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Background/Aim: The duration of pembrolizumab use in actual daily practice might be shorter than that in clinical trials because termination of pembrolizumab therapy is at the discretion of the physician. We retrospectively reviewed the response to pembrolizumab in Japanese patients with metastatic urothelial carcinoma (mUC) in relation to the time to response (TTR). Patients and Methods: The records of 165 patients treated with pembrolizumab for mUC were retrospectively analyzed. Response was evaluated at 2, 4, 6 and 8 months. TTR along with time to best response were analyzed. Phase II-III clinical trials were also reviewed to compare the TTR and time to best overall response. Results: The median patient age was 70 years. The objective response rate in the total cohort was 27.1% (42 out of 155 patients). Median TTR was 2.4 months and the time to best response was 3.1 months. Radiological evaluation at each time point significantly predicted overall survival (OS). Considering the evaluation of response at 2, 4, 6 and 8 months, the response at later time points tended to predict OS better. Multivariate analysis showed that the evaluation of response at 8 months (hazard ratio=1.91, 95% confidence interval=1.16-3.16 months; p

Background/Aim: In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intra-venous (IV) route. Materials and Methods: Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. Results: Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). Conclusion: High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.

To assess the real-world clinical benefit of re-challenging chemotherapy after pembrolizumab in patients with metastatic urothelial carcinoma (mUC), as there have been several reports suggesting that programmed cell death protein-1/programmed death-ligand 1inhibitors can restore platinum sensitivity.Of 236 patients treated with pembrolizumab, we excluded 45 patients who did not experience progressive disease (PD) for pembrolizumab during the follow-up and 86 patients who discontinued pembrolizumab by the diagnosis of PD followed by the best supportive care. A total of 105 patients were identified for a logistic regression propensity score model to compare the survival outcomes between patients treated with continuing pembrolizumab (80) and re-challenging chemotherapy (25) after the diagnosis of PD for pembrolizumab.A median overall survival (OS) from PD for pembrolizumab was 11 months in 105 patients. Of 25 patients treated with re-challenging chemotherapy, platinum-including chemotherapy (gemcitabine and cisplatin; gemcitabine/cisplatin/paclitaxel [GCP]; methotrexate and vinblastine and adriamycin and cisplatin; and methotrexate and carboplatin and vinblastine MCAVI) was offered in 20 patients (80%). The objective response rate (ORR) for the first-line chemotherapy in the 105 patients was 30%, with a comparable ORR in 25 patients treated with re-challenging chemotherapy of 28%. GCP as a re-challenging regimen was offered in 12 of 25 (48%) patients. The ORR for the GCP regimen was 50%. Propensity score matching was performed using putative clinical factors, from which 34 patients were identified as pair-matched groups. The OS for patients treated with re-challenging chemotherapy was significantly longer than continuing pembrolizumab (a median of 13.9 and 5.8 months, respectively: P = 0.048).Re-challenging chemotherapy including platinum agents after PD with pembrolizumab offers clinical benefits in patients with mUC.

Background Randomized trials showed the survival benefits of the combined use of androgen receptor axis-targeted agents with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer (mHSPC), regardless of the risk. However, treating patients with low-risk mHSPC with such intensive treatment is still debatable. Methods This retrospective study included 155 low-risk patients among 467 mHSPC patients treated in our affiliated institutions. The association between predictive factors and treatment outcomes was estimated using the Kaplan–Meier method and log-rank test. Predictive factors for castration resistant prostate cancer (CRPC)-free survival were investigated using Cox regression analyses. Results During the median follow-up of 39 months, 38.7% of patients developed CRPC and 14.2% died. In the multivariate analyses, a presence of Gleason pattern 5 (hazard ratio [HR] 2.04), high alkaline phosphatase (HR 1.007) and high lactate dehydrogenase (HR 1.009) were significant predictive factors for shorter CRPC-free survival. Finally, 155 patients were stratified into favorable- and unfavorable-risk groups based on the numbers of the predictive factors. The overall survival (OS) in the unfavorable-risk group (total scores: 2–3) was significantly worse than that of the favorable-risk group (total score: 0–1) (P = 0.02). This prognostic model was assessed with 50 low-risk mHSPC patients from the external validation dataset and found both the time to CRPC, and the OS in the unfavorable-risk group was significantly worse than that of the favorable-risk group (P Conclusions The combination of Gleason pattern 5, high alkaline phosphatase and lactate dehydrogenase can predict those with worse OS in low-risk mHSPC patients.

Pembrolizumab has now become a standard of care in metastatic urothelial carcinoma (mUC), although the treatment effect of the drug substantially differs among individuals. Emerging evidence suggests that radiotherapy exerts a synergistic effect with PD-1 blockade. We sought to elucidate the survival outcomes in patients who underwent palliative radiation with the pembrolizumab treatment.We retrospectively investigated our multi-institutional dataset of 235 platinum-refractory mUC patients treated with pembrolizumab as second-line treatment, collected from January 2018 and October 2021. Propensity score matching was performed to reduce biases by potential confounding factors for overall survival (OS).With a median follow-up of 6.8 months, the median OS from the initiation of pembrolizumab was 13 months in 235 patients. Palliative radiation was performed in 71 (30.2%) patients for whom the median radiation dose and fraction were 30 Gy and 10 fractions, respectively. Irradiated sites were bone in 24 (33.8%), lymph node in 17 (23.9%), lung in 3 (4.2%), brain in 8 (11.3%), and other sites in 19 (26.8%). OS from the initiation of pembrolizumab was significantly longer in patients who underwent concurrent palliative radiation with pembrolizumab (39 patients: median OS: 21 months) than in both patients with palliative radiation before pembrolizumab (32 patients: median OS: 9 months) (p = 0.001) and those without palliative radiation throughout the follow-up (164 patients: median OS: 13 months) (p = 0.019). After the propensity-score matching by putative confounding factors, longer OS in patients treated with concurrent palliative radiation with pembrolizumab (n = 36) was still observed compared to patients without the concurrent palliative radiation (n = 36) in the pair matched cohort (median OS of 29 and 13 months, respectively, p = 0.033).Our findings suggest that the concurrent administration of palliative radiation with pembrolizumab offers a favorable effect on OS in platinum-refractory mUC patients.

We note the risk of paradoxical embolism in patients with congenital heart defects with a right‐to‐left shunt. These patients should be managed to ensure that abdominal aortic thrombi are not overlooked when their clinical conditions change.

Fetuses with congenital long QT syndrome (LQTS) may experience life-threatening arrhythmias, such as torsade de pointes (TdP), and/or functional atrioventricular block. However, trans-maternal pharmacotherapy for these cases is rarely reported and management practices have yet to be established. The fetus of a mother with genetically-confirmed LQTS type 2 (LQT2) presented with complex arrhythmias, diagnosed via magnetocardiography as ventricular arrhythmias (including TdP), at 28 weeks of gestation. After initiation of trans-maternal nadolol administration at 15 mg/d initial dosage and 30 mg/d subsequent dosage, the frequency of fetal ventricular arrhythmias decreased and almost disappeared within several days. The mother gave birth to the baby at full term without significant complications in either the mother or fetus. This is the first report that demonstrates the efficacy and safety of trans-maternal administration of nadolol for treatment of symptomatic LQT2 fetuses with TdP.

Patients with end-stage renal disease (ESRD) have a low nutritional status and a high mortality risk. The geriatric nutritional risk index (GNRI) is a predictive marker of malnutrition. However, the association between unplanned hemodialysis (HD) and GNRI with mortality remains unclear. In total, 162 patients underwent HD at our hospital. They were divided into two groups: those with unplanned initiation with a central venous catheter (CVC; n = 62) and those with planned initiation with prepared vascular access (n = 100). There were no significant differences in sex, age, malignant tumor, hypertension, and vascular disease, while there were significant differences in the times from the first visit to HD initiation (zero vs. six times, p

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR &gt, 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p &lt, 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

A method for optimally designing RL and RC snubber circuits is presented to reduce the electromagnetic interference caused by parasitic LC resonance. The Q factor of the resonance is used as the design criteria. Optimum snubber parameters are determined analytically and uniquely by using a simplified equivalent circuit of the resonant loop and deriving an analytical formula for the Q factor as a function of the snubber parameters. The optimally designed snubbers can adequately adjust the Q factor to any design target. They can also minimize the increases in the negative effects of the snubbers, i.e., overshoot and power loss. The method was applied to RL and RC snubbers to be added to a synchronous buck converter. The effects of the snubbers were reproduced by simulation program with integrated circuit emphasis (SPICE) simulation to validate the method from the perspective of resonance damping, overshoot, and power loss. The results showed that the damping effects obtained with the optimized snubbers met the Q factor design targets. They also demonstrate that the parameters are optimum in terms of suppressing overshoot and power loss. These results indicate that the method is suitable for optimizing RL and RC snubbers to damp parasitic LC resonance.

Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response.The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed.The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007).The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.

For improving directivity of a tubular wave coupler (TWC), we examined the dimension dependence of transfer characteristics of the TWC. Directivity was improved by making the conductor injecting disturbance into the inner conductor of TWC thicker. Its position has little to do with directivity. Simulation results show that the TWC with a shorter inner conductor improves the directivity.

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial carcinoma, although it is unknown whether the efficacy of pembrolizumab in patients previously treated with curative CRT varies from the results of benchmark trials.MethodsWe retrospectively assessed whether the survival benefit of pembrolizumab differs between patients previously treated with TC or CRT as radical treatment. A total of 212 patient records were collected for a logistic regression propensity score model. An independent dataset with next-generation sequencing (n=289) and PD-L1 Combined Positive Score (CPS: n=266) was analyzed to assess whether CRT-recurrent tumor harbors distinct CD274/PD-L1 profiles.ResultsPropensity score matching was performed using putative clinical factors, from which 30 patients in each arm were identified as pair-matched groups. There was no significant difference in overall survival from the initiation of pembrolizumab (p=0.80) and objective response rate (p=0.59) between CRT and TC treatment groups. In the independent 289 BC cohort, 22 samples (7.6%) were collected as CRT-recurrent tumors. There was no significant difference in CD274 mRNA expression level between CRT-naïve and CRT-recurrent tumors. The compositions of CD274 isoforms were comparable among all isoforms detected from RNAseq between CRT-naïve (n=267) and CRT-recurrent (n=22) tumors. No actionable exonic mutation in CD274 was detected in CRT-recurrent tumors. PD-L1 CPS was positively correlated with CD274 mRNA expression level, and PD-L1 CPS was comparable between CRT-naïve and CRT-recurrent tumors.ConclusionsThe efficacy of pembrolizumab for patients previously treated with CRT was similar to those treated with TC. The enhanced tumor regression by combining programmed cell death protein 1/PD-L1 inhibitor and CRT might be expected only in the concurrent administration.

A synthesis of chiral homoallylic nitriles by the iridium-catalyzed allylation of cyanoacetates followed by Krapcho demethoxycarbonylation has been developed. A wide range of homoallylic nitriles were obtained with a high enantioselectivity (>95–99% ee). These compounds are useful chiral building blocks because further synthetic elaboration starting from a nitrile or terminal alkene is possible.

A purpose of this work is providing a SCA resistance evaluation method that can associate the evaluation result with design criteria of countermeasure circuits at the system level. A method evaluating the SCA resistance of cryptographic circuits based on the signal-to-noise ratio (SNR) of the side-channel trace is examined. Here, it is assumed that SNR is used as SCA resistance design targets and the targets are determined based on analytically derived relationship between the SNR and correlation coefficients calculated in SCA. This work has experimentally verified that the SNR and correlation coefficients calculated from measured side-channel traces satisfy the relationship. A printed circuit board (PCB) with a field-programmable gate array (FPGA) implementing an advanced encryption standard (AES) circuit was used as an equipment under test, and the core power supply voltage fluctuation of the FPGA was measured on the PCB as side-channel trace. The SNR is calculated using a signal component obtained from the trace when encrypting a random plaintext set and a noise component obtained from the trace when encrypting a constant plaintext set. The correlation coefficient is calculated based on the correlation power analysis. The SNR was changed in the range of 20 dB by changing measurement conditions, and the relationship was examined. As a result, the SNRs and the correlation coefficients of the measured trace obeyed the analytical relational expression.

Signal-to-noise ratio (SNR) of side-channel traces leaked from cryptographic ICs can be a candidate of system-designer-friendly design index in security evaluation against the side-channel attack (SCA). A method to calculate SNR of side-channel traces from measured side-channel traces was proposed for the scenario of the byte-by-byte attack on AES cryptographic circuits. The proposed method was a simple extension of an SNR calculation method for the brute force attack scenario proposed in a previous study. Measured SNRs according to the methods were validated by comparison with analytical formulas. Results suggested that the proposed method could provide SNRs of side-channel traces accurately.

