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BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
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Anticorpos Monoclonais Humanizados , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Adjuvantes Imunológicos , Platina , Estudos RetrospectivosRESUMO
AIMS: We aimed to assess the oncological impact of micrometric extent of invasion in patients with pT1 bladder cancer (BCa) who underwent en-bloc resection for bladder tumour (ERBT). METHODS AND RESULTS: We retrospectively analysed the records and specimens of 106 pT1 high-grade BCa patients who underwent ERBT. The extent of invasion, such as depth from basal membrane, number of invasive foci, maximum width of invasive focus, muscularis mucosae invasion and infiltration pattern (pattern A: solid sheet-like, nodular or nested growth, pattern B: trabecular, small cluster or single-cell pattern) were evaluated by a single genitourinary pathologist. The end-points were recurrence-free (RFS) and progression-free survival (PFS). Within a median follow-up of 23 months, overall, 36 patients experienced recurrence and 13 patients experienced disease progression. The 2-year PFS differed significantly depending on depth from basal membrane (< 1.3 mm: 94.8% versus ⧠1.3 mm: 65.2%, P = 0.005), maximum width of invasive focus (< 4 mm: 91.7% versus ⧠4 mm: 62.3%, P < 0.001), muscularis mucosae (MM) invasion (above MM = 96.1% versus into or beyond MM = 64.8%, P = 0.002) and infiltration pattern (pattern A: 100% versus pattern B: 83.3%, P = 0.037). In a multivariable analysis, MM invasion [hazard ratio (HR) = 4.54, 95% confidence interval (CI) = 1.25-16.5] and maximum width of invasive focus ⧠4 mm (HR = 4.79, 95% CI = 1.25-16.5) were independent prognostic factors of progression. CONCLUSIONS: En-bloc resection facilitates the evaluation of pathologic variables that might be useful in predicting disease recurrence and progression. In particular, not only the MM invasion but also the maximum width of invasion focus, reflecting the invasive volume, appear to be reliable prognosticators for disease progression.
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Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia/patologia , Cistectomia/métodos , Adulto , Estadiamento de Neoplasias , Invasividade Neoplásica , Progressão da Doença , Intervalo Livre de DoençaRESUMO
While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron-rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations.
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Since inorganic nanoparticles have unique properties that differ from those of bulk materials, their material applications have attracted attention in various fields. In order to utilize inorganic nanoparticles for functional materials, they must be dispersed without agglomeration. Therefore, the surfaces of inorganic nanoparticles are typically modified with organic ligands to improve their dispersibility. Nevertheless, the relationship between the tail group structure in organic ligands and the dispersibility of inorganic nanoparticles in organic solvents remains poorly understood. We previously developed amphiphilic ligands that consist of ethylene glycol chains and alkyl chains to disperse inorganic nanoparticles in a variety of organic solvents. However, the structural requirements for amphiphilic ligands to "flexibly" disperse nanoparticles in less polar to polar solvents are still unclear. Here, we designed and synthesized several phosphonic acid ligands for structure-function relationship studies of flexdispersion. Dynamic light scattering analysis and visible light transmittance measurements revealed that the ratio of alkyl/ethylene glycol chains in organic ligands alone does not determine the dispersibility of the nanoparticles in organic solvents, but the arrangement of the individual chains also has an effect. From a practical application standpoint, it is preferable to design ligands with ethylene glycol chains on the outside relative to the particle surface.
