between the groups in terms of serum PSA levels, pathological Gleason score (GS), and pathological stage were assessed. The change in GS over time in organ-confined disease and in patients whose PSA was below 10 ng/ml was also analyzed.
The mean PSA levels dropped significantly over the 12-year period (p<0.001). The frequency of organ-confined disease increased (55.7% vs. 64.7% vs. 62.9% vs. 63.5%, p=0.043). The frequency of patients with a GS of 8 or more decreased (38.9% vs. 25.7% vs. 18.2% vs. 19.7%) and the frequency of patients with a GS of 6 or less increased (15.0% vs. 18.9% vs. 26.7% vs. 18.2%, p=0.003). However, the vast majority (more than 70%) of all cases had a high GS (7 or greater) at all time points. The GS distribution did not change over time in patients whose PSA levels were below 10 ng/ml or in those who had organ-confined disease.
In 2000 to 2011, the preoperative PSA, pathological stage, and pathological GS dropped. However, the majority of the prostate cancers in Korean men were poorly differentiated, even when the patients had organ-confined disease or their PSA levels were less than 10 ng/ml.
Korea; Neoplasm grading; Prostatic neoplasms
To assess the validity of the 2009 TNM classification for renal cell carcinoma (RCC) and compare its ability to predict survival relative to the 2002 classification.
Materials and Methods
We identified 1,691 patients who underwent radical nephrectomy or partial nephrectomy for unilateral, sporadic RCC between 1989 and 2007. Cancer-specific survival was estimated by the Kaplan-Meier method and was compared among groups by the log-rank test. Associations of the 2002 and 2009 TNM classifications with death from RCC were evaluated by Cox proportional hazards regression models. The predictive abilities of the two classifications were compared by using Harrell's concordance (c) index.
There were 234 deaths from RCC a mean of 38 months after nephrectomy. According to the 2002 primary tumor classification, 5-year cancer-specific survival was 97.6% in T1a, 92.0% in T1b, 83.3% in T2, 61.9% in T3a, 51.1% in T3b, 40.0% in T3c, and 33.6% in T4 (p for trend<0.001). According to the 2009 classification, 5-year cancer-specific survival was 83.2% in T2a, 83.8% in T2b, 62.6% in T3a, 41.1% in T3b, 50.0% in T3c, and 26.1% in T4 (p for trend<0.001). The c index for the 2002 primary tumor classification was 0.810 in the univariate analysis and increased to 0.906 in the multivariate analysis. The c index for the 2009 primary tumor classification was 0.808 in the univariate analysis and increased to 0.904 in the multivariate analysis.
Our data suggest that the predictive ability the 2009 TNM classification is not superior to that of the 2002 classification.
Kidney neoplasms; Mortality; Neoplasm staging; Prognosis; Renal cell carcinoma
We compared the efficacy of radical cystectomy (RC) and non-RC treatment [transurethral resection of bladder tumor (TURB) only, partial cystectomy, or TURB followed by radiotherapy] in octogenarians with muscle-invasive bladder cancer (MIBC).
Materials and Methods
A total of 177 patients aged 80 years or more underwent TURB at our institute, and 41 patients had MIBC according to the histologic examination. Fourteen patients with lymph node or distant metastasis were excluded, and 27 patients were ultimately included. Patients were stratified by treatment modality (RC vs. non-RC), Charlson Comorbidity Index (low CCI vs. high CCI), and clinical tumor stage (organ-confined disease vs. extravesical disease). The effects of several variables on cancer-specific and overall survival were assessed.
Of the 27 patients, 11 (41%) underwent RC and 16 (59%) underwent non-RC treatment. Patients in the RC group were younger and more likely to have low CCI scores. There were no significant differences in overall or cancer-specific survival in the RC and non-RC groups. Patients with clinically organ-confined disease had better survival outcomes than did those with extravesical disease. Stratification of patients by CCI indicated that overall survival was better in patients with low CCI scores (p=0.013), although cancer-specific survival was similar in the two CCI groups. Univariate and multivariate analysis indicated that clinical tumor stage and CCI were independently associated with overall survival.
RC in octogenarians with MIBC does not improve overall survival compared with other treatment modalities. However, clinically organ-confined disease and low CCI score were associated with better overall survival.
