Treatment trends in patients with de novo metastatic prostate cancer in the era of upfront combination therapy.

OBJECTIVES: The objective of this study is to assess the trends in treatment selection for patients with de novo metastatic castration-sensitive prostate cancer in the era of upfront combination therapy. METHODS: This multicenter retrospective study included 595 patients treated with either upfront combination therapy (upfront novel hormonal therapies and taxane-based chemotherapy) or vintage therapy (androgen deprivation therapy with or without bicalutamide) between 2016 and 2021. High tumor burden metastatic disease was defined when a patient met the CHAARTED or LATITUDE criteria. We evaluated trends in treatment selection and reasons for selecting vintage therapy. RESULTS: Of the 595, 123 and 472 patients were classified as having low and high tumor-burden disease, respectively. The Use of upfront combination therapy was found to be rapidly increasing with utilization rates of 72% and 54% in 2021 for high and low tumor-burden disease, respectively. Multivariable logistic regression analysis found older age, poor performance status, and nonacademic center were significantly associated with the selection of vintage therapy. Of the 163 patients who received vintage hormone therapy after approval of upfront therapy, 74.2% had a specific reason for avoiding upfront therapy. The reasons for selecting vintage therapy included refusal (39.8%), older age (67.6%), frailty (56.3%), and comorbidity (40.8%). Furthermore, 16.9% of patients declined upfront combination therapy due to cost concerns. CONCLUSION: Upfront combination therapy use has 72% and 54% prevalence among patients with high and low tumor burden diseases, respectively, in this current practice. Older age, poor performance status, and facility bias were negatively associated with the use of upfront combination therapy.

Trends in the use of local intervention for metastatic hormone-naïve prostate cancer: A multicenter retrospective study.

OBJECTIVE: To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone-naïve prostate cancer (mHNPC) in real-world practice. METHODS: This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC-free survival in the intervention group. RESULTS: The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis-targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate-specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC-free survival. CONCLUSIONS: The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.

Trends in the age of hospitalized patients with urological cancers: A 17-year experience.

OBJECTIVES: To investigate the impact of global aging on the trends in the age of hospitalized patients with a urological cancer diagnosis. METHODS: We retrospectively evaluated a cumulative total of 10 652 cases of referred patients (n = 6637) with a urological disease who were hospitalized in our institution between January 2005 and December 2021. We compared age and the proportion of patients aged ≥80 years among patients who were hospitalized in the urological ward between the period of 2005-2013 and that of 2014-2021. RESULTS: We identified 8168 hospitalized patients with urological cancer. The median age was significantly increased in patients with urological cancer between the periods of 2005-2013 and 2014-2021. The proportion of hospitalized patients with urological cancer aged ≥80 years was significantly increased between the periods of 2005-2013 (9.3%) and 2014-2021 (13.8%). The median ages of the patients with urothelial cancer (UC) and renal cell carcinoma (RCC), but not the median age of those with prostate cancer (PC), were significantly increased between the study periods. The proportion of hospitalized patients with UC, but not the proportions of those with PC and RCC, aged ≥80 years was significantly increased between the study periods. CONCLUSIONS: The age of patients with urological cancer who were hospitalized in the urological ward and the proportion of patients with UC aged ≥80 years significantly increased over the entire study period.

Effects of apalutamide dose reduction on skin-related adverse events in patients with advanced prostate cancer: A multicenter retrospective study.

BACKGROUND: We aimed to evaluate the effects of apalutamide dose reduction on skin-related adverse events (AEs) and castration-resistant prostate cancer (CRPC)-free survival in patients with advanced prostate cancer (PC). METHODS: We retrospectively evaluated 35 patients with nonmetastatic CRPC and 72 patients with treatment-naïve metastatic castration-sensitive PC (mCSPC) who were treated with apalutamide. The primary outcome was the effect of apalutamide dose reduction on skin-related AEs. The secondary outcomes were the effect of apalutamide dose reduction on skin-related AEs in patients with small body size, postskin AE apalutamide discontinuation rate, and CRPC-free survival in patients with mCSPC treated with upfront apalutamide plus androgen deprivation therapy. RESULTS: Of the 107 patients, 65 (60.7%) and 42 (39.3%) were treated with full and reduced doses of apalutamide, respectively. The skin-related AE rate was not significantly different between the groups (55% vs. 43%, p = 0.761). In the group receiving reduced apalutamide dose, the incidence of skin-related AEs was significantly lower in patients with small body sizes (body weight <67 kg and body mass index <24 kg/m2 ) than in those with other body sizes. The postskin AE apalutamide discontinuation rate was significantly differed between patients receiving the full (50%) and reduced (16.7%) doses. In the 72 patients with mCSPC, CRPC-free survival was not significantly different between the full and reduced dose groups. CONCLUSION: Apalutamide dose reduction was not significantly associated with the incidence of skin-related AEs. However, dose reduction in patients with small body sizes may alleviate skin-related AEs without sacrificing oncological outcomes.

Oncological and functional outcomes of female reproductive organ-sparing radical cystectomy and ileal neobladder construction.

