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The diagnosis and awareness of transthyretin amyloidosis cardiomyopathy (ATTR-CM) in heart failure with left ventricular ejection fraction (LVEF) > 40% remains under-recognized. This study aimed to investigate the prevalence and characteristics of ATTR-CM in patients with heart failure with LVEF > 40%. Patients with LVEF > 40% and maximal left ventricular wall thickness (MWT) > 10 mm who underwent bone scintigraphy were retrospectively investigated. Patients with a definite cause of heart failure were excluded. ATTR-CM was diagnosed when grade 2 or 3 myocardial uptake was observed on scintigraphy. Among 97 patients (male, 62.5%; median age, 69 years), 13 (13.4%) were diagnosed with ATTR-CM (wild type, 69.2%; hereditary type, 30.8%). Age or biomarker levels did not differ significantly; however, all patients with ATTR-CM were male. The ATTR-CM group had a significantly higher prevalence of polyneuropathy or carpal tunnel syndrome than the non-ATTR-CM group, accompanied by a longer PR interval, thicker MWT, larger left atrial volume index, and higher E/e'. Accordingly, ATTR was present in a substantial number, particularly among men. Clinicians should suspect ATTR when a male patient exhibits neurologic symptoms, diastolic dysfunction, and a long PR interval.
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Neuropatias Amiloides Familiares , Insuficiência Cardíaca , Volume Sistólico , Humanos , Masculino , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/complicações , Feminino , Idoso , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Prevalência , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/diagnóstico por imagem , Idoso de 80 Anos ou mais , Função Ventricular EsquerdaRESUMO
BACKGROUND: Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs). METHODS: The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model. RESULTS: The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model. CONCLUSIONS: The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.
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INTRODUCTION: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown effectiveness against HER2-positive breast cancer. This makes neoadjuvant chemotherapy (NAC) a valuable option for treating both early and advanced stages of the disease. The tumor's response to HER2-targeted NAC provides crucial prognostic information. Additionally, it allows for tailoring adjuvant treatment strategies for HER2+ breast cancer based on pathological responses. This study aimed to investigate the clinicopathological factors that influence tumor response. METHODS: We retrospectively analyzed 122 patients diagnosed with HER2+ breast cancer. These patients received NAC and HER2-directed therapy between January 2018 and December 2022 at the Pusan National University Yangsan Hospital. Following surgery, tumor response was evaluated, categorizing patients into two groups: pathological complete response (pCR) and non-pCR groups. We analyzed data on various factors, including age, NAC regimen, type of breast and axillary surgery, clinical stage (cTNM), historical grade, and preoperative levels of carcinoembryonic antigen, cancer antigen 15-3 (CA 15-3), estrogen receptor (ER), progesterone receptor (PR), HER2, p53, and KI-67. RESULTS: Out of the 122 patients, 75 achieved pCR, while 47 did not. Most clinicopathological factors showed no significant difference between the pCR and non-pCR groups. However, several factors were associated with a higher pCR rate: normal preoperative CA 15-3 levels (odds ratio [OR]: 3.74, confidence interval [CI]: 1.19-11.72, p = 0.02), preoperative ER positivity (OR: 2.65, CI: 1.25-5.59, p = 0.01), PR negativity (OR: 3.92, CI: 1.82-8.45, p < 0.05), and strong preoperative HER2 immunohistochemistry (IHC) 3+ staining. Multivariate analysis confirmed that PR negativity (OR: 2.8, CI: 1.23-6.42, p = 0.01) and strong preoperative HER2 IHC 3+ staining (OR: 0.18, CI: 0.03-0.84, p = 0.04) were independent predictors of a higher pCR rate. CONCLUSIONS: A pCR after NAC impacts patient prognosis and influences the choice of adjuvant treatment for HER2+ breast cancer. Clinicopathological factors can help predict responses to HER2-targeted NAC. In our study, pre-ER/PR negativity, high pre-HER2 levels, and normal CA 15-3 levels were found to be potential predictors of pCR. These findings may contribute to developing more effective treatment strategies for HER2+ breast cancer.