Aged; Comorbidity; Cystectomy; Urinary bladder neoplasms
High-risk localized prostate cancer traditionally includes patients with clinical T3 disease but also includes those with apparently localized disease but with adverse prognostic factors such as a Gleason score of 8 to 10, prostate-specific antigen of more than 20 ng/ml, or extensive disease on biopsy. In the past, these patients were treated primarily with radiation therapy due to concerns that surgery was not likely to be curative and was associated with a high incidence of side-effects. In addition, the lack of randomized trials comparing curative treatments for high-risk prostate cancer makes treatment decisions in this patient population difficult. Several retrospective series have reported the long-term efficacy of radical prostatectomy monotherapy in a high-risk population, showing that the 5-year cancer-specific survival rate was more than 80% and the 5-year biochemical recurrence-free survival rate was about 50%. In addition, comparisons of different treatment options by means of nonrandomized trials have shown improved outcomes with surgery compared with radiation therapy or observation. Thus, there is renewed interest in radical prostatectomy as the primary treatment for patients with high-risk prostate cancer. Here, we reviewed the outcomes of radical prostatectomy, with or without neoadjuvant or adjuvant therapies, in high-risk patients and what is known about the choice and timing of adjuvant therapies.
Prostatectomy; Prostatic neoplasms; Risk assessment
Glycogen synthase kinase 3α/β (GSK3α/β) is a constitutively active serine/threonine kinase involved in multiple physiological processes, such as protein synthesis, stem cell maintenance and apoptosis, and acts as a key suppressor of the Wnt-β-catenin pathway. In the present study, we examined the therapeutic potential of a novel GSK3 inhibitor, CG0009, in the breast cancer cell lines, BT549, HS578T, MDA-MB-231, NCI/ADR-RES, T47D, MCF7 and MDA-MB-435, from the NCI-60 cancer cell line panel. Assessment of cytotoxicity, apoptosis and changes in estrogen-signaling proteins was performed using cell viability assays, Western blotting and quantitative real-time PCR. CG0009 enhanced the inactivating phosphorylation of GSK3α at Ser21 and GSK3β at Ser9 and simultaneously decreased activating phosphorylation of GSK3β at Tyr216, and induced caspase-dependent apoptosis independently of estrogen receptor α (ERα) expression status, which was not observed with the other GSK3 inhibitors examined, including SB216763, kenpaullone and LiCl. CG0009 treatment (1 µmol/L) completely ablated cyclin D1 expression in a time-dependent manner in all the cell lines examined, except T47D. CG0009 alone significantly activated p53, leading to relocation of p53 and Bax to the mitochondria. GSK3 inhibition by CG0009 led to slight upregulation of the β-catenin target genes, c-Jun and c-Myc, but not cyclin D1, indicating that CG0009-mediated cyclin D1 depletion overwhelms the pro-survival signal of β-catenin, resulting in cell death. Our findings suggest that the novel GSK3 inhibitor, CG0009, inhibits breast cancer cell growth through cyclin D1 depletion and p53 activation, and may thus offer an innovative therapeutic approach for breast cancers resistant to hormone-based therapy.
The purpose of this article was to announce the establishment of the multicenter Korean Prostate Cancer Database (K-CaP) and to provide urologists with details about K-CaP's methodology.
Materials and Methods
The initial participating K-CaP institutions include five medical centers in Korea. First, we registered prostate cancer patients who underwent radical prostatectomy as the basic background data. K-CaP is poised to combine these initial observational longitudinal studies with those of other eligible institutions as the database grows. All current prostate cancer patients in Korea are able to be registered into the Web-based database system and thereby have a role in several observational studies. The structure of the database for K-CaP was developed by matching it with the respective data from different studies. The operability of the K-CaP database system was verified by using the existing databases from three participating institutions.
The analysis of clinicopathologic characteristics of patients with the use of the Web-based database was successfully conducted. We confirmed the accurate operation of the Web-based database system without any difficulties.
We are announcing the establishment of K-CaP the first database of comprehensive observational longitudinal studies about prostate cancer in Korea. The database will be successfully maintained by sufficiently and continuously updating all patient data covering several treatments. Complete statistical results for registered prostate cancer patients are forthcoming for the basic background data to establish the database. Even though much trial and error are expected during the development process, we expect that K-CaP will eventually become one of the most powerful longitudinal observation databases.