OBJECTIVES: To examine the oncological and urinary functional outcomes of reproductive organ-sparing radical cystectomy (ROS-RC) and U-shaped ileal neobladder construction in females compared with male patients. METHODS: We retrospectively examined 357 patients (281 male and 76 female) with muscle-invasive bladder cancer who were treated with RC plus U-shaped ileal neobladder construction between May 1996 and July 2021. All female patients were treated with ROS-RC. We compared disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and urinary functional outcomes between male and female patients. We evaluated the effect of gender on DFS, CSS, and OS. Furthermore, urinary functional outcomes were evaluated in 140 males and 48 females using a pressure-flow study at 3, 6, 9, and 12 months postoperatively. RESULTS: Female patients were considerably older than male patients at the time of radical cystectomy. No significant difference was noted in the tumor stage preoperatively. The multivariable Cox regression analysis with an inverse probability treatment weighted model revealed that the female gender was not significantly related to DFS, CSS, and OS. Moreover, urinary functions at 12 months were not markedly different between males and females, except for the capacity of the neobladder, detrusor pressure, and maximum urethral closure pressure. CONCLUSIONS: This study demonstrates that female patients with ROS-RC and U-shaped ileal neobladder construction did not significantly correlate with worse oncological outcomes. The combination of ROS-RC and U-shaped ileal neobladder construction might attain adequate urinary function without sacrificing oncologic outcomes.

Deletion of Herp facilitates degradation of cytosolic proteins.

Although intracellular stresses are believed to be involved in the process of neurodegeneration, it is not fully understood how one stress/stress response affects another. Herp is an endoplasmic reticulum (ER)-located membrane protein proposed to function in ER-associated degradation (ERAD). Herp is strongly induced by ER stress but rapidly degraded by proteasome. To elucidate the effect of Herp expression on proteolytic stress caused by impairment of the ubiquitin-proteasome system (UPS), we utilized 293T Herp knockdown (KD) cells and F9 Herp knockout cells. Knockdown of Herp gene unexpectedly facilitated the degradation of Parkinson's disease-associated cytosolic proteins such as alpha-synuclein and its binding partner, synphilin-1, and improved cell viability during proteasomal inhibition. A similar tendency was observed in F9 Herp knockout cells transfected with synphilin-1. Herp temporarily bound to alpha-synuclein, synphilin-1 and the E3 ligase SIAH1a during proteolytic stress but not during ER stress. Furthermore, deletion of Herp enhanced the amount of ubiquitinated protein in the cytosol during proteasomal inhibition, although it did not affect the activity or expression of proteasome. These results suggest that ERAD molecule Herp may delay the degradation of cytosolic proteins at the ubiquitination step.

A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.

Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca(2+) in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca(2+) homeostasis. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08136FP].

A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress.

The enhancement of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). During a search for compounds that regulate ER stress, a dibenzoylmethane (DBM) derivative 14-26 (2,2'-dimethoxydibenzoylmethane) was identified as a novel neuroprotective agent. Analysis in SH-SY5Y cells and in PC12 cells revealed that the regulation of ER stress by 14-26 was associated with its anti-oxidative property. 14-26 prevented the production of reactive oxygen species (ROS) when the cells were exposed to oxidants such as hydrogen peroxide and 6-hydroxydopamine (6-OHDA) or an ER stressor brefeldin A (BFA). 14-26 also prevented ROS-induced damage in both the ER and the mitochondria, including the protein carbonylation in the microsome and the reduction of the mitochondrial membrane potential. Further examination disclosed the presence of the iron-chelating activity in 14-26. In vivo, 14-26 suppressed both oxidative stress and ER stress and prevented neuronal death in the substantia nigra pars compacta (SNpc) after injection of 6-OHDA in mice. These results suggest that 14-26 is an antioxidant that protects dopaminergic neurons against both oxidative stress and ER stress and could be a therapeutic candidate for the treatment of PD.

Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation.

Enhanced endoplasmic reticulum (ER) stress has been implicated in various pathological situations including inflammation. During a search for compounds that regulate ER stress, we identified vaticanol B, a tetramer of resveratrol, as an agent that protects against ER stress-induced cell death. Vaticanol B suppressed the induction of unfolded protein response-targeted genes such as glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) after cells were treated with ER stressors. Analysis in the mouse macrophage cell line RAW 264.7 revealed that vaticanol B also possesses a strong anti-inflammatory activity. Production of a variety of inflammatory modulators such as tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2) was inhibited by vaticanol B to a much greater extent than by monomeric or dimeric resveratrol after exposure of cells to lipopolysaccharide. Further investigations to determine the common mechanisms underlying the regulation of ER stress and inflammation by vaticanol B disclosed an important role for vaticanol B in regulation of basic gene expression and in prevention of the protein leakage from the ER into the cytosol in both conditions. These results suggest that vaticanol B is a novel anti-inflammatory agent that improves the ER environment by reducing the protein load on the ER and by maintaining the membrane integrity of the ER.