Pre-first-line chemotherapy risk stratification for overall survival in advanced urothelial carcinoma in sequential therapy era.

PURPOSE: To explore pre-treatment risk factors for overall survival (OS) in advanced urothelial carcinoma (UC) patients treated with first-line (1L) chemotherapy in sequential therapy (ST) era. Additionally, to evaluate the proportion of patients who were not able to undergo subsequent immune checkpoint inhibitor (ICI) therapy according to the subgroups stratified by the risk factors. METHODS: A multicenter retrospective study was conducted. Metastatic or locally advanced UC patients treated between 2017 and 2022 were included. The Kaplan-Meier method with the log-rank test and multivariate Cox regression models were used to address OS. RESULTS: Three hundred and fourteen patients treated with 1L chemotherapy were included in the study and 57 (18.2%) patients were not able to proceed to subsequent ICI therapy. Pre-chemotherapy risk factors for OS in 314 patients were ECOG-PS 1 or more, having no primary site resection, C-reactive protein (CRP) level of 3 mg/dL or more, and non-cisplatin-based regimen. Patients having 3 or 4 risk factors had higher risk for not being able to receive ST (Mann-Whitney U test, P < 0.001). As risk factors for OS in 230 patients who were able to receive ST, having no primary site resection, a neutrophil to lymphocyte ratio of 3 or more, and the presence of liver metastasis were identified. CONCLUSION: We reported the risk factors for OS in advanced UC patients treated with 1L chemotherapy in ST era. Patients with high risk for OS may not be able to proceed to subsequent ICI therapy even in the ST era.

14- and 17-Membered Macrocycles Containing Amide, Amino, and Carbamate Groups in The Monocyclic Skeleton: An Accidental Byproduct Obtained from a Residue after Separation.

A 14-membered cyclic compound (3) containing amide, amino, and carbamate groups, which was serendipitously obtained in the oily residue after the separation of 4-benzyl-1,4,7,10-tetraazacyldododecane-2,6-dione (2a) and 4,16-dibenzyl-1,4,7,10,13,16,19,22-octaazacyclo-tetracosane-2,6,14,18-tetraone (2b), is reported. The structure of 3 is formally a CO2 insertion between positions 3 and 4 of the 12-membered ring in 2a. The CO2 insertion was confirmed in the synthesis of diethyl 2,2'-(benzylazanediyl)diacetate (1) by the reaction of benzylamine with ethyl bromoacetate using K2CO3 as the base. In addition, the selective synthesis of 3 and ethyl N-benzyl-N-((2-ethoxy-2-oxoethoxy)carbonyl)glycinate (5) and their kinetic behavior are reported. The reaction of 5 with triethylenetetramine afforded a 17-membered macrocycle (7), which was obtained in an 18% yield. Compounds 6 and 8 were prepared from 3 and 7 by introducing benzyl groups to improve their solubility in organic solvents. Titration experiments using 1H NMR showed that both 6 and 8 exhibit Li+ selectivity.

Regioselective Coordination toward Silver(I) Ions by Bis- and Tris(Tetra-Armed Cyclen)s via Differential Electron Density of Aromatic Side Arms.

Four types of bis- and tris(tetra-armed cyclen)s were prepared. 2MF is a bis(tetra-armed cyclen) with electron-rich side arms (three 4-methoxybenzyl groups) and electron-deficient side arms (three 3,5-difluorobenzyl groups), connected by a 4,4'-dimethyl-1,1'-biphenyl moiety. 3MFM is a tris(tetra-armed cyclen) with 4-methoxybenzyl and 3,5-difluorobenzyl groups introduced on both ends and the central cyclen, respectively. 4MFM is a V-shaped analogue of 3MFM. 3FMF is a tris(tetra-armed cyclen) where the aromatic side arms at both ends and the central cyclen of 3MFM are exchanged. The regioselective coordination of silver(I) ions by these ligands is reported. Initially, we added Ag+ ions to a compound (2MF) that consists of tetra-armed cyclen with 4-methoxybenzyl groups as an electron-donating substituent on the aromatic rings and 3,5-difluorobenzyl groups as an electron-withdrawing substituent. 1H NMR and 19F{1H} NMR spectroscopy exhibited that the cyclen with the 4-methoxybenzyl groups formed a complex with Ag+ ions first, followed by the cyclen with the 3,5-difluorobenzyl groups. Next, we employed a compound (3MFM) with three cyclen units, where the cyclen at each end was functionalized with three 4-methoxybenzyl groups, and the central cyclen was functionalized with two 3,5-difluorobenzyl groups. Upon adding Ag+ ions, we observed that the cyclen units at both ends formed complexes with Ag+ ions initially, followed by the central cyclen forming a complex with Ag+ ions. When we used 4MFM, which is a V-shaped compound, the Ag+-induced-1H NMR chemical shift changes are almost the same results as the 3MFM. Furthermore, we synthesized a compound (3FMF) by interchanging the substituents on the cyclen units at the ends and the center. Interestingly, the order of the complex formation was reversed in this compound. These results demonstrated that tuning the electron density on the aromatic side arms through substituents makes it possible to achieve regioselective coordination with Ag+ ions in bis- or tris(tetra-armed cyclen)s.