Database; K-CaP; Korea; Prostate neoplasms
There are still debates on the benefit of mass screening for prostate cancer (PCA) by prostate specific antigen (PSA) testing, and on systemized surveillance protocols according to PSA level. Furthermore, there is a paucity of literature on current practice patterns according to PSA level in the Korean urologic field. Here, we report the results of a nationwide, multicenter, retrospective chart-review study.
Materials and Methods
Overall 2122 Korean men (>40 years old, PSA >2.5 ng/mL) were included in our study (from 122 centers, in 2008). The primary endpoint was to analyze the rate of prostate biopsy according to PSA level. Secondary aims were to analyze the detection rate of PCA, the clinical features of patients, and the status of surveillance for PCA according to PSA level.
The rate of prostate biopsy was 7.1%, 26.3%, 54.2%, and 64.3% according to PSA levels of 2.5-3.0, 3.0-4.0, 4.0-10.0, and >10.0 ng/mL, respectively, and the PCA detection rate was 16.0%, 22.2%, 20.2%, and 59.6%, respectively. At a PSA level >4.0 ng/mL, we found a lower incidence of prostate biopsy in local clinics than in general hospitals (21.6% vs. 66.2%, respectively). A significant proportion (16.6%) of patients exhibited high Gleason scores (≥8) even in the group with low PSA values (2.5-4.0 ng/mL).
We believe that the results from this nationwide study might provide an important database for the establishment of practical guidelines for the screening and management of PCA in Korean populations.
Mass screening; prostate biopsy; prostate specific antigen
To evaluate the treatment outcome and prognostic factor after postoperative radiotherapy in retroperitoneal sarcoma.
Materials and Methods
Forty patients were treated with surgical resection and postoperative radiotherapy for retroperitoneal sarcoma from August 1990 to August 2008. Treatment volume was judged by the location of initial tumor and surgical field, and 45-50 Gy of radiation was basically delivered and additional dose was considered to the high-risk area.
The median follow-up period was 41.4 months (range, 3.9 to 140.6 months). The 5-year overall survival (OS) was 51.8% and disease free survival was 31.5%. The 5-year locoregional recurrence free survival was 61.9% and distant metastasis free survival was 50.6%. In univariate analysis, histologic type (p = 0.006) was the strongest prognostic factor for the OS and histologic grade (p = 0.044) or resection margin (p = 0.032) had also effect on the OS. Histologic type (p = 0.004) was unique significant prognostic factor for the actuarial local control.
Retroperitoneal sarcoma still remains as a poor prognostic disease despite the combined modality treatment including surgery and postoperative radiotherapy. Selective dose-escalation of radiotherapy or combination of effective chemotherapeutic agent must be considered to improve the treatment result especially for the histopathologic type showing poor prognosis.
Sarcoma; Retroperitoneal; Radiotherapy; Postoperative; Outcome
Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration.
Cancer patients were treated twice with autologous CD34+ hematopoietic stem cell-derived, GM-CSF/IFN-γ-differentiated DCs pulsed with autologous tumor lysate and KLH, by 4-week interval. Following each subcutaneous injection of therapeutic DCs, low-dose (200 MIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. To determine the DC vaccine-induced immunological alterations, the KLH-specific lymphocyte proliferation, number of IFN-γ secreting T cells (ELISPOT assay), NK activity and the cytokine modulation were measured.
Cultured-DCs expressing HLA-DR, CD11c, CD83, and B7.1/B7.2 produced IL-12p70. After vaccination, the patients tolerated it. Clinical response was observed in one RCC patient as stable disease. However DC-vaccine related antigen-specific immune responses including peripheral blood lymphocyte proliferation and the number of IFN-r secreting cells were induced in six patients without clear correlation with clinical responses. Also NK activity was induced significantly in six patients after vaccination. DC vaccine-related decrease of TGF-β level or increase of IL-12p70 level and decline of CD4+CD25+ T cells were observed in three patients. However only in the RCC patient whose disease stabilized, combination of stimulatory as well as inhibitory immune alterations including induction of IFN-γ secreting T cell with reduction of CD4+ CD25+ T cell were correlated with clinical responses.
