Abstract
Although recent clinical trials of new therapeutic agents for metastatic urothelial carcinoma have shown prolonged overall survival, there are few real-world evidence. To assess the impact ...of new therapeutic agents, we performed retrospective analysis for consecutive 158 metastatic urothelial carcinoma patients who performed systemic therapy in our institution between May 2008 and August 2023. We defined a period from May 2008 to December 2017, when pembrolizumab was first introduced to the clinical setting in the new therapeutic agents for metastatic urothelial carcinoma in Japan, as “pre new drug era” and a period from January 2018 to August 2023 as “post new drug era”. We compared overall survival between pre- and post- new drug era using Kaplan–Meier method with log rank test. Median overall survival of pre- and post- new drug era were 14.5 months (95% confidence intervals: 11.6–16.7) and 23.1 months (95% confidence intervals: 14.5-NA), respectively (p < 0.001). Five-year survival rate of pre- and post- new drug era was 7.0% (95% confidence intervals: 2.3–15.3) and 36.3% (95% confidence intervals: 21.4–51.5), respectively. Multivariable Cox proportional hazards regression analysis of factors associated with overall survival showed that enfortumab vedotin administration, administration of second-line or more systemic therapy, best overall response of SD, PR and CR in first-line systemic therapy, higher serum albumin and lower CRP were factors for overall survival prolongation. Introduction of new therapeutic agents for metastatic urothelial carcinoma contributed to the improvement of overall survival in comparison with the era without these agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
SpaceOAR, a polyethylene-glycol hydrogel, reduces rectal radiation exposure during radiation therapy for prostate cancer. Previously, our group reported the modified technique of hydrogel ...insertion, which achieves greater separated distance at prostate-apex. This study aimed to investigate the impact of separated distance at prostate-apex and our modifier technique, on radiation exposure reduction during proton beam therapy (PBT). We included 330 patients undergoing PBT with the relative biological effectiveness (RBE) of 63 Gray (Gy) for localized prostate cancer, and categorized them into groups 0 (no spacer,
n
= 141), 1 (separated distance of spacer at the prostate-apex level < 7.5 mm,
n
= 81), and 2 (distance ≥ 7.5 mm,
n
= 108). The rectal volumes to receive 30–60 Gy (RBE), was estimated and described as Rectal V30–60 (ml) in 10 Gy increments. The Rectal V30–60 (ml) was significantly lower in group 2 than in group 1, and in group 1 than in group 0. After propensity score matching, the multivariate logistic regression analysis revealed that the most significant factor to reduce radiation exposure was our modified technique of hydrogel insertion. Therefore, using a hydrogel spacer to expand the prostate–rectum distance not only at prostate-mid to prostate-base level but also at the prostate-apex level can reduce the radiation exposure in PBT for prostate cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The objective of this study is to compare the efficacy of apalutamide and bicalutamide in combination with androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer ...(mHSPC). We retrospectively collected the data of about 330 patients with metastatic hormone-sensitive prostate cancer at our hospital and affiliated hospitals between December 2013 and August 2023. Sixty-one patients were administered apalutamide (240 mg/day) with androgen deprivation therapy (group A), and 269 patients were administered bicalutamide (80 mg/day) with androgen deprivation therapy (group B). Propensity score matching was used to adjust for clinical background factors between the two groups. PSA progression-free survival and overall survival were significantly longer in group A than in group B among the matched patients. Apalutamide therapy was a significant independent factor for OS in matched patients. The second progression-free survival of group A was significantly longer than that of group B in matched patients. Patients treated with apalutamide achieved ≥ 90% PSA decline from baseline faster and in larger numbers than those with bicalutamide. Apalutamide combined with ADT may be superior to bicalutamide alone in terms of OS and PSA-PFS in patients with mHSPC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose Tumor contact length is defined as the amount of prostate cancer in contact with the prostatic capsule. We evaluated the ability of magnetic resonance imaging determined tumor contact length ...to predict microscopic extracapsular extension compared to existing predictors of extracapsular extension. Materials and Methods We retrospectively analyzed the records of 111 consecutive patients with magnetic resonance imaging/ultrasound fusion targeted, biopsy proven prostate cancer who underwent radical prostatectomy from January 2010 to July 2013. Median patient age was 64 years and median prostate specific antigen was 8.9 ng/ml. Clinical stage was cT1 in 93 cases (84%) and cT2 in 18 (16%). Postoperative pathological analysis confirmed pT2 in 71 patients (64%) and pT3 in 40 (36%). We evaluated 1) in the radical prostatectomy specimen the correlation of microscopic extracapsular extension with pathological cancer volume, pathological tumor contact length and Gleason score, 2) the correlation between microscopic extracapsular extension and magnetic resonance imaging tumor contact length, and 3) the ability of preoperative variables to predict microscopic extracapsular extension. Results Logistic regression analysis revealed that pathological tumor contact length correlated better with microscopic extracapsular extension than the predictive power of pathological cancer volume (0.821 vs 0.685). The Spearman correlation between pathological and magnetic resonance imaging tumor contact length was r = 0.839 (p <0.0001). ROC AUC analysis revealed that magnetic resonance imaging tumor contact length outperformed cancer core involvement on targeted biopsy and the Partin tables to predict microscopic extracapsular extension (0.88 vs 0.70 and 0.63, respectively). At a magnetic resonance imaging tumor contact length threshold of 20 mm the accuracy for diagnosing microscopic extracapsular extension was superior to that of conventional magnetic resonance imaging criteria (82% vs 67%, p = 0.015). We developed a predicted probability plot curve of extracapsular extension according to magnetic resonance imaging tumor contact length. Conclusions Magnetic resonance imaging determined tumor contact length could be a promising quantitative predictor of microscopic extracapsular extension.
