Efficacy, tolerability, and safety of teverelix DP in patients with advanced prostate cancer: A multicenter, open-label, phase 2 trial.

BACKGROUND: Teverelix drug product (DP) is a novel injectable gonadotropin-releasing hormone antagonist. METHODS: An adaptive phase 2, open-label, multicenter trial was conducted in patients with advanced prostate cancer to evaluate the efficacy and safety of a combined subcutaneous (SC) and intramuscular (IM) loading dose regimen of teverelix DP of 120 mg SC + 120 mg IM (Group 1; N = 9) or 180 mg SC + 180 mg IM (Group 2; N = 41) administered at a single visit, followed by 6-weekly SC maintenance doses of 120 mg (Group 1) or 180 mg (Group 2), up to Day 168. The primary endpoint was the proportion of patients achieving castration levels with serum testosterone <0.5 ng/mL at Day 28 with a target castration rate of 90%. Injection sites were inspected by the investigator at every visit and reactions (ISRs) were proactively recorded. RESULTS: The target castration rate was reached in Group 2 (97.5%) but not in Group 1 (62.5%). The castration rates were not maintained to Day 42 (Group 2: 82.5%; Group 1: 50.0%). Suppression of testosterone to castrate levels occurred rapidly (median time: 2 days for both groups). Suppression of testosterone, prostate-specific antigen, follicle-stimulating hormone, and luteinizing hormone was sustained throughout the treatment period, being more prominent with the higher dose. The adverse event (AE) profile was similar between groups. The most common AEs were injection-site induration (n = 40: 80.0%), injection-site erythema (n = 35: 70.0%), and hot flush (n = 21: 42.0%). Most ISRs were Grade 1. CONCLUSION: Overall, the teverelix DP doses were generally well-tolerated but did not adequately maintain castration levels.

Effect of Clinical Parameters on Risk of Death from Cancer after Radical Prostatectomy in Men with Localized and Locally Advanced Prostate Cancer.

Background: The study aimed to assess predictors and to identify patients at increased risk of prostate-cancer-specific mortality (CSM) after radical prostatectomy (RP). Methods: A total of 2421 men with localized and locally advanced PCa who underwent RP in 2001−2017 were included in the study. CSM predictors were assessed using multivariate competing risk analysis. Death from other causes was considered a competing event. Cumulative CSM and other-cause mortality (OCM) were calculated in various combinations of predictors. Results: During the median 8 years (interquartile range 4.4−11.7) follow-up, 56 (2.3%) of registered deaths were due to PCa. Cumulative 10 years CSM and OCM was 3.6% (95% CI 2.7−4.7) and 15.9% (95% CI 14.2−17.9), respectively. The strongest predictors of CSM were Grade Group 5 (GG5) (hazard ratio (HR) 19.9, p < 0.0001), lymph node invasion (HR 3.4, p = 0.001), stage pT3b-4 (HR 3.1, p = 0.009), and age (HR 1.1, p = 0.0007). In groups created regarding age, stage, and GG, cumulative 10 years CSM ranged from 0.4−84.9%, whereas OCM varied from 0−43.2%. Conclusions: CSM after RP is related to GGs, pathological stage, age, and combinations of these factors, whereas other-cause mortality is only associated with age. Created CSM and OCM plots can help clinicians identify patients with the most aggressive PCa who could benefit from more intensive or novel multimodal treatment strategies.

Impact of the 2014 International Society of Urological Pathology Grading System on Concept of High-Risk Prostate Cancer: Comparison of Long-Term Oncological Outcomes in Patients Undergoing Radical Prostatectomy.

