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Introduction Double‐negative prostate cancer, an androgen receptor–independent prostate cancer without features of neuroendocrine tumors, is refractory to treatment but could be an ideal candidate for individualized treatment. Case presentation An 85‐year‐old patient with metastatic castration‐resistant prostate cancer without prostate‐specific antigen progression presented with local recurrence and liver and lung metastases 6 months after orchiectomy and apalutamide. A liver tumor biopsy led to a diagnosis of double‐negative prostate cancer. FoundationOne® CDx showed BRCA2 mutation and high tumor mutation burden. Olaparib and pembrolizumab were administered sequentially, and the patient responded to each treatment for 5 months until radiographic progression. Conclusion Sequential use of olaparib and pembrolizumab may be effective for double‐negative prostate cancer with BRCA2 mutations and high tumor mutation burden.

Abstract Ice nucleation is a crucial process in nature and industries; however, the role of the free surface of water in this process remains unclear. To address this, we investigate the microscopic freezing process using brute-force molecular dynamics simulations. We discover that the free surface assists ice nucleation through an unexpected mechanism. The surface-induced negative pressure enhances the formation of local structures with a ring topology characteristic of Ice 0-like symmetry, promoting ice nucleation despite the symmetry differing from ordinary ice crystals. Unlike substrate-induced nucleation via water-solid interactions that occurs directly on the surface, this negative-pressure-induced mechanism promotes ice nucleation slightly inward the surface. Our findings provide a molecular-level understanding of the mechanism and pathway behind free-surface-induced ice formation, resolving the longstanding debate. The implications of our discoveries are of substantial importance in areas such as cloud formation, food technology, and other fields where ice nucleation plays a pivotal role.

Introduction While immune checkpoint inhibitors represent the mainstream treatment for metastatic renal cell carcinoma, a standardized approach following immune checkpoint inhibitors remains unclear. We report a case of metastatic renal cell carcinoma treated with nivolumab rechallenge. Case presentation A 60‐year‐old male with metastatic melanoma was referred to the urology division due to right renal cancer. He was undergoing nivolumab treatment for metastatic melanoma. Radical nephrectomy revealed clear cell renal cell carcinoma, pT3a. Two months post‐surgery, multiple metastases were identified. Despite subsequent administration of interferon‐α, axitinib, and temsirolimus, the metastases progressed. Consequently, nivolumab rechallenge and palliative radiotherapy were initiated, resulting in a durable response for 20 months. However, disease progression occurred, and he died of cancer 4 years after nephrectomy. Conclusion This is the first report of nivolumab rechallenge in metastatic renal cell carcinoma. Although the utility remains unclear, this case suggests that some patients may benefit from nivolumab rechallenge.

Abstract Some low-coordination materials, including water, silica, and silicon, exhibit polyamorphism, having multiple amorphous forms. However, the microscopic mechanism and kinetic pathway of amorphous-amorphous transition (AAT) remain largely unknown. Here, we use a state-of-the-art machine-learning potential and local structural analysis to investigate the microscopic kinetics of AAT in silicon after a rapid pressure change. We find that the transition from low-density-amorphous (LDA) to high-density-amorphous (HDA) occurs through nucleation and growth, resulting in non-spherical interfaces that underscore the mechanical nature of AAT. In contrast, the reverse transition occurs through spinodal decomposition. Further pressurisation transforms LDA into very-high-density amorphous (VHDA), with HDA serving as an intermediate state. Notably, the final amorphous states are inherently unstable, transitioning into crystals. Our findings demonstrate that AAT and crystallisation are driven by joint thermodynamic and mechanical instabilities, assisted by preordering, occurring without diffusion. This unique mechanical and diffusion-less nature distinguishes AAT from liquid-liquid transitions.

Abstract Immuno-oncology (IO) combination therapy is utilized as a first-line systemic treatment for advanced renal cell carcinoma. However, evidence supporting the use of cabozantinib after IO combination therapy is lacking. We retrospectively analyzed patients who received second-line cabozantinib after IO combination therapy using the Japanese Urological Oncology Group (JUOG) database. In total, 254 patients were enrolled in the JUOG global study, and 118 patients who received second-line cabozantinib comprised the study cohort. The objective response rate, disease control rate, second-line cabozantinib progression-free survival (PFS), and overall survival from second-line for overall were 32%, 75%, 10.5 months, and not reached, respectively, for first-line IO-IO therapy were 37%, 77%, 11.1 months, and not reached, respectively, versus 24%, 71%, 8.3 months, and not reached, respectively, for first-line IO-tyrosine kinase inhibitor therapy. In univariate and multivariate analyses, discontinuation of first-line treatment because of progressive disease and liver metastasis were independent risk factors for PFS. All-grade adverse events occurred in 72% of patients, and grade 3 or higher adverse events occurred in 28% of patients. Second line-cabozantinib after first-line IO combination therapy for advanced renal cell carcinoma was expected to be effective after either IO-IO or IO-TKI treatment and feasible in real-world practice.

