Prediction of adverse cardiovascular events in children using artificial intelligence-based electrocardiogram.

BACKGROUND: Convolutional neural networks (CNNs) have emerged as a novel method for evaluating heart failure (HF) in adult electrocardiograms (ECGs). However, such CNNs are not applicable to pediatric HF, where abnormal anatomy of congenital heart defects plays an important role. ECG-based CNNs reflecting neurohormonal activation (NHA) may be a useful marker of pediatric HF. This study aimed to develop and validate an ECG-derived marker of pediatric HF that reflects the risk of future cardiovascular events. METHODS: Based on 21,378 ECGs from 8324 children, a CNN was trained using B-type natriuretic peptide (BNP) and the occurrence of major adverse cardiovascular events (MACEs). The output of the model, or the electrical heart failure indicator (EHFI), was compared with the BNP regarding its ability to predict MACEs in 813 ECGs from 295 children. RESULTS: EHFI achieved a better area under the curve than BNP in predicting MACEs within 180 days (0.826 versus 0.691, p = 0.03). On Cox univariable analyses, both EHFI and BNP were significantly associated with MACE (log10 EHFI: hazard ratio [HR] = 16.5, p < 0.005 and log10 BNP: HR = 4.4, p < 0.005). The time-dependent average precisions of EHFI in predicting MACEs were 32.4%-67.9% and 1.6-7.5-fold higher than those of BNP in the early period. Additionally, the MACE rate increased monotonically with EHFI, whereas the rate peaked at approximately 100 pg/mL of BNP and decreased in the higher range. CONCLUSIONS: ECG-derived CNN is a novel marker of HF with different prognostic potential from BNP. CNN-based ECG analysis may provide a new guide for assessing pediatric HF.

Hemodynamic simulation of complete transposition of the great arteries for optimal treatment strategies based on its circulatory physiology.

Our study aimed to elucidate the role of different shunts and provide novel insights into optimal treatment approaches for complete transposition of the great arteries (TGA), which is characterized by unique and complicated circulatory dynamics. We constructed a computational cardiovascular TGA model and manipulated cardiovascular parameters, such as atrial septal defect (ASD) and patent ductus arteriosus (PDA) sizes, to quantify their effects on oxygenation and hemodynamics. In addition, ASD flow patterns were investigated as innovative indications for balloon atrial septostomy (BAS). Our model of TGA with an intact ventricular septum (TGA-IVS) showed that a large ASD can achieve sufficient mixing for survival without PDA, and the presence of PDA is detrimental to oxygen delivery. A treatment strategy for TGA-IVS that enlarges the ASD as much as possible by BAS and PDA closure would be desirable. In TGA with a ventricular septal defect (TGA-VSD), the VSD allows for higher oxygenation and reduces the detrimental effects of PDA on systemic circulation. In TGA-VSD, both strategies of enlarging the ASD by BAS with a closed PDA and adjusting the PDA in response to pulmonary vascular resistance (PVR) reduction without BAS may be effective. The simulated ASD flow patterns showed that the sharp peak left-to-right flow pattern in systole (σ-wave) reflected the hemodynamically significant ASD size, independent of PDA, VSD, and PVR. The ASD flow pattern visualized by Doppler echocardiography provides clinical insights into the significance of an ASD and indications for BAS, which are not readily apparent through morphological assessment.NEW & NOTEWORTHY Complete transposition of the great arteries (TGA) represents complex and unique circulation that is dependent on blood mixing through multiple interacting shunts. Consequently, the role of each shunt and the treatment strategy remain unclear. We developed a mathematical model of TGA circulation, revealing the significant influence of atrial septal defect (ASD) on oxygenation and hemodynamics. The blood flow pattern through the ASD reflects its hemodynamic impact and helps determine treatment strategies.

The Clinical Course and Treatment of a Case of Refractory Systemic Juvenile Myasthenia Gravis Successfully Treated with Thymectomy.

Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.

P4HA1 Promotes Cell Migration and Colonization in Hypopharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: This study aimed to identify key molecules associated with the survival of patients with hypopharyngeal squamous cell carcinoma (HpSCC) by combining in silico and in vitro analyses. MATERIALS AND METHODS: Differentially expressed genes (DEGs) were screened using the Gene Expression Omnibus database. For DEGs, we performed functional enrichment and protein-protein interaction network analyses to identify potential biological functions and hub genes. Functional analysis of HpSCC cell lines verified the critical roles of the hub genes. RESULTS: DEGs were associated with the extracellular matrix. Among the hub genes, high expression of prolyl 4-hydroxylase subunit alpha 1 (P4HA1) was significantly associated with shorter survival. In addition, P4HA1 knockdown inhibited cell migration and colonization. Suppression of cell proliferation was demonstrated using P4HA1-selective inhibitors. CONCLUSION: P4HA1 may be a useful therapeutic target for the treatment of HpSCC.