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Damage to the cerebellum results in dysfunctional standing postural control. Patients with cerebellar ataxia have a larger sway in the center of gravity (COG) while standing. Transcranial direct current stimulation (tDCS) has been applied in the rehabilitation of patients with central nervous system disorders; however, its effect on COG sway in patients with cerebellar ataxia remains unknown. We aimed to confirm the effects of anodal cerebellar tDCS (ctDCS) combined with physical therapy on COG sway in a patient with cerebellar ataxia using a retrospective ABA single-case study design. This study involved a patient with left cerebellar hemorrhage. Walking and postural balance rehabilitation were conducted in phase A. Anodal ctDCS was combined with the walking and postural balance rehabilitation in phase B. We measured COG sway in the open- and closed-eyes standing conditions daily throughout all the phases. In the open-eyes standing condition, there was no significant change in COG sway in phase B. Conversely, in the closed-eyes standing condition, the circumferential area, total sway path length, and anteroposterior sway path length decreased in phase B. No change was observed in the mediolateral sway path length. The combination of anodal ctDCS and physical therapy may decrease COG sway in patients with cerebellar ataxia in the closed-eyes standing condition, and its effect may be greater in the anteroposterior direction.
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Cerebellar transcranial direct current stimulation (ctDCS) modulates cerebellar cortical excitability in a polarity-dependent manner and affects inhibitory pathways from the cerebellum. The cerebellum modulates spinal reflex excitability via the vestibulospinal tract and other pathways projecting to the spinal motor neurons; however, the effects of ctDCS on the excitability of spinal motor neurons and vestibulospinal tract remain unclear. The experiment involved 13 healthy individuals. ctDCS (sham-ctDCS, anodal-ctDCS, and cathodal-ctDCS) was applied to the cerebellar vermis at 2 mA with an interval of at least 3 days between each condition. We measured the maximal M-wave (Mmax) and maximal H-reflex (Hmax) in the right soleus muscle to assess the excitability of spinal motor neurons. We applied galvanic vestibular stimulation (GVS) for 200 ms at 100 ms before tibial nerve stimulation to measure Hmax conditioned by GVS (GVS-Hmax) and calculated the change rate of Hmax by GVS as the excitability of vestibulospinal tract. We measured the Mmax, Hmax, and GVS-Hmax before, during, and after ctDCS in the sitting posture. No main effects of tDCS condition, main effects of time, or interaction effects were observed in Hmax/Mmax or the change rate of Hmax by GVS. It has been suggested that ctDCS does not affect the excitability of spinal motor neurons and vestibulospinal tract, as measured by neurophysiological methods, such as the H-reflex, in healthy individuals in a sitting posture. Effect of ctDCS on other descending pathways to spinal motor neurons, the neurological mechanism of tDCS and the cerebellar activity during the experiment may have contributed to these results. Therefore, we need to investigate the involvement of the cerebellum in Hmax/Mmax and the change rate of Hmax by GVS under different neuromodulation techniques and postural conditions.
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BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) may reduce mortality and improve neurological outcomes in patients with cardiac arrest. We updated our existing meta-analysis and trial sequential analysis to further evaluate ECPR compared to conventional CPR (CCPR). METHODS: We searched three international databases from 1 January 2000 through 1 November 2023, for randomised controlled trials or propensity score matched studies (PSMs) comparing ECPR to CCPR in both out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). We conducted an updated random-effects meta-analysis, with the primary outcome being in-hospital mortality. Secondary outcomes included short- and long-term favourable neurological outcome and survival (30 days-1 year). We also conducted a trial sequential analysis to evaluate the required information size in the meta-analysis to detect a clinically relevant reduction in mortality. RESULTS: We included 13 studies with 14 pairwise comparisons (6336 ECPR and 7712 CCPR) in our updated meta-analysis. ECPR was associated with greater precision in reducing overall in-hospital mortality (OR 0.63, 95% CI 0.50-0.79, high certainty), to which the trial sequential analysis was concordant. The addition of recent studies revealed a newly significant decrease in mortality in OHCA (OR 0.62, 95% CI 0.45-0.84). Re-analysis of relevant secondary outcomes reaffirmed our initial findings of favourable short-term neurological outcomes and survival up to 30 days. Estimates for long-term neurological outcome and 90-day-1-year survival remained unchanged. CONCLUSIONS: We found that ECPR reduces in-hospital mortality, improves neurological outcome, and 30-day survival. We additionally found a newly significant benefit in OHCA, suggesting that ECPR may be considered in both IHCA and OHCA.