Abstract The ultimate fate of a glass former upon cooling has been a fundamental problem in condensed matter physics and materials science since Kauzmann. Recently, this problem has been challenged by a model with an extraordinary glass-forming ability effectively free from crystallisation and phase separation, two well-known fates of most glass formers, combined with a particle-size swap method. Thus, this system is expected to approach the ideal glass state if it exists. However, we discover exotic compositional order as the coexistence of space-spanning network-like structures formed by small-large particle connections and patches formed by medium-size particles at low temperatures. Therefore, the glass transition is accompanied unexpectedly by exotic compositional ordering inaccessible through ordinary structural or thermodynamic characterisations. Such exotic compositional ordering is found to have an unusual impact on structural relaxation dynamics. Our study thus raises fundamental questions concerning the role of unconventional structural ordering in understanding glass transition.

Abstract Ions exhibit highly ion-specific complex behaviours when solvated in water, which remains a mystery despite the fundamental importance of ion solvation in nature, science, and technology. Here we explain these ion-specific properties by the ion-induced hierarchical dipolar, translational, and bond-orientational orderings of ion hydration shell under the competition between ion-water electrostatic interactions and inter-water hydrogen bonding. We first characterise this competition by a new length λ HB(q), explaining the ion-specific effects on solution dynamics. Then, by continuously tuning ion size and charge, we find that the bond-orientational order of the ion hydration shell highly develops for specific ion size and charge combinations. This ordering drastically stabilises the hydration shell; its degree changes the water residence time around ions by 11 orders of magnitude for main-group ions. These findings are fundamental to ionic processes in aqueous solutions, providing a physical principle for electrolyte design and application.

Introduction Several retrospective studies have demonstrated the efficacy of progressive site‐directed therapy for oligoprogressive castration‐resistant prostate cancer. However, eligible patients for progressive site‐directed therapy in these studies were limited to oligoprogressive castration‐resistant prostate cancer with bone or lymph node metastases without visceral metastases, and little is known about the efficacy of progressive site‐directed therapy for oligoprogressive castration‐resistant prostate cancer with visceral metastases. Case presentation We report a case with castration‐resistant prostate cancer previously treated with enzalutamide and docetaxel, in which only a solitary lung metastasis was identified throughout the course of treatment. The patient underwent thoracoscopic pulmonary metastasectomy with a diagnosis of repeat oligoprogressive castration‐resistant prostate cancer. Only androgen deprivation therapy was continued and his prostate‐specific antigen levels remained undetectable for 9 months after surgery. Conclusion Our case suggests that progressive site‐directed therapy may be effective for carefully selected repeat OP‐CRPC with a lung metastasis.

Abstract Background The significance of metastasis-directed therapy for oligometastatic prostate cancer has been widely discussed, and targeted therapy for progressive sites is a feasible option as a multidisciplinary treatment for castration-resistant prostate cancer (CRPC). When oligometastatic CRPC with only bone metastases progresses after targeted therapy, it tends to progress as multiple bone metastases. The progression of oligometastatic CRPC after targeted therapy may be due in part to the presence of micrometastatic lesions that, though undetected on imaging, were present prior to targeted therapy. Thus the systemic treatment of micrometastases in combination with targeted therapy for progressive sites is expected to enhance the therapeutic effect. Radium-223 dichloride (radium-223) is a radiopharmaceutical that selectively binds to sites of increased bone turnover and inhibits the growth of adjacent tumor cells by emitting alpha rays. Therefore, for oligometastatic CRPC with only bone metastases, radium-223 may enhance the therapeutic effect of radiotherapy for active metastases. Methods This phase II, randomized trial of Metastasis-Directed therapy with ALpha emitter radium-223 in men with oligometastatic CRPC (MEDAL) is designed to assess the utility of radium-223 in combination with metastasis-directed radiotherapy in patients with oligometastatic CRPC confined to bone. In this trial, patients with oligometastatic CRPC with three or fewer bone metastases on whole-body MRI with diffusion-weighted MRI (WB-DWI) will be randomized in a 1:1 ratio to receive radiotherapy for active metastases plus radium-223 or radiotherapy for active metastases alone. The prior use of androgen receptor axis-targeted therapy and prostate-specific antigen doubling time will be used as allocation factors. The primary endpoint will be radiological progression-free survival against progression of bone metastases on WB-DWI. Discussion This will be the first randomized trial to evaluate the effect of radium-223 in combination with targeted therapy in oligometastatic CRPC patients. The combination of targeted therapy for macroscopic metastases with radiopharmaceuticals targeting micrometastasis is expected to be a promising new therapeutic strategy for patients with oligometastatic CRPC confined to bone. Trial registration Japan Registry of Clinical Trials (jRCT) (jRCTs031200358); Registered on March 1, 2021, https://jrct.niph.go.jp/latest-detail/jRCTs031200358

Abstract The X-linked human glutamate receptor subunit 3 (GRIA3) gene (MIM *305915, Xq25) encodes ionotropic α amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor subunit 3, which mediates postsynaptic neurotransmission. Variants in this gene can cause a variety of neurological disorders, primarily reported in male patients. Here, we report a female patient with developmental and epileptic encephalopathy who carries the novel de novo GRIA3 variant NM_007325.5: c.1982T > C: p.Met661Thr.

