Quantum error correction with silicon spin qubits.

Future large-scale quantum computers will rely on quantum error correction (QEC) to protect the fragile quantum information during computation1,2. Among the possible candidate platforms for realizing quantum computing devices, the compatibility with mature nanofabrication technologies of silicon-based spin qubits offers promise to overcome the challenges in scaling up device sizes from the prototypes of today to large-scale computers3-5. Recent advances in silicon-based qubits have enabled the implementations of high-quality one-qubit and two-qubit systems6-8. However, the demonstration of QEC, which requires three or more coupled qubits1, and involves a three-qubit gate9-11 or measurement-based feedback, remains an open challenge. Here we demonstrate a three-qubit phase-correcting code in silicon, in which an encoded three-qubit state is protected against any phase-flip error on one of the three qubits. The correction to this encoded state is performed by a three-qubit conditional rotation, which we implement by an efficient single-step resonantly driven iToffoli gate. As expected, the error correction mitigates the errors owing to one-qubit phase-flip, as well as the intrinsic dephasing mainly owing to quasi-static phase noise. These results show successful implementation of QEC and the potential of a silicon-based platform for large-scale quantum computing.

Fast universal quantum gate above the fault-tolerance threshold in silicon.

Fault-tolerant quantum computers that can solve hard problems rely on quantum error correction1. One of the most promising error correction codes is the surface code2, which requires universal gate fidelities exceeding an error correction threshold of 99 per cent3. Among the many qubit platforms, only superconducting circuits4, trapped ions5 and nitrogen-vacancy centres in diamond6 have delivered this requirement. Electron spin qubits in silicon7-15 are particularly promising for a large-scale quantum computer owing to their nanofabrication capability, but the two-qubit gate fidelity has been limited to 98 per cent owing to the slow operation16. Here we demonstrate a two-qubit gate fidelity of 99.5 per cent, along with single-qubit gate fidelities of 99.8 per cent, in silicon spin qubits by fast electrical control using a micromagnet-induced gradient field and a tunable two-qubit coupling. We identify the qubit rotation speed and coupling strength where we robustly achieve high-fidelity gates. We realize Deutsch-Jozsa and Grover search algorithms with high success rates using our universal gate set. Our results demonstrate universal gate fidelity beyond the fault-tolerance threshold and may enable scalable silicon quantum computers.

B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity.

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.

TRAF6 signaling in T cells is crucial for the pathogenicity of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an incurable chronic autoimmune disease affecting the central nervous system (CNS). Although IL-17-producing helper T (Th17) cells are thought to be one of the exacerbating factors in MS, the underlying pathogenic mechanism is incompletely understood. TNF receptor-associated factor 6 (TRAF6) deficient T cells exhibited enhanced Th17 cell differentiation, however, the physiological relevance of TRAF6 in T cells remains unknown. Here, we induced experimental autoimmune encephalomyelitis (EAE) in T cell-specific TRAF6 deficient (TRAF6ΔT) mice to investigate the role of TRAF6 in T cells during the course of MS using an EAE model. Although Th17 cell differentiation was enhanced in TRAF6ΔT mice, mutant mice were resistant to EAE. In contrast, TRAF6 loss did not affect regulatory T-cell differentiation. Consistent with the severity of EAE, a small number of infiltrating T cells and a small area of demyelination were observed in the CNS of TRAF6ΔT mice. Moreover, myelin oligodendrocyte glycoprotein-induced IL-17 production in TRAF6-deficient T cells was significantly suppressed. We further confirmed lower levels of CD69 and granulocyte-macrophage colony-stimulating factor in Th17 cells of TRAF6ΔT mice than in wild-type mice. In contrast, the expression of IL-10 and cytotoxic T-lymphocyte-associated protein 4 in T cells was significantly elevated in the absence of TRAF6 because of enhanced T-cell receptor signaling. Collectively, TRAF6 signaling in T cells contributes to the pathogenesis of EAE by regulating the pathogenicity and autoantigen reactivity of Th17 cells.

Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

GM-CSF-producing CCR2+ CCR6+ Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice.

Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C-C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2+ CCR6+ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2+ CCR6+ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.

Relapse and side effects of steroid therapy beyond 3 years in autoimmune pancreatitis: A multicenter retrospective study.

BACKGROUND: The impact of extended steroid administration on patients with autoimmune pancreatitis after a 3-year maintenance period remains poorly understood. This study analyzed the advantage and disadvantage of continuing steroid therapy beyond 3 years. METHODS: In this retrospective multicenter study across 17 institutions, patients who successfully completed 3 years of maintenance therapy without experiencing relapse were categorized into two groups: the maintenance therapy discontinuation group, who discontinued steroid therapy after the initial 3-year period, and maintenance therapy continuation group, who continued steroid therapy beyond 3 years. The cumulative relapse rate after 3 years of maintenance therapy was the primary outcome. Relapse predictors were compared using the Gray test for cumulative relapse incidence by specific factor. RESULTS: Of 211 patients, 105 experienced no relapse during the 3-year maintenance therapy and were divided into two groups: 69 in the maintenance therapy discontinuation group and 36 in the maintenance therapy continuation group. The relapse rate was lower in the maintenance therapy continuation group than in the maintenance therapy discontinuation group (P = 0.035). Predictors of relapse after 3 years included cessation of maintenance therapy (hazard ratio [HR] = 3.76; 95 % confidence interval [CI] = 1.07-13.3, P = 0.040) and renal involvement (HR = 2.88; 95 % CI = 1.04-7.99, P = 0.042). The maintenance therapy continuation group showed a significantly higher prevalence of macrovascular complications, compared with the maintenance therapy discontinuation group (P = 0.005). CONCLUSIONS: Cessation of steroid maintenance therapy and renal involvement were predictors of relapse after 3 years of maintenance therapy. However, the long-term use of steroids may increase the risk of macrovascular complications.

Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis.

INTRODUCTION: Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED: This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION: Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.

Treatment patterns and prognosis in patients with Bacillus Calmette-Guérin-exposed high-risk non-muscle invasive bladder cancer: a real-world data analysis.

PURPOSE: The International Bladder Cancer Group designated the subgroup that is resistant to Bacillus Calmette-Guérin (BCG) but does not meet the criteria for BCG-unresponsive NMIBC as "BCG-exposed high-risk NMIBC" to guide optimal trial design. We aimed to investigate the treatment patterns and prognoses of patients with BCG-exposed NMIBC. METHODS: We conducted a retrospective chart review of 3283 patients who received intravesical BCG therapy for NMIBC at 14 participating institutions between January 2000 and December 2019. Patients meeting the criteria for BCG-exposed and BCG-unresponsive NMIBC, as defined by the Food and Drug Administration and International Bladder Cancer Group, were selected. To compare treatment patterns and outcomes, high-risk recurrence occurring more than 24 months after the last dose of BCG was defined as "BCG-treated NMIBC." In addition, we compared prognoses between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. RESULTS: Of 3283 patients, 108 (3.3%), 150 (4.6%), and 391 (11.9%) were classified as having BCG-exposed, unresponsive, and treated NMIBC, respectively. BCG-exposed NMIBC demonstrated intermediate survival curves for intravesical recurrence-free and progression-free survival, falling between those of BCG-unresponsive and treated NMIBC. Among patients with BCG-exposed NMIBC, 48 (44.4%) received BCG rechallenge, which was the most commonly performed treatment, and 19 (17.6%) underwent early cystectomy. No significant differences were observed between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. CONCLUSIONS: The newly proposed definition of BCG-exposed NMIBC may serve as a valuable disease subgroup for distinguishing significant gray areas, except in cases of BCG-unresponsive NMIBC.

Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.

