Therapeutic efficacy and safety of biweekly administration of enfortumab vedotin for urothelial carcinoma.

OBJECTIVES: Enfortumab vedotin (EV) is an established pharmacotherapy for metastatic urothelial carcinoma (mUC); however, its adverse events (AEs) cannot be overlooked. The study investigated the efficacy and safety of biweekly EV administration. METHODS: Patients with mUC who received EV at our institution were included in the study. Eligible patients were classified into two groups as follows: those who received EV on a standard schedule (standard group) and those who received EV on a biweekly schedule (biweekly group); the treatment outcomes and AEs between the two groups were compared. RESULTS: Nine and 19 patients were in the standard group and biweekly groups, respectively. The progression-free survival, overall survival, and overall response rate were not significantly different between the two groups. AEs following EV administration, such as decreased appetite (P < .01), pruritus (P < .01), rash maculopapular (P < .01), anemia (P = .04), and liver dysfunction (P = .04), were significantly more frequent in the standard group. Grade 3 or higher AEs, such as pruritus (P = .03) and rash maculopapular (P < .01), were significantly more frequent in the standard group. Furthermore, significantly more patients in the standard group had to be given a reduced dose due to adverse events (P = .02). CONCLUSIONS: Biweekly administration of EV may be safer without compromising therapeutic efficacy than the standard schedule.

Does radical cystectomy have a better prognosis than bladder conservative treatment in the real world?

PURPOSE: To compare the prognosis and quality of life between radical cystectomy and bladder conservative treatment for muscle invasive bladder cancer in the real world. MATERIALS AND METHODS: Patients treated for muscle invasive bladder cancer without metastases were retrospectively evaluated for overall survival, progression-free survival, and rehospitalization. RESULTS: Of the 141 patients, 62 underwent bladder conservative treatment and 79 underwent radical cystectomy. Patients who underwent radical cystectomy had significantly better progression-free survival (HR: 1.83, 95% CI: 1.12-3.00; p < 0.01) and overall survival (HR: 1.82, 95% CI: 0.99-3.34; p = 0.03) than those who underwent conservative treatment. However, there was no significant difference in prognosis between patients who refused to undergo radical cystectomy and those who underwent. In addition, rehospitalization rates for complications and additional treatment were significantly higher in patients who received conservative treatment (69.3% vs. 34.2%; p < 0.01), and the length of hospital stay was also prolonged compared to patients who received radical cystectomy (26 vs. 9 days; p = 0.03). CONCLUSIONS: Overall, conservative treatment had a significantly poorer prognosis than radical cystectomy, but there was no significant difference in prognosis when comparing patients who refused radical cystectomy and received conservative treatment with those who received radical cystectomy. However, hospitalization rates and length of stay were significantly worse for patients who chose conservative treatment, which may lead to a decline in quality of life.

Comprehensive analysis of perioperative hypotension in photodynamic diagnosis-assisted transurethral resection of bladder tumor with 5-aminolevulinic acid.

OBJECTIVE: Intraoperative hypotension remains a serious adverse event of photodynamic diagnosis-assisted transurethral resection of bladder tumor with oral administration of 5-aminolevulinic acid. We conducted a re-analysis of perioperative hypotension in photodynamic diagnosis-assisted transurethral resection of the bladder tumor with oral 5-aminolevulinic acid to ascertain its safety. METHODS: A total of 407 cases who underwent transurethral resection of bladder tumors in our institution were reviewed (274 cases for the PDD group with photodynamic diagnosis and 133 for the white light (WL) group without). A classification of hypotension severity was devised to identify risk factors for clinically troublesome hypotension. The distribution of hypotension severity in each of the PDD and WL groups was compared. Additionally, the patient background and perioperative data by hypotension severity were compared only in the PDD group. RESULTS: More patients with moderate and severe hypotension were noted in the PDD group. The renal function was lower with increasing hypotension severity in the PDD group. More patients on general anesthesia were included in the mild and moderate hypotension group, whereas more patients on spinal anesthesia were included in the severe hypotension group. Furthermore, the frequency of side effects other than hypotension tended to increase with hypotension severity. CONCLUSIONS: Renal function impairment and the other adverse effects of 5-aminolevulinic acid may be risk factors for severe hypotension. Mild or moderate hypotension may be caused by general anesthesia and severe hypotension may be caused by spinal anesthesia. To elucidate specific risk factors, further case-control studies are warranted.