A Structure-Adaptive Ligand: The Conformation Changes to Fit with the Lengths and Angles of Tetravalent Bis-Paraquat Guests.

A flexible cylindrical cryptand (1b) with two m-phenylene-26-crown-8 ethers has been prepared, and its complexing properties with respect to tetravalent cationic bis-paraquat guests have been investigated. Diffusion-ordered spectroscopy nuclear magnetic resonance (NMR) and titration experiments using cold electrospray ionization mass spectrometry and 1H NMR revealed that 1b has versatile complexing properties with respect to tetravalent cationic guests used despite the guest molecules' length and shape.

Cosmosen: Octa-Armed 24-Membered Cyclic Octaamine Synthesized from a Byproduct in the Preparation of 4-Benzyl-2,6-dioxocyclen.

The synthesis of an octa-armed 24-membered cyclic octaamine (1) is reported. When 4-benzyl-1,4,7,10-tetraazacyclododecane-2,6-dione (3a) was prepared by the reaction of diethylenetriamine with diethyl N-benzyliminodiacetate (2), a dimeric macrocycle (3b) was obtained as a byproduct in a 5% yield. An octa-armed 24-membered cyclic octaamine (1), named Cosmosen, was prepared via the reductive amination and reduction of 3b. The binding constants for the 1:1 and 2:1 (Ag+/1) complexation of 1 were estimated to be ca. 7.9 and 13.9, respectively, by titration experiments using UV-vis spectrometry in methanol and chloroform (v/v, 9:1) solutions at 298 K.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in urological malignancies: a multi-center retrospective study.

INTRODUCTION: We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients. MATERIALS AND METHODS: We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists. RESULTS: Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m2 were significant predictors for ARONJ. CONCLUSION: ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.

Argentivorous Molecules with Oxyethylene Chains in Side-Arms: Silver Ion-Induced Selectivity Changes toward Alkali Metal Ions.

Argentivorous molecules with mono, di, tri, tetra, and penta-oxyethylene chains in aromatic side-arms were prepared (L1-L5). Titration experiments using proton nuclear magnetic resonance and cold electrospray ionization (cold-spray ionization, CSI) mass spectrometry showed that silver ions were trapped in the cyclen moiety and the arranged oxyethylene chains of the side-arms when two equivalents of silver ions were added. The silver complexes formed by adding one equivalent of silver ion to L2-L5 bind alkali metal ions using the oxyethylene chains; alkali metal ion-induced CSI mass spectral changes of L2-L5 were measured in the absence and presence of silver ions to compare the binding properties of the ligand for Li+, Na+, and K+ ions. As a result, the intensity ratios of [L + H + M]2+/[L + H]+ in L1-L3 were almost zero or very low. L4 and L5, which have tetra(oxyethylene) and penta(oxyethylene) chains, respectively, bind a larger size of alkali metal ions. On the other hand, in the presence of silver ions, the ratio for [L + Ag + M]2+/[L + H]+ (M = Li, Na, K) in L2-L5 was increased. The highest [L + Ag + M]2+/[L + H]+ ratios for K+ were observed in L4 and L5, while selectivity for Na+ was observed in the case of L2 and L3. These results indicate that the increased binding ability and selectivity by L2-L5 are due to the arrangement of oxyethylene chains by the conformational change of the aromatic side-arms. The Ag+-induced carbon-13 nuclear magnetic resonance spectral changes suggested that the second and third oxyethylene units, close to the benzene, are involved in the coordination of the second metal ion.

Argentivorous Molecules with Chromophores in Side Arms: Silver Ion-Induced Turn On and Turn Off of Fluorescence.

The synthesis of argentivorous molecules (L1 and L2) having two chromophores (4-(anthracen-9-yl)benzyl or 4-(pyren-1-yl)benzyl groups) and two benzyl groups and the fluorescence properties of their silver complexes in a solution and the solid state are reported. A crystallographic approach for the Ag+ complexes with L1 and L2 revealed that the observed fluorescence changes stem from the excimer formation and extinction of fluorescent. Furthermore, binding stabilities of L1 and L2 toward Ag+ ions were estimated by the Ag+-induced UV-vis and PL spectral changes.