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Prostate Imaging Reporting and Data System (PI-RADS) score, a reporting system of prostate MRI cases, has become a standard prostate cancer (PCa) screening method due to exceptional diagnosis performance. However, PI-RADS 3 lesions are an unmet medical need because PI-RADS provides diagnosis accuracy of only 30-40% at most, accompanied by a high false-positive rate. Here, we propose an explainable artificial intelligence (XAI) based PCa screening system integrating a highly sensitive dual-gate field-effect transistor (DGFET) based multi-marker biosensor for ambiguous lesions identification. This system produces interpretable results by analyzing sensing patterns of three urinary exosomal biomarkers, providing a possibility of an evidence-based prediction from clinicians. In our results, XAI-based PCa screening system showed a high accuracy with an AUC of 0.93 using 102 blinded samples with the non-invasive method. Remarkably, the PCa diagnosis accuracy of patients with PI-RADS 3 was more than twice that of conventional PI-RADS scoring. Our system also provided a reasonable explanation of its decision that TMEM256 biomarker is the leading factor for screening those with PI-RADS 3. Our study implies that XAI can facilitate informed decisions, guided by insights into the significance of visualized multi-biomarkers and clinical factors. The XAI-based sensor system can assist healthcare professionals in providing practical and evidence-based PCa diagnoses.
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INTRODUCTION: Robot-assisted radical cystectomy (RARC) has gained momentum in the management of muscle invasive bladder cancer (MIBC). Predictors of RARC outcomes are not thoroughly studied. We aim to investigate the implications of preoperative hydronephrosis on oncological outcomes. PATIENTS AND METHODS: This study analysed data from the Asian RARC consortium, a multicentre registry involving nine Asian centres. Cases were divided into two groups according to the presence or absence of pre-operative hydronephrosis. Background characteristics, operative details, perioperative outcomes, and oncological results were reviewed. Outcomes were (1) survival outcomes, including 10-year disease-free survival (DFS) and overall survival (OS), and (2) perioperative and pathological results. Multivariate regression analyses were performed on survival outcomes. RESULTS: From 2007 to 2020, 536 non-metastatic MIBC patients receiving RARC were analysed. 429 had no hydronephrosis (80.0%), and 107 (20.0%) had hydronephrosis. Hydronephrosis was found to be predictive of inferior DFS (HR = 1.701, p = 0.003, 95% CI = 1.196-2.418) and OS (HR = 1.834, p = 0.008, 95% CI = 1.173-2.866). Subgroup analysis demonstrated differences in the T2-or-above subgroup (HR = 1.65; p = 0.004 in DFS and HR = 1.888; p = 0.008 in OS) and the T3-or-above subgroup (HR = 1.757; p = 0.017 in DFS and HR = 1.807; p = 0.034 in OS). CONCLUSIONS: The presence of preoperative hydronephrosis among MIBC patients carries additional prognostic implications on top of tumour staging. Its importance in case selection needs to be highlighted.
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BACKGROUND: Cachexia and sarcopenia are common among heart failure (HF) patients and are linked to poor outcomes. As serum creatinine levels are influenced by both renal function and muscle mass, our study aimed to investigate the relationship between serum creatinine levels and mortality in acute HF patients. METHODS: We enrolled 5198 consecutive acute HF patients from the Korea Acute Heart Failure (KorAHF) registry, excluding those on renal replacement therapy. Patients were categorized into five groups based on their discharge serum creatinine levels: low (< 0.6 mg/dL), reference (0.6-0.89 mg/dL), upper normal (0.9-1.19 mg/dL), high (1.2-1.49 mg/dL), and very high (≥ 1.5 mg/dL). The primary endpoint was post-discharge all-cause mortality. RESULTS: The mean creatinine level was 1.20 ± 0.88 mg/dL. Notably, 335 (6.4%) patients had serum creatinine levels < 0.6 mg/dL. These patients were younger (mean age, 67 years) and more likely to have a low BMI (< 18.5 kg/m2) compared to the reference group (15.3% vs. 6.4%). Over a median follow-up of 975 days, 1743 (34.8%) patients died. We observed a J-shaped relationship between serum creatinine levels and mortality, with both low and high levels associated with increased mortality. After adjusting for covariates, including age, sex, body mass index, diabetes, hypertension, smoking, malignancy, atrial fibrillation on electrocardiography, levels of C-reactive protein, sodium, hemoglobin, albumin, brain natriuretic peptide, de novo heart failure, use of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists, patients with serum creatinine levels < 0.6 mg/dL had a 33% higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.06 to 1.66) compared to those with levels of 0.6-0.89 mg/dL. However, BUN, which is not affected by muscle metabolism, exhibited a linear relationship with mortality. CONCLUSIONS: Among acute HF patients, there exists a J-shaped relationship between discharge serum creatinine levels and mortality, highlighting the increased mortality risk in individuals with very low serum creatinine levels.