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Reanimação Cardiopulmonar , Humanos , Reanimação Cardiopulmonar/métodos , Oxigenação por Membrana Extracorpórea/métodos , Parada Cardíaca/terapia , Parada Cardíaca/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Parada Cardíaca Extra-Hospitalar/mortalidadeRESUMO
BACKGROUND: We evaluated the applicability of automated citation screening in developing clinical practice guidelines. METHODS: We prospectively compared the efficiency of citation screening between the conventional (Rayyan) and semi-automated (ASReview software) methods. We searched the literature for five clinical questions (CQs) in the development of the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock. Objective measurements of the time required to complete citation screening were recorded. Following the first screening round, in the primary analysis, the sensitivity, specificity, positive predictive value, and overall screening time were calculated for both procedures using the semi-automated tool as index and the results of the conventional method as standard reference. In the secondary analysis, the same parameters were compared between the two procedures using the final list of included studies after the second screening session as standard reference. RESULTS: Among the five CQs after the first screening session, the highest and lowest sensitivity, specificity, and positive predictive values were 0.241 and 0.795; 0.991 and 1.000; and 0.482 and 0.929, respectively. In the secondary analysis, the highest sensitivity and specificity in the semi-automated citation screening were 1.000 and 0.997, respectively. The overall screening time per 100 studies was significantly shorter with semi-automated than with conventional citation screening. CONCLUSION: The potential advantages of the semi-automated method (shorter screening time and higher discriminatory rate for the final list of studies) warrant further validation.
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Guias de Prática Clínica como Assunto , Software , Carga de Trabalho , Humanos , Estudos Prospectivos , Carga de Trabalho/estatística & dados numéricos , Sensibilidade e Especificidade , JapãoRESUMO
BACKGROUND: International guidelines recommend emergency coronary angiography in patients after out-of-hospital cardiac arrest (OHCA) with ST-segment elevation on 12lead electrocardiography. However, the association between time to revascularization and outcomes remains unknown. This study aimed to evaluate the association between time to revascularization and outcomes in patients with OHCA due to ST-segment-elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI). METHODS: This multicenter, retrospective, nationwide observational study included patients aged ≥18 years with OHCA due to STEMI who underwent PCI between 2014 and 2020. The time of the first return of spontaneous circulation (ROSC) was defined as the time of first ROSC during resuscitation, regardless of the pre-hospital or in-hospital setting. The primary outcome was a 1-month favorable neurological outcome, defined as cerebral performance category 1 or 2. Multivariable logistic regression analysis was used to assess the association between the time to revascularization and favorable neurological outcomes. RESULTS: A total of 547 patients were included in this analysis. The multivariable logistic regression analysis showed that a shorter time from the first ROSC to revascularization was associated with 1-month favorable neurological outcomes (63/86 [73.3%] in the time from the first ROSC to revascularization ≤60 min group versus 98/193 [50.8%] in the >120 min group; adjusted OR, 0.26; 95% CI, 0.11-0.56; P for trend, 0.015). CONCLUSIONS: Shorter time to revascularization was significantly associated with 1-month favorable neurological outcomes in patients with OHCA due to STEMI who underwent PCI.