Background: Unexpected adverse pathology is a major concern in surgical management of clinically localised renal cell carcinoma (RCC). Further studies are needed to improve preoperative risk stratification. Objective: To define and classify tumour shape irregularity (TSI) based on preoperative imaging, and to investigate its effect on pathological and oncological outcomes in clinically localised RCC. Design, setting, and participants: We retrospectively analysed 474 patients with cT1-2N0M0 RCC managed by partial or radical nephrectomy. Preoperative dynamic computed tomography was used to define and classify TSI, graded as 1 (completely elliptical shape), 2 (elliptical shape with minor and focal protrusions), or 3 (nonelliptical shape presenting with major and/or extensive protrusions). Intervention: Partial or radical nephrectomy. Outcome measurements and statistical analysis: A logistic regression analysis evaluated the risk factors for pT3a upstaging and Fuhrman grade 3–4. A Cox proportional hazard analysis assessed preoperative variables for recurrence-free survival (RFS). Results and limitations: The median tumour size was 3.5 cm, and 94 patients (20%) had (R)adius (tumour size as maximal diameter), (E)xophytic/endophytic properties of tumour, (N)earness of tumour deepest portion to collecting system or sinus, (A)nterior (a)/posterior (p) descriptor, and (L)ocation relative to polar lines (RENAL) score ≥10. TSI was graded as 1, 2, and 3 in 214 (45%), 151 (32%), and 109 (23%) patients, respectively. Higher TSI was significantly associated with a larger tumour size and a higher RENAL score. Overall, pT3a upstaging and Fuhrman grade 3–4 were observed in 45 (9.5%) and 116 patients (31% in 380 clear cell RCC cases), respectively. The incidence of pT3a upstaging and Fuhrman grade 3–4 was significantly higher in patients with higher TSI (0.5%, 8.6%, and 28% for pT3a upstaging and 12%, 33%, and 60% for Fuhrman grade 3–4 in TSI 1, 2, and 3 groups, respectively). In multivariable analyses, higher TSI was independently associated with adverse pathological outcomes. During the median follow-up of 6.0 yr, 49 patients (10%) developed recurrence. Multivariable analyses demonstrated that older age and higher TSI were independent risk factors for worse RFS. The limitations include the retrospective design. Conclusions: TSI may be a useful adjunct in preoperative risk stratification for adverse pathology and recurrence after surgery in clinically localised RCC. Patient summary: Tumour shape irregularity is significantly associated with unfavourable pathological outcomes, that is, locally advanced stage or high-grade cancer, and with a higher recurrence rate after surgery in patients with clinically localised renal cell carcinoma. Preoperative evaluation of the tumour shape may help in patient counselling and treatment decisions.

The accurate classification of kidney tumors necessitates the utilization of various diagnostic techniques. Within the domain of medical imaging tests, the integration of multi-modal medical imaging represents an innovative approach to enhance diagnostic precision. However, the integration of multi-modal medical imaging faces a critical challenge: the insufficiency of correspondingly paired data across modalities, resulting in a paucity of training samples for neural networks. To mitigate this limitation, generative artificial intelligence, specifically generative models capable of generating additional data, thereby addressing the gap in the multi-modal medical imaging record. In our work, our primary objective is to improve the classification results that outperform an existing method of using single-modal medical images. To achieve this, we harness the wealth of information of multi-modal data derived from Contrast-Enhanced Computed Tomography (CECT) and Magnetic Resonance Imaging (MRI), along with their respective subtypes, to determine which specific modality or pair contributes the most effectively to classification. Our work introduces the comprehensive comparison between the different multi-modal fusion techniques, in which the Area Under the Curve (AUC) serves as the benchmark for performance evaluation. Moreover, this work tackles the problem of the unavailability of kidney tumor data by partially recovering from the available data using Conditional CycleGAN, which is part of the image-to-image translation that maps between two different image domains. Through the employment of multi-modal fusion techniques and our proposed recovery of missing data, our research has yielded superior classification results than single-modal classification approaches.

In this research, we proposed a two-stage pipeline for segmenting urinary stones. The first stage U-Net generated the map localizing the urinary organs in full abdominal x-ray images. Then, this map was used for creating partitioned images input to the second stage U-Net to reduce class imbalance and was also used in stone-embedding augmentation to increase a number of training data. The U-Net model was trained with the combination of real stone-contained images and synthesized stone-embedded images to segment urinary stones on the partitioned input images. In addition, we proposed to use an inverse weighting method in the focal Tversky loss function in order to rebalance lesion size. The U-Net model using our proposed pipeline produced a 71.28% pixel-wise $F_{2}$ score and a 69.82% region-wise $F_{2}$ score, which were 2.88% and 7.63%, respectively, higher than those of a baseline method. Experimental results showed that the proposed method improved urinary stone segmentation results, especially for small stones and stones in uncommon locations.