Data indicated that DC vaccine combined with IL-2 is well tolerated without major side effects. DC vaccine induced the specific immunity against introduced antigen. Combinatorial alterations of immunological parameters indicating antigen-specific immune induction along with reduction of inhibitory immunity were correlated with clinical responses in DC vaccine treated patients.
Dendritic cell vaccine; Renal cell carcinoma; Breast cancer; Phase I/II trial; Immune response
The prognosis of patients with malignant pheochromocytoma is poor, but the predictive factors are not well understood. We aimed to identify the clinical characteristics predictive of malignancy after initial surgical removal in patients with pheochromocytoma.
Materials and Methods
We retrospectively reviewed the records of 152 patients diagnosed with pheochromocytoma, including 5 (3.3%) with metastasis at the time of the initial surgical excision and 12 (7.9%) who developed metastasis during follow-up. To determine the factors predictive of malignancy, we compared clinical, radiographical, and urinary chemical findings between patients with benign and malignant disease. Mean follow-up was 41.5 months (range, 0.9-298 months) after surgery.
Malignant tumors were significantly larger than benign tumors (11.1±4.0 cm vs. 6.2±3.4 cm, p<0.001), and postoperative persistence of arterial hypertension was more frequent after removal of malignant than benign tumors (p=0.001). Among the 147 patients without metastatic disease at diagnosis, those who developed metastasis had significantly lower concentrations of urinary catecholamine metabolites per unit of tumor, including vanillylmandelic acid (1.2 vs. 3.7 mg/day/cm, p=0.049), epinephrine (4.5 vs. 168.9 µg/day/cm, p=0.008), and norepinephrine (13.1 vs. 121.8 mg/day/cm, p<0.001). The overall 5-year metastasis-free survival rate was 84.4% and was significantly higher in patients with smaller tumors (≤5.5 vs. >5.5 cm; 90.6% vs. 81.2%, p=0.025) and higher 24-hour secretion of vanillylmandelic acid (>2.1 vs. ≤2.1 mg/day/cm; 94.9% vs. 70.9%, p=0.019).
Large tumor size (>5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (≤2.1 mg/day/cm) were significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis-free survival and mandating more rigorous follow-up after surgery.
Adrenal gland neoplasms; Catecholamines; Pheochromocytoma; Tumor burden
To analyze the biochemical recurrence-free and cancer-specific survival after radical prostatectomy in a consecutive series of patients with prostate cancer.
Materials and Methods
We retrospectively reviewed data for 1,822 patients who underwent radical prostatectomy with pelvic lymph node dissection at our institution between 1990 and 2009. After excluding 498 patients who were treated with neoadjuvant androgen deprivation therapy or who were followed up for ≤6 months, we included 1324 patients (mean age, 64.4 years; mean prostate-specific antigen [PSA] level, 12.3 ng/ml). We assessed patient age at the time of surgery, preoperative PSA concentration, biopsy and pathologic Gleason scores, pathologic stage, surgical margin status, disease progression, and survival.
The mean follow-up time was 40 months (range, 6-193 months). The 5- and 10-year biochemical recurrence-free survival rates were 73.2% and 66.2%, respectively, and the 10-year cancer-specific survival rate was 92.4%. The mean time from surgery to biochemical recurrence was 18 months. In the multivariate analysis, Gleason score (4+3 vs. 2-6, p=0.004; 8-10 vs. 2-6, p<0.001), pathologic stage (pT3a vs. pT2, p=0.001; pT3b-4 vs. pT2, p<0.001; pN1 vs. pT2, p<0.001), and resection margin status (p<0.001) were statistically significant predictors of biochemical recurrence, with only pathologic stage (pT3b-4 vs. pT2, p=0.006; pN1 vs. pT2, p=0.010) being a statistically significant predictor of cancer-specific survival.
Radical prostatectomy resulted in favorable cancer control in more than 70% of patients after 5 years and a low (<10%) cancer-specific mortality rate after 10 years. The factors predictive of biochemical recurrence were Gleason score, pathologic stage, and resection margin status.
Prostatectomy; Prostatic neoplasms
Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil®) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E2 and interferon-α. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-α (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-α (T), TNF-α and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods.