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Reanimação Cardiopulmonar , Parada Cardíaca Extra-Hospitalar , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Adolescente , Adulto , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Parada Cardíaca Extra-Hospitalar/terapia , Estudos Retrospectivos , Ressuscitação , Angiografia Coronária , Resultado do TratamentoRESUMO
BACKGROUND: The pathogenesis and pathophysiology of traumatic coagulopathy during traumatic brain injury is not well understood, and the appropriate treatment strategy for this condition has not been established. This study aimed to evaluate the coagulation phenotypes and their effect on prognosis in patients with isolated traumatic brain injury. METHODS: In this multicenter cohort study, we retrospectively analyzed data from the Japan Neurotrauma Data Bank. Adults with isolated traumatic brain injury (head abbreviated injury scale > 2; abbreviated injury scale of any other trauma < 3) who were registered in the Japan Neurotrauma Data Bank were included in this study. The primary outcome was the association of coagulation phenotypes with in-hospital mortality. Coagulation phenotypes were derived using k-means clustering with coagulation markers, including prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen (FBG), and D-dimer (DD) on arrival at the hospital. Multivariable logistic regression analyses were conducted to calculate the adjusted odds ratios of coagulation phenotypes with their 95% confidence intervals (CIs) for in-hospital mortality. RESULTS: In total, 556 patients were enrolled and five coagulation phenotypes were identified. The median (interquartile range) score for the Glasgow Coma Scale was 6 (4-9). Cluster A (n = 129) had the closest to normal coagulation values; cluster B (n = 323) had a mild high DD phenotype; cluster C (n = 30) had a prolonged PT-INR phenotype with a higher frequency of antithrombotic medication in elderly patients than in younger patients; cluster D (n = 45) had a low amount of FBG, high DD, and prolonged APTT phenotype with a high incidence of skull fracture; and cluster E (n = 29) had a low amount of FBG and extremely high DD phenotype with high energy trauma and a high incidence of skull fracture. In the multivariable logistic regression analysis, the association of clusters B, C, D, and E with in-hospital mortality yielded the corresponding adjusted odds ratios of 2.17 (95% CI 1.22-3.86), 2.61 (95% CI 1.01-6.72), 10.0 (95% CI 4.00-25.2), and 24.1 (95% CI 7.12-81.3), respectively, relative to cluster A. CONCLUSIONS: This multicenter, observational study identified five different coagulation phenotypes of traumatic brain injury and showed associations of these phenotypes with in-hospital mortality.
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Transtornos da Coagulação Sanguínea , Lesões Encefálicas Traumáticas , Fraturas Cranianas , Adulto , Humanos , Idoso , Estudos Retrospectivos , Estudos de Coortes , Lesões Encefálicas Traumáticas/complicações , Transtornos da Coagulação Sanguínea/epidemiologia , Transtornos da Coagulação Sanguínea/etiologia , Prognóstico , Fibrinogênio , Fenótipo , Análise por Conglomerados , Fraturas Cranianas/complicaçõesRESUMO
PURPOSE: This study investigated whether inducing valgus alignment and shifting the load laterally through high tibial osteotomy (HTO) alone decreases the extent of medial meniscus extrusion (MME) in the setting of medial meniscus posterior root tear(MMPRT) using ultrasound evaluation. METHODS: Eight fresh-frozen human cadaveric knee specimens were tested using a six-degree-of-freedom robotic testing system and ultrasound. Each specimen was tested in five conditions: (1) intact, (2) MMPRT, (3) medial meniscus repair (MMR), (4) combined medial open-wedge HTO + MMR, and (5) HTO + MMPRT. Measurements were obtained over the medial collateral ligament (MCL, central image) and posterior to the MCL (posterior image) with a 250 N axial load at 0°, 30°, and 90° of knee flexion. Statistical analysis was performed using a two-factor repeated-measures ANOVA. RESULTS: MME was significantly greater in HTO + MMPRT(0°: 2.44 ± 0.41mm, 30°: 2.47 ± 0.37mm, 90°: 2.41 ± 0.28mm) than HTO + MMR in central images (mean difference +0.83 mm, p < .001). No significant difference was found between HTO + MMPRT and MMPRT in MME . MMR had significantly less MME than MMPRT (mean difference -0.58mm, p < .001, posterior image at 0°and central image at 90°, p=.002). HTO + MMR showed significantly less MME than MMR alone at 30° and 90° knee flexion in central image (30°: -0.38 ± 0.05mm, 90°: -0.45 ± 0.06mm, p < .001) and 90° knee flexion in posterior image (-0.38 ± 0.08mm, p = .004). CONCLUSION: HTO alone did not decrease MME in the setting of MMPRT, while MMR alone decrease MME after MMPRT. Additionally, HTO + MMR decreases MME aftrer MMPRT compared to MMR alone, although the clinical significance was uncertain. CLINICAL RELEVANCE: The findings of this study provide clinicians with valuable insights for improving MME. HTO alone does not decrease MME in cases of MMPRT.
