Biomimetic Design of a Robustly Stabilized Folded State Enabling Seed-Initiated Supramolecular Polymerization under Microfluidic Mixing.

We have investigated the folding and assembly behavior of a cystine-based dimeric diamide bearing pyrene units and solubilizing alkyl chains. In low-polarity solvents, it forms a 14-membered ring through double intramolecular hydrogen bonds between two diamide units. The spectroscopic studies revealed that the folded state is thermodynamically unstable and eventually transforms into more energetically stable helical supramolecular polymers that show an enhanced chiral excitonic coupling between the transition dipoles of the pyrene units. Importantly, compared to an alanine-based monomeric diamide, the dimeric diamide exhibits a superior kinetic stability in the metastable folded state, as well as an increased thermodynamic stability in the aggregated state. Accordingly, the initiation of supramolecular polymerization can be regulated using a seeding method even under microfluidic mixing conditions. Furthermore, taking advantage of a self-sorting behavior observed in a mixture of l-cysteine- and d-cysteine-based dimeric diamides, a two-step supramolecular polymerization was achieved by stepwise addition of the corresponding seeds.

Site-specific differences in survival among upper and lower tract urothelial carcinoma patients treated with radical surgery.

BACKGROUND: It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or higher tumours. METHODS: In total, 307 patients with pT3 or higher urothelial carcinoma without distant metastasis who underwent radical cystectomy for bladder urothelial carcinoma (N = 127, 41.4%) or radical nephroureterectomy for upper tract urothelial carcinoma (N = 180, 58.6%) at Keio University Hospital and three affiliated hospitals between 1994 and 2017 were enrolled. Oncological outcomes were compared between bladder urothelial carcinoma and upper tract urothelial carcinoma using Cox regression analysis. RESULTS: Significantly higher rates of male patients, smokers, neoadjuvant chemotherapy, lymph node involvement and lymphovascular invasion were observed in the bladder urothelial carcinoma group. The incidence of regional lymph node or local recurrence was higher in patients with bladder urothelial carcinoma than in those with upper tract urothelial carcinoma, while that of lung metastasis was lower. In all patients, bladder urothelial carcinoma was independently associated with disease recurrence (hazard ratio (HR) 1.504, P = 0.035) in addition to neoadjuvant chemotherapy and lymphovascular invasion. Bladder urothelial carcinoma was also independently associated with cancer death (HR = 1.998, P = 0.002) as well as lymphovascular invasion. Following the exclusion of patients who received neoadjuvant chemotherapy, bladder urothelial carcinoma remained an independent risk factor for disease recurrence and cancer death (HR = 1.702, P = 0.010 and HR = 1.888, P = 0.013, respectively). CONCLUSIONS: Bladder urothelial carcinoma may follow worse prognosis compared to upper tract urothelial carcinoma, particularly that with a high pathological stage.

High Absolute Monocyte Count Predicts Poor Clinical Outcome in Patients with Castration-Resistant Prostate Cancer Treated with Docetaxel Chemotherapy.

BACKGROUND: The association of peripheral monocyte count and prostate cancer progression is not well characterized. OBJECTIVE: Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated with docetaxel chemotherapy. METHODS: We retrospectively reviewed the medical records of 214 CRPC patients who received docetaxel therapy and were used as the training and validation set. Docetaxel at a dose of 75 mg/m2 was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). RESULTS: In the training set, the median age was 73.0 years, and the median prostate-specific antigen (PSA) value was 31.7 ng/ml at initial treatment. The median OS and PFS were 23.0 months (range 1.20-84.0) and 11.2 months (range 3.6-78.0), respectively. According to multivariable Cox regression analysis, AMC ≥400/uL, PSA level ≥20 ng/ml, and Hb <10 mg/dL were associated with increased risk of PSA progression [hazard ratio (HR) 2.06, p = 0.005; HR 2.39, p = 0.002; and HR 2.38, p = 0.024, respectively]. Moreover, multivariate analysis for OS indicated that AMC ≥400/uL, pretreatment PSA level ≥20 ng/ml, presence of visceral metastasis, and alkaline phosphatase ≥284 U/L were independent prognostic factors for shortened OS (HR 2.07, p = 0.004; HR 2.18, p = 0.007; HR 2.11, p = 0.011; and HR 1.67, p = 0.048, respectively). According to the validation set, high AMC remained an independent prognostic factor for PFS and OS (HR 2.26, p = 0.001; and HR 3.10, p < 0.001, respectively). CONCLUSIONS: Elevated monocyte counts were associated with aggressive tumor features and poor survival outcomes of patients with CRPC treated with docetaxel chemotherapy.

Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience.

PURPOSE: Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. RESULTS: On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. CONCLUSIONS: Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

Predictive factors for severe and febrile neutropenia during docetaxel chemotherapy for castration-resistant prostate cancer.