AIM: This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients. METHODS: One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy. RESULTS: After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed. CONCLUSION: Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

The impact of second transurethral resection on survival outcomes in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin therapy.

OBJECTIVE: Several guidelines recommended that second transurethral resection should be performed in patients with diagnosis of high-risk non-muscle-invasive bladder cancer. However, therapeutic benefits of second transurethral resection before bacillus Calmette-Guérin intravesical instillation were conflicting amongst previous studies. We investigated the prognostic impact of second transurethral resection before bacillus Calmette-Guérin instillation in high-risk non-muscle-invasive bladder cancer patients. METHODS: This retrospective study included 3104 non-muscle-invasive bladder cancer patients who received bacillus Calmette-Guérin instillations between 2000 and 2019 at 31 collaborative institutions. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors of intravesical recurrence, disease progression, cancer-specific mortality and overall mortality. RESULTS: In the entire population, patients undergoing second transurethral resection (33%, 1026/3104) had a lower risk of intravesical recurrence on univariate analysis (hazard ratio 0.85, 95% confidence interval 0.73-0.98, P = 0.027), although it did not remain significant on multivariate analysis (hazard ratio 0.90, 95% confidence interval 0.76-1.07, P = 0.24). Subgroup analysis revealed that, in pT1 patients (n = 1487), second transurethral resection was significantly correlated with a lower risk of intravesical recurrence on multivariate analysis (hazard ratio 0.80, 95% confidence interval 0.64-1.00, P = 0.048), but lower risks of disease progression (hazard ratio 0.75, 95% confidence interval 0.56-1.00, P = 0.049), cancer-specific mortality (hazard ratio 0.54, 95% confidence interval 0.35-0.85, P = 0.007) and overall mortality (hazard ratio 0.73, 95% confidence interval 0.55-0.97, P = 0.027) on univariate analysis. CONCLUSIONS: Second transurethral resection confers accurate pathological staging and could be used to safely select good candidates for intravesical bacillus Calmette-Guérin instillation. We further confirm that second transurethral resection could confer an oncological benefit in pT1 bladder cancer patients treated by bacillus Calmette-Guérin instillation, and so strongly recommend second transurethral resection in this patient population.

Investigation of severe acute respiratory syndrome coronavirus 2 infection status in solid organ transplant recipients treated with tixagevimab/cilgavimab.

INTRODUCTION: Tixagevimab and cilgavimab (T/C) are neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be used to prevent SARS-CoV-2 infection in solid organ transplant (SOT) recipients. However, their neutralizing activity against recent variants was reduced, raising concerns regarding the emergence of breakthrough coronavirus diseases 2019 (COVID-19). This study aimed to investigate the status of the COVID-19 breakthrough after T/C administration. METHODS: We retrospectively investigated breakthrough COVID-19 in SOT recipients administered T/C at Kyoto University Hospital, Japan, from November 2022 to March 2023. Patients were monitored for 6 months after T/C administration. SARS-CoV-2 infection was diagnosed using polymerase chain reaction or antigen tests. The monthly incidence rates of SARS-CoV-2 infection were calculated using the person-time method. RESULTS: T/C were administered to 67 SOT recipients (liver, 16; lung, 36; and kidney, 15), of whom five were infected with SARS-CoV-2. All five cases were classified as mild, and none of these patients required admission to the intensive care unit (ICU) or died. All infected individuals tested positive for SARS-CoV-2 after March 2023, when T/C-resistant subvariant strains became predominant. The monthly incidence rate of SARS-CoV-2 infection, calculated using the person-time method, suggested an increasing trend. CONCLUSIONS: During the T/C-resistant variant epidemic, SARS-CoV-2 infections were identified even after T/C administration, suggesting that the prophylactic effects of T/C were invalid. Therefore, emerging variants must be carefully monitored and characterized to determine appropriate antiviral strategies, such as the use of suitable neutralizing antibodies.