Colloidal gels, sparse particle networks with large voids, are fundamental model systems of disordered porous materials. Unlike dense amorphous solids, they exhibit significant volumetric deformation while expelling solvents when subjected to external compression. Despite their importance in both natural and industrial settings, the relationship between their network microstructure and compressive yielding behavior has remained elusive. To address this problem, we employ confocal microscopy and a specially designed sample cell to observe the gravity-induced collapsing of colloidal gels at a single-particle level. The experimental insight gained is complemented by simulation results for gravitational collapse and homogeneous uniaxial compression. We find that, during compression, the microstructure of gels is uniquely determined solely by the local volume fraction. This relationship remains independent of the deformation strain history but is subtly influenced by the preparation history of the initial state. In contrast, compressive stress evolves as a unique function of local volume fraction, unaffected by both preparation and strain history, as long as the interparticle interaction remains identical. Moreover, we unveil that local yielding occurs in highly strained, narrow network domains, while highly stressed particles form chainlike structures to support the external stress. These findings suggest that colloidal gels undergoing compressive plastic deformation mechanically self-organize into a unique history-independent state to satisfy mechanical balance in a quasistatic condition, providing crucial microscopic insights into the compressive yielding behavior of particle network materials.

Free electron mobility ( μ _free ) in 4H-SiC(0001) MOSFETs with gate oxides annealed in NO or POCl _3 was calculated in a wide range of effective normal field ( E _eff ) from 0.02 to 2 MV cm ^−1 , taking account of scattering by fixed charges and trapped electrons. The present calculation indicates that the Hall mobility in the high- E _eff region experimentally obtained for NO-annealed MOSFETs (14 cm ^2 V ^−1 s ^−1 at 1.1 MV cm ^−1 ) is much lower than that for POCl _3 -annealed MOSFETs (41 cm ^2 V ^−1 s ^−1 ) due to severe Coulomb scattering by electrons trapped at a very high density of interface states.

Understanding the precise role of hydrodynamic interactions in the self-organization of circle-swimming active matter is an exciting avenue. Here, in a mixture of counter-rotating disks, the authors show that phase separation formed the largest size structure directly, without domain coarsening, and is driven by the inverse cascade phenomena characteristic of 2D turbulence.

The incidence of renal cell carcinoma (RCC) has risen worldwide over the past few decades, and this has been associated with a stage shift. Survival outcomes of RCC depend largely on the stage at diagnosis. Although overall mortality has stabilized or declined in most countries, survival remains poor in late-stage disease, suggesting early detection may improve overall survival outcomes. A number of potential candidate screening tools have been considered (including urinary dipstick, blood- and urine-based biomarkers, ultrasound, and computed tomography [CT]), though it may be that a combination of these approaches may be optimal. Ultimately, the sensitivity and specificity of the chosen screening tool will determine the rate of false positives and false negatives, which must be minimized. One of the key challenges is the relatively low prevalence of the disease, which might be overcome by performing risk-stratified screening or screening for more than one condition (such as combined lung and kidney cancer screening). Both approaches have been shown to be acceptable to the general public, and they may maximize the efficiency of screening while reducing harms. Indeed, quantifying benefits and harms of screening is key (including the impact on overdiagnosis and quality of life). Whether screening for RCC will lead to a stage shift and the impact on survival are the decisive missing pieces of information that will determine whether the screening program might be adopted into clinical practice (along with feasibility, acceptability, and cost-effectiveness).

Introduction SDH Gene mutation is known to be a common cause of pheochromocytoma/paraganglioma and renal cell carcinoma. Here, we report a case of succinate dehydrogenase B‐deficient paraganglioma, which has a high risk of metastasis and recurrence, complicated by succinate dehydrogenase‐deficient renal cell carcinoma, which is rare and accounts for approximately 0.1% of all renal cell carcinomas. Case presentation A 50‐year‐old man underwent en bloc resection of a retroperitoneal tumor and the right kidney for retroperitoneal paraganglioma and right renal tumor. Both tumors showed negative expressions of succinate dehydrogenase B in immunostaining. The patient was diagnosed with succinate dehydrogenase‐deficient paraganglioma and succinate dehydrogenase‐deficient renal cell carcinoma. Seventeen months later, retroperitoneal lymphadenectomy revealed lymph node metastasis of the paraganglioma. Deletion of the SDHB gene was revealed by genome sequencing of the lymph node. Conclusion This is the first reported case of synchronously diagnosed succinate dehydrogenase‐deficient paraganglioma and succinate dehydrogenase‐deficient renal cell carcinoma.

Fracture during fatigue loading is known to occur in materials for small strains, below the yield strain. Here, coarse-grain simulations of a model amorphous material reveals that the onset strain at which irreversible deformation occurs is the same for fatigue as it is for monotonic loading.