Objective: To investigate the relationship between the new International Society of Urological Pathology (ISUP) grading system, biochemical recurrence (BCR), clinical progression (CP) and cancer related death (CRD) after open radical prostatectomy (RP) and determine whether the 2014 ISUP grading system influences the concept of high-risk prostate cancer (HRPCa). Patients and Methods: A total of 1,754 men who underwent RP from 2005 to 2017 were identified from a database at a single tertiary institution. Histopathology reports were reassessed according to the 2014 ISUP grading system. All preoperative, pathological, and clinical follow-up data were obtained. Univariable and multivariable Cox regression, Kaplan-Meier and log-rank analyses were performed. Results: At a median (quartiles) follow-up of 83 (48-123) months, 446 men (25.4%) had BCR, 77 (4.4%) had CP and 39 (2.2%) died from cancer. Grade groups 1, 2, 3, 4, and 5 were detected in 404 (23%), 931 (53.1%), 200 (11.4%), 93 (5.3%), and 126 (7.2%), respectively. 10-year biochemical progression free survival difference between Grade group 3 and 4 was minor but significant (log-rank p = 0.045). There was no difference between Grade groups 3 and 4 comparing 10-year clinical progression free and 10-year cancer specific survival: p = 0.82 and p = 0.39, respectively. Group 5 had the worst survival rates in comparison with other groups (from p < 0.005 to p < 0.0001) in all survival analyses. Pathological stage (hazard ratio (HR) 2.6, p < 0.001), positive surgical margins (HR 2.2, p < 0.0001) and Grade group (HR 10.4, p < 0.0001) were independent predictors for BCR. Stage and Grade group were detected as independent predictors for CP-HR 6.0, p < 0.0001 and HR 35.6, p < 0.0001, respectively. Only Grade group 5 (HR 12.9, p = 0.001) and pT3b (HR 5.9, p = 0.001) independently predicted CRD. Conclusions: The new ISUP 2014 grading system is the most significant independent predictor for BCR, CP, and CRD. Grade group 3 and 4 had similar long-term disease progression survival rates and could potentially be stratified in the same risk group. High-risk cancer associated only with group 5.

Dutasteride for the prevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia: results of a phase III randomized open-label 3-year trial.

PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is a potential precursor of prostate cancer (PCa), and patients with HGPIN are at high risk for PCa development. Objective of our study was to evaluate the efficacy of dutasteride 0.5 mg in PCa prevention among men with isolated HGPIN on biopsy. METHODS: This prospective, randomized, phase III, open-label 3-year trial assessed dutasteride versus active surveillance in patients with HGPIN. Patients were randomized to dutasteride 0.5 mg daily or active surveillance. Per-protocol prostate biopsies were performed at 6, 12, 24, and 36 months until cancer detection or study end. The primary end point was cancer-free survival (CFS). An intention-to-treat analysis was done for patients who underwent at least one per-protocol biopsy. An efficacy analysis was done for patients who completed the study. CFS was evaluated using Kaplan-Meier and log-rank analysis. RESULTS: In total, 220 men were randomized (dutasteride, n = 107; surveillance, n = 113). PCa was detected in 47.6: 49.1 % in the surveillance group and 45.9 % in the treatment group (p = 0.66). The detected PCa differentiation by Gleason score (GS) was GS 6 in 76.9 %, GS 7 in 19.8 %, and GS ≥ 8 in 3.3 %, with no difference between groups. The 3-year PCa-free survival was 43.6 % in the surveillance and 49.6 % in the dutasteride group (log rank p = 0.57). Limitations include a relatively high non-adherence rate, open-label design, and baseline sextant biopsy scheme. CONCLUSIONS: Dutasteride 0.5 mg for 3 years did not lower the PCa detection rate but did not worsen detected PCa characteristics in men with HGPIN.

Comparison of long-term results after nephron-sparing surgery and radical nephrectomy in treating 4- to 7-cm renal cell carcinoma.