Bis-Argentivorous Molecules Bridged by Phenyl and 4,4'-Biphenyl Groups: Structural and Dynamic Behavior of Silver Complexes.

Bis-argentivorous molecules (La and Lb), which have phenyl and 4,4'-biphenyl groups as linkers, have been prepared. The structures of Ag+ complexes with the new ligands (La and Lb) were investigated in solution and the solid state. The CSI-MS and 1H NMR titration of La and Lb with Ag+ show 1:1 and 1:2 complexes depending on the [Ag+]:[L] ratios. In the solid-state structures, single crystals of La and Lb with 2 equiv of Ag+ were prepared. X-ray crystallography of the silver(I) complexes with La and Lb showed that an intramolecular racemic structure (Δ(δδδδ)Λ(λλλλ) form) and a racemic mixture of Δ(δδδδ)Δ(δδδδ) and Λ(λλλλ)Λ(λλλλ) forms were formed, respectively. The dynamic 1H NMR studies suggest the following: (i) the activation entropies (ΔS⧧) of the side arm rotations in the Ag+ complex with La were all negative, indicating restricted rotation of the side arms due to their shortness, and (ii) the ΔS⧧ values of the Ag+ complexes with Lb were negative only when the side arms of both cyclens rotated simultaneously, and the ΔS⧧ values for the 1:1 and 1:2 complexes were positive when one cyclen side arm was rotated. These values of ΔS⧧ indicate that the biphenyl side arms between the two cyclens are not long enough to rotate the ring freely.

Complications within 90 days after radical cystectomy for bladder cancer: results of a multicenter prospective study in Japan.

PURPOSE: We prospectively evaluated the 90-day postoperative mortality and morbidity of open radical cystectomy by using a standardized reporting methodology. Additionally, we assessed the preoperative characteristics to determine risk factors for major complications. METHODS: This multicenter prospective study included 185 consecutive patients undergoing open radical cystectomy from October 2010 through March 2014. Postoperative complications within 90 days were recorded and graded according to the modified Clavien-Dindo classification. RESULTS: Totally, 328 postoperative complications were observed in 149 patients (80.5%). Of these events, 73 (22.2%) were high grade (≥ Grade III), and developed in 46 patients (24.9%). Three patients (1.6%) died postoperatively. Urinary tract infection, wound complications, and paralytic ileus were common complications that occurred in 55 (29.7%), 42 (22.7%) and 41 (22.2%) patients, respectively. Ureteroenteric stricture was diagnosed in 13 of the 151 patients (8.6%) undergoing intestinal urinary diversion. Emergency room visits were required for 13 patients (7.0%) and readmission after discharge was needed for 36 (19.5%). A body mass index ≥ 25 kg/m2, smoking history and Charlson Comorbidity Index ≥ 2 were independent risk factors for high-grade complications, and their odds ratios (95% confidence intervals) were 2.357 (1.123-4.948), 2.843 (1.225-6.596) and 3.025 (1.390-6.596), respectively. CONCLUSIONS: Open radical cystectomy is associated with a high incidence of postoperative complications. Most, however, are of low grade. Our results suggest that obesity, a smoking history, and increasing comorbidity are risk factors for major complications.

Palonosetron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting during gemcitabine/cisplatin in urothelial cancer patients.

OBJECTIVES: To evaluate the appearance of chemotherapy-induced nausea and vomiting, and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-hydroxytryptamine 3-receptor antagonists and dexamethasone during gemcitabine and cisplatin chemotherapy in patients with advanced urothelial cancer. METHODS: We carried out a multi-institutional study including 122 patients who received gemcitabine and cisplatin for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled chemotherapy-induced nausea and vomiting events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake. RESULTS: First-generation 5-hydroxytryptamine 3-receptor antagonists (ondansetron or granisetron) plus dexamethasone were used for 75 patients (cohort 1), and palonosetron with dexamethasone plus aprepitant for 47 patients (cohort 2). Patients in cohort 2 had significantly higher complete response (defined as no emetic episodes and no rescue medication use) rates than those in cohort 1 during the overall phase in the first cycle (85.7% vs 65.3%, P = 0.012), and all cycles (78.7% vs 50.7%, P = 0.0019) of gemcitabine and cisplatin. Patients in cohort 2 were more likely to achieve more favorable chemotherapy-induced nausea and vomiting control; that is, a lower grade of nausea, vomiting or anorexia, lower incidence of rescue therapy required, and shorter time to become chemotherapy-induced nausea- and vomiting-free than patients in cohort 1. CONCLUSIONS: The present results show that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in urothelial cancer patients treated with gemcitabine and cisplatin than first-generation 5-hydroxytryptamine 3-receptor antagonists plus dexamethasone.