In classical nucleation theory, structural order in the liquid phase is not considered. But simulations of supercooled liquids now show that crystal-like liquid preordering play an essential role in nucleation and growth processes - calling for extensions of the classical theory.

Abstract Background We conducted a multicenter, retrospective study on the efficacy and safety of naldemedine in thoracic cancer patients using opioids in clinical practice. Methods We retrospectively evaluated thoracic cancer patients treated with naldemedine at 10 institutions in Japan. Clinical data of patients administered naldemedine between June 2017 and August 2019 were extracted from electronic medical records. Inclusion criteria were as follows: (i) patients hospitalized for at least seven days before and after naldemedine administration, and (ii) those whose frequency of defecation was entered in the medical records. Results Forty patients were analyzed, and defecation frequency was observed for at least seven days before and after naldemedine administration. The response rate was 65.0% (95% CI: 50.2%–79.7%). The number of defecations increased significantly after naldemedine administration in the overall population, as well as among only those who defecated

Phase separation phenomenon is a possible mechanism for important biological functions, from facilitating transcription by condensate formation, to the transport of cargo in the cell. This paper puts forward viscoelastic phase separation as a previously overlooked mechanism that could explain peculiar features of living cells such as network-like morphologies.

Abstract Background Wisconsin syndrome is a congenital anomaly caused by a 3q interstitial deletion. It is associated with characteristic facies and developmental delays. Only 33 cases with a deletion estimated to be in the associated region 3q25 have been reported. Case report We present the case of a 5-year-old Japanese girl with a 3q24q25.2 deletion. Her facial features corresponded to the Wisconsin syndrome phenotype, and she exhibited brain volume laterality, which has not been reported previously. Conclusion The clinical features of our case may contribute to narrowing down the list of candidate genes of Wisconsin syndrome.

A urinary stone is a type of abnormality that occurs frequently in the urinary system. An automated segmentation of urinary stones is important for assisting medical doctors in early diagnosis and further treatment. While deep learning techniques are effective for image segmentation, they require a large number of datasets to achieve high accuracy. We proposed a GAN-based augmentation technique for creating synthetic images based on stone and non-stone mask inputs in order to improve the segmentation network’s performance by increasing the number and diversity of training data. The synthetic training images were generated from stone-contained images and stone-free images using existing stone ground truth and corresponding stone location maps, respectively. To segment urinary stones from full abdominal x-ray images, we trained the MultiResUnet model using both original stone-contained and our proposed synthetic samples. The proposed method obtained a 69.59% pixel-wise $F_{1}$ score and a 68.14% region-wise $F_{1}$ score, which achieved an improvement of 2.12% and 2.13%, respectively, over a model trained with only the original stone-contained dataset.

BackgroundSeveral markers of inflammation have been associated with oncologic outcomes. Prognostic markers are not well-defined for renal cell carcinoma (RCC). We sought to investigate the association of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and De Ritis ratio with mortality in RCC.MethodsMulti-center retrospective analysis of patients undergoing surgery for RCC. Primary outcome of interest was all-cause mortality (ACM). Secondary outcomes were non-cancer mortality (NCM) and cancer-specific mortality (CSM). Elevated NLR was defined as ≥2.27, elevated PLR as ≥165, and elevated De Ritis ratio as ≥ 2.72. Multivariable cox regression analysis (MVA) was conducted to elucidate risk factors for primary and secondary outcomes, and Kaplan-Meier analysis (KMA) was used to evaluate survival outcomes comparing elevated and non-elevated NLR, PLR, and De Ritis ratio.Results2656 patients were analyzed (874 patients had elevated NLR; 480 patients had elevated PLR and 932 patients had elevated De Ritis). Elevated NLR was a significant predictor of ACM (HR 1.32, 95% CI: 1.07-1.64, p=0.003) and NCM (HR 1.79, 95% CI: 1.30-2.46, p

Tailoring the crystallization kinetics of materials is important for targeting applications. Here the authors observe a remarkable dependence of crystallization and vitrification kinetics and attribute it to systematic bonding changes for a class of materials between metallic and covalent bonding.

Nonphononic vibrations originating from disordered structures have garnered significant attention as a fundamental feature of glasses that distinguishes them from crystals. Recently, we discovered that one-dimensional (1D) stringlike vibrations without volume change are responsible for the boson peak in the reduced density of states of two-dimensional (2D) glasses [Y.-C. Hu and H. Tanaka, Nat. Phys. 18, 669 (2022)1745-247310.1038/s41567-022-01628-6]. Here we investigate the vibrational properties of three-dimensional (3D) model glasses with isotropic repulsive and attractive interactions and find that the boson peak arises from stringlike quasilocalized transverse vibrations in these 3D systems. These results suggest that stringlike vibrations are the universal origin of the boson peak in both 2D and 3D model glasses, as long as the interaction is isotropic. Furthermore, we confirm that the characteristic frequency of the quasilocalized transverse vibrations, i.e., the boson peak frequency, coincides with the Ioffe-Regel limit of transverse phonons. These results imply the boson peak originates from the frequency-resonant scattering of transverse phonons by quasilocalized vibrations rather than phonon scattering due to elastic inhomogeneity. Our findings provide insights into the origin of low-temperature glass anomalies and inspire further research.