BACKGROUND: The aim of this study is to identify factors that increase the occurrence of severe neutropenia (SN) and febrile neutropenia (FN) during docetaxel treatment for castration-resistant prostate cancer (CRPC). METHODS: We retrospectively reviewed 258 courses during the first three cycles among 95 patients. Docetaxel at a dose of 75 mg/m(2) was administered every 3 or 4 weeks. Patient background, laboratory data, and bone scan results were collected to assess predictive factors for SN and FN. We defined SN as an absolute neutrophil count (ANC) of <500/mm(3) and defined FN as an ANC of <1000/mm(3) with a body temperature of >38.3 °C. RESULTS: The mean age of the patients was 72.6 ± 6.4 years and the mean prostate-specific antigen was 135.4 ± 290.9 ng/ml. During the first three courses of treatment, SN occurred in 72.6% of patients and FN occurred in 9.5 % of patients. Univariate analysis demonstrated that age ≥ 75 years (p = 0.002), number of comorbidities ≥ 1.2 (p = 0.008 and p = 0.006) and previous external beam radiation therapy (EBRT) (p = 0.001) were predictive factors for the development of SN or FN. In multivariate analysis, significant predictors of SN or FN were age ≥ 75 years (hazard ratio [HR] 5.77; p = 0.004) and previous EBRT (HR 14.5; p = 0.012). According to the subgroup analysis dividing SN and FN separately, multivariate analysis also revealed that age ≥ 75 years and previous EBRT were also significant predictors for developing SN (HR 5.09; p = 0.023, HR 12.7; p = 0.020, respectively) and for developing FN (HR 5.45; p = 0.042, HR 7.72; p = 0.015, respectively). CONCLUSIONS: Patients aged ≥ 75 years and with a history of localized radiation therapy are at higher risk for significant neutropenic events and require closer surveillance.

Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy: association with primary tumor location.

PURPOSE: To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). METHODS: A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. RESULTS: A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). CONCLUSIONS: This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma.

BACKGROUND: Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. METHODS: A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. RESULTS: Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. CONCLUSIONS: This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi-institutions.

OBJECTIVES: To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. PATIENTS AND METHODS: A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. RESULTS: The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). CONCLUSIONS: Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

[Vesicovaginal fistula after sexual intercourse: a case report].

A 53-year old female visited our hospital with a complaint of continuous urinary incontinence after sexual intercourse. She had been diagnosed with carcinoma of uterine cervix stage I b2 and had undergone radical hysterectomy and radiation therapy (45 Gy). Cystoscopy revealed vesicovaginal fistula in the trigone which measured almost 3 cm. We repaired it by transabdominal and vaginal routes 5 days after the injury. She was discharged with a Foley catheter. Three months after the operation, cystography revealed improvement of vesicovaginal fistula.

Can urologists introduce the concept of "oligometastasis" for metastatic bladder cancer after total cystectomy?

We investigated whether the concept of oligometastasis may be introduced to the clinical management of metastatic bladder cancer patients. Our study population comprised 128 patients diagnosed with metastatic bladder cancer after total cystectomy at our 6 institutions between 2004 and 2014. We extracted independent predictors for identifying a favorable. Occurrence that fulfilled all 4 criteria which were independently associated with cancer-specific death was defined as oligometastasis: a solitary metastatic organ; number of metastatic lesions of 3 or less; the largest diameter of metastatic foci of 5cm or less; and no liver metastasis. We evaluated differences in clinical outcomes between patients with oligometastasis (oligometastasis group) and those without oligometastasis (non-oligometastasis group). Overall, there were 43 patients in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 53.3%, which was significantly higher than that in the non-oligometastasis group (16.1%, p<0.001). A multivariate analysis revealed that non-oligometastasis (p<0.001), not performing salvage chemotherapy (p<0.001), and not performing metastatectomy (p=0.028) were independent risk factors for cancer-specific death. In the subgroup of 83 patients who received salvage chemotherapy, 30 were in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 55.0%, which was significantly higher than that in the non-oligometastasis group (22.0%, p=0.005). Non-oligometastasis (p=0.009) was the only independent risk factor for cancer-specific death. We presented that urothelial carcinoma with oligometastasis had a favorable prognosis and responded to systemic chemotherapy. Oligometastasis may be treated as a separate entity in the field of metastatic urothelial carcinoma.

[Clinical study of six cases of pyourachus at our hospital].

We encountered 6 patients with pyourachus (male, 1; female, 5) who ranged in age from 17 to 58 years (mean, 41 years) during the 7 years from 1993 to 1999. Three of them had a history of gynecological surgery, and 2 had a history of appendectomy. Improvement was observed in one patient with conservative therapy alone, but the other 5 patients underwent surgery. Preoperatively, 2 patients underwent drainage, one of them through the umbilicus, and the other through a position on the midline percutaneously. Pathological examination in the 5 patients revealed no evidence of cancer. With reference to postoperative complications, adhesive ileus was recognized in 1 case one year postoperatively but no other complications were noted in the other 5 cases. No evidence of recurrence has been seen in any of these patients to date.

Amination of N-aryl prolinol via ring expansion and contraction: application to the chiral ligand for the catalytic asymmetric reaction.

Chiral diaminophosphines 4 were prepared from (S)-prolinol-derived aminophosphine oxide 5 by bromination with ring expansion followed by amination with ring contraction and reduction, using trichlorosilane. In the presence of 4 as a ligand, palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (11) with a dialkyl malonate-BSA-LiOAc system was successfully carried out with good enantioselectivities (up to 98% ee).