Fibrinogen-to-lymphocyte Ratio Predicts the Outcomes of Hypopharyngeal Squamous Cell Carcinoma Treated With Definitive Radiotherapy.

BACKGROUND/AIM: Previous studies have identified several inflammatory biomarkers that are useful as prognostic biomarkers for various cancer types. However, the fibrinogen-to-lymphocyte ratio (FLR) has not been addressed in head and neck squamous cell carcinoma. Here, we aimed to examine the value of pretreatment FLR as a prognostic marker in patients who received definitive radiotherapy for hypopharyngeal squamous cell carcinoma (HpSCC). PATIENTS AND METHODS: This retrospective study included 95 patients treated with definitive radiotherapy for HpSCC between 2013 and 2020. The prognostic factors for progression-free (PFS) and overall (OS) survival were identified. RESULTS: The optimal cut-off value of pretreatment FLR for discriminating PFS was 2.46. Based on this value, 57 and 38 patients were classified into groups with high and low FLR, respectively. A high FLR was significantly associated with advanced local disease and overall stage, and with the development of synchronous second primary cancer compared with a low FLR. The high FLR group had significantly lower PFS and OS rates than the low FLR group. Multivariate analysis showed that having a high pretreatment FLR was an independent prognostic factor for poorer PFS and OS [PFS: hazard ratio (HR)=2.14, 95% confidence interval (CI)=1.09-4.19, p=0.026; OS: HR=2.86, 95% CI=1.14-7.20, p=0.024]. CONCLUSION: The FLR has a clinical effect on PFS and OS in patients with HpSCC, suggesting that it has potential application as a prognostic factor for patients with HpSCC.

FosL1 Regulates Regional Metastasis of Head and Neck Squamous Cell Carcinoma by Promoting Cell Migration, Invasion, and Proliferation.

BACKGROUND/AIM: We evaluated the impact of FosL1, a member of the activated protein-1 family, on the pathways leading to regional metastasis of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We examined the influence of small interfering RNA (siRNA) and short heparin RNA (shRNA) mediated knockdown of FosL1 on cell migration, invasion, and proliferation in vitro as well as on regional metastasis in vivo. The prognostic significance of FosL1 was also analyzed using the Kaplan- Meier plotter using data from an HNSCC patient database. RESULTS: Down-regulation of FosL1 inhibited cell migration, invasion, and proliferation in vitro, decreased the incidence of regional metastases, and prolonged the survival of mice in vivo. We also determined that HNSCC patients with higher expression levels of FosL1 had a significantly shorter survival time than those with low expression of FosL1. CONCLUSION: FosL1 plays a crucial role in promoting cell migration, invasion, and proliferation in HNSCC.

Establishment of PDX-derived salivary adenoid cystic carcinoma cell lines using organoid culture method.

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC.

Primary definitive radiotherapy with or without chemotherapy for squamous cell carcinoma of the temporal bone.

We aimed to evaluate the impact of concurrent chemoradiotherapy (CCRT) on the survival of patients with squamous cell carcinoma of the temporal bone. We retrospectively analyzed the data of 13 consecutive patients who were treated by definitive radiation therapy (RT) or CCRT as the initial treatment between 1999 and 2012. There were 5 patients with stage II disease, 5 with stage III, and 3 with stage IV, as classified according to the University of Pittsburgh system. Among these, 2, 4, and 3 patients, respectively, were treated by CCRT; whereas the remaining (3 patients with stage II and 1 with stage III) were treated by RT alone. Median follow-up duration was 39 months (12-106 months) in all cases, and 61.5 months (17-70 months) in censored cases. The 5-year overall survival (OS) rates were 51 % in all patients, and 40, 100, and 0 % in patients with stage II, stage III, and stage IV disease, respectively. In patients with stage II and III disease, the 5-year OS rates were 80 % in the CCRT group and 50 % in the RT-alone group. We found better prognosis in patients with stage II and III disease who were treated by CCRT. Only 2 patients treated by CCRT experienced adverse events more than grade 3, which were neutropenia and dermatitis. There was no late adverse event of bony necrosis. Our study results indicate that CCRT is safe and very effective as a first-line treatment for stage II and III squamous cell carcinoma of the temporal bone.