Normally the diffusionless solid-to-solid transition between phases are driven by athermal processes, due to strain being overwhelmingly dominant. Here, the authors present a unique series of in-situ particle level observations of the solid-to-solid transition in colloidal particles suspended in a solvent, revealing new transition pathways.

The domain growth in phase separation is usually believed to be controlled by material transport. Tateno and Tanaka find that when phase separation causes strong dynamic asymmetry between the two phases, mechanical relaxation dominates and leads to a universally valid scaling law

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4–78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0–9) and 6 (range: 1–17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2–4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Introduction The efficacy of salvage local therapy after external beam radiotherapy has recently gained attention. However, a challenge with these therapies is the risk of significant genitourinary and gastrointestinal toxicity. Focal brachytherapy may be a treatment option because of its potential to reduce side effects. Case presentation A patient with castration‐resistant prostate cancer was found to be free of metastases on whole‐body magnetic resonance imaging following external beam radiotherapy, and prostate biopsy revealed a localized recurrence in the ventral prostate. The patient underwent salvage focal brachytherapy and had a prostate‐specific antigen progression‐free survival of 23 months. No adverse effects were observed following salvage brachytherapy. Conclusion Our case suggests that salvage focal brachytherapy may be an effective local treatment option for nonmetastatic castration‐resistant prostate cancer that has relapsed after external beam radiotherapy, wherein the lesion is confined to a small area within the prostate.

Abstract Radiotherapy plus immune checkpoint inhibitors can potentially induce synergistic antitumor immune responses. However, little clinical evidence is established regarding their combination therapy. Here, we aimed to assess whether radiotherapy to the primary tumor impacts on the efficacy of pembrolizumab in advanced urothelial cancer. We retrospectively reviewed 98 advanced urothelial cancer patients receiving pembrolizumab in a second‐ or later‐line setting using our multicenter cohort. Patients were categorized according to a history of radiotherapy to the primary tumor: patients previously exposed to radiotherapy to the primary tumor (Radiotherapy group, 17 patients [17%]) and those not (Nonradiotherapy group, 81 patients [83%]). The associations of radiotherapy to the primary tumor with objective response and survival were evaluated. The Radiotherapy group showed a significantly higher objective response ratio than did the Non‐radiotherapy group (65% vs 19%; P

The liquid state is one of the fundamental and essential states of matter, but its physical understanding is far behind the other states, such as the gas and solid states, due to the difficulties associated with the high density causing many-body correlations and the lack of long-range order. Significant open problems in liquid science include glass transition, crystallization, and water's anomalies. Austen Angell has contributed tremendously to these problems and proposed many new concepts of fundamental importance. In this article, we review how these concepts have influenced our work on liquid physics, focusing on the roles of liquid structural ordering in glass transition, crystallization, and water's anomalies.

Glass materials are solid, like crystals, but lack long-range order, whilst the origin of their solidity remains elusive. Tong et al. show that the emergent solidity of glasses is induced by self-organization of percolation of force-bearing network appeared at the non-equilibrium glass transition upon cooling.

The glass-forming materials exhibit dynamical slowing down together with spatial heterogeneity at microscales, but their origin remains debated. Tong and Tanaka show that this phenomenon can be unified based on a structural order parameter capable of detecting subtle ordering in instantaneous liquid states.

The efficacy and safety of naldemedine for opioid-induced constipation in patients with cancer has not been investigated in clinical practice. We conducted a multicenter, retrospective study to assess the effects of naldemedine among 10 Japanese institutions between June 2017 and August 2019. We evaluated the number of defecations 7 days before and after naldemedine administration. A total of 149 patients (89 male) with a median age of 72 years (range, 38–96) were included. The performance status was 0–1, 2, and ≥3 in 40, 38, and 71 patients, respectively. The median opioid dose in oral morphine equivalents was 30 mg/day (range: 7.5–800 mg). We observed 98 responders and 51 non-responders. The median number of defecations increased significantly in the 7 days following naldemedine administration from three to six (p < 0.0001). Multivariate analysis revealed that an opioid dose p = 0.042] was significantly correlated with the effect of naldemedine. Diarrhea was the most common adverse event (38.2%) among all grades. The efficacy and safety of naldemedine in clinical practice are comparable to those of prospective studies, suggesting that it is effective in most patients.

