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A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs. Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.

Agents that target PD‐1 and PD‐L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non‐muscle‐invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle‐invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD‐1/PD‐L1/LAG3/TIGIT), divided into two clusters. There was a “hot cluster” (25%) consisting of patients with a high expression of these markers and a “cold cluster” (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high‐grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high‐grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy. We identified the dynamics of the tumor microenvironment in bladder cancer as a whole and identified candidate molecules as therapeutic targets for recurrent non‐muscle‐invasive bladder cancer, e.g., after BCG therapy. We further indicated the potential of FGFR inhibitors as a useful modality to improve the immunologically cold environment and prevent stage progression in patients with non‐muscle‐invasive bladder cancer.

CXCR5 is a chemokine receptor that promotes B cell follicular formation and antibody production. Indeed, CXCR5 has been found to be expressed in a variety of cancers; however, the role of CXCR5 expression in clear-cell renal cell carcinoma (ccRCC) remains unclear. We aimed to determine the impact of cellular CXCR5 expression on cancer outcomes, the PD-1/PD-L1 axis, and genetic states in patients with ccRCC. First, multiplex immunofluorescence staining for CXCR5, CD4, CD8, and AE1/AE3, along with automated single-cell counting, was performed to assess cellular CXCR5 expression in ccRCC and its association with prognosis. Second, the tumour microenvironment (TME) was analysed, with a focus on the relationship between the PD-1/PD-L1 axis and CXCR5 expression. Finally, an integrated analysis of CXCR5 expression and genomic mutation information was conducted to reveal the genetic background underlying CXCR5 expression. A total of 105 ccRCC patients were included. Among the 696,964 cells analysed, the distribution of CXCR5-expressing cells was as follows: 30% CXCR5 + CD4 + cells, 9% CXCR5 + CD8 + cells, and 26% CXCR5 + AE1/AE3 + cells. Survival analysis revealed that tumours with low-CXCR5 + CD8 + cells had a poor prognosis; TME analysis revealed a relationship between low-CXCR5 + CD8 + status and a highly suppressive PD-L1-positive immune environment. Genomic analysis revealed a correlation between low-CXCR5 + CD8 + status and high rates of alterations in chromatin remodelling genes, including PBRM1 . This study highlights the significance of CXCR5 + CD8 + cells in ccRCC, demonstrating their clinical implications and revealing the immunogenomic landscape underlying CXCR5 expression.

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle‐invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa‐4N0‐2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2‐4N0‐2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer‐specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non‐MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC. We conducted a multicenter cohort study describing the clinicopathological characteristics of muscle‐invasive bladder recurrence developed after surgical management of upper tract urothelial carcinoma.

Organic Light‐Emitting Diodes To prevent short‐circuit defects of OLEDs caused by dust particles on substrates, Yoshiyuki Suzuri and colleagues report on the particle coverage properties of the spin‐coated hole injection layer in article number 2201695. Quantitatively contaminating the substrate surface with size‐controlled SiO2 particles, PEDOT:PSS was spin‐coated, resulting in coverage up to SiO2 particles 10 to 20 times larger than the film thickness.

Objective To investigate whether dose reductions in cisplatin due to renal dysfunction were associated with worse clinical outcomes in metastatic urothelial carcinoma (UC) patients. Patients and methods One hundred and fifty one metastatic UC patients who received first‐line gemcitabine plus cisplatin (GC) salvage chemotherapy without a previous history of peri‐surgical chemotherapy were included in this retrospective study. Patients with endogenous creatinine clearance of 60 mL/min or more were treated with a full dose of cisplatin, while those with 45‐59 and 30‐44 mL/min were treated with 75% and 50% doses, respectively. Patients were divided into three groups based on the average administered dose of cisplatin of 100% (Group A, N = 43), 99%‐75% (Group B, N = 59), and less than 75% (Group C, N = 49), and therapeutic responses and the toxicity of GC were compared. Results Complete response rates were 9.3%, 13.6%, and 14.3% in groups A, B, and C, respectively. One‐year progression‐free survival rates were 22.9%, 31.1%, and 36.7% in groups A, B, and C with no significant differences. One‐year cancer‐specific survival rates were 56.1%, 71.1%, and 68.3% in groups A, B, and C with no significant differences. A multivariate Cox's regression analysis showed that the dose of cisplatin was not an independent prognostic factor for disease progression and cancer death. Furthermore, there were no significant differences in the incidence of severe adverse events. Conclusions Dose reductions in cisplatin due to renal dysfunction did not worsen clinical outcomes for metastatic UC.

Short‐circuit defects caused by microscale dust particles in organic light‐emitting diodes (OLEDs) cause a decrease in production yield and hinder cost reduction. An organic layer coating by solution process is used to prevent short‐circuit defects of particles on a substrate. In this study, the coverage properties of a coated organic layer on size‐controlled particles are revealed. The surface of the substrate with size‐controlled SiO2 particles with a diameter of 0.2–5 µm is quantitatively contaminated, and the particle coverage properties of the solution‐processed hole injection layer are investigated. From the results of the leakage current measurement and cross‐sectional observation by a transmission electron microscope, it is observed that devices with 50 nm‐spin‐coated poly (3,4‐ethylenedioxythiophene): poly(styrene sulfonate) can cover SiO2 particles up to 1 µm in diameter without any increase in leakage current. It is revealed that larger‐sized particles cause electric defects, albeit with a low probability, owing to the larger space under the particles. To fabricate OLEDs with a high yield, the shape of the coverage at the bottom of the particle is important in preventing electric defects. The results of this study are useful not only for OLEDs but also for printed and coated devices. To prevent short‐circuit defects caused by dust particles on substrates, the particle coverage properties of the spin‐coated hole injection layer are reported. Quantitatively contaminating the substrate surface with size‐controlled SiO2 particles, poly(3,4‐ethylenedioxy‐thiophene):poly(styrene sulfonate) is spin‐coated, resulting in coverage up to SiO2 particles 10–20 times larger than the film thickness.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39−) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39− T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

In this paper, we propose a method for generating reaching motions for the insertion of flat cables. Despite the need to insert flat cables into sockets in the circuit assembly of various electronic devices, there has been little research on automating the insertion flat cables that are already fixed on one side to the circuit board. In this regard, we focus on the generation of reaching motions in the posture for grasping such flat cables. Our method uses deep reinforcement learning in a simulation environment, and the features extracted from the image and the pose of the manipulator are used as states. For the transfer from the simulation environment to the real-world environment, we use a CycleGAN-based domain adaptation method. We conducted experiments under several different conditions in a real-world environment to verify operation of the trained agent. The results demonstrated that the success rate of the generated reaching motions exceeded 70% under all conditions.