OBJECTIVE: The aim of our study was to compare long-term oncological outcomes following nephron-sparing surgery (NSS) and radical nephrectomy (RN) for renal cell carcinoma (RCC) 4 to 7 cm in diameter. MATERIAL AND METHODS: The study included patients who underwent RN or NSS for RCC 4 to 7 cm in diameter between 1998 and 2009. The studied groups were compared with respect to the patients' age, sex, physical status according to the American Society of Anesthesiologists Physical classification, histological type, stage, tumor size, grade, duration of the operation, and complications. Survival was established using the Kaplan-Meier method. The risk factors for survival were analyzed using a multivariate Cox regression model. RESULTS: During the study, 351 patients underwent surgery: 317 patients (90.3%) underwent RN, and 34 (9.7%), NSS. The compared groups differed with respect to tumor size (P=0.001) and stage (P=0.006). The overall estimated 12-year survival was 53.7% after RN and 55.2% after NSS (log-rank test P=0.437). The 12-year cancer-specific survival in the RN and NSS groups was 69.6% and 80.6%, respectively (log-rank test P=0.198). Pathological stage and patients' age were the major factors affecting both overall and cancer-specific survival. The type of surgery (NSS or RN) had no effect on survival. CONCLUSIONS: Our study showed that nephron-sparing surgery is a safe technique compared with radical nephrectomy that ensures good oncological control in the treatment of renal cell carcinoma measuring 4 to 7 cm and may be proposed as the treatment of choice for renal tumors not only up to 4 cm, but also 4 to 7 cm in size.

Factors predicting Gleason score 6 upgrading after radical prostatectomy.

OBJECTIVES: Prostate cancer Gleason score 6 is the most common score detected on prostatic biopsy. We analyzed the clinical parameters that predict the likelihood of Gleason score upgrading after radical prostatectomy. METHODS: The study population consisted of 241 patients who underwent radical retropubic prostatectomy between Feb 2002 and Dec 2007 for Gleason score 6 adenocarcinoma. The influence of preoperative parameters on the probability of a Gleason score upgrading after surgery was evaluated using multivariate logistic regression and ROC curves. RESULTS: Gleason score upgrade was found in 92 of 241 patients (38.2%). Multivariate logistic regression analysis showed that only percentage of cancer in dominant lobe and prostate weight were significant predictors for Gleason score upgrading (p = 0.043 and p = 0.006, respectively). ROC curves showed that prostate weight and PSA density were only two independent significant parameters for prediction of upgrade (AUC - 0.634, p <0.0001 and 0.604, p = 0.006, respectively). Gleason score upgrading was observed to be accompanied by significantly higher rates of extra prostatic extension (p <0.001) and seminal vesicle invasion (p = 0.002). CONCLUSIONS: Almost forty percent of tumors graded Gleason 6 at biopsy are Gleason 7 at surgery. Upgraded tumors significantly associated with adverse pathological features. The probability of Gleason score upgrade can be predicted using prostate weight and PSA density as independent parameters.

Outcome of surgery in locally advanced pT3a prostate cancer.

INTRODUCTION: The aim of this study is to present the oncologic outcomes and to determine prognostic parameters of overall (OS), cancer specific survival (CSS), disease progression free survival (DPFS) and biochemical progression free survival (BPFS) after surgery for pT3a prostate cancer (PCa). MATERIAL AND METHODS: Between 2002 and 2007, a pT3a stage after radical prostatectomy was detected in 126 patients at our institution. Kaplan-Meier analysis was used to calculate OS, CSS, DPFS and BPFS. Cox regression was used to identify predictive factors of survival. RESULTS: Five-year OS, CSS, DPFS and BPFS rates were 96%, 98.7%, 97.3% and 60%, respectively. Among patients with prostate specific antigen (PSA) <10 ng/ml and PSA >20 ng/ml the 5-year OS was 98.8% and 80%, respectively, whereas 5-year BPFS was 66% and 16.6%, respectively. Survival was different when comparing surgery Gleason score ≤7 and ≥8. 5-year OS and BPFS were 98% vs. 80%, and 62.6% vs. 27.3%, respectively. Specimen Gleason score and preoperative PSA were significant predictors of BPFS. The risk of biochemical progression increased up to 2-fold when a Gleason score ≥8 was present at final pathology. CONCLUSIONS: In locally advanced pT3 PCa, surgery can yield very good cancer control and survival rates especially in cases with PSA <10 ng/ml and Gleason score ≤7. PSA and Gleason score after surgery are the most significant predictors of outcomes after radical prostatectomy.