Preoperative imaging differentiation between ChRCC and RO is difficult with conventional subjective evaluation, and the development of quantitative analysis is a clinical challenge. Forty-nine patients underwent partial or radical nephrectomy preceded by MRI and followed by pathological diagnosis with ChRCC or RO (ChRCC: n = 41, RO: n = 8). The whole-lesion volume of interest was set on apparent diffusion coefficient (ADC) maps of 1.5T-MRI. The importance of selected texture features (TFs) was evaluated, and diagnostic models were created using random forest (RF) analysis. The Mean Decrease Gini as calculated through RF analysis was the highest for mean_ADC_value. ChRCC had a significantly lower mean_ADC_value than RO (1.26 vs. 1.79 × 10−3 mm2/s, p < 0.0001). Feature selection by the Boruta method identified the first-quartile ADC value and GLZLM_HGZE as important features. ROC curve analysis showed that there was no significant difference in the classification performances between the mean_ADC_value-only model and the Boruta model (AUC: 0.954 vs. 0.969, p = 0.236). The mean ADC value had good predictive ability for the distinction between ChRCC and RO, comparable to that of the combination of TFs optimized for the evaluated cohort. The mean ADC value may be useful in distinguishing between ChRCC and RO.

The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28; p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group (HR, 0.11; p = 0.014). In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS.

The genus Nocardia usually infect immunocompromised patients. Pulmonary nocardiosis is the most common Nocardia-induced infection while central nervous system (CNS) is the most common extrapulmonary site to develop nocardial disease. Approximately 54 % cases of previously reported nocardial brain abscesses were solitary lesions, while 38 % cases had multiple lesions; but miliary-like ring enhancing lesions have not been reported previously.We present a case of immunocompetent patient with miliary-like cerebrospinal lesions caused by Nocardia beijingensis. A 68-year-old Japanese man presented with acute-onset headache, vomiting, and progressive disturbance of consciousness. A contrasted magnetic resonance imaging (MRI) scan showed countless miliary-like ring-shaped enhancing lesions on the patient’s whole brain, brain stem, and cervical spinal cord. A brain biopsy was performed and Kinyoun stain suggested that the brain lesions were abscesses caused by Nocardia species. 16S ribosomal RNA sequencing identified Nocardia beijingensis as the causative microorganism. The trimethoprim/sulfamethoxazole regimen was continued for 7 months and the patient showed good improvement with recovery of consciousness.Clinical manifestation of Nocardia beijingensis infection is poorly studied. Further cases are needed to be accumulated.

BackgroundVitamins and minerals are routinely administered by total parenteral nutrition (TPN). However, in Japan, adjustments in iron dosage are difficult because blended mineral preparations are often used. It is therefore unclear whether the iron content is appropriate in cases of long-term TPN. The aim of the study was to assess the influence of iron administration by long-term TPN on iron deposition in post-mortem liver samples isolated from older deceased patients.MethodsLiver tissues were collected from post-mortem autopsies of 187 patients over a period of 15 years. Samples were stained with Prussian blue and histologically evaluated from Grade 0-V by at least three different observers. Specimens with positive and negative iron staining were compared, and positive samples were grouped according to the level and distribution of the staining. Post-mortem blood obtained from the subclavian vein during autopsy was also analysed. Samples were collected for the measurement of unsaturated serum iron, serum iron, albumin, prealbumin, hepcidin, and IL-6 concentrations.ResultsIron accumulation in the liver was significantly higher in male patients (p = 0.005) with a history of surgery (p = 0.044) or central vein administration of iron (pConclusionsChronic intravenous administration of iron was associated with iron deposition in the liver, even when given the minimum recommended dosage. In long-term TPN patients, the iron dose should therefore be carefully considered.

Prognostic accuracy of the quick sequential organ failure assessment (qSOFA) score for mortality may be limited in elderly patients. Using our multi-institutional database, we classified obstructive acute pyelonephritis (OAPN) patients into young and elderly groups, and evaluated predictive performance of the qSOFA score for in-hospital mortality. qSOFA score ≥ 2 was an independent predictor for in-hospital mortality, as was higher age, and Charlson comorbidity index (CCI) ≥ 2. In young patients, the area under the curve (AUC) of the qSOFA score for in-hospital mortality was 0.85, whereas it was 0.61 in elderly patients. The sensitivity and specificity of qSOFA score ≥ 2 for in-hospital mortality was 80% and 80% in young patients, and 50% and 68% in elderly patients, respectively. For elderly patients, we developed the CCI-incorporated qSOFA score, which showed higher prognostic accuracy compared with the qSOFA score (AUC, 0.66 vs. 0.61, p < 0.001). Therefore, the prognostic accuracy of the qSOFA score for in-hospital mortality was high in young OAPN patients, but modest in elderly patients. Although it can work as a screening tool to determine therapeutic management in young patients, for elderly patients, the presence of comorbidities should be considered at the initial assessment.

The onion-like multilamellar structure is ubiquitous in various soft materials, such as surfactant solutions, biological membranes, and block copolymers, as well as hard materials such as carbon. Onions appear to be perfectly spherical, giving the impression that it has a point-symmetric, seamless, and defect-free internal structure. Here, we focus on surfactant onions formed in the sponge phase and experimentally study whether the interior of surfactant onions is defect-free and isolated from the surrounding matrix or not. By directly observing the coalescence process between onions and a planar lamellar domain with optical microscopy, we have demonstrated that the onions do not have a completely closed structure but have a linear array of defects along the radial direction formed upon onion formation. In other words, the onion structure is symmetric axially but not spherically, like the plant-onion structure. This discovery of the hidden breakdown of spherical symmetry sheds fresh light on the onion's internal topology and formation mechanism.

