The periosteum provides a stromal defence against cancer invasion into the bone.

The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells.

Diffusion-Dominated Luminescence Dynamics of CsPbBr3 Studied Using Cathodoluminescence and Microphotoluminescence Spectroscopy.

Time-resolved or time-correlation measurements using cathodoluminescence (CL) reveal the electronic and optical properties of semiconductors, such as their carrier lifetimes, at the nanoscale. However, halide perovskites, which are promising optoelectronic materials, exhibit significantly different decay dynamics in their CL and photoluminescence (PL). We conducted time-correlation CL measurements of CsPbBr3 using Hanbury Brown-Twiss interferometry and compared them with time-resolved PL. The measured CL decay time was on the order of subnanoseconds and was faster than PL decay at an excited carrier density of 2.1 × 1018 cm-3. Our experiment and analytical model revealed the CL dynamics induced by individual electron incidences, which are characterized by highly localized carrier generation followed by a rapid decrease in carrier density due to diffusion. This carrier diffusion can play a dominant role in the CL decay time for undoped semiconductors, in general, when the diffusion dynamics are faster than the carrier recombination.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. METHODS: We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. RESULTS: Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001). CONCLUSIONS: This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

A single-center retrospective comparative analysis of urinary continence in robotic prostatectomy with a combination of umbilical ligament preservation and Hood technique.

OBJECTIVES: Data available on the effect of the recently developed Hood technique and its modified iterations in robot-assisted radical prostatectomy on postoperative urinary continence are insufficient. We evaluated the time to achieve urinary continence with the modified Hood technique compared with the standard or umbilical ligament preservation robot-assisted radical prostatectomy. METHODS: This retrospective analysis examines patient records for those who underwent robot-assisted radical prostatectomy at the Jyoban Hospital of Tokiwa Foundation in Fukushima, Japan, from 2017 to 2021. The main outcome was to determine significant differences in the time taken to achieve urinary continence among the three procedure types. We employed the Kaplan-Meier survival analysis to estimate the time to achieve urinary continence in the three procedure types of robot-assisted radical prostatectomy. Additionally, we used a Cox regression hazard model to evaluate the association between the time to achieve urinary continence and the procedure types. RESULTS: We considered 196 patients in this study. The estimated rates of achieving urinary continence at 6 months following standard, umbilical ligament preservation, and modified Hood technique robot-assisted radical prostatectomy were 77.6%, 89.5%, and 100%, respectively. The multivariable Cox hazard regression model showed that patients who underwent the modified Hood technique were significantly more likely to achieve urinary continence than those who underwent the standard robot-assisted radical prostatectomy. CONCLUSIONS: The modified Hood technique achieved better urinary continence outcomes, with all patients with the procedure achieving urinary continence at 6 months. Further randomized controlled trials are required to validate this finding.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Detection rate and variables associated with incidental prostate cancer by holmium laser enucleation of the prostate.

OBJECTIVES: Holmium laser enucleation of the prostate is well-established and effective for bladder outlet obstruction due to benign prostatic hyperplasia. The objective of this study was to examine the detection rate of incidental prostate cancer by holmium laser enucleation of the prostate and variables associated with them. METHODS: A total of 612 patients were enrolled. We retrospectively examined the detection rate of incidental prostate cancer and perioperative variables associated with them. RESULTS: Forty-nine of 612 patients were diagnosed with incidental prostate cancer. Univariate logistic regression analysis showed that higher prostate-specific antigen density (odds ratio 3.34, 95% confidence interval 1.02-10.94, P = 0.05), higher prostate-specific antigen density of the transition zone (odds ratio 2.28, 95% confidence interval 1.02-5.09, P = 0.04), and findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.71, 95% confidence interval 1.70-13.1, P = 0.003; transition zone: odds ratio 3.46, 95% confidence interval 1.74-6.86, P < 0.001; peripheral and transition zones: odds ratio 6.00, 95% confidence interval 1.51-23.8, P = 0.01) were significantly associated with incidental prostate cancer. Multivariate logistic regression analysis showed that findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.36, 95% confidence interval 1.49-12.8, P = 0.001; transition zone: odds ratio 3.54, 95% confidence interval 1.75-7.16, P < 0.001; peripheral and transition zones: odds ratio 6.14, 95% confidence interval 1.53-24.5, P = 0.01) was an independent risk factor for incidental prostate cancer. CONCLUSION: The detection rate of incidental prostate cancer was 8.0%, and findings of the prostate cancer on magnetic resonance imaging were an independent predictive factor for incidental prostate cancer.

Association of tumor burden with outcome in first-line therapy with nivolumab plus ipilimumab for previously untreated metastatic renal cell carcinoma.

OBJECTIVES: To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. RESULTS: The median tumor burden was 63.0 cm (interquartile range: 34.2-125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73-9.70] vs. 12.5 [4.77-24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11-4.45], P = 0.0242). CONCLUSIONS: Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Bandgap modulation in photoexcited topological insulator Bi2Te3 via atomic displacements.

The atomic and electronic dynamics in the topological insulator (TI) Bi2Te3 under strong photoexcitation were characterized with time-resolved electron diffraction and time-resolved mid-infrared spectroscopy. Three-dimensional TIs characterized as bulk insulators with an electronic conduction surface band have shown a variety of exotic responses in terms of electronic transport when observed under conditions of applied pressure, magnetic field, or circularly polarized light. However, the atomic motions and their correlation between electronic systems in TIs under strong photoexcitation have not been explored. The artificial and transient modification of the electronic structures in TIs via photoinduced atomic motions represents a novel mechanism for providing a comparable level of bandgap control. The results of time-domain crystallography indicate that photoexcitation induces two-step atomic motions: first bismuth and then tellurium center-symmetric displacements. These atomic motions in Bi2Te3 trigger 10% bulk bandgap narrowing, which is consistent with the time-resolved mid-infrared spectroscopy results.

The neutrophil-osteogenic cell axis promotes bone destruction in periodontitis.

The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune-bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil-osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.

A Propensity Score-Matched Analysis of Perioperative Outcomes of Holmium Laser Enucleation of the Prostate Between Lumenis Pulse 120H and VersaPulse Select 80W.

Objectives: Holmium laser enucleation of the prostate (HoLEP) is a valid and safe procedure for the treatment of benign prostatic hyperplasia. This study aimed to examine the perioperative outcomes of HoLEP using a new laser platform, Lumenis Pulse™ 120H, and a previous laser platform, VersaPulse Select 80W. Methods: A total of 612 patients who underwent holmium laser enucleation were enrolled, including 188 and 424 patients who underwent enucleation using Lumenis Pulse 120H and VersaPulse Select 80W, respectively. They were matched using propensity scores with preoperative patient characteristics, and the differences between the two groups, including operative time, enucleated specimen, transfusion rate, and complication rate, were examined. Results: Propensity score-matched cohort comprised 364 patients with 182 in the Lumenis Pulse 120H group (50.0%) and 182 in the VersaPulse Select 80W group (50.0%). Operative time was significantly shorter with Lumenis Pulse 120H (55.2 ± 34.4 vs 101.4 ± 54.3 minutes, p < 0.001). In contrast, no significant differences were seen in resected specimen weight (43.8 ± 29.8 vs 39.6 ± 22.6 g, p = 0.36), rate of incidental prostate cancer (7.7% vs 10.4%, p = 0.36), transfusion rate (0.6% vs 1.1%, p = 0.56), and perioperative complication rates, including urinary tract infection, hematuria, urinary retention, and capsular perforation (5.0% vs 5.0%, 4.4% vs 2.7%, 0.5% vs 4.4%, 0.5% vs 0%, respectively, p = 0.13). Conclusions: Lumenis Pulse 120H improved the operative time significantly, which is regarded as one of the disadvantages of HoLEP.

Robot-assisted radical prostatectomy following holmium laser enucleation of the prostate: perioperative, functional, and oncological outcomes.

Robot-assisted radical prostatectomy with previous holmium laser enucleation of the prostate is challenging, and few studies have analyzed its perioperative, functional, and oncological outcomes. Here we retrospectively evaluated 298 robot-assisted radical prostatectomies, including 25 with and 273 without previous holmium laser enucleation of the prostate, performed in 2015-2022. Regarding perioperative outcomes, operative and console times were significantly longer in the previous holmium laser enucleation of the prostate group. In contrast, the estimated blood loss was similar between groups, and there were no transfusions or intraoperative complications. Multivariable Cox hazard regression analysis of the functional outcomes of postoperative urinary continence showed that body mass index, intraoperative bladder neck repair, and nerve sparing were independently associated factors, whereas a history of holmium laser enucleation of the prostate was not. Similarly, a history of holmium laser enucleation of the prostate was not associated with biochemical recurrence; however, positive surgical margins and seminal vesicle invasion were independent risk factors of biochemical recurrence. Our findings revealed that robot-assisted radical prostatectomy after holmium laser enucleation of the prostate was safe and raised no concerns of postoperative urinary incontinence or biochemical recurrence. Therefore, robot-assisted radical prostatectomy may be a treatment option for patients with prostate cancer after holmium laser enucleation of the prostate.

Comparison of the Impact of Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Dual Combination Therapy and Immune Checkpoint Inhibitor Plus Tyrosine Kinase Inhibitor Combination Therapy in Patients with Advanced Renal Cell Carcinoma.

BACKGROUND: The prognostic impact of immune-related adverse events during immune checkpoint inhibitor-based combination therapy for advanced renal cell carcinoma remains unclear, especially in terms of differences between regimens. OBJECTIVE: We aimed to clarify the prognostic impact of immune-related adverse events in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor dual combination therapy (IO-IO) or immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (IO-TKI). METHODS: We retrospectively evaluated the data of 148 patients who received immune checkpoint inhibitor-based combination therapy as first-line therapy. Patients were divided into two groups based on regimens, namely IO-IO and IO-TKI. The associations between immune-related adverse event development and outcomes, such as progression-free survival, overall survival, and objective response rate, were compared between the two groups. RESULTS: In the IO-IO and IO-TKI groups, 67 of 91 (74%) and 31 of 57 (54%) patients, respectively, experienced at least one immune-related adverse event and the rate was significantly higher in the IO-IO group (p = 0.0204), where immune-related adverse events development was significantly associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0102), and a higher objective response rate (p = 0.0028). A multivariate analysis revealed immune-related adverse event development as an independent factor for longer progression-free survival (hazard ratio, 0.25; p < 0.0001) and overall survival (hazard ratio, 0.42; p = 0.0287). There were no significant associations between immune-related adverse events and progression-free survival, overall survival, or objective response rate in the IO-TKI group. CONCLUSIONS: The development of immune-related adverse events was positively associated with the outcome of patients with advanced renal cell carcinoma treated with IO-IO combination therapy; no such correlation was observed for IO-TKI combination therapy.

Cryoablation for atrial tachycardia with cycle length variability originating from the vicinity of the sinus node.

This case is about atrial tachycardia with cycle length variability originating from the vicinity of the sinus node and diagnostic pacing maneuvers to assess the tachycardia circuit were not achieved. Activation mapping revealed that the origin of atrial tachycardia was 15 mm away from the sinus node and the phrenic nerve was captured by pacing at the posterior portion of atrial tachycardia. A multipolar catheter was placed in the right brachiocephalic vein to capture the right phrenic nerve by pacing. The absence of phrenic nerve palsy was confirmed by palpation of constant diaphragmatic movement. The cryoablation could be safely and efficiently performed without ablation-induced injury of sinus node and phrenic nerve palsy by confirming constant diaphragmatic movement. The efficacy of cryoablation in the vicinity of the conduction system and phrenic nerve will be increasingly confirmed in the future. Learning Objective: Cryoablation for atrial tachycardia might be more safe and effective in terms of ablation-induced injury of conduction system and phrenic nerve palsy compared with conventional radiofrequency ablation when diagnostic pacing maneuvers are not able to estimate the circuit due to variability of tachycardia cycle length.

Identification of an intronic enhancer regulating RANKL expression in osteocytic cells.

The bony skeleton is continuously renewed throughout adult life by the bone remodeling process, in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms. Osteocytes regulate bone remodeling by producing the osteoclast differentiation factor RANKL (encoded by the TNFSF11 gene). However, the precise mechanisms underlying RANKL expression in osteocytes are still elusive. Here, we explored the epigenomic landscape of osteocytic cells and identified a hitherto-undescribed osteocytic cell-specific intronic enhancer in the TNFSF11 gene locus. Bioinformatics analyses showed that transcription factors involved in cell death and senescence act on this intronic enhancer region. Single-cell transcriptomic data analysis demonstrated that cell death signaling increased RANKL expression in osteocytic cells. Genetic deletion of the intronic enhancer led to a high-bone-mass phenotype with decreased levels of RANKL in osteocytic cells and osteoclastogenesis in the adult stage, while RANKL expression was not affected in osteoblasts or lymphocytes. These data suggest that osteocytes may utilize a specialized regulatory element to facilitate osteoclast formation at the bone surface to be resorbed by linking signals from cellular senescence/death and RANKL expression.