Dendritic Cells; Prostatic Neoplasms; Cancer Vaccines; Immunotherapy
To analyze the preoperative clinical and pathological characteristics of patients with pT0 prostate cancer.
Materials and Methods
We retrospectively reviewed the records of 702 patients who underwent radical prostatectomy (RP) at our institution between January 2004 and July 2008 for clinically localized prostate cancer. If there was no evidence of residual tumor in the pathological specimen of the prostate, a patient was staged as pT0. Patients with pT0 disease were compared with a control group of patients who were operated on during the same period.
Overall, 9 (1.3%) patients were staged as pT0 on the pathologic examination. Significant differences were observed between the pT0 group and the control patients in the biopsy Gleason score (p=0.004), the number of positive cores on biopsy (p=0.018), the tumor length of positive cores (p<0.001), and prostate volume (p=0.015). Cutoff values predictive of pT0 tumor status were defined as a biopsy Gleason score sum ≤6, 2 or fewer positive biopsy cores, tumor length on biopsy ≤2 mm, and prostate volume >30 cm3. Whereas 8 of the 9 (88.9%) pT0 patients showed all of these characteristics, only 55 of the 693 (7.9%) control patients fulfilled the criteria. The combination suggested above afforded a sensitivity of 88.8% and a specificity of 92.1% for the prediction of pT0 status.
The frequency of pT0 prostate cancer seen on RP was 1.3%. A combination of clinicopathological features, incorporating a biopsy Gleason score, the number of positive biopsy cores, tumor length on biopsy, and prostate volume, was useful to predict pT0 stage on RP.
Biopsy; Neoplasm staging; Prostatectomy; Prostatic neoplasms
In order to gain insight into the physicians' awareness of and attitude towards management of overactive bladder (OAB) in males, we performed a nationwide survey of the current strategies that urologists use to diagnose and manage OAB in male patients.
Materials and Methods
A probability sample was taken from the Korean Urological Association Registry of Physicians, and a random sample of 289 Korean urologists were mailed a structured questionnaire that explored how they manage benign prostatic hyperplasia (BPH).
A total of 185 completed questionnaires were returned. The consent rate in the survey was 64.5%. Eighty-one (44%) urologists believed that of all males with lower urinary tract symptoms (LUTS), 20% or more had OAB and 72 (39%) believed that 10-20% had OAB. Half of the urologists surveyed believed that the most bothersome symptom in male OAB patients was nocturia. Seventy-three percent of respondents reported that they prescribed alpha blockers with anticholinergics for first line management, while 19% of urologists prescribed alpha blocker monotherapy but not anticholinergics for OAB patients. Though acute urinary retention (AUR) was considered the anticholinergic adverse event of most concern, the most frequently observed adverse event was dry mouth (95%).
The present study provides insights into urologist views of male OAB. There is a discrepancy between the awareness of urologists and actual patterns of diagnosis and treatment of male OAB. This finding indicates the need to develop further practical guidelines based on solid clinical data.
Overactive bladder; physician's practice patterns; bladder outlet obstruction; benign prostatic hyperplasia; anticholinergics
Transglutaminase 4 is a member of enzyme family that catalyzes calcium-dependent posttranslational modification of proteins. Although transglutaminase 4 has been shown to have prostate-restricted expression pattern, little is known about the biological function of transglutaminase 4 in human. To gain insight into its role in prostate, we analyzed the expression status of human transglutaminase 4 in benign prostate hyperplasia (BPH) and prostate cancer (PCa). Unexpectedly, RT-PCR and nucleotide sequence analysis showed four alternative splicing variants of transglutaminase 4: transglutaminase 4-L, -M (-M1 and -M2) and -S. The difference between transglutaminase 4-M1 and -M2 is attributed to splicing sites, but not nucleotide size. The deduced amino acid sequences showed that transglutaminase 4-L, -M1 and -M2 have correct open reading frames, whereas transglutaminase 4-S has a truncated reading frame. RT-PCR analysis of clinical samples revealed that transglutaminase 4-M and -S were detected in all tested prostate tissue (80 BPH and 48 PCa). Interestingly, transglutaminase 4-L was found in 56% of BPH (45 out of 80) and only in 15% of PCa (7 out of 48). However, transglutaminase 4-L expression did not correlate with serum prostate-specific antigen (PSA) level, prostate volumes or PSA densities. These results will provide a clue to future investigation aiming at delineating physiological and pathological roles of human transglutaminase 4.
alternative splicing; prostate hyperplasia; prostatic neoplasms; transglutaminase 4
To assess the efficacy and safety of treating Korean patients with metastatic hormone-refractory prostate cancer (HRPC) using docetaxel plus prednisolone chemotherapy.
Materials and Methods
This was a retrospective cohort study performed in 98 patients with metastatic HRPC between October 2003 and April 2008. After screening, 72 patients fit the eligibility criteria for inclusion in this study. Treatment consisted of 5 mg prednisolone twice daily and 75 mg/m2 docetaxel once every 3 weeks.
Patient demographic characteristics included: median age 67 years (range, 51~86), median ECOG performance status 1 (0~2), Gleason score ≥8 in 61 patients (86%), and median serum PSA 45.5 ng/mL (range, 3.7~2,420.0). A total of 405 cycles of treatment were administered with a median 6 cycles (range, 1~20) per patient. The median docetaxel dose-intensity was 24.4 mg/m2/week (range, 17.5~25.6). A PSA response was seen in 51% of 63 evaluable patients at 12 weeks and maximal PSA decline ≥50% in 59% of 70 evaluable patients. Tumor response was evaluated in 13 patients, 4 patients achieved PR, and 5 patients had SD with a response rate of 31%. With a median follow-up duration of 23.1 months (95%CI, 16.7~29.5), the median time to PSA progression was 5.1 months (95%CI, 4.5~5.8) and median overall survival was 22.8 months (95%CI, 16.6~29.1). Nine (13%) patients experienced grade 3 or higher febrile neutropenia.
This chemotherapy regimen (docetaxel every 3 weeks plus prednisolone daily) demonstrated a strong response in Korean patients with metastatic HRPC, while the toxicity profile was manageable and similar to that observed in Western patients.
Hormone-refractory prostate cancer; Chemotherapy; Docetaxel; Prednisolone; Febrile neutropenia
Dendritic cell (DC)-based tumor vaccine is an attractive modality for the treatment of hormone-refractory prostate cancer (HRPC) because it has some efficacy and few side effects in patients with poor general conditions. The aim of this study was to establish which is the most effective DC vaccine for the treatment of HRPC. We compared DC vaccine sensitized with tumor lysate and a fusion vaccine of DCs and tumor cells.
Materials and Methods
The DU145 cancer cell line was purchased from the American Type Culture Collection. DCs were cultured from peripheral blood monocytes. Peripheral blood monocytes were cultured in RPMI 1640 medium supplemented with interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and 10% fetal calf serum. Tumor necrosis factor-alpha was added on day 7 to support maturation. Functional activity was measured in three groups: the DC single-culture group, the DC culture group with DC vaccine sensitized with tumor lysates, and the DC culture group prepared with tumor fusion vaccine made from irradiated tumor cells and monocyte-derived DCs by the polyethylene glycol method.
By FACS analysis, the rate of DC-tumor fusion vaccine was 20.3±3%. The IL-12 level produced by the DC-tumor fusion vaccine was significantly higher than that of DCs pulsed with tumor lysate (p<0.05). Also, the generation of interferon-γ by tumor-specific T cells in the DC-tumor fusion vaccine group was superior to that of DCs pulsed with tumor lysate (p<0.05). In addition, the T cells of the tumor lysate-pulsed DCs and tumor fusion vaccine had 1.6 and 2.5 times the functional activity, respectively, of the DC single-culture group in killing tumor cells in the cytotoxicity assay.
The DC-tumor fusion vaccine seems to be more effective than DC single-culture or DC-tumor lysate vaccine in the treatment of HRPC.