Improving the countermeasures against side-channel attacks (SCAs) increases the cost of both designing the countermeasures and evaluating SCA resistance. This may force cryptographic ICs to remain vulnerable. The increased cost is due to an indispensable procedure where a large number of side-channel traces need to be analyzed in order to evaluate the SCA resistance. In this work, a low-cost method to design and evaluate countermeasures using the signal-to-noise ratio (SNR) of side-channel traces as design and evaluation criteria is proposed. The method combines two existing methods: a prediction method of correlation coefficients between side-channel traces and a power model based on the SNR of the side-channel traces, and an estimation method of the number of traces needed to disclose the secret key based on the correlation coefficients. We construct a method to measure the SNR of side-channel traces and validate it for the design and evaluation criteria. In our method, the SNR is first calculated from signal and noise variances extracted from side-channel traces by increasing the number of averaging in side-channel trace measurements, and then the correlation coefficients and the number of traces for key-disclose are estimated on the basis of the calculated SNR. We confirmed that the estimated correlation coefficient and the number of traces for key-disclose were in good agreement with the corresponding measured ones. This result demonstrates that the proposed method can accurately measure the SNR of side-channel traces.

Ultrasound (US) imaging is a widely used imaging technique. The use of US contrast agents such as microbubbles, which consist of phospholipids and are filled with perfluorocarbon gases, has become an indispensable component of clinical US imaging, while molecular US imaging has recently attracted significant attention in combination with efficient diagnostics. The avidin&ndash, biotin interaction method is frequently used to tether antibodies to microbubbles, leading to the development of a molecular targeting US imaging agent. However, avidin still has limitations such as immunogenicity. We previously reported that lipid-based nanobubbles (NBs) containing perfluorocarbon gas are suitable for US imaging and gene delivery. In this paper, we report on the development of a novel antibody modification method for NBs using Fc-region-binding polypeptides derived from protein A/G. First, we prepared anti-CD146 antibody-modified NBs using this polypeptide, resulting in high levels of attachment to human umbilical vein endothelial cells expressing CD146. To examine their targeting ability and US imaging capability, the NBs were administered to tumor-bearing mice. The contrast imaging of antibody-modified NBs was shown to be prolonged compared with that of non-labeled NBs. Thus, this antibody modification method using an Fc-binding polypeptide may be a feasible tool for developing a next-generation antibody-modified US imaging agent.

An underwater vehicle for deep-sea operation should be as light as possible; therefore, development of premium structural materials such as titanium alloy, glass, and carbon-fiber-reinforced plastic (CFRP) for external pressure hulls has been ongoing. Engineering ceramics is one of the candidate materials, and the study of engineering ceramics has been underway for many years; however practical applications have been limited.The main purpose of this study is to establish the methodology of fabrication of ceramics pressure hulls for deep-sea submergence services. As the first step, prototypes of the spherical shells were fabricated from engineering ceramics, and their local radii of curvatures and wall thickness were precisely measured. In addition to these measurements, the strain on hemispheres and their collapse strength were measured by pressure tests in order to evaluate the relationship between spherical irregularities and collapse strength. The strength-to-weight ratios of fabricated pressure hulls were significantly higher than that of syntactic foam for deep-sea operations, therefore it is expected that engineering ceramics can be among the promising structural materials for lightening of an underwater vehicle's body.

The Japan Marine Science and Technology Center (JAMSTEC) has been, and is now promoting the “OD21” program (i.e., “Ocean drilling in the 21st century”). This is the first plan in the world to utilize deep-water riser-drilling technologies for scientific drilling. One of the important factors for the success of this program is the development of a high-performance drilling vessel. Since 1990, JAMSTEC has been continuing a technological study of a riser-drilling vessel for scientific studies with an operational capability in waters up to 4000 m deep. It was decided to start the construction with a two-phase plan: a vessel with a riser operation for waters up to 2500 m deep will be constructed in the initial stage, and then the vessel will be modified to a 4000-m depth capability. In the development process of the vessel, named Chikyu, many new technical developments have taken place, such as drilling/coring equipment, a dynamic positioning system, etc. Thus, the Chikyu is expected to contribute to ocean engineering and other work, in addition to scientific advances.