Background and Objectives: Naldemedine is a peripherally acting μ-opioid receptor antagonist that improves opioid-induced constipation. Although clinical trials have excluded patients with poor performance status (PS) and those started on naldemedine early after opioid initiation, clinical practice has used naldemedine for the same patients. Therefore, we investigated the treatment patterns of naldemedine in a real-world setting. Materials and Methods: This was a multicenter, retrospective chart review study of opioid-treated patients with cancer receiving naldemedine. Adverse events that occurred within 7 days of naldemedine initiation were evaluated in those who received one or more doses of the same. Effectiveness was assessed in patients who used naldemedine for more than 7 days. Results: A total of 296 patients satisfied the eligibility criteria, among whom 129 (43.6%) had a PS of ≥3 and 176 (59.5%) started naldemedine within 2 weeks of opioid initiation. Moreover, 203 (79.6%) patients had ≥3 bowel movements per week. Incidences of all grades of diarrhea and abdominal pain were 87 (29.4%) and 12 (4.1%), respectively. No patient had grade 4 or higher adverse events. Conclusions: Although nearly half of the patients receiving naldemedine in clinical practice belonged to populations that were not included in the clinical trials, our results suggested that naldemedine in clinical practice had the same efficacy and safety as that in clinical trials.

More than a year ago, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization, with the world approaching its fourth wave. During this period, vaccines were developed in a much shorter period than thought possible, with the initiation of the pertinent vaccination. However, oral cavities have come under renewed scrutiny worldwide because saliva, a mixture of salivary secretions, pharyngeal secretions, and gingival crevicular fluid, have not only been shown to contain infective viral loads, mediating the route of SARS-CoV-2 transmission via droplet, aerosol, or contagion, but also used as a sample for viral RNA testing with a usefulness comparable to the nasopharyngeal swab. The oral cavity is an important portal for ingress of SARS-CoV-2, being an entryway to the bronchi, alveoli, and rest of the lower respiratory tract, causing inflammation by viral infection. Moreover, angiotensin-converting enzyme 2, a host receptor for SARS-CoV-2, coupled with proteases responsible for viral entry have been found to be expressed on the tongue and other oral mucosae, suggesting that the oral cavity is the site of virus replication and propagation. Furthermore, there is a possibility that the aspiration of oral bacteria (such as periodontal pathogens) along with saliva into the lower respiratory tract may be a complicating factor for COVID-19 because chronic obstructive pulmonary disease and diabetes are known COVID-19 comorbidities with a greater risk of disease aggravation and higher death rate. These comorbidities have a strong connection to chronic periodontitis and periodontal pathogens, and an oral health management is an effective measure to prevent these comorbidities. In addition, oral bacteria, particularly periodontal pathogens, could be proinflammatory stimulants to respiratory epithelia upon its exposure to aspirated bacteria. Therefore, it may be expected that oral health management not only prevents comorbidities involved in aggravating COVID-19 but also has an effect against COVID-19 progression. This review discusses the significance of oral health management in SARS-CoV-2 infection in the era of “the new normal with COVID-19” and COVID-19 prevention with reference to the hypothetical mechanisms that the authors and the other researchers have proposed.

The rotational Brownian motion of colloidal spheres in dense suspensions reflects local hydrodynamics and contact forces, which are both key to nonlinear rheological phenomena such as shear-thickening and jamming, and transport in crowded environments, including intracellular migration and blood flow. To fully elucidate the role of rotational dynamics experimentally, it is crucial to measure the translational and rotational motion of all spheres simultaneously. Here, we directly access hydrodynamic and frictional coupling in colloidal suspensions up to arbitrarily high volume fractions using compositionally uniform colloidal spheres with an off-center, fully embedded core. We reveal interparticle hydrodynamic rotation-rotation coupling in charged colloidal crystals. We also find that higher local crystallinity in denser hard-sphere crystalline sediments enhances rotational diffusivity and that nearly arrested particles exhibit a stick-slip rotational motion due to frictional coupling. Our findings shed new light on the largely unexplored, local rotational dynamics of spherical particles in dense particulate materials.

Glass is characterized by stochastic and slow structural relaxation dynamics, whose details remain elusive due to its complicated kinetic processes. Here, the authors show that avalanche-like dynamics in both ageing and devitrifying glasses are governed by thermodynamic initiation and a transient loss in mechanical stability.

The nature of the phenomenon of so-called ‘liquid-liquid transitions’ in molecular liquids is a long-standing debate. Here, the authors demonstrate the reversibility and first-order nature of the liquid-liquid transition in triphenyl phosphite via flash differential scanning calorimetry.

The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti–programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti–PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti–PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti–PD-1 treatment alone. The mice treated with CRT/postirradiation anti–PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti–PD-1 treatment efficacy in UC.