α1-blocker tamsulosin as initial treatment for patients with benign prostatic hyperplasia: 5-year outcome analysis of a prospective multicenter study.

OBJECTIVE: To comprehensively analyze the 5-year outcomes of tamsulosin treatment for patients with benign prostatic hyperplasia. METHODS: Tamsulosin (0.2 mg/day) was given to 112 patients who had International Prostate Symptom Scores ≥8. They were prospectively followed for 5 years with periodic evaluation. If tamsulosin had to be discontinued, the reason was determined. Treatment failure was considered in the case of disease progression (postvoid residual urine volume ≥200 mL, acute urinary retention, febrile urinary tract infection or hydronephrosis as a result of bladder outlet obstruction), conversion to other α1-blockers or need for surgery. An intention-to-treat analysis was carried out. RESULTS: A total of 34 patients (30.4%) continued the same medication for the overall study period, whereas 78 patients (69.6%) discontinued the medication. International Prostate Symptom Scores, Benign Prostatic Hyperplasia Problem Index and Quality of Life Index were significantly improved over the 5-year period. Treatment failure was observed in 21 patients (18.8%). Baseline prostate volume and postvoid residual urine volume were independent factors to predicting treatment failure. A total of 21 patients (18.8%) discontinued tamsulosin because of an improvement of symptoms. They were younger and had lower prostate-specific antigen levels than the remaining 91 patients. Their symptoms were stable even 1 year after termination of therapy. CONCLUSIONS: Long-term efficacy of tamsulosin was observed, although only a small portion of patients continued the treatment. α1-blocker monotherapy might be not appropriate for achieving a good long-term outcome in patients with a large prostate volume and a large amount of postvoid residual urine volume. Persistent improvement of symptoms, even after termination of tamsulosin, was observed in young patients with low prostate-specific antigen levels.

Argentivorous molecules with chromophores: dependence of their fluorescence intensities on the distance between a donor and an acceptor.

We have prepared new argentivorous molecules (L2 and L3) having different linker lengths between cyclen and anthracene units. The structures of Ag+ complexes with the new ligands were investigated in solution and solid states. The silver(I) ion-induced 1H NMR and UV-vis spectral changes of L2 and L3 showed the presence of 1 : 1 complexes. The solid-state structures of the Ag+ complexes with L2 and L3 are stable 1 : 1 complexes because four aromatic side-arms wrap the Ag+ incorporated in the cyclen unit. A photo-induced electron transfer (PET) effect that depends on the length of the linker connecting the nitrogen atoms of cyclen to the chromophore is also investigated. The result indicates a linear (log) correlation between the donor-chromophore average distances of the optimized structures calculated by DFT calculations and fluorescence intensities (log I), and the PET effect becomes ineffective at about 12 Å in this system.

Three new nortriterpene glycosides and two new triterpene glycosides from the bulbs of Scilla scilloides.

Three new norlanostane-type triterpene glycosides, scillanostasides A, B, and C, and two new lanostane-type triterpene glycosides, scillanostasides D and E, were isolated from the bulbs of Scilla scilloides Druce (Liliaceae) along with one known norlanostane-type triterpene heptaglycoside, scillascilloside G-1. Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence.

Does Baseline Prostate Volume Affect the Short-Term Outcome of Tamsulosin?

OBJECTIVE: To investigate the short-term efficacy of tamsulosin treatment for patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) according to baseline prostate volume (PV). METHODS: Tamsulosin, 0.2 mg/day, was prospectively given to 112 patients aged 50 years or older who had International Prostate Symptom Scores (IPSS) ≥ 8. The short-term efficacy was analyzed using the IPSS, quality of life (QOL) index, BPH problem index (BPI), maximum flow rate (Qmax ) and postvoid residual urine volume (PVR) at 4 weeks and 3 months after treatment considering the estimated PV at baseline. RESULTS: Of the 112 patients, 81 and 31 had PV of < 35 and ≥ 35 mL, respectively. The IPSS was significantly improved in patients with PV of < 35 mL (17.8 ± 5.9 at baseline, 13.5 ± 7.0 at 4 weeks, 11.9 ± 6.1 at 3 months) and in those with PV of ≥ 35 mL (17.4 ± 6.7 at baseline, 13.1 ± 7.0 at 4 weeks, 13.4 ± 6.2 at 3 months). There was no significant difference in the changes of the IPSS between the groups in a combined analysis model (P = 0.559). In addition, the model revealed no significant differences in changes in the QOL index, BPI, Qmax and PVR. CONCLUSION: The short-term efficacy of tamsulosin is observed irrespective of baseline PV. Thus, α1-blocker monotherapy should be considered for all patients with BPH/LUTS to rapidly relieve symptoms, although the long-term outcome is not promising for patients with a large PV at baseline.