Impact of prostate position-based image-guidance in intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.

Clinical factors predicting the outcome of salvage radiotherapy for patients with biochemical recurrence after radical prostatectomy.

BACKGROUND: It remains unclear which patients with biochemical recurrence after prostatectomy are most suitable for salvage radiotherapy. We evaluated the parameters related to outcomes. METHODS: We retrospectively evaluated patients who underwent salvage therapy for biochemical recurrence after prostatectomy between 2005 and 2019. This study aimed to evaluate biochemical recurrence-free survival (bRFS) after salvage radiotherapy and elucidate the parameters associated with bRFS. The bRFS rate was calculated using the Kaplan-Meier method, and the parameters associated with bRFS were evaluated using Cox regression analysis. RESULTS: This study included 67 patients treated with salvage radiotherapy with a median age of 67 years at salvage radiotherapy. The median follow-up period after salvage radiotherapy was 7.3 years. The 5-year bRFS rate following salvage radiotherapy was 47.1%. Univariate analysis showed that PSA doubling time < 6 months, positive surgical margin, and pathological Gleason score ≥ 8 were significantly associated with shorter bRFS (p < 0.001, p = 0.036, p = 0.047, respectively). Multivariable analysis showed that a PSA doubling time < 6 months and positive surgical margins were significantly associated with shorter bRFS (p = 0.001 and p = 0.018, respectively). No serious adverse events were observed. CONCLUSIONS: In our hospital, approximately half of the patients are under long-term control with salvage radiotherapy. A PSA doubling time of < 6 months and positive surgical margins were suggested to be associated with poor outcomes of salvage radiotherapy.

Rapidly progressive cognitive impairment resulting in heavy psychosocial burden in a patient with Fabry disease undergoing hemodialysis: a case report.

BACKGROUND: Long-term enzyme replacement therapy (ERT) may improve prognosis in the patients with Fabry disease (FD), however, detail psychosocial burden has not been focused on long life expectancy. We experienced a male case of FD under ERT, he was placed on hemodialysis and presented rapidly progressive cognitive function. CASE PRESENTATION: A 51-year-old male patient with FD has been receiving ERT from age of 38 years. Hemodialysis was initiated at the age of 47 years. The patient experienced several attacks of cerebral infarction, and brain images demonstrated wide-spread asymptomatic ischemic lesions. His behavior became problematic at the age of 51 years. He often exhibited restlessness during hemodialysis sessions and failure to communicate effectively. The patient experienced impairment of attention and executive function, topographical disorientation, and amnesia. Consequently, it was necessary for medical staff and family members to monitor his behavior for safe extracorporeal circulation and daily life activities. Annual standardized neuropsychiatric testing revealed worsening of cognitive performance. CONCLUSIONS: Despite treating with long-term ERT, it is necessary to determine the psychosocial burden derived from the progression of cognitive impairment in patients with FD undergoing hemodialysis.

Early and late outcomes of congenital biliary dilatation in pediatric patients.

BACKGROUND: This study aimed to reveal the early and late postoperative complications and outcomes after surgery for congenital biliary dilatation (CBD) by reviewing cases over the past 40 years. METHODS: We retrospectively evaluated 59 patients with CBD who underwent radical surgery for complications and outcomes, based on medical records. Early complications were defined as those requiring treatment within 5 years of the initial operation. Late complications were defined as those treated more than 5 years later. RESULTS: The median age at the first surgery was 37 months. Regarding biliary reconstruction, 54 of the 59 patients (91.5%) underwent hepaticojejunostomy. Although three patients underwent cholecystoduodenostomy and one patient underwent hepaticoduodenostomy, all were converted to hepaticojejunostomy after a median of 12.5 years. One patient developed synchronous biliary carcinoma and underwent pancreaticoduodenectomy. Early complications occurred in seven patients with 10 events (surgical site infection, n = 3 bile leakage, n = 3; ileus, n = 3; bile duct obstruction, n = 1 and intussusception, n = 1). Late complications occurred in nine patients with 12 events (ileus, n = 3; anastomotic stricture, n = 3; hepatolithiasis, n = 3; asynchronous biliary carcinoma, n = 2; pancreatolithiasis, n = 1). Two of the three patients with hepatolithiasis underwent hepatectomy refractory to the endoscopic approach. Two patients developed asynchronous biliary carcinoma at 34 and 13 years after last operation; both ultimately died of the carcinoma. Only 35 patients (61.4%) underwent a follow-up examination. A total of 11 female patients (45.8%) eventually married, and all successfully gave birth. CONCLUSION: Although the long-term prognosis is excellent with complete cyst excision and hepaticojejunostomy, we emphasize the importance of long-term follow-up.