Prostatic neoplasms; Dendritic cells; Cancer vaccines
We developed nomograms to predict disease recurrence in patients with Ta, T1 transitional cell carcinoma of the bladder. Thirty-eight training hospitals participated in this retrospective multicenter study. Between 1998 and 2002, a total of 1,587 patients with newly diagnosed non-muscle invasive bladder cancer were enrolled in this study. Patients with prior histories of bladder cancer, non-transitional cell carcinoma, or a follow-up duration of less than 12 months were excluded. With univariate and multivariate logistic regression analyses, we constructed nomograms to predict disease recurrence, and internal validation was performed using statistical techniques. Three-year and five-year recurrence-free rates were 64.3% and 55.3%, respectively. Multivariate analysis revealed that age (hazard ratio [HR]=1.437, p<0.001), tumor size (HR=1.328, p=0.001), multiplicity (HR=1.505, p<0.001), tumor grade (HR=1.347, p=0.007), concomitant carcinoma in situ (HR=1.611, p=0.007), and intravesical therapy (HR=0.681, p<0.001) were independent predictors for disease recurrence. Based on these prognostic factors, nomograms for the prediction of disease recurrence were developed. These nomograms can be used to predict the probability of disease recurrence in patients with newly diagnosed Ta, T1 transitional cell carcinoma of the bladder. They may be useful for patient counseling, clinical trial design, and patient follow-up planning.
Carcinoma, Transitional Cell; Urinary Bladder; Recurrence; Nomograms
The short-term safety and efficacy of zoledronic acid for the treatment of skeletal metastasis was evaluated in patients with hormone-refractory prostate cancer.
Patients and Methods
A total of 19 hormone-refractory prostate cancer patients with bone metastases were enrolled. All patients received up to six infusions of zoledronic acid (4 mg, given intravenously over 15 minutes, every 3 - 4 weeks). Safety was assessed by monitoring a`dverse events and serum creatinine levels. Efficacy was assessed by monitoring skeletal-related events, brief pain inventory score, quality of life score, type of pain medication, and analgesic score. Mean age of patients was 67.3 years (46 - 86 years), mean time from diagnosis of bone metastases was 27.6 months (0 - 117 months), and mean time from diagnosis of hormone-refractory disease was 7.5 months (0 - 26 months).
There was no clinically significant change in serum creatinine levels. Eleven adverse events (musculoskeletal disorders and systemic disorders) in 8 patients were classed as having a possible relationship to study drug. Fifteen patients completed six courses of zoledronic acid infusion. There were no significant changes in the brief pain inventory composite scores, quality of life questionnaire scores or analgesic score. No new skeletal-related events developed during the treatment period.
Zoledronic acid administered in this study as a 15-minute infusion demonstrated an acceptable and well-known safety profile in patients with refractory prostate cancer with bone metastases. However, prospective placebo-controlled clinical trials are required to elucidate the efficacy of zoledronic acid.
Prostatic neoplasms; neoplasm metastasis; zoledronic acid
Lymph node involvement is the most important prognostic factor of rectal cancer. Cancer originating from sites other than the rectum rarely metastasizes to the mesorectal lymph node. We report a rectal cancer patient with a synchronous metastatic prostatic carcinoma to the mesorectal lymph node.
Mesorectal; Lymph node; Prostatic carcinoma
We analyzed the prostate cancer data of 317 Korean men with clinically localized prostate cancer who underwent radical prostatectomy at Asan Medical Center between June 1990 and November 2003 to construct nomograms predicting the pathologic stage of these tumors, and compared the outcome with preexisting nomograms. Multinomial log-linear regression was performed for the simultaneous prediction of organ-confined disease (OCD), extracapsular extension (ECE), seminal vesicle invasion (SVI) and lymph node metastasis (LNM) using serum prostate-specific antigen (PSA), Gleason score and clinical stage. Nomograms representing percent probabilities were constructed and compared with those presented by Partin et al. by calculating areas under the receiver operating characteristics (ROC) curves. Median serum PSA at surgery was 10.8 ng/mL, and median biopsy Gleason score was 7. Overall OCD, ECE, SVI and LNM rates were 59.6%, 20.5%, 11.7% and 8.2%, respectively, and areas under the curves were 0.724, 0.626, 0.662, and 0.794, respectively. Pathologic stage of localized prostate cancer in Korean men may be predicted using the Partin table, with acceptable accuracy for OCD and LNM, but less so for ECE and SVI.
Prostatic Neoplasms; Korean; Prediction; Comparison; Nomograms
The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.
A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines.
Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines.
This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression.