[Two Cases of Bleeding from the Ileal Conduit Due to Ectopic Varices].

Case 1 : A 75-year-old man was emergently admitted to our hospital with a complaint of continuous bleeding from the ileal conduit. The conduit was constructed by a total pelvic resection for sigmoid colon cancer that invaded the urinary bladder 24 years ago. Swollen cutaneous mucosa was seen around the ileal conduit, but no obvious bleeding spot was observed. The contrast-enhanced computed tomographic (CT) scan and 3D visualization revealed varices extending to the abdominal wall. Percutaneous transhepatic embolization successfully stopped the bleeding, but it was needed again after two years. Case 2 : A 72-yearold man with a history of open cystectomy and ileal conduit for bladder cancer came to our hospital two years after the surgery, complaining of continuous bleeding from the conduit. The skin around the stoma site was discolored purple, but no obvious bleeding site or bloody urine was observed. The CT scan similar to Case 1 revealed varices in the ileal conduit, and percutaneous transhepatic embolization successfully stopped the bleeding, but it was needed again after five months. After that, three months passed without recurrence.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

Patient characteristics correlate with diagnostic performance of photodynamic diagnostic assisted transurethral resection of bladder tumors: A retrospective, single-center study.

BACKGROUND: Identification of patient subclasses that correlate with the diagnostic performance of photodynamic diagnostic (PDD)-assisted transurethral resection of bladder tumors (TURBT) may improve outcomes. METHODS: Data were extracted from patients that underwent PDD-assisted TURBT at the University of Tsukuba Hospital between 2018 and 2023. Sensitivity and specificity were evaluated based on PDD findings (excluding WL findings) and pathology results. Cluster analysis using uniform manifold approximation and projection and k-means methods was performed, focusing on patients with malignant lesions. RESULTS: A total of 267 patients and 2082 specimens were extracted. Sensitivity was lowest with regard to BCG treatment (53.7 %), followed by flat lesions (57.2 %), urine cytology class ≥ III (62.9 %), and recurrent tumors (64.5 %). In the cluster analysis of 231 patients with malignant lesions, two showed lower sensitivity: Cluster 3 (62.4 %), consisting of patients with recurrent tumors and post-BCG treatment, and Cluster 4 (55.7 %), consisting of patients with primary tumors and urine cytology class ≥ III. Clusters 1 and 2, consisting of patients without BCG treatment and patients with lower urine cytology classes, exhibited higher sensitivities (94.4 % and 87.7 %). Among all clusters, Cluster 4 had the highest proportion of specimens which were negative for both PDD and white light (WL) findings but actually had malignant lesions (20.8 %). CONCLUSIONS: PDD-assisted TURBT sensitivity was lower in subclasses after BCG treatment or with cytology class III or higher. Random biopsy for PDD/WL double-negative lesions may improve diagnostic accuracy in these subclasses.

Glycoprotein nonmetastatic melanoma protein B impacts the malignant potential of bladder cancer cells through its hem-immunoreceptor tyrosine-based activation motif.

Bladder cancer is one of the most common cancers among men worldwide. Although multiple genomic mutations and epigenetic alterations have been identified, an efficacious molecularly targeted therapy has yet to be established. Therefore, a novel approach is anticipated. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that is highly expressed in various cancers. In this study, we evaluated bladder cancer patient samples and found that GPNMB protein abundance is associated with high-grade tumors, and both univariate and multivariate analyses showed that GPNMB is a prognostic factor. Furthermore, the prognosis of patients with high GPNMB levels was significantly poorer in those with nonmuscle invasive bladder cancer (NMIBC) than in those with muscle invasive bladder cancer (MIBC). We then demonstrated that knockdown of GPNMB in MIBC cell lines with high GPNMB inhibits cellular migration and invasion, whereas overexpression of GPNMB further enhances cellular migration and invasion in MIBC cell lines with originally low GPNMB. Therefore, we propose that GPNMB is one of multiple driver molecules in the acquisition of cellular migratory and invasive potential in bladder cancers. Moreover, we revealed that the tyrosine residue in the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) is required for GPNMB-induced cellular motility.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

OBJECTIVES: We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. METHODS: A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥ 4 and < 4 cases/year, respectively. RESULTS: A total of 91 men and 97 women were included, with a median age of 64 years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n = 152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P = 0.026). Multivariate analysis revealed age over 60 years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. CONCLUSIONS: The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

Adult genitourinary sarcoma: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

Variant allele frequency changes in TP53 predict pembrolizumab response in patients with metastatic urothelial carcinoma.