Decreased febrile neutropenia during inpatient chemotherapy for urologic cancer during coronavirus disease 2019 pandemic.

Since 2020, the coronavirus disease 2019 pandemic has led to the widespread practice of hand hygiene and wearing face masks, not only among medical personnel, but also among the general population. Thus, the impact of the coronavirus disease 2019 pandemic on the incidence of febrile neutropenia should be verified. This study aimed to examine the incidence of febrile neutropenia in hospitalized patients receiving chemotherapy at Kanazawa University Hospital. Among inpatients at the Department of Urology receiving chemotherapy, we compared the incidence of febrile neutropenia between 317 cases in 2018-2019 and 276 cases in 2020. We retrospectively analyzed the factors of febrile neutropenia via binomial logistic regression analysis based on patient characteristics and the characteristics of primary diseases, with statistical significance set at p < 0.05. Febrile neutropenia occurred in 20/317 cases in 2018-2019 and 1/276 cases in 2020, with a significant decrease in the latter (p = 0.005). In a multivariate analysis, we identified the following independent risk factors for febrile neutropenia: non-coronavirus disease 2019 era (p = 0.005), first course of therapy (p = 0.005), malnutrition (p = 0.032), and past history of febrile neutropenia (p = 0.018). Due to the coronavirus disease 2019 pandemic, hygiene policies for medical personnel and quarantine measures for patients were thoroughly implemented. Therefore, the incidence of febrile neutropenia in 2020 decreased to 1/15 of the previous incidence. Thus, the hygiene for medical personnel and patients during the expected period of chemotherapy-induced neutropenia is important for febrile neutropenia prevention.

Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis.

The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.

Postoperative functional and cancer control evaluation of conventional and Retzius-sparing robot-assisted radical prostatectomy: Comparison of selected cases by propensity score matching.

AIM: Although many reports have shown that Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) is effective for postoperative urinary continence, the postoperative voiding status and sexual function associated with this technique have not yet been adequately compared with those associated with conventional RARP (C-RARP). In this study, the lower urinary tract function, erectile function, and cancer control after C-RARP and RS-RARP were compared chronologically. MATERIALS AND METHODS: We selected 50 cases of C-RARP and RS-RARP each by propensity score matching and evaluated them over time using various questionnaires. Urinary continence recovery rates and biochemical recurrence (BCR)-free survival rates were calculated using the Kaplan-Meier method and compared between the two groups using the log-rank test. RESULTS: When urinary continence was defined as 0 pads per day, 0 pads per day + 1 security linear, or ≤1 pad per day, the postoperative improvement in urinary continence was better with RS-RARP over the course of up to 1 year for all definitions. The International Consultation on Incontinence Questionnaire-Short Form total scores and the Overactive Bladder Symptom Scores were better in the postoperative RS-RARP group. There were no significant differences in the International Prostate Symptom Score total score, QOL score, and erectile hardness score between the two groups during the observation period. The BCR-free survival did not differ significantly between the two groups CONCLUSIONS: Postoperative urinary continence was better in the RS-RARP group than in the C-RARP group; however, the voiding function, erectile function, and cancer control did not differ significantly.

Comparison of postoperative urinary continence and incontinence types between conventional and Retzius-sparing robot-assisted radical prostatectomy.

AIMS: This study aimed to investigate the postoperative urinary continence rate and incontinence types compared over time between conventional robot-assisted radical prostatectomy (C-RARP) and Retzius-sparing RARP (RS-RARP). METHODS: All 61 cases were selected from the C-RARP and RS-RARP by propensity score matching, and the pad scale, 24-h pad weight test, and International consultation on incontinence questionnaire-short form (ICIQ-SF) were followed-up over time up to 12 months. RESULTS: The probability of urinary continence per pad scale evaluation differed according to how it was defined: the continence rate 12 months after C-RARP and RS-RARP were 94% and 95% for 1 pad/day, 85% and 92% for 1 security pad/day, 61% and 85% for no pad use, respectively, which were all significantly better with RS-RARP. The results of the 24-h pad weight test were significantly better with RS-RARP at both 3 and 12 months, with median C-RARP versus RS-RARP values of 5 versus 1 g and 2 versus 0 g, respectively. In terms of types of urinary incontinence, the rates of postoperative stress urinary incontinence (SUI) increased in both procedures but to a lesser extent in RS-RARP. Other types of urinary incontinence, such as urge incontinence and terminal dribbling, did not differ significantly before and after surgery and between the two procedures. CONCLUSIONS: Postoperative urinary continence was better with RS-RARP than with C-RARP per all follow-up parameters until 12 months postoperatively. Postoperative SUI was significantly lower with RS-RARP than with C-RARP, which was considered the main reason for better postoperative urinary continence with RS-RARP.