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Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib-tamoxifen in patients with HR+/HER2- advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1-32.4) with palbociclib-tamoxifen and 11.1 months (95% CI, 7.4-14.6) with placebo-tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43-0.85; P = 0.002). Palbociclib-tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44-1.21) with palbociclib-tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib-tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo-tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2- advanced breast cancer, palbociclib-tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib-tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.
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Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.
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Neoplasias , Medicina de Precisão , Sequenciamento Completo do Genoma , Humanos , Neoplasias/genética , Neoplasias/terapia , Sequenciamento Completo do Genoma/métodos , Medicina de Precisão/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Mutação , Adulto , Genômica/métodos , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estudos Prospectivos , Oncologia/métodos , Genoma HumanoRESUMO
Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.
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Compostos Benzidrílicos , Senescência Celular , Transição Epitelial-Mesenquimal , Glucosídeos , Diálise Peritoneal , Fibrose Peritoneal , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucosídeos/farmacologia , Compostos Benzidrílicos/farmacologia , Diálise Peritoneal/efeitos adversos , Senescência Celular/efeitos dos fármacos , Masculino , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fibrose Peritoneal/patologia , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/prevenção & controle , Peritônio/patologia , Peritônio/efeitos dos fármacos , Peritônio/metabolismo , Camundongos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glucose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Células Cultivadas , Dano ao DNA/efeitos dos fármacosRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.
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Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Combinação de Medicamentos , Terapia Neoadjuvante , Oxaliplatina , Ácido Oxônico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Ácido Oxônico/uso terapêutico , Ácido Oxônico/administração & dosagem , Terapia Neoadjuvante/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Idoso , Adulto , GastrectomiaRESUMO
Robot-assisted laparoscopic radical prostatectomy (RALP) has improved patient recovery, but achieving optimal functional outcomes remains a challenge, especially early urinary continence. The Modified Apical Dissection (MAD) technique has been suggested to improve early continence compared to conventional RALP. A comprehensive search of PubMed, Embase, and Cochrane Central databases was conducted to identify studies on MAD from inception to March 2024. The risk of bias was evaluated using the ROBINS-I tool. Primary outcomes assessed included urinary continence, positive surgical margin rate, biochemical recurrence rates, and complication rates. Out of 789 studies screened initially, we selected 8 studies that met our inclusion criteria. Our analysis showed that patients who underwent the MAD technique had a significantly higher likelihood of achieving early urinary continence compared to those undergoing conventional RALP at the initial follow-up (Odds Ratio [OR] = 4.0, 95% CI = 1.87-8.57). This advantage continued at 1 month (OR = 5.44, 95% CI = 2.98-9.92), 3 months (OR = 5.36, 95% CI = 2.26-12.71), and 6 months (OR = 5.18, 95% CI = 1.51-17.75), though no significant difference was noted at 12 months. There were no significant differences in positive surgical margin rate or biochemical recurrence rate between MAD and conventional RALP. The overall complication rate was 10.9% (95% CI = 8.10-14.06), with most complications being classified as minor (Clavien-Dindo I-II). In summary, our meta-analysis suggests that the MAD technique may lead to earlier recovery of urinary continence without compromising oncologic outcomes in patients undergoing RALP. While there are published studies on the outcomes of MAD, only a few have the appropriate design with a comparison group needed for meta-analysis and discussing various endpoints. More randomized controlled trials are necessary, but the current literature still lacks retrospective studies with comparison groups.