Tertiary Lymphoid Tissues Are Microenvironments with Intensive Interactions between Immune Cells and Proinflammatory Parenchymal Cells in Aged Kidneys.

SIGNIFICANCE STATEMENT: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets. BACKGROUND: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear. METHODS: We performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments. RESULTS: Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF κ B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN γ upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN γ -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs. CONCLUSIONS: These findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation.

Prostate cancer and liquid biopsies: Clinical applications and challenges.

Liquid biopsy has emerged as a valuable and minimally invasive tool for real-time detection of clinically actionable abnormalities across various cancer types. Its applicability is particularly compelling in the realm of prostate cancer, where novel therapeutic agents, including those targeting DNA repair systems, are under development. Despite these advancements, challenges persist in effectively screening for prostate cancer, enhancing risk stratification, and determining optimal approaches for treating advanced disease. Consequently, there is a pressing need for improved biomarkers to aid clinicians in decision-making within these contexts. Cell-free DNA and extracellular vesicle analysis have demonstrated promise in diagnosis, prognostication, assessment of treatment responses, and identification of emerging mechanisms of resistance. Nevertheless, obstacles must be addressed before liquid biopsies can be integrated into routine clinical practice. These challenges encompass preanalytical considerations such as sample collection and storage, methods of extracellular vesicle isolation and enrichment, and the need for enhanced interpretation of generated sequencing data. This review provides a comprehensive overview of current clinical opportunities in managing prostate cancer through blood-based liquid biopsy, highlighting the progress made, and acknowledging the challenges that remain. Additionally, we discuss the next steps required for the effective implementation of liquid biopsies in guiding personalized treatment strategies for prostate cancer.

Real-world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan.

OBJECTIVES: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre-enfortumab vedotin era, many patients could not receive third-line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real-world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third-line treatment. METHODS: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. RESULTS: At the median follow-up of 28.5 months, the median overall survival from first-line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second- and third-line treatment. Notably, 52% had their treatment terminated before the opportunity for third-line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil-to-lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first-line treatment were independent risk factors for not proceeding to third-line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. CONCLUSIONS: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects.

J-AVENUE: A retrospective, real-world study evaluating patient characteristics and outcomes in patients with advanced urothelial carcinoma treated with avelumab first-line maintenance therapy in Japan.

OBJECTIVES: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first-line maintenance + best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression-free following first-line platinum-based chemotherapy. We report findings from J-AVENUE (NCT05431777), a real-world study of avelumab first-line maintenance therapy in Japan. METHODS: Medical charts of patients with advanced urothelial carcinoma without disease progression following first-line platinum-based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression-free survival. RESULTS: In 79 patients analyzed, median age was 72 years (range, 44-86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first-line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment-free interval before avelumab was 4.9 weeks. With avelumab first-line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3-6.4), and median progression-free survival was 6.1 months (95% CI, 3.6-9.7). CONCLUSIONS: Findings from J-AVENUE show the effectiveness of avelumab first-line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression-free survival to JAVELIN Bladder 100 and previous real-world studies, supporting its use as a standard of care.