Conformationally Fixed Chiral Bisphosphine Ligands by Steric Modulators on the Ligand Backbone: Selective Synthesis of Strained 1,2-Disubstituted Chiral cis-Cyclopropanes.

A new series of C1-symmetric P-chirogenic bisphosphine ligands of the type (R)-5,8-Si-Quinox-tBu3 (Silyl = SiMe3, SiEt3, SiMe2Ph) have been developed. The bulky silyl modulators attached to the ligand backbone fix the phosphine substituents to form rigid chiral environments that can be used for substrate recognition. The ligand showed high performances for a copper(I)-catalyzed asymmetric borylative cyclopropanation of bulky silyl-substituted allylic electrophiles to afford higher disfavored 1,2-cis-silyl-boryl-cyclopropanes than the other possible isomers, trans-cyclopropane and allylboronate (up to 97% yield; 98% ee; cis/trans = >99:1; cyclopropane/allylboronate = >99:1). Detailed computational studies suggested that the highly rigid phosphine conformation, which is virtually undisturbed by the steric interactions with the bulky silyl-substituted allyl electrophiles, is key to the high stereo- and product-selectivities. Furthermore, the detailed computational analysis provided insight into the mechanism of the stereoretention or -inversion of the chiral alkylcopper(I) intermediate in the intramolecular cyclization.

Usefulness of serum CCL2 as prognostic biomarker in prostate cancer: a long-term follow-up study.

OBJECTIVE: Prostate-specific antigen is considered the most useful biomarker for prostate cancer, but not in all cases. In a previous study, we have shown that a risk classification combining prostate-specific antigen ≥100 ng/mL and chemokine (CC motif) ligand 2 ≥ 320 pg/mL can predict survivals. We investigated the long-term usefulness of serum chemokine (CC motif) ligand 2 as a complementary biomarker to prostate-specific antigen and developed a novel risk classification system. METHODS: Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital between 2007 and 2013, and 255 patients with histologically diagnosed prostate cancer were included in this study. We retrospectively examined the efficacy of serum chemokine (CC motif) ligand 2 as a prognostic biomarker. RESULTS: Patients with chemokine (CC motif) ligand 2 ≥ 320 pg/mL exhibited a significantly shorter overall survival, prostate cancer-specific survival and castration-resistant prostate cancer-free survival than those with chemokine (CC motif) ligand 2 < 320 pg/mL. Multivariate analysis was performed to determine whether chemokine (CC motif) ligand 2 was a useful prognostic factor. Independent significant predictors of worse overall survival were prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8 and chemokine (CC motif) ligand 2 ≥ 320 pg/dL. Prognostic predictors of prostate cancer-specific survival or cancer-free survival in multivariate analysis were prostate-specific antigen ≥ 100 ng/mL and Gleason score ≥ 8. A novel risk classification system was created to predict overall survival in patients based on the number of risk factors present (chemokine (CC motif) ligand 2 ≥ 320 pg/mL, prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8). Scores 2 or 3, 1 and 0 indicated Poor, Intermediate and Good risk groups, respectively. CONCLUSIONS: This study demonstrated the utility of serum chemokine (CC motif) ligand 2 level as a predictive biomarker of long-term overall survival in prostate cancer. A novel risk classification system that predicts long-term overall survival based on the combined indications of chemokine (CC motif) ligand 2 level, prostate-specific antigen level and Gleason score may be a useful prognostic tool for prostate cancer.

Backbone-Modified C2-Symmetrical Chiral Bisphosphine TMS-QuinoxP*: Asymmetric Borylation of Racemic Allyl Electrophiles.