Prognoses for patients with metastatic urothelial carcinoma (mUC) have improved with pembrolizumab treatment, an immune checkpoint inhibitor, but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is required. The present study retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using targeted sequencing of 77 genes from 16 patients with mUC during pembrolizumab treatment. A total of 11 (68.8%) patients demonstrated ≥2 genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher compared with that in the ctDNA-negative group (72.7 vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, these data suggest that profiling of ctDNA in plasma, particularly TP53, may be useful for predicting and monitoring therapeutic responses to pembrolizumab in patients with mUC.

Complete Response to Enfortumab Vedotin in a Hemodialysis Patient with Metastatic Urothelial Carcinoma: A Case Report.

Enfortumab vedotin (EV) is an antibody-drug conjugate and a promising agent for metastatic urothelial carcinoma (mUC). However, evaluations in end-stage renal disease patients undergoing hemodialysis are unreported. Here, we report such a case. A 74-year-old woman with mUC, on hemodialysis for complete urinary tract extirpation, was diagnosed with multiple pulmonary metastases after treatment with gemcitabine-carboplatin followed by pembrolizumab. As third-line therapy, she received a standard dose of EV. She achieved complete response after 2 cycles without grade 3 or higher adverse events, demonstrating the utility of EV in this setting.

Observation of large spin conversion anisotropy in bismuth.

While the effective g-factor can be anisotropic due to the spin-orbit interaction (SOI), its existence in solids cannot be simply asserted from a band structure, which hinders progress on studies from such viewpoints. The effective g-factor in bismuth (Bi) is largely anisotropic; especially for holes at T-point, the effective g-factor perpendicular to the trigonal axis is negligibly small (<0.112), whereas the effective g-factor along the trigonal axis is very large (62.7). We clarified in this work that the large anisotropy of effective g-factor gives rise to the large spin conversion anisotropy in Bi from experimental and theoretical approaches. Spin-torque ferromagnetic resonance was applied to estimate the spin conversion efficiency in rhombohedral (110) Bi to be 17 to 27%, which is unlike the negligibly small efficiency in Bi(111). Harmonic Hall measurements support the large spin conversion efficiency in Bi(110). A large spin conversion anisotropy as the clear manifestation of the anisotropy of the effective g-factor is observed. Beyond the emblematic case of Bi, our study unveiled the significance of the effective g-factor anisotropy in condensed-matter physics and can pave a pathway toward establishing novel spin physics under g-factor control.

Octupole-driven magnetoresistance in an antiferromagnetic tunnel junction.

The tunnelling electric current passing through a magnetic tunnel junction (MTJ) is strongly dependent on the relative orientation of magnetizations in ferromagnetic electrodes sandwiching an insulating barrier, rendering efficient readout of spintronics devices1-5. Thus, tunnelling magnetoresistance (TMR) is considered to be proportional to spin polarization at the interface1 and, to date, has been studied primarily in ferromagnets. Here we report observation of TMR in an all-antiferromagnetic tunnel junction consisting of Mn3Sn/MgO/Mn3Sn (ref. 6). We measured a TMR ratio of around 2% at room temperature, which arises between the parallel and antiparallel configurations of the cluster magnetic octupoles in the chiral antiferromagnetic state. Moreover, we carried out measurements using a Fe/MgO/Mn3Sn MTJ and show that the sign and direction of anisotropic longitudinal spin-polarized current in the antiferromagnet7 can be controlled by octupole direction. Strikingly, the TMR ratio (about 2%) of the all-antiferromagnetic MTJ is much larger than that estimated using the observed spin polarization. Theoretically, we found that the chiral antiferromagnetic MTJ may produce a substantially large TMR ratio as a result of the time-reversal, symmetry-breaking polarization characteristic of cluster magnetic octupoles. Our work lays the foundation for the development of ultrafast and efficient spintronic devices using antiferromagnets8-10.

Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice.

Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8-12 h in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice showed decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition.

Improved survival of poor-risk non-seminomatous germ cell tumor patients: real-world data from a single institute in Japan.

OBJECTIVES: The International Germ Cell Cancer Collaborative Group Update Consortium showed the improved survival of patients with a non-seminomatous germ cell tumor. We updated the survival data of the non-seminomatous germ cell tumor patients treated at our hospital. PATIENTS AND METHODS: We analyzed the outcomes of 138 patients treated in 1981-2018. We compared the survival of the patients treated in the early (1981-99) and later (2000-18) periods and determined the groups' progression-free survival and overall survival using the Kaplan-Meier method. We used a web-based application of the International Germ Cell Cancer Collaborative Group Update model to calculate each patient's predicted 3-year progression-free survival. RESULTS: The 5-year progression-free survival rates of the good, intermediate and poor prognosis groups were 91, 83 and 64%, and their 5-year overall survival rates were 97, 89 and 82%, respectively. There were no significant differences in the progression-free survival or overall survival of the good and intermediate prognosis groups by treatment year. The 5-year progression-free survival of the poor prognosis group was almost identical in both treatment year (60 and 65%, respectively). By contrast, the 5-year overall survival in the later period (85%) was higher than that in the early period (70%). The median-predicted 3-year progression-free survival rates of the good, intermediate and poor prognosis groups were 92, 83 and 51% (P < 0.01), respectively. The concordance index for the good, intermediate and poor prognosis groups were 0.56, 0.79 and 0.67, respectively. CONCLUSION: The survival of our poor prognosis non-seminomatous germ cell tumor patients improved over time. The 5-year overall survival of patients treated in 2000-18 reached 85%.

Whole-Blood Gene Expression Profiles Correlate with Response to Immune Checkpoint Inhibitors in Patients with Metastatic Renal Cell Carcinoma.

In metastatic renal cell carcinoma (mRCC), the clinical response to immune checkpoint inhibitors (ICIs) is limited in a subset of patients and the need exists to identify non-invasive, blood-based, predictive biomarkers for responses. We performed RNA sequencing using whole-blood samples prospectively collected from 49 patients with mRCC prior to the administration of ipilimumab (IPI) and/or nivolumab (NIVO) to determine whether gene expression profiles were associated with responses. An analysis from 33 mRCC patients with complete responses (n = 5), partial responses (n = 14), and progressive disease (n = 14) showed 460 differentially expressed genes (DEGs) related to immune responses between the responder and non-responder groups with significant differences. A set of 14 genes generated from the initial 460 DEGs accurately classified responders (sensitivity 94.7% and specificity 50.0%) while consensus clustering defined clusters with significantly differing response rates (92.3% and 35.0%). These clustering results were replicated in a cohort featuring 16 additional SD patients (49 total patients): response rates were 95.8% and 48.0%. Collectively, whole-blood gene expression profiles derived from mRCC patients treated with ICIs clearly differed by response and hierarchical clustering using immune response DEGs accurately classified responder patients. These results suggest that such screening may serve as a predictor for ICI responses in mRCC patients.

Clinicopathological features of adrenal malignancies: Analysis of hospital-based cancer registry data in Japan.

OBJECTIVE: To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC). PATIENTS AND METHODS: We used a hospital-based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012-2015. For survival analysis, we used data from the 2008-2009 cohort to estimate 5-year overall survival (OS) by the Kaplan-Meier method. RESULTS: A total of 989 adrenal malignancies were identified in the 2012-2015 cohort. The most common histologies were ACC (26.4%), diffuse large B-cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over-70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008-2009 cohort, the 5-year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1- and 2-year OS rates of 25.0% and 12.5%. CONCLUSION: In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies.