The role of high-grade prostatic intraepithelial neoplasia for biochemical relapse of prostate carcinoma after radical prostatectomy.

UNLABELLED: The objective of the study was to evaluate the relationship between high-grade intraepithelial neoplasia diagnosed after radical retropubic prostatectomy and the clinical and pathological characteristics of prostate cancer, and to evaluate the time to biochemical relapse of the disease within the groups of high-grade prostatic intraepithelial neoplasia (HGPIN) and non-HGPIN patients. MATERIAL AND METHODS: Patients, clinically diagnosed with local prostate carcinoma at the Clinic of Urology, Kaunas University of Medicine, during 2003-2007 and treated with radical retropubic prostatectomies, were distributed into two groups according to the HGPIN detected in the postoperative material: HGPIN and non-HGPIN. The two groups were compared in terms of preoperative and postoperative characteristics. The patients who were followed up for at least 12 months were included into the study. The biochemical relapse of prostate cancer was determined if there were two consecutive rises of prostate-specific antigen (PSA) level above 0.2 ng/mL or according to the attending physician's opinion, there was a need for adjuvant treatment even with onetime rise of PSA level above 0.2 ng/mL. RESULTS: There was no significant difference between the HGPIN and non-HGPIN groups in terms of time to biochemical relapse and frequency of biochemical relapses, time before surgery, the timing of the HGPIN diagnosis, age, or PSA level. After radical prostatectomy, patients in the HGPIN group were found to have significantly more often poorer cancer cell differentiation according to the Gleason score (≥7 vs. <7; P=0.001) and higher TNM stage (T3a,b vs. T2a,b,c; P=0.001). Fewer positive resection margins were diagnosed in the HGPIN group (P=0.05). The groups did not differ in terms of the degree of differentiation according to the Gleason score or perineural invasion (P=0.811 and P=0.282, respectively). CONCLUSIONS: HGPIN was more often associated with the characteristics of the poor prognosis for relapse of prostate cancer: poorer tumor cell differentiation according to the Gleason score and more cases of higher TNM stage. HGPIN did not have any influence on biochemical relapse of the disease during the short-term follow-up.

[Importance of repeat laterally directed sextant prostate biopsy for detection of prostate cancer in high-risk patients]. / Pakartotiniu krastiniu sekstantiniu prostatos biopsiju reiksme nustatant prostatos vezi padidejusios rizikos pacientams.

UNLABELLED: Our purpose was to evaluate the relevance of repeat laterally directed sextant prostate biopsy for detection of prostate cancer in high-risk patients. MATERIAL AND METHODS: Our study included 195 men at high risk for prostate cancer (elevated prostate-specific antigen level and/or abnormal prostate detected by digital rectal examination). We consulted the patients in outpatient department of Kaunas University of Medicine Hospital during 2003-2007. We performed transrectal ultrasound-guided laterally directed sextant prostate biopsy in every patient. For the patients with benign histological findings and increased risk of prostate cancer, laterally directed sextant biopsies were repeated. RESULTS: Prostate cancer was detected in 30.3% of patients (59/195) on the first prostate biopsy, in 13.1% (11/84) on the second prostate biopsy, in 10.3% (4/39) on the third, and in 7.7% (1/13) on the forth biopsy. After all biopsies, prostate cancer was detected in 38.5% (75/195) of patients, and it differed significantly from the percentage of prostate cancer cases detected on the first biopsy (30.3%, P=0.04). We detected 78.7% (59/75) of all prostate cancer cases by the first laterally directed sextant prostate biopsy. The rest 21.3% (16/75) of cases we detected by repeat biopsies. The second laterally directed sextant prostate biopsy revealed additional 14.6% (n=11) of prostate cancer cases and increased the detection of prostate cancer to 93.3% (70/75). At the time of the first prostate biopsy, prostate cancer was diagnosed most frequently when patients had both risk factors: elevated prostate-specific antigen level and abnormal digital prostate examination; prostate cancer was diagnosed in 45.3% of these patients. The odds ratio to detect prostate cancer by the first biopsy in patients with elevated prostate-specific antigen level and abnormal digital prostate examination was 3.7, and odds ratio to detect prostate cancer by repeat biopsies was 4.7. CONCLUSIONS: Repeat ultrasound-guided laterally directed sextant prostate biopsies reveal more cases of prostate cancer as compared to the first prostate biopsy. The majority of prostate cancer cases (93.3%) are detected by the first and second laterally directed sextant prostate biopsies. After the first negative prostate biopsy, we recommend to repeat prostate biopsy in high-risk patients.

[Importance of prostate volume for detection of prostate cancer by first sextant biopsy in high-risk patients]. / Prostatos turio reiksme nustatant prostatos vezi pirmaja sekstantine biopsija dideles rizikos pacientams.

UNLABELLED: The aim of this study was to evaluate the relevance of prostate gland volume, transitional zone volume, and transitional zone index for the detection of prostate cancer by the first sextant biopsy. MATERIAL AND METHODS: A total of 121 men with high risk of prostate cancer were included in our study (prostate-specific antigen level higher than 4 ng/mL and/or pathological digital rectal examination). We consulted the patients in Outpatient Department of Kaunas University of Medicine Hospital during 2003-2006. Total prostate volume and transition zone volume were measured, and all patients underwent transrectal ultrasound-guided sextant biopsy of the prostate. According to histological results of prostate biopsy, patients were divided into two groups: benign group (benign prostate hyperplasia and high-grade intraepithelial neoplasia) and prostate cancer group. Statistical analysis was made by SPSS (Statistical Package for Social Sciences) 12.0.1 for Windows. RESULTS: After histological examination, prostate cancer was detected in 20.7% of patients (n=25). Prostate cancer was found in 24.6% of patients with a total prostate volume of less than 60 cm3 and only in 8.2% of patients with a total prostate volume greater than 60 cm3 (P=0.026). Prostate cancer was found in 27.1% of patients with transition zone volume smaller than 30 cm3 and only in 7.5% of patients with transition zone volume greater than 30 cm3 (P=0.007). A statistically significant difference was found when patients were divided into the groups according to transition zone index: when transition zone index was lower than 0.45, prostate cancer was detected in 37.1% of patients, and when transition zone index was higher than 0.45, prostate cancer was observed in 9.1% of patients (P=0.001). The possibility to detect prostate cancer was 5.9 times higher in patients with transition zone index lower than 0.45. CONCLUSIONS: Prostate cancer detection rate by first sextant prostate biopsy in patients with elevated prostate-specific antigen level and/or pathological digital rectal examination was higher when total prostate volume was less than 60 cm3, transition zone was less than 30 cm3, and transition zone index was less than 0.45.

[Primary peritonitis caused by group A beta-hemolytic streptococcus]. / A grupes beta-hemolizinio streptokoko sukeltas pirminis peritonitas.

A rare case of primary peritonitis caused by group A beta-hemolytic streptococcus in previously healthy woman is presented. The entry site of infection was tonsillitis. Infection was complicated by soft-tissue infection of abdominal and thoracic wall, associated with toxic shock. Streptococcus growth was obtained in the cultures from the tonsils and blood. The patient underwent surgery: laparoscopy, laparotomy and multiple incisions in the phlegmon site. The lasting administration of penicillin caused recovery.