Inactivated hemagglutinating virus of Japan envelope (HVJ‐E) has an antitumor effect and tumor immunity. We undertook an open‐label, phase I, dose‐escalation study in patients with ...castration‐resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ‐E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28‐day treatment cycles. The primary end‐points were to evaluate the safety and tolerability of GEN0101 and determine its recommended dose. The secondary end‐points were to analyze the antitumor effect and tumor immunity. Three patients received 30 000 mNAU GEN0101 and 6 received 60 000 mNAU. There was no dose‐limiting toxicity, and the recommended dose of GEN0101 was defined as 60 000 mNAU. Radiographically, 1 patient had stable disease and 2 had progressive disease in the low‐dose group, whereas 5 patients had stable disease and 1 had progressive disease in the high‐dose group. Three patients in the high‐dose group showed reduction in lymph node metastasis. Prostate‐specific antigen increase rates in the high‐dose group were suppressed more than those in the low‐dose group. Natural killer cell activity was enhanced in 2 patients of the low‐dose group and in 5 patients in the high‐dose group. In conclusion, intratumoral and s.c. injections of GEN0101 were well‐tolerated and feasible to use. The study is registered with the UMIN Clinical Trials Registry (no. UMIN000017092).
Inactivated hemagglutinating virus of Japan envelope (HVJ‐E) has an antitumor effect and tumor immunity. We undertook an open‐label, phase I, dose‐escalation study in patients with castration‐resistant prostate cancer (CRPC). Intratumoral and s.c. injections of GEN0101 were well‐tolerated and feasible to use; antitumor effects were observed in patients with CRPC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
γ-Glutamylcyclotransferase (GGCT) is highly expressed in multiple types of cancer tissues and its knockdown suppresses the growth of cancer cells in vitro and in vivo. Although GGCT is a promising ...target for cancer therapy, the mechanisms underlying the antitumor effects remain unclear. The knockdown of GGCT inhibited the MEK-ERK pathway, and activated the tumor suppressor retinoblastoma gene (RB) at the protein level in cancer cell lines. c-Met was down-regulated by the knockdown of GGCT in cancer cells and its overexpression attenuated the dephosphorylation of RB and cell cycle arrest induced by the knockdown of GGCT in lung cancer A549 cells. STAT3 is a transcription factor that induces c-Met expression. STAT3 phosphorylation and its nuclear expression level were decreased in GGCT-depleted A549 and prostate cancer PC3 cells. The simultaneous knockdown of AMPK and GGCT restored the down-regulated expression of c-Met, and attenuated the dephosphorylation of STAT3 and MEK-ERK-RB induced by the knockdown of GGCT in PC3 cells. An intraperitoneal injection of a GGCT inhibitor decreased c-Met protein expression in a mouse xenograft model of PC3 cells. These results suggest that the knockdown of GGCT activates the RB protein by inhibiting the STAT3-c-Met-MEK-ERK pathway via AMPK activation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To define a normal range for PSA values (ng/mL) by age and create a prediction model for prostate cancer incidence. We conducted a retrospective analysis using 263,073 observations of PSA values in ...Japanese men aged 18-98 years (2007-2017), including healthy men and those diagnosed with prostate cancer. Percentiles for 262,639 PSA observations in healthy men aged 18-70 years were calculated and plotted to elucidate the normal fluctuation range for PSA values by age. Univariable and multivariable logistic regression analyses were performed to develop a predictive model for prostate cancer incidence. PSA levels and PSA velocity increased with age in healthy men. However, there was no difference in PSA velocity with age in men diagnosed with prostate cancer. Logistic regression analysis showed an increased risk of prostate cancer for PSA slopes ranging from 0.5 to 3.5 ng/mL/year. This study provides age-specific normal fluctuation ranges for PSA levels in men aged 18-75 years and presents a novel and personalized prediction model for prostate cancer incidence. We found that PSA slope values of > 3.5 ng/mL/year may indicate a rapid increase in PSA levels caused by pathological condition such as inflammation but are unlikely to indicate cancer risk.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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