A new C2-symmetrical P-chirogenic bisphosphine ligand with silyl substituents on the ligand backbone, (R,R)-5,8-TMS-QuinoxP*, has been developed. This ligand showed higher reactivity and enantioselectivity for the direct enantioconvergent borylation of cyclic allyl electrophiles than its parent ligand, (R,R)-QuinoxP* (e.g., for a piperidine-type substrate: 95% ee vs 76% ee). The borylative kinetic resolution of linear allyl electrophiles was also achieved using (R,R)-5,8-TMS-QuinoxP* (up to 90% ee, s = 46.4). An investigation into the role of the silyl groups on the ligand backbone using X-ray crystallography and computational studies displayed interlocking structures between the phosphine and silyl moieties of (R,R)-5,8-TMS-QuinoxP*. The results of DFT calculations revealed that the entropy effect thermodynamically destabilizes the dormant dimer species in the catalytic cycle to improve the reactivity. Furthermore, in the direct enantioconvergent case, detailed calculations indicated a pronounced enantioselective recognition of carbon-carbon double bonds, which is virtually unaffected by the chirality at the allylic position, as a key for the borylation from both enantiomers of racemic allyl electrophiles.

Androgen receptor signaling-targeted therapy and taxane chemotherapy induce visceral metastasis in castration-resistant prostate cancer.

BACKGROUND: Visceral metastasis (VM), an important poor prognostic factor of prostate cancer (PC), is not commonly observed in castration sensitive status but is often observed after castration-resistant progression. However, the site, timing of emergence, and incidence of VM in castration-resistant patients have not yet been fully elucidated. METHODS: Demographic, surgical, pathological, and follow-up data of PC patients treated at Kanazawa University Hospital between January 2000 and December 2016 were retrospectively analyzed using their medical charts. From this data, risk factors of VM and survival of patients with VM were elucidated. RESULTS: Of 1364 patients, 21 (1.5%) had VM at diagnosis. Of 179 (13.1%) castration-resistant patients, 55 experienced emergence of new VM during treatment course. Incidence of new VM, especially nonlung, such as liver and adrenal metastases, increased significantly in proportion with the number of prescribed treatments. Multivariate analysis revealed that T stage, M stage, age, and treatment history with androgen receptor (AR) signaling-targeted agents and/or taxanes significantly increased the risk of VM. Compared with the group with VM at diagnosis, survival after diagnosis of VM following treatment was significantly shorter. CONCLUSION: Although sequential use of new AR signaling-targeted agents and taxanes for castration-resistant PC (CRPC) is a standard treatment strategy, it often results in development of VM. Elucidating the mechanisms of VM are essential to improve survival in patients with CRPC.

A new flavonoid derivative exerts antitumor effects against androgen-sensitive to cabazitaxel-resistant prostate cancer cells.

BACKGROUND: Our previous report has shown that the flavonoid 2'-hydroxyflavanone (2'-HF) showed inhibition of androgen receptor (AR) activity against androgen-sensitive prostate cancer (PCa) cells, LNCaP, and exhibited antitumor effects against androgen-insensitive PCa cells, PC-3, and DU145. In the present study, we prepared a derivative of 2'-HF, 16MS7F1924, and confirmed the effects of this derivative on PCa cells. METHODS: The antiproliferation effects of 16MS7F1924 were investigated in PCa cells using LNCaP, PC-3, DU145 and docetaxel-resistant and cabazitaxel-resistant cell lines of PC-3-TxR/CxR and DU145-TxR/CxR. Prostate-specific antigen (PSA) and AR expression level in whole cells and the nucleus were confirmed in LNCaP by reverse transcriptase polymerase chain reaction and Western blot analysis. AR activity in LNCaP cells was confirmed by luciferase assay using PSA promoter-driven reporter. To analyze the antiproliferative effects, cell-based assays using flow cytometry, immunocytochemistry, and TUNEL assay as well as Western blot analysis were employed. Furthermore, PC-3, DU145 and each chemoresistant strain of human PCa cells were subcutaneously xenografted. The antitumor effects of 16MS7F1924 were evaluated in vivo. RESULTS: 16MS7F1924 showed antitumor effect on all PCa cells in a dose-dependent manner. 16MS7F1924 reduced the expression of PSA messenger RNA (mRNA) and protein and inhibited AR activity in a dose-dependent manner, while expression of AR protein and mRNA was reduced by 16MS7F1924. 16MS7F1924 induced mitotic catastrophe and apoptosis. Apoptotic cells were increased in a dose-dependent manner, and the apoptosis was mediated through the Akt pathway. Tumor growth was safely and significantly inhibited by both intraperitoneal and oral administration of 16MS7F1924 in vivo. CONCLUSION: 16MS7F1924 had sufficient antitumor activity against androgen-sensitive and cabazitaxel-resistant PCa cells and may be useful as a novel therapeutic agent overcoming hormone- and chemoresistant PCas.

Synthesis of Fluoroalkyl Sulfides via Additive-Free Hydrothiolation and Sequential Functionalization Reactions.

A modular synthetic method, involving a hydrothiolation, silylation, and fluoroalkylation, for the construction of highly functionalized fluoroalkyl sulfides has been developed. The use of aprotic polar solvents enables the additive-free chemoselective hydrothiolation of tetrafluoroethylene, trifluorochloroethylene, and hexafluoropropene with various thiols. The stepwise functionalization reactions convert the hydrothiolated intermediates into the tetrafluoroethyl sulfides in high efficiency. The method avoids the use of the environmental pollutant Halon-2402, which was employed as a building block in a reported synthetic route.

The effectiveness of high-dose-rate brachytherapy with external beam radiotherapy for clinically locally advanced and node-positive prostate cancer: long-term results of a retrospective study.

BACKGROUND: No standard treatment exists for locally advanced prostate cancer (PC). This study evaluated the long-term treatment outcomes and toxicity in patients with clinically locally advanced and/or lymph node (LN)-positive PC who underwent high-dose-rate brachytherapy (HDR-BT) with external beam radiotherapy (EBRT). METHODS: The treatment outcomes and toxicities of 152 patients with PC who underwent HDR-BT with EBRT and had at least 2 years of observation were examined. The treatment dose was 19- and 13-Gy HDR-BT in two and single fractions, respectively, both combined with external irradiation of 46 Gy in 23 fractions. Long-term androgen deprivation therapy (ADT) for patients harboring very high-risk tumors was used in combination. RESULTS: The median observation period was 59.7 (24.4-182.1) months. The 5-year prostate cancer-specific and recurrence-free (RFS) survival rates were 99.0% and 91.8%, respectively, with only two PC mortalities. When 5-year RFS was examined for each parameter, RFS was significantly lower in pre-radiotherapy (pre-RT) prostate-specific antigen (PSA) > 0.5 ng/mL (77.1%; p = 0.008), and presence of LN metastasis (68.1%; p = 0.017). Multivariable analysis demonstrated that pre-RT PSA (HR, 4.68; 95% CI, 1.39-15.67; p = 0.012) and presence of LN metastasis (HR, 4.70; 95% CI, 1.24-17.74; p = 0.022) were independent recurrence predictors. The 5-year cumulative incidence rate of grade ≥ 2 toxicities in genitourinary and gastrointestinal tracts were 15.4% and 1.3%, respectively. CONCLUSIONS: HDR-BT combined with EBRT and long-term ADT shows promising disease control and tolerant toxicities for clinically locally advanced and LN-positive PC.

Transvaginal polytetrafluoroethylene mesh surgery for pelvic organ prolapse: 1-year clinical outcomes.

OBJECTIVES: To evaluate the safety and efficacy of transvaginal mesh surgery using a polytetrafluoroethylene mesh to treat pelvic organ prolapse. METHODS: This prospective observational study included women undergoing transvaginal mesh surgery for pelvic organ prolapse that used new polytetrafluoroethylene mesh cut into a shape similar to that of Elevate. We evaluated the subjective and objective outcomes at 3 and 12 months, as well as postoperative complication rates. RESULTS: This study included 55 patients. The pelvic organ prolapse quantification scores improved significantly at 3 and 12 months after surgery compared with scores before surgery. In four patients (7.3%), a pelvic examination showed stage 2 objective recurrence without subjective symptoms. Clavien-Dindo grades 2 and 3 perioperative complications were observed in 9.1% and 1.8% of the patients, respectively. Vaginal mesh exposure occurred in one patient (1.8%) at the time of the 3-month follow-up evaluation. The mesh was exposed at the proximal midline of the anterior vaginal wall. CONCLUSIONS: These findings show the safe and effective use of the polytetrafluoroethylene mesh for transvaginal mesh surgery.

Cleavage of C(sp3)-F Bonds in Trifluoromethylarenes Using a Bis(NHC)nickel(0) Complex.

The first example of the oxidative addition of a C(sp3)-F bond in trifluoromethylarenes to a nickel(0) complex is described. A nickel(0) complex that bears two N-heterocyclic carbene (NHC) ligands of low steric demand is able to cleave C(sp3)-F bonds of trifluoromethylarenes to afford the corresponding trans-difluorobenzyl nickel(II) fluoride complexes. Isolation and characterization studies suggested that the cleavage of the C(sp3)-F bond proceeds via an η2-arene nickel(0) complex. Taking advantage of the reactivity of these nickel(II) fluoride complexes, we developed a catalytic hydrodefluorination of trifluoromethylarenes using hydrosilanes. A computational study indicated that the electron-rich nickel(0) center supported by two relatively small NHC ligands cleaves the C(sp3)-F bond via a syn-SN2' mechanism.

Is the C-C Motif Ligand 2-C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?

C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing the recruitment of tumor-associated macrophages into the tumor microenvironment. The role of CCL2 in cancer progression has gradually been understood, and various preclinical cancer models elucidate that CCL2 and its receptor C-C chemokine receptor 2 (CCR2) are attractive targets for intervention in cancer development. However, clinically available drugs that regulate the CCL2-CCR2 axis as anticancer agents are not available at this time. The complete elucidation of not only the oncological but also the physiological functions of the CCL2-CCR2 axis is required for achieving a satisfactory effect of the CCL2-CCR2 axis-targeted therapy.

CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells.

Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel-resistant and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145-TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145-TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel.

Coffee diterpenes kahweol acetate and cafestol synergistically inhibit the proliferation and migration of prostate cancer cells.

BACKGROUND: Coffee inhibits the progression of prostate cancer; however, the direct mechanism through which coffee acts on prostate cancer cells remains unclear. This study aimed to identify the key compounds of coffee that possess anti-cancer effects and to investigate their mechanisms of action. METHODS: The anti-proliferation and anti-migration effects of six potentially active types of coffee compounds, including kahweol acetate, cafestol, caffeine, caffeic acid, chlorogenic acid, and trigonelline hydrochloride, were evaluated using LNCaP, LNCaP-SF, PC-3, and DU145 human prostate cancer cells. The synergistic effects of these compounds were also investigated. Apoptosis-related and epithelial-mesenchymal transition-related proteins, androgen receptor in whole cell and in nucleus, and chemokines were assessed. A xenograft study of SCID mice was performed to examine the in vivo effect of coffee compounds. RESULTS: Among the evaluated compounds, only kahweol acetate and cafestol inhibited the proliferation and migration of prostate cancer cells in a dose-dependent manner. The combination treatment involving kahweol acetate and cafestol synergistically inhibited proliferation and migration (combination index <1) with the induction of apoptosis, the inhibition of epithelial-mesenchymal transition, and decrease in androgen receptor, resulting in the reduction of nuclear androgen receptor in androgen receptor-positive cells. Moreover, kahweol acetate and cafestol downregulated CCR2 and CCR5 without an increase in their ligands, CCL2 and CCL5. The xenograft study showed that oral administration of kahweol acetate and cafestol significantly inhibited tumor growth. CONCLUSION: Kahweol acetate and cafestol synergistically inhibit the progression of prostate cancer. These coffee compounds may be novel therapeutic candidates for prostate cancer.

Intraoperative hypotension caused by oral administration of 5-aminolevulinic acid for photodynamic diagnosis in patients with bladder cancer.

OBJECTIVE: To analyze perioperative blood pressure in patients undergoing transurethral resection of bladder tumor with photodynamic diagnosis. METHODS: A total of 109 consecutive patients who underwent photodynamic diagnosis-assisted transurethral resection of bladder tumor at Kanazawa University, Kanazawa, Ishikawa, Japan, were included in this study and considered as the photodynamic diagnosis group. Clinical data were collected, and perioperative systolic bladder pressure and vasopressor usage were analyzed. In contrast, consecutive patients who previously underwent conventional transurethral resection of bladder tumor (without the use of oral 5-aminolevulinic acid) were used as the control group. RESULTS: The systolic blood pressure before anesthesia, lowest systolic blood pressure from the anesthesia induction to the start of operation and lowest systolic blood pressure during operation were significantly lower in the photodynamic diagnosis group. The rate of vasopressor use was significantly higher in the photodynamic diagnosis group. On multivariate analysis, we found that general anesthesia and regular use of renin-angiotensin system inhibitor were associated with an increased risk of hypotension (lowest systolic blood pressure from the anesthesia induction to the start of operation <80 mmHg). CONCLUSIONS: Oral intake of 5-aminolevulinic acid can obviously cause a drop in intraoperative blood pressure in patients undergoing transurethral resection of bladder tumor. Therefore, urologists and anesthesiologists should consider withdrawal of renin-angiotensin system inhibitors and monitor the blood pressure during photodynamic diagnosis-assisted transurethral resection of bladder tumor.