Perpendicular full switching of chiral antiferromagnetic order by current.

Electrical control of a magnetic state of matter lays the foundation for information technologies and for understanding of spintronic phenomena. Spin-orbit torque provides an efficient mechanism for the electrical manipulation of magnetic orders1-11. In particular, spin-orbit torque switching of perpendicular magnetization in nanoscale ferromagnetic bits has enabled the development of stable, reliable and low-power memories and computation12-14. Likewise, for antiferromagnetic spintronics, electrical bidirectional switching of an antiferromagnetic order in a perpendicular geometry may have huge impacts, given its potential advantage for high-density integration and ultrafast operation15,16. Here we report the experimental realization of perpendicular and full spin-orbit torque switching of an antiferromagnetic binary state. We use the chiral antiferromagnet Mn3Sn (ref. 17), which exhibits the magnetization-free anomalous Hall effect owing to a ferroic order of a cluster magnetic octupole hosted in its chiral antiferromagnetic state18. We fabricate heavy-metal/Mn3Sn heterostructures by molecular beam epitaxy and introduce perpendicular magnetic anisotropy of the octupole using an epitaxial in-plane tensile strain. By using the anomalous Hall effect as the readout, we demonstrate 100 per cent switching of the perpendicular octupole polarization in a 30-nanometre-thick Mn3Sn film with a small critical current density of less than 15 megaamperes per square centimetre. Our theory reveals that the perpendicular geometry between the polarization directions of current-induced spin accumulation and of the octupole persistently maximizes the spin-orbit torque efficiency during the deterministic bidirectional switching process. Our work provides a significant basis for antiferromagnetic spintronics.

Chirality-Induced Magnetoresistance Due to Thermally Driven Spin Polarization.

Chirality-induced current-perpendicular-to-plane magnetoresistance (CPP-MR) originates from current-induced spin polarization in molecules. The current-induced spin polarization is widely recognized as a fundamental principle of chiral-induced spin selectivity (CISS). In this study, we investigate chirality-induced current-in-plane magnetoresistance (CIP-MR) in a chiral molecule/ferromagnetic metal bilayer at room temperature. In contrast to CPP-MR, CIP-MR observed in the present study requires no bias charge current through the molecule. The temperature dependence of CIP-MR suggests that thermally driven spontaneous spin polarization in chiral molecules is the key to the observed MR. The novel MR is consistent with recent CISS-related studies, that is, chiral molecules in contact with a metallic surface possess a finite spin polarization.

Laparoendoscopic single-site surgery for urachal remnant with extraperitoneal approach through a suprapubic port.

INTRODUCTION: No standard procedure has been established for laparoendoscopic single-site surgery for urachal remnants (LESS-U). This study aimed to report the novel surgical techniques and initial outcomes of laparoendoscopic single-site surgery with an extraperitoneal approach through a suprapubic port for urachal remnants (spLESS). METHODS: Fifty-five patients (median age, 27 years; range, 15-69 years) who underwent LESS-U were analyzed. To overcome the limitations inherent in the conventional procedure (LESS-U through an umbilical port: uLESS), we modified the port placement and approached via the extraperitoneal space. spLESS is a novel procedure which reduces intestinal damage caused by the extraperitoneal approach and overcomes incomplete resection of the urachal remnant, especially in the bladder dome. Three trocars are inserted into the extraperitoneal space through a suprapubic port in spLESS, and complete resection of the urachal remnant from the umbilicus to the bladder is performed with an appropriate incision line. Patient characteristics and perioperative results were retrospectively collected. Cosmetic outcomes were prospectively evaluated using self-administered questionnaires (body image and photo-series questionnaire). RESULTS: spLESS and uLESS were performed in 43 and 12 patients, respectively. No differences were observed between the perioperative results. The cosmetic outcomes were compared between the groups using body image and photo-series questionnaires. No patient developed major complications; there was no recurrence in either group. CONCLUSIONS: spLESS is a novel procedure which can completely resect the urachal remnant and reduce the risk of intestinal damage. spLESS is a safe, effective, and feasible procedure with high postoperative cosmesis.