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OBJECTIVES: We aimed to develop and validate a simple scoring system to predict in-hospital mortality after endoscopic variceal ligation (EVL) for esophageal variceal bleeding. METHODS: Data from a 13-year study involving 46 Japanese institutions were split into development (initial 7 years) and validation (last 6 years) cohorts. The study subjects were patients hospitalized for esophageal variceal bleeding and treated with EVL. Variable selection was performed using least absolute shrinkage and selection operator regression, targeting in-hospital all-cause mortality as the outcome. We developed the Hospital Outcome Prediction following Endoscopic Variceal Ligation (HOPE-EVL) score from ß coefficients of multivariate logistic regression and assessed its discrimination and calibration. RESULTS: The study included 980 patients: 536 in the development cohort and 444 in the validation cohort. In-hospital mortality was 13.6% and 10.1% for the respective cohorts. The scoring system used five variables: systolic blood pressure (<80 mmHg: 2 points), Glasgow Coma Scale (≤12: 1 point), total bilirubin (≥5 mg/dL: 1 point), creatinine (≥1.5 mg/dL: 1 point), and albumin (<2.8 g/dL: 1 point). The risk groups (low: 0-1, middle: 2-3, high: ≥4) in the validation cohort corresponded to observed and predicted mortality probabilities of 2.0% and 2.5%, 19.0% and 22.9%, and 57.6% and 71.9%, respectively. In this cohort, the HOPE-EVL score demonstrated excellent discrimination ability (area under the curve [AUC] 0.890; 95% confidence interval [CI] 0.850-0.930) compared with the Model for End-stage Liver Disease score (AUC 0.853; 95% CI 0.794-0.912) and the Child-Pugh score (AUC 0.798; 95% CI 0.727-0.869). CONCLUSIONS: The HOPE-EVL score practically and effectively predicts in-hospital mortality. This score could facilitate the appropriate allocation of resources and effective communication with patients and their families.
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INTRODUCTION: This study evaluated the correlation between postoperative knee joint line obliquity after medial open-wedge high tibial osteotomy and patient-reported outcome measures excluding excessively overcorrected knees. This study further identified preoperative radiological factors related to the increased postoperative knee joint line obliquity. MATERIALS AND METHODS: We retrospectively evaluated patients who underwent medial open-wedge high tibial osteotomy between March 2013 and March 2021. Postoperative excessively overcorrected knees with hip-knee-ankle angle > 7° were excluded. We investigated radiological parameters and patient-reported outcome measures preoperatively and at the last follow-up. The following radiologic parameters were measured: hip-knee-ankle angle, weight-bearing line ratio, mechanical medial proximal tibial angle, mechanical lateral distal femoral angle, lateral distal tibial angle, joint line convergent angle, knee joint line obliquity, ankle joint line obliquity, hip abduction angle, tibial posterior slope, Carton-Deschamps index, and patella tilting angle. Clinical outcomes were evaluated using Japanese knee outcome measures. This assessment criterion is based on the Western Ontario McMaster Universities Arthritis Index and MOS Short Form 36. Multiple regression analysis was performed to evaluate the association between postoperative knee joint line obliquity and patient-reported outcome measures or preoperative radiological factors (P < .05). RESULTS: A total of 52 knees were included. The mean age at the time of the surgery was 61.6 ± 9.0 years and the mean follow-up period was 30.6 ± 10.1 months. Increased postoperative knee joint line obliquity was associated with lower Japanese knee outcome measures. The preoperative hip-knee-ankle angle was significantly associated with postoperative knee joint line obliquity. CONCLUSIONS: Increased knee joint line obliquity after medial open-wedge high tibial osteotomy is associated with inferior clinical outcomes. Care should be given to the center of the rotational angulation in around-knee osteotomy to avoid postoperative increased knee joint line obliquity. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.