The add-on effect of solifenacin for patients with remaining overactive bladder after treatment with tamsulosin for lower urinary tract symptoms suggestive of benign prostatic obstruction.

OBJECTIVES: To investigate the add-on effect of solifenacin for Japanese men with remaining overactive bladder (OAB) symptoms after tamsulosin monotherapy for lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) in real-life clinical practice. METHODS: Patients aged ≥ 50 having remaining OAB symptoms (≥ 3 of OAB symptom score (OABSS) with ≥2 of urgency score) after at least 4 weeks treatment by 0.2 mg of tamsulosin for BPO/LUTS received 2.5 or 5.0 mg of solifenacin for 12 weeks. The International Prostate Symptom Score (IPSS), QOL index and OABSS, maximum flow rate (Qmax) and postvoid residual urine volume (PVR) were determined. RESULTS: A total of 48 patients (mean age 72.5 years) completed the study. There were significant improvement in IPSS (15.1 to 11.2) and QOL index (4.2 to 3.0) by add-on of solifenacin. Although the IPSS storage symptom score was significantly improved, there were no changes observed in the IPSS voiding symptom score. The OABSS showed significant improvement (8.0 to 4.8). No changes were observed in Qmax and PVR. CONCLUSIONS: Under the supervision of an experienced urologist, the additional administration of solifenacin to patients with BPO/LUTS treated with tamsulosin, is effective in controlling remaining OAB symptoms.

Gatifloxacin treatment for chronic prostatitis: a prospective multicenter clinical trial.

Antimicrobial treatment is usually used for chronic prostatitis. However, the efficacy of such treatment has not been fully evaluated. We conducted a study to evaluate the efficacy of gatifloxacin for patients with chronic prostatitis using the Japanese version of the National Institutes of Health Chronic Prostatitis Symptom Index (JPN-NIH CPSI). The study included 46 patients for final analysis. Patients who were younger than 65 years of age were treated with 200 mg gatifloxacin twice daily, and those who were 65 years and older were treated with 100 mg gatifloxacin twice daily, for 4-8 weeks. The study consisted of 10 patients in category II, 13 in category IIIA, 11 in category IIIB, and 12 who were unclassified. The gatifloxacin treatment resulted in significant reductions in the scores on the JPN-NIH CPSI. Of the total number of patients, 58.1% and 27.9% were 25% and 50% responders, respectively, 4 weeks after treatment, and these figures improved to 66.7% and 33.3%, respectively, 8 weeks after treatment. No significant difference was found in the changes in symptom scores between Category II and Category IIIA/IIIB groups. In conclusion, gatifloxacin treatment improved the symptoms in patients with chronic bacterial and nonbacterial prostatitis. This study is the first in this country to evaluate the efficacy of antimicrobial treatment for chronic prostatitis by using the NIH CPSI.

Prevalence of female sexual dysfunction symptoms and its relationship to quality of life: a Japanese female cohort study.

OBJECTIVES: To clarify the age prevalence of female sexual dysfunction and the factors that contribute to the varying frequency of sexual intercourse and satisfaction with sexual life in Japanese women. METHODS: Of 8956 participants (median age 57 years, range 17 to 88) in a Japanese female cohort study, 5042 (56.3%) responded. We evaluated 2095 women aged 30 to 69 years (median 48) who completed a questionnaire that queried about their sexual life. RESULTS: When women in their 30s were compared with those in their 60s, we found that the prevalence of the symptom of orgasmic disorder, sexual desire disorder, arousal disorder, and lubrication disorder had increased significantly from 15.2% to 32.2%, 27.7% to 57.9%, 29.7% to 57.9%, and 12.5% to 51.2%, respectively. Multivariate analysis showed that the rigidity of the partner's erection, orgasm, and arousal contributed significantly to sexual frequency and foreplay and orgasm to satisfaction with sexual life. CONCLUSIONS: The prevalence of female sexual dysfunction increased with age. The results of multivariate analysis indicated that favorable sexual function is important to maintain the opportunity for sexual intercourse in both men and women and that foreplay and orgasm are essential for satisfactory sexual life in women.