Impact of Body Mass Index on Outcomes in an Asian population of Advanced Renal Cell Carcinoma and Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors.

OBJECTIVES: To clarify the impact of body mass index (BMI) on treatment outcomes including survival, tumor response, and adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) or urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs) in an Asian population. METHODS: We retrospectively evaluated 309 patients with advanced RCC or UC who received ICIs between September 2016 and July 2021. The patients were divided into high- (i.e., ≥25 kg/m2) and low-BMI (<25 kg/m2) groups according to the BMI at the time of treatment initiation. RESULTS: Overall, 57 patients (18.4%) were classified into the high-BMI group. In RCC patients treated with ICIs as first-line therapy or UC treated with pembrolizumab, progression-free survival (PFS) (p = 0.309; p = 0.842), overall survival (OS) (p = 0.701; p = 0.983), and objective response rate (ORR) (p = 0.163; p = 0.553) were comparable between the high- and low-BMI groups. In RCC patients treated with nivolumab monotherapy as later-line therapy, OS (p = 0.101) and ORR (p = 0.102) were comparable, but PFS was significantly longer in the high-BMI group (p = 0.0272). Further, multivariate analysis showed that BMI was not an independent factor of PFS or OS in all the treatment groups (any, p>0.05). As for AE profiles, in nivolumab monotherapy, the rate was significantly higher in the high-BMI group (p = 0.0203), whereas in the other two treatments, the rate was comparable. CONCLUSIONS: BMI was not associated with survival or response rates of advanced RCC or UC patients treated with ICIs in an Asian population. AEs might frequently develop in high-BMI patients with RCC in nivolumab monotherapy.

Duration and Influencing Factors of Postoperative Urinary Incontinence after Robot-Assisted Radical Prostatectomy in a Japanese Community Hospital: A Single-Center Retrospective Cohort Study.

OBJECTIVES: Post-operative urinary incontinence (PUI) after robotic-assisted radical prostatectomy (RARP) is an important complication; PUI occurs immediately after postoperative urethral catheter removal, and, although approximately 90% of patients improve within one year after surgery, it can significantly worsen their quality of life. However, information is lacking on its nature in community hospital settings, particularly in Asian countries. The purposes of this study were to investigate the time required to recover from PUI after RARP and to identify its associated factors in a Japanese community hospital. METHODS: Data were extracted from the medical records of 214 men with prostate cancer who underwent RARP from 2019 to 2021. We then calculated the number of days elapsed from the surgery to the initial outpatient visit confirming PUI recovery among the patients. We estimated the PUI recovery rate using the Kaplan-Meier product limit method and evaluated associated factors using the multivariable Cox proportional hazards model. RESULTS: The PUI recovery rates were 5.7%, 23.4%, 64.6%, and 93.3% at 30, 90, 180, and 365 days following RARP, respectively. After an adjustment, those with preoperative urinary incontinence experienced significantly slower PUI recovery than their counterparts, while those with bilateral nerve sparing experienced recovery significantly sooner than those with no nerve sparing. CONCLUSION: Most PUI improved within one year, but a proportion of those experiencing recovery before 90 days was smaller than previously reported.

Comparison of Outcomes Between Therapeutic Combinations Based on Immune Checkpoint Inhibitors or Tyrosine Kinase Inhibitor Monotherapy for First-Line Therapy of Patients with Advanced Renal Cell Carcinoma Outside of Clinical Trials: A Real-World Retrospective Multi-Institutional Study.

BACKGROUND: Clinical trials have demonstrated the superior efficacy of immune checkpoint inhibitor (ICI)-based combination therapy over sunitinib, a multi-target tyrosine kinase inhibitor (TKI), in patients with advanced renal cell carcinoma. However, such benefits have not been elucidated in populations outside of clinical trials. METHODS: We retrospectively evaluated data from 467 patients with advanced renal cell carcinoma who received ICI-based combination therapy or TKIs, as first-line therapy. Clinical outcome was compared between ICI-based combination therapy and TKIs in each population divided according to trial eligibility. RESULTS: Among 152 patients treated with ICI-based combination therapy and 315 patients treated with TKIs, 76 (50.0%) and 156 (49.5%) were trial ineligible, respectively. Overall survival (p = 0.0072) and objective response rate (p < 0.0001) were significantly higher in ICI-based combination therapy than in TKIs, but progression-free survival was comparable (p = 0.681). In the trial-eligible population, overall survival was longer (p = 0.0906) and the objective response rate was significantly higher (p = 0.0124) in ICI-based combination therapy than in TKIs. In the trial-ineligible population, overall survival (p = 0.0208) and objective response rate (p = 0.0006) were significantly higher with ICI-based combination therapy than with TKIs. A multivariate analysis also showed that ICI-based combination therapy was independently associated with prolonged overall survival (hazard ratio, 0.47; p = 0.0016). Regardless of trial eligibility, progression-free survival did not differ between ICI-based combination therapy and TKIs (trial eligible: p = 0.287; trial ineligible: p = 0.0708). CONCLUSIONS: The present study, using real-world data, provides evidence indicating the therapeutic benefit of ICI-based combination therapy over TKIs for advanced renal cell carcinoma was more statistically significant in the trial-ineligible population than in the trial-eligible population.

Attosecond-Resolved Coherent Control of Lattice Vibrations in Thermoelectric SnSe.

Manipulating lattice vibrations is the cornerstone to achieving ultralow thermal conductivity in thermoelectrics. Although spatial control by novel material designs has been recently reported, temporal manipulation, which can shape thermoelectric properties under nonequilibrium conditions, remains largely unexplored. Here, taking SnSe as a representative, we have demonstrated that in the ultrafast pump-pump-probe spectroscopy, electronic and lattice coherences inherited from optical excitations can be exploited independently to manipulate phonon oscillations in a highly selective manner. Specifically, when the pump-pump delay time (tmod) is in the electronic coherence time range, the amplitude, frequency, and lifetime of all phonon modes are simultaneously following the optical cycle. While extending tmod into the lattice coherence time range, the amplitude of each coherent phonon mode can be selectively manipulated according to its intrinsic period without changing the frequency and lifetime. This work opens up exciting avenues to temporally and discriminatorily manipulate phononic processes in thermoelectric materials.

Efficacy and Safety of Immunotherapy-Based Combinations as First-Line Therapy for Metastatic Renal Cell Carcinoma in Patients Who Do Not Meet Trial Eligibility Criteria.

BACKGROUND: Data regarding the efficacy and safety profiles of immune checkpoint inhibitors (ICIs) for metastatic renal cell carcinoma (mRCC) trial-ineligible patients in the real world remain unclear. OBJECTIVES: The aim of this study was to clarify the impact of trial eligibility on ICI-based combination therapy for mRCC. PATIENTS AND METHODS: We collected clinical data of mRCC patients receiving ICIs since 2016, and 222 patients were registered. Among these patients, we evaluated 93 patients treated with ICI-based combination therapy, including nivolumab plus ipilimumab, pembrolizumab plus axitinib, or avelumab plus axitinib, as first-line therapy. Patients were classified into the trial-ineligible group when they had at least one of the following factors at the time of treatment initiation: Karnofsky performance status (KPS) < 70%, hemoglobin level < 9.0 g/dL, estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2, platelet count < 100,000/µL, neutrophil count < 1500/µL, non-clear cell histology, or brain metastasis. The remaining patients were classified into the trial-eligible group. RESULTS: Forty-eight patients (52%) were classified into the trial-ineligible group. The frequency of patients with trial-ineligible factors was highest for low eGFR (n = 20, 45%), followed by non-clear cell histology (n = 17, 36%) and low KPS score (n = 12, 25%). There was no significant difference in progression-free survival (median: 24.0 vs. 11.0 months, p = 0.416), overall survival (1-year rate: 87.0% vs. 85.3%, p = 0.634), or objective response rate (52% vs. 42%, p = 0.308) between the trial-eligible and -ineligible patients. The incidence rate of adverse events was higher in the trial-eligible patients than in the trial-ineligible patients (91% vs. 75%, p = 0.0397); however, the rate of grade 3 or higher adverse events was comparable between the two groups (42% vs. 40%, p = 0.796). CONCLUSIONS: There are many trial-ineligible patients in the real world. Nevertheless, the efficacy and safety of ICI-based combination therapy in trial-ineligible patients were non-inferior compared with those of trial-eligible patients.