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Osteoartrite do Joelho , Humanos , Estudos Retrospectivos , Osteoartrite do Joelho/cirurgia , Extremidade Inferior , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Tíbia/cirurgia , OsteotomiaRESUMO
Electrochemical or photochemical single-electron oxidation of bench-stable substrates can generate radical cations that offer unique reactivities as intermediates in various bond-formation processes. Such intermediates can potentially take part in both radical and ionic bond formation; however, the mechanisms involved are complicated and not fully understood. Herein, we report electrochemical radical cation aza-Wacker cyclizations under acidic conditions, which are expected to proceed via radical cations generated by single-electron oxidation of alkenes.
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Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.
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Esclerose Lateral Amiotrófica , Sarcoma , Masculino , Feminino , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Regiões 3' não Traduzidas/genética , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Espinhas Dendríticas/metabolismo , Mutação , Proteínas de Ligação a RNA/genética , RNA Mensageiro/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Sarcoma/genética , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Masculino , Feminino , Humanos , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
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Carcinoma de Células de Transição , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Neoplasias da Bexiga Urinária , Humanos , Inibidores da Bomba de Prótons , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metformina/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: We aimed to assess the clinical, oncological, and pathological impact of en bloc resection of bladder tumors (ERBT) compared with conventional transurethral resection of bladder tumors (cTURBT) for pT1 high-grade (HG) bladder cancer. PATIENTS AND METHODS: We retrospectively analyzed the record of 326 patients (cTURBT: n = 216, ERBT: n = 110) diagnosed with pT1 HG bladder cancer at multiple institutions. The cohorts were matched by one-to-one propensity scores based on patient and tumor demographics. Recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and perioperative and pathologic outcomes were compared. The prognosticators of RFS and PFS were analyzed using the Cox proportional hazard model. RESULTS: After matching, 202 patients (cTURBT: n = 101, ERBT: n = 101) were retained. There were no differences in perioperative outcomes between the two procedures. The 3-year RFS, PFS, and CSS were not different between the two procedures (p = 0.7, 1, and 0.7, respectively). Among patients who underwent repeat transurethral resection (reTUR), the rate of any residue on reTUR was significantly lower in the ERBT group (cTURBT: 36% versus ERBT: 15%, p = 0.029). Adequate sampling of muscularis propria (83% versus 93%, p = 0.029) and diagnostic rates of pT1a/b substaging (90% versus 100%, p < 0.001) were significantly better in ERBT specimen compared with cTURBT specimen. On multivariable analyses, pT1a/b substaging was a prognosticator of disease progression. CONCLUSIONS: In patients with pT1HG bladder cancer, ERBT had similar perioperative and mid-term oncologic outcomes compared with cTURBT. However, ERBT improves the quality of resection and specimen, yielding less residue on reTUR and yielding superior histopathologic information such as substaging.
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Neoplasias da Bexiga Urinária , Humanos , Estudos Retrospectivos , Pontuação de Propensão , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Cistectomia , Procedimentos Cirúrgicos Urológicos/métodosRESUMO
BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.
Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , População do Leste Asiático , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Neurônios Motores/patologiaRESUMO
Small yet brightly emitting fluorophores should find fundamental and practical applications in both academic and industrial settings. In this report, tetrahydrobenzodifuran is used as the core architecture to create novel single-benzene fluorophores. The key for realizing unique and powerful photophysical properties is the combination of the construction of symmetrical push-pull motifs and the restriction of bond rotations to suppress molecular motions that cause non-radiative transitions.