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Laparoscopia , Prostatectomia , Neoplasias da Próstata , Procedimentos Cirúrgicos Robóticos , Prostatectomia/métodos , Prostatectomia/efeitos adversos , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Masculino , Laparoscopia/métodos , Laparoscopia/efeitos adversos , Neoplasias da Próstata/cirurgia , Margens de Excisão , Incontinência Urinária/etiologia , Incontinência Urinária/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Dissecação/métodos , Próstata/cirurgiaRESUMO
BACKGROUND: Chemotherapy-related cardiotoxicity is a significant concern because it is a major cause of morbidity. This study aimed to provide in-depth information on the symptoms of chemotherapy-related cardiotoxicity (CRCT) by exploring literature that concurrently reports the types and symptoms of CRCT in patients with breast cancer. METHODS: A scoping review was performed according to an a priori protocol using the Joanna Briggs Institute's guidelines. The participants were patients with breast cancer. The concept was the literature of specifically reported symptoms directly matched with CRCT and the literature, in English, from 2010, and the context was open. The search strategy included four keywords: "breast cancer," "chemotherapy," "cardiotoxicity," and "symptoms." All types of research designs were included; however, studies involving patients with other cancer types, animal subjects, and symptoms not directly related to CRCT were excluded. Data were extracted and presented including tables and figures. RESULTS: A total of 29 articles were included in the study, consisting of 23 case reports, 4 retrospective studies, and 2 prospective studies. There were no restrictions on the participants' sex; however, all of them were women, except for one case report. The most used chemotherapy regimens were trastuzumab, capecitabine, and doxorubicin or epirubicin. The primary CRCT identified were myocardial dysfunction and heart failure, followed by coronary artery disease, pulmonary hypertension, and other conditions. Major tests used to diagnose CRCT include echocardiography, electrocardiography, serum cardiac enzymes, coronary angiography, computed tomography, and magnetic resonance imaging. In all case reports, CRCT was diagnosed through an incidental checkup according to the patient's symptom presentation; however, only 10 of these studies showed a baseline checkup before chemotherapy. The five most common CRCT symptoms were dyspnea, chest pain, peripheral edema, fatigue, and palpitations, which were assessed by patient-reported symptom presentation rather than using a symptom assessment tool. Dyspnea with trastuzumab treatment and chest pain with capecitabine treatment were particularly characteristic. The time for first symptom onset after chemotherapy ranged from 1 hour to 300 days, with anthracycline-based regimens requiring 3-55 days, trastuzumab requiring 60-300 days, and capecitabine requiring 1-7 days. CONCLUSIONS: This scoping review allowed data mapping according to the study design and chemotherapy regimens. Cardiac assessments for CRCT diagnosis were performed according to the patient's symptoms. There were approximately five types of typical CRCT symptoms, and the timing of symptom occurrence varied. Therefore, developing and applying a CRCT-specific and user-friendly symptom assessment tool are expected to help healthcare providers and patients manage CRCT symptoms effectively.
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Antineoplásicos , Neoplasias da Mama , Cardiotoxicidade , Humanos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , Feminino , Antineoplásicos/efeitos adversosRESUMO
Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.
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Displasia Arritmogênica Ventricular Direita , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Linhagem Celular , Adulto , Sítios de Splice de RNA/genética , Diferenciação CelularRESUMO
Purpose: Severe lymphopenia (SLP) has emerged as a significant prognostic factor in glioblastoma. Intensity-modulated radiation therapy (IMRT)-based radiation therapy (RT) is suggested to minimize the risk of SLP. This study aimed to evaluate SLP incidence based on multi-institutional database in patients with GBM treated with IMRT and develop a predictive nomogram. Patients and methods: This retrospective study reviewed data from 348 patients treated with IMRT-based concurrent chemoradiation therapy (CCRT) at two major hospitals from 2016 to 2021. After multivariate regression analysis, a nomogram was developed and internally validated to predict SLP risk. Results: During treatment course, 21.0% of patients developed SLP and SLP was associated with poor overall survival outcomes in patients with GBM. A newly developed nomogram, incorporating gender, pre-CCRT absolute lymphocyte count, and brain mean dose, demonstrated fair predictive accuracy (AUC 0.723). Conclusions: This study provides the first nomogram for predicting SLP in patients with GBM treated with IMRT-based CCRT, with acceptable predictive accuracy. The findings underscore the need for dose optimization and radiation planning to minimize SLP risk. Further external validation is crucial for adopting this nomogram in clinical practice.