Prognostic factors for local control in patients receiving radiation therapy for early glottic cancer: anterior commissure involvement and effect of chemoradiotherapy.

To assess the prognostic factors for local control in patients with early glottic cancer, we retrospectively analyzed the data of 130 consecutive patients who were treated by definitive radiation therapy (RT) or concurrent chemoradiotherapy (CRT) for early glottic squamous cell carcinoma (UICC sixth edition T1N0M0 and T2N0M0) at Kanagawa cancer center between 1999 and 2011. There were 63 patients with T1 cancer and 67 patients with T2 cancer. Twenty-one patients with T2 tumors were treated by chemoradiotherapy (CRT). The median follow-up period was 73 months (range, 22-165 months). The 5-year local control (LC) rate in all patients was 81 %. The 5-year LC rates in the patients with T1 and T2 cancer were 89 and 74 %, respectively. Univariate analysis showed that a higher T stage (T2) (p = 0.0301), anterior commissure involvement (p < 0.000001), and habitual drinking (p = 0.054) were correlated with decreased local control rate. Multivariate analysis identified only anterior commissure involvement as a significant prognostic factor for local control (LC rate 91 vs. 51 %, risk ratio 5.3, 95 % CI 2.3-12, p < 0.001). In the patients with T2 cancer, there was no statistically significant difference in the LC rate between patients who received RT alone and those who received CRT (RT alone 76 % vs. CRT 67 %; p = 0.832). The findings of this study suggest that anterior commissure involvement is a significant factor influencing the prospect of local control. CRT was not found to be effective for T2 patients in this study.

Molecular characterization of genes encoding isoamylase-type debranching enzyme in tuberous root of sweet potato, Ipomoea batatas (L.) Lam.

Isoamylase (ISA) is a starch debranching enzyme that removes α-1,6-glucosidic linkages in α-polyglucans such as amylopectin. From previous studies, plant isoamylases have been shown to play a crucial role in amylopectin biosynthesis; however, little is known about their function in storage root tissues of plants such as cassava, yam and sweet potato. In this study, we isolated cDNA clones and characterized the cDNA nucleotide sequences of three genes (IbISA1, IbISA2, IbISA3) encoding isoamylase from sweet potato (Ipomoea batatas (L.) cv. White Star). Deduced amino acid sequences of the three isolated IbISAs have the specific regions that are highly conserved among the α-amylase family members. The product of IbISA2 is predicted to be enzymatically inactive, like other plant ISA2s, due to replacement of amino acid residues that are important for hydrolytic reaction. qRT-PCR analysis demonstrated that expression of IbISA2 was higher than that of the other two IbISAs (IbISA1 and IbISA3) in tuberous root at 109 days after planting, at which stage of tuberous root was at which stage tuberous roots were almost fully developed almost developed. This expression pattern observed in our experiments was different from that in other sink organs, such as seeds (endosperms), indicating that orchestration of ISA gene expression may depend on the differences in sink organ type between tuberous roots and seeds. The molecular characterization of three IbISA genes and their expression analysis in this study will contribute to further studies on starch biosynthesis in sweet potato, especially in storage root.

Definitive radiotherapy for early-stage hypopharyngeal squamous cell carcinoma.

The present study analyzed the outcomes of patients with early-stage hypopharyngeal squamous cell carcinoma (HPSCC) treated with radical radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). We retrospectively reviewed the clinical records of 33 patients with early-stage HPSCC who underwent RT or CCRT between January 1999 and December 2011. Of the 33 patients who were treated, 12 had Stage I and 21 had Stage II disease. Patients with Stage I were typically treated with RT, while patients with Stage II were treated with CCRT (concurrent chemotherapy: 5FU, cisplatin or TS-1). The median follow-up period was 81 months, ranging from 15 to 155 months. The 5-year overall survival rates, cause specific survival rates, locoregional control rates, and progression-free survival rates were 58, 75, 56, and 49 %, respectively. Of the 33 patients, 51 % experienced second primary malignancies. Esophageal carcinoma occurred in several cases, and was diagnosed either during screening after treatment for the second primary malignancy or simultaneously with the second primary malignancy. Advanced-stage second malignancies significantly influenced the survival of the patients and the control rate for HPSCC. Treatment emphasizing the quality of life after treatment is needed, if a poor prognosis is expected because of advanced-stage second primary malignancy.