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Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, was the first approved cancer immunotherapy agent. However, IL-2 is associated with systemic toxicity due to binding with its ligand IL-2Rα, such as vascular leakage syndrome, limiting its clinical applications. Despite efforts to extend the half-life of IL-2 and abolish IL-2Rα interactions, the risk of toxicity remains unresolved. In this study, we developed the bispecific fusion protein MB2033, comprising a novel IL-2 variant (IL-2v) connected to anti-programmed death ligand 1 (PD-L1) via a silenced Fc domain. The IL-2v of MB2033 exhibits attenuated affinity for IL-2Rßγ without binding to IL-2Rα. The binding affinity of MB2033 for PD-L1 is greater than that for IL-2Rßγ, indicating its preferential targeting of PD-L1+ tumor cells to induce tumor-specific immune activation. Accordingly, MB2033 exhibited significantly reduced regulatory T cell activation, while inducing comparable CD8+ T cell activation to recombinant human IL-2 (rhIL-2). MB2033 induced lower immune cell expansion and reduced cytokine levels compared with rhIL-2 in human peripheral blood mononuclear cells, indicating a decreased risk of peripheral toxicity. MB2033 exhibited superior anti-tumor efficacy, including tumor growth inhibition and complete responses, compared with avelumab monotherapy in an MC38 syngeneic mouse model. In normal mice, MB2033 was safer than non-α IL-2v and tolerable up to 30 mg/kg. These preclinical results provide evidence of the dual advantages of MB2033 with an enhanced safety and potent clinical efficacy for cancer treatment.
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Antígeno B7-H1 , Interleucina-2 , Proteínas Recombinantes de Fusão , Animais , Camundongos , Humanos , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Feminino , Camundongos Endogâmicos C57BL , Imunoterapia/métodos , Linhagem Celular Tumoral , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologiaRESUMO
BACKGROUND: Pre-haemodialysis (HD) serum creatinine levels are reliable and inexpensive markers of muscle mass and important predictors of survival in patients with stable chronic HD. We aimed to assess whether changes in pre-HD serum creatinine levels during a 2-year period are linked to long-term patient survival. METHODS: We retrospectively analysed patients enrolled in a periodic HD quality assessment program. Of the 21 846 participants in the fourth HD quality assessment program, 13 765 were presented in the fifth, of which 10 299 eligible patients were included in this study. We assessed the change in serum creatinine levels over 2 years. The patients were categorized into the following three groups: stable group (patients with change in serum creatinine < 1 mg/dL during 2 years of HD, n = 5664), increasing group (patients with increase in serum creatinine ≥ 1 mg/dL, n = 2419) and decreasing group (patients with decrease in serum creatinine ≥ 1 mg/dL, n = 2216). RESULTS: The duration of HD at baseline was 62-83 months, with diabetic kidney disease being the most common cause of kidney failure in 36.4% of patients. The 5-year patient survival rates in the stable, increasing and decreasing groups were 69.1%, 71.3% and 66.8%, respectively. The decreasing group had poorer patient survival than the other two groups (P = 0.083 for stable vs. increasing group; P = 0.011 for stable vs. decreasing group; P < 0.001 for increasing vs. decreasing group). There was no significant difference in the cardiovascular event-free survival rate among the three groups. Multivariable Cox regression analyses revealed the highest hazard ratio (HR) for mortality in the decreasing group (HR 1.33, 95% confidence interval [CI] 1.21-1.45, P < 0.001 vs. stable group; HR 1.50, 95% CI 1.34-1.69, P < 0.001 vs. increasing group). The increasing group exhibited a lower risk of mortality than the stable group (HR 0.88, 95% CI 0.81-0.97, P = 0.008). Subgroup analyses based on age, HD vintage, sex, Charlson comorbidity index score, presence of diabetes and baseline serum creatinine level tertiles revealed that the decreasing group exhibited the highest mortality among all subgroups. CONCLUSIONS: Our results demonstrate that changes in pre-HD serum creatinine levels over 2 years of HD were associated with all-cause mortality in patients undergoing HD. This finding suggests a simple and promising approach for clinicians in the prognosis and management of patients undergoing HD.
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Creatinina , Diálise Renal , Humanos , Masculino , Creatinina/sangue , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Biomarcadores/sangueRESUMO
Purpose: Managing recurrent inguinal hernias is complex, and choosing the right surgical approach (laparoscopic vs. open) is vital for patient outcomes. This study compared the outcomes of using the same vs. different surgical approaches for initial and subsequent hernia repairs. Methods: We retrospectively analyzed patients who underwent recurrent inguinal hernia repair at Seoul National University Bundang Hospital between January 2014 and May 2023. Patients were divided into the "concordant" and "discordant" groups, comprising patients who underwent same and different approaches in both surgeries, respectively. Preoperative baseline characteristics, index surgery data, postoperative outcomes, and recurrence rates were analyzed and compared. Results: In total, 131 patients were enrolled; the concordant and discordant groups comprised 31 (open, n = 19; laparoscopic, n = 12) and 100 patients (open to laparoscopic, n = 68; laparoscopic to open, n = 32), respectively. No significant differences were observed in the mean operation time (50.5 ± 21.7 minutes vs. 50.2 ± 20.0 minutes, P = 0.979), complication rates (6.5% vs. 14.0%, P = 0.356), or 36-month cumulative recurrence rates (9.8% vs. 9.8%; P = 0.865). The mean postoperative hospital stay was significantly shorter in the discordant than in the concordant group (1.8 ± 0.7 vs. 1.4 ± 0.6, P = 0.003). Conclusion: Most recurrent inguinal hernia repairs were performed using the discordant surgical approach. Overall, concordance in the surgical approach did not significantly affect postoperative outcomes. Therefore, the selection of the surgical approach based on the patient's condition and surgeon's preference may be advisable.
RESUMO
Baker's cysts (BCs) are known to be associated with intra-articular pathologies. BCs can be classified into 2 types: simple and complicated. Although some studies have focused on BC using magnetic resonance imaging (MRI), which is the gold standard examination, no study has compared knee MRI features in patients with simple and complicated BCs. To assess the relationship between the type of BC (simple vs complicated) and other knee pathologies using MRI. Seventy patients who underwent knee MRI examination due to symptomatic knee were retrospectively recruited from April 2011 to April 2021 at a single hospital. In the knee MRI images, the following were assessed: type (simple or complicated), morphology, volume of BCs, thickness of the suprapatellar recess, presence of synovial proliferation of the suprapatellar recess, grade of knee joint effusion, presence of meniscal tear, and extent of meniscal extrusion. The patients were classified into 2 groups according to the type of BC: simple BC and complicated BC. The differences between the 2 groups were evaluated for all variables. Finally, 52 patients were included in this study, 15 were classified as "simple BC" group and 37 as "complicated BC" group. The volume of complicated BC (median: 4.6, interquartile range - IQR: 1.6-12.4) was significantly greater than that of simple BC (median: 0.7, IQR: 0.3-3.7; Pâ =â .007). The presence of synovial proliferation in the suprapatellar recess was significantly higher in complicated BC (91.9%) than that in simple BC (46.7%; Pâ =â .001). The thickness of the suprapatellar recess was significantly greater in complicated BC (median: 7.5, IQR: 5.8-10.7) than that in simple BC (median: 4.3, IQR: 2.3-7.6; Pâ =â .020). The medial meniscus extrusion was greater in complicated BC (median: 4.1, IQR: 2.8-5.1) than that in simple BC (median: 2.5, IQR: 1.8-4.4; Pâ =â .037). After adjusting these P-values using the Holm method, only the presence of synovial proliferation in the suprapatellar recess remained significant (Pâ =â .010). Using knee MRI images, we demonstrated that complicated BCs are more associated with intra-articular pathologies than simple BCs; such as cyst volume, amount of the knee joint effusion, synovial proliferation and medial meniscal extrusion. Among them, the presence of synovial proliferation was the most significant factor associated with complicated BCs.
Assuntos
Articulação do Joelho , Imageamento por Ressonância Magnética , Cisto Popliteal , Humanos , Cisto Popliteal/diagnóstico por imagem , Cisto Popliteal/patologia , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Adulto , IdosoRESUMO
Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .