Publications by authors named "Takeshi Tsuda"

65 Publications

Rapid Growth of Left Atrial Thrombus in a Pediatric Heart Transplant Recipient.

Ann Thorac Surg 2021 Apr 21. Epub 2021 Apr 21.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE. Electronic address:

We report on a 10-year-old female who rapidly developed a left atrial (LA) mass two months after orthotopic heart transplant. Nine days prior to detection of the mass, she received high-dose corticosteroids for acute cellular rejection (grade 2). Despite negative echocardiogram five days prior to detection, a large echogenic mass was noted in the LA (18 x 12 x 24 mm); it was surgically resected after unsuccessful anticoagulation treatment. Pathogenesis of this LA thrombus remains uncertain, but immunosuppression, acute rejection, and high-dose steroid therapy may have contributed. Surgical thrombectomy is a safe and effective treatment option for LA thrombus.
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.021DOI Listing
April 2021

A Case of Cochlear Implant Replacement Requiring Full-Thickness Skin Grafting.

Ear Nose Throat J 2021 Mar 23:145561321996837. Epub 2021 Mar 23.

Department of Otorhinolaryngology, 13707National Hospital Organization Osaka, Osaka City, Japan.

Cochlear implants improve the quality of life of patients with bilateral severe sensorineural hearing loss. Normally, patients with cochlear implants can continue to use the devices for years without any complications. However, equipment failure or infection at the implant site could develop in some patients, and this might often necessitate implant replacement. Although cochlear implant replacement surgery itself is not a major risk in most cases, extensive tissue resection will be required in cases involving infection, and the insertion site of the temporal bone implant will need to be changed. We encountered a case of skin necrosis at the temporal bone implant site caused by constant external irritation from the temple of an eyeglass frame. The patient underwent cochlear implant replacement surgery involving full-thickness skin grafting from the abdomen. Thereafter, the patient's condition improved. Full-thickness skin grafting can be useful in cases of extensive skin defects encountered during cochlear implant replacement.
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http://dx.doi.org/10.1177/0145561321996837DOI Listing
March 2021

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

Ther Adv Med Oncol 2021 27;13:1758835921998588. Epub 2021 Feb 27.

Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama-City, Hiroshima, Japan.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study.

Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate.

Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.
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http://dx.doi.org/10.1177/1758835921998588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917867PMC
February 2021

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

BMC Cancer 2021 Jan 12;21(1):57. Epub 2021 Jan 12.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.

Background: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib.

Methods: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E.

Results: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161).

Conclusion: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.
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http://dx.doi.org/10.1186/s12885-020-07777-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802126PMC
January 2021

A Rare Case of Prostate Carcinoma Metastasis in the Orbital Apex.

Ear Nose Throat J 2020 Nov 20:145561320973783. Epub 2020 Nov 20.

Department of Otorhinolaryngology, National Hospital Organization Osaka National Hospital, Osaka City, Osaka, Japan.

Prostate cancer (PC) is prone to bone metastases, but very rarely it can spread to soft tissues. In the head and neck region, PC can metastasize to the orbital soft tissue, causing various symptoms such as vision loss. In this report, we describe the case of a 79-year-old man with PC metastasis in the orbital apex. He presented to an ophthalmologist at our hospital with progressively worsening vision in his left eye over 3 to 4 months. He complained of a drooping eyelid in the same eye; thus, intracranial disease was suspected. Closer inspection with head computed tomography revealed a space-occupying lesion from the orbit to the posterior ethmoid sinus, and he was referred to our department. He had a history of PC, and we performed endoscopic sinus surgery for the diagnosis of malignancy, including metastasis of PC. As a result, the mass was diagnosed as PC metastasis by pathological examination. The patient began androgen blockade therapy and 3 months postoperatively, magnetic resonance imaging revealed that the extraconal orbital mass had decreased significantly. It is important to determine the metastases of PC in the paranasal region when the patient has a preexisting medical history.
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http://dx.doi.org/10.1177/0145561320973783DOI Listing
November 2020

Low-dose prostaglandin E1 is safe and effective for critical congenital heart disease: is it time to revisit the dosing guidelines?

Cardiol Young 2021 Jan 3;31(1):63-70. Epub 2020 Nov 3.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Introduction: Prostaglandin E1 is used to maintain ductal patency in critical congenital heart disease (CHD). The standard starting dose of prostaglandin E1 is 0.05 µg/kg/minute. Lower doses are frequently used, but the efficacy and safety of a low-dose regimen of prostaglandin E1 has not been established.

Methods: We investigated neonates with critical CHD who were started on prostaglandin E1 at 0.01 µg/kg/minute. We reviewed 154 consecutive patients who were separated into three anatomical groups: obstruction to systemic circulation, obstruction to pulmonary circulation, and inadequate mixing (d-transposition of the great arteries). Treatment failure rates and two commonly reported side effects, respiratory depression and seizure, were studied.

Results: A total of 26 patients (17%) required a dose increase in prostaglandin E1. Patients with pulmonary obstruction were more likely to require higher doses than patients with systemic obstruction (15/49, 31% versus 9/88, 10%, p = 0.003). Twenty-eight per cent of patients developed respiratory depression and 8% of patients needed mechanical ventilation. Prematurity (<37 week gestation) was the primary risk factor for respiratory depression. No patient required dose escalation or tracheal intubation while on transport. No patient had a seizure attributed to prostaglandin E1.

Conclusions: Prostaglandin E1 at an initial and maintenance dose of 0.01 µg/kg/minute was sufficient to maintain ductal patency in 83% of our cohort. The incidence of respiratory depression requiring mechanical ventilation was low and was mostly seen in premature infants. Starting low-dose prostaglandin E1 at 0.01 µg/kg/minute is a safe and effective therapy for critical CHD.
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http://dx.doi.org/10.1017/S1047951120003297DOI Listing
January 2021

Skull Base Metastasis of Breast Cancer With Oculomotor and Trochlear Nerve Palsy.

Ear Nose Throat J 2020 Oct 9:145561320963676. Epub 2020 Oct 9.

Department of Otorhinolaryngology-Head and Neck Surgery, 13013Osaka University Graduate School of Medicine, Osaka, Japan.

Skull base metastatic tumors are rare. Breast cancer in particular can cause bone metastases after a long period of time. A 70-year-old woman presented with multiple cranial nerve palsy. Magnetic resonance imaging revealed a lesion that extended from the orbit to the base of the skull, and the patient was referred to our department. Ophthalmological evaluation showed left visual acuity impairment, left oculomotor nerve palsy, and left trochlear nerve palsy. Endoscopic biopsy performed 5 years after the completion of breast cancer treatment revealed skull base metastases. In unilateral multiple cranial nerve palsy, the possibility of skull base metastases should be considered.
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http://dx.doi.org/10.1177/0145561320963676DOI Listing
October 2020

A Case of Ceruminous Adenocarcinoma Not Otherwise Specified (NOS) in the External Auditory Canal.

Ear Nose Throat J 2020 Aug 30:145561320954128. Epub 2020 Aug 30.

Department of Otorhinolaryngology, 13707National Hospital Organization Osaka National Hospital, Osaka City, Osaka, Japan.

External auditory canal cancer is a rare disease which can be treated by surgery or chemoradiation. The most common histological type is squamous cell carcinoma, but rare types such as adenocarcinoma have been reported and are thought to be derived from the ceruminous glands. Here, we present a case of ceruminous adenocarcinoma, not otherwise specified (NOS) in the external auditory canal. A 72-year-old woman was referred to our department with discomfort due to a mass in the external ear canal. No typical symptoms of malignancy, such as pain or bleeding, were noted at the initial examination. The patient underwent a total excision under local anesthesia as a diagnostic treatment. She was diagnosed with ceruminous adenocarcinoma, NOS based on the results of immunostaining of the excised specimen, and is currently being followed up as an outpatient. Adenocarcinoma is thought to originate from the cerumen glands of the ear canal and the lack of specific symptoms may make it difficult to differentiate it from benign tumors. Although adenocarcinoma, NOS has been reported in the head and neck region, there have been no reported cases occurring in the external ear canal, and to the best of our knowledge, this is the first report.
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http://dx.doi.org/10.1177/0145561320954128DOI Listing
August 2020

Experience with online lectures about endoscopic sinus surgery using a video conferencing app.

Auris Nasus Larynx 2020 Dec 28;47(6):1083-1085. Epub 2020 Jul 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan.

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http://dx.doi.org/10.1016/j.anl.2020.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386604PMC
December 2020

Overfeeding and obesity in young children with positive pressure ventilation via tracheostomy following cardiac surgery.

Cardiol Young 2020 Oct 3;30(10):1397-1404. Epub 2020 Aug 3.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Objectives: Infants with CHD requiring positive pressure ventilation via tracheostomy are especially vulnerable to malnutrition following cardiac surgery. Current post-operative feeding recommendations may overestimate the caloric needs.

Design: We retrospectively studied infants requiring tracheostomy after cardiac surgery. Anthropometric and nutritional data were collected, including caloric goals, weight-for-age z score, length-for-age z score, and weight-for-length z score. Changes in anthropometrics over time were compared to ascertain the impact of nutritional interventions. Data were shown as mean ± standard deviation.

Results: Nineteen infants with CHD required tracheostomy at 160 ± 109 days (7-364 days), 13 had reparative surgery, and 6 had palliative surgery for single ventricle. The indications for tracheostomy consisted of airway abnormality/obstruction (n = 13), chronic respiratory failure (n = 7), and/or vocal cord paresis (n = 2). Initial maintenance nutritional target was set at 100-130 cal/kg per day. Fourteen patients (73.7%) became obese (maximum weight-for-length z score: 2.59 ± 0.47) under tracheostomy and gastrostomy feeding, whereas five patients did not (weight-for-length z score: 0.2 ± 0.83). Eight obese patients (weight-for-length z score: 2.44 ± 0.85) showed effective reduction of obesity within 6 months (weight-for-length z score: 0.10 ± 0.20; p < 0.05 compared with pre-adjustment) after appropriate feeding adjustment (40-90 cal/kg per day). Overall mortality was high (31.6%) in this population.

Conclusion: Standard nutritional management resulted in overfeeding and obesity in young children with CHD requiring positive pressure ventilation via tracheostomy. Optimal nutritional management in this high-risk population requires close individualised management by multidisciplinary teams.
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http://dx.doi.org/10.1017/S1047951120002073DOI Listing
October 2020

Sudden cardiac death in children and young adults without structural heart disease: a comprehensive review.

Rev Cardiovasc Med 2020 Jun;21(2):205-216

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

Sudden cardiac death (SCD) is a rare clinical encounter in pediatrics, but its social impact is immense because of its unpredicted and catastrophic nature in previously healthy individuals. Unlike in adults where the primary cause of SCD is related to ischemic heart disease, the etiology is diverse in young SCD victims. Although certain structural heart diseases may be identified during autopsy in some SCD victims, autopsy-negative SCD is more common in pediatrics, which warrants the diagnosis of sudden arrhythmic death syndrome (SADS) based upon the assumption that the usual heart rhythm is abruptly replaced by lethal ventricular arrhythmia. Despite current advances in molecular genetics, the causes of more than half of SADS cases remain unanswered even after postmortem genetic testing. Moreover, the majority of these deaths occur at rest or during sleep even in the young. Recently, sudden unexpected death in epilepsy (SUDEP) has emerged as another etiology of SCD in children and adults, suggesting critical involvement of the central nervous system (CNS) in SCD. Primary cardiac disorders may not be solely responsible for SCD; abnormal CNS function may also contribute to the unexpected lethal event. In this review article, we provide an overview of the complex pathogenesis of SADS and its diverse clinical presentation in the young and postulate that SADS is, in part, induced by unfortunate miscommunication between the heart and CNS via the autonomic nervous system.
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http://dx.doi.org/10.31083/j.rcm.2020.02.55DOI Listing
June 2020

A Case of Endonasal Endoscopic Surgery for Intraorbital Metastasis of Gastric Ring Cell Carcinoma.

Ear Nose Throat J 2020 Jul 22:145561320943372. Epub 2020 Jul 22.

Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.

Gastric signet ring cell carcinoma has well-known metastatic features, including peritoneal dissemination and carcinomatous lymphangitis of the lung, but no intraorbital metastases were reported previously. A woman in her 60s developed left eye pain, sudden vision loss, and headache 12 years after gastric cancer treatment. Symptoms did not improve despite steroid pulses. Craniotomy showed no malignant findings. The patient was referred to our department for symptomatic relief and biopsy due to the lack of a definitive diagnosis and no improvement in her ocular pain. Endonasal endoscopic surgery was performed for diagnostic purposes and to relieve symptoms through orbital decompression. Preoperative computed tomography examination revealed a tumor at the left medial orbit, extending to the orbital apex. Orbital decompression through the open left medial orbital wall was performed with biopsy of the intraorbital tumor. Pathological findings were consistent with metastatic signet ring cell carcinoma. Pain and subjective improvement of visual acuity were noted the day after surgery. Twelve months postoperatively, diplopia remains, but there has been no worsening of symptoms.
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http://dx.doi.org/10.1177/0145561320943372DOI Listing
July 2020

Propensity score analysis of overall survival between first- and second-generation EGFR-TKIs using real-world data.

Cancer Sci 2020 Oct 5;111(10):3705-3713. Epub 2020 Aug 5.

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs.
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http://dx.doi.org/10.1111/cas.14560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541013PMC
October 2020

Early Surgical Closure of Atrial Septal Defect Improves Clinical Status of Symptomatic Young Children with Underlying Pulmonary Abnormalities.

Pediatr Cardiol 2020 Aug 9;41(6):1115-1124. Epub 2020 May 9.

Nemours Cardiac Center, Division of Cardiology, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Rd., Wilmington, DE, 19803, USA.

Elective closure of atrial septal defect (ASD) is usually recommended during preschool ages. However, ASD may contribute to deteriorating health in the presence of significant comorbidity and, thus, may need earlier closure. There is a lack of clarity regarding the indications for and outcomes after ASD closure in infancy and early childhood. We investigated the benefits and safety of surgical ASD closure in symptomatic patients under 2 years of age. Retrospective chart review was conducted in patients who underwent surgical ASD closure within the first 2 years of life. Of 31 symptomatic ASD patients, 22 had persistent respiratory symptoms, 24 failure to thrive, and 9 pulmonary hypertension. Overall, 26 patients (84.0%) showed clinical improvement after ASD closure, including improved respiratory status (17/22; 77.3%), resumption of normal growth (15/24; 62.5%), and resolution of pulmonary hypertension (7/7; 100%, 2 patients unable to assess postoperatively). Two medically complicated patients died a few months after surgery unrelated to surgical complications. Four out of 8 ventilator-dependent patients were weaned from mechanical ventilation within 1 month after ASD closure. Closure of ASD did not improve those patients with highly advanced lung disease and/or medically complex conditions including underlying genetic abnormalities. Surgical complications were uncommon. Postoperative hospital stay was 4 to 298 days (median 8 days). The majority of our patients demonstrated significant clinical improvement after ASD closure. Early ASD closure is safe and beneficial for symptomatic infants and young children with associated underlying pulmonary abnormalities, especially bronchopulmonary dysplasia.
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http://dx.doi.org/10.1007/s00246-020-02361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223328PMC
August 2020

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

J Allergy Clin Immunol 2020 03 5;145(3):843-854.e4. Epub 2020 Feb 5.

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan; Institute for Open and Transdisciplinary Research Initiatives, Suita City, Osaka, Japan. Electronic address:

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases.

Objective: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS.

Methods: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis.

Results: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model.

Conclusions: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.
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http://dx.doi.org/10.1016/j.jaci.2019.12.893DOI Listing
March 2020

Effective myocardial perfusion and concomitant haemodynamic status determine the clinical diversity of anomalous left coronary artery from the pulmonary artery.

Cardiol Young 2020 Mar 22;30(3):362-368. Epub 2020 Jan 22.

Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

Background: Anomalous left coronary artery from the pulmonary artery is a rare congenital heart disease (CHD) with diverse clinical presentations despite the same anatomy. Factors determining this heterogeneous presentation are not well understood.

Method And Results: We retrospectively investigated 14 patients (12 females) who underwent surgical repair of anomalous left coronary artery from the pulmonary artery. These patients were divided into three groups based upon the severity of initial presentation: (1) severe, life-threatening condition (n = 5), (2) mild-to-moderate distress (n = 6), and (3) asymptomatic (n = 3). All patients presented with left ventricular dilation and retrograde flow in left coronary artery by echocardiogram. Eight patients in (1) and (2) presented with severe left ventricular dysfunction. All but one showed abnormal ECG consistent with myocardial ischemia or infarction. Asymptomatic patients had preserved left ventricular systolic function despite ischemic findings on ECG. In 13 patients after surgical repair, all but one normalised left ventricular geometry and systolic function, suggesting nearly full myocardial recovery upon improvement of myocardial perfusion; 8 patients had residual echogenic papillary muscle with variable degree of mitral regurgitation.

Conclusions: Evidence of myocardial ischemic injury was present in all patients with anomalous left coronary artery from the pulmonary artery regardless of their initial presentation. Retrograde flow in left coronary artery, implying collateral vessel development from right coronary artery to left coronary artery, was noted in all patients, yet only few patients had preserved systolic function at the time of diagnosis. The balance between effective myocardial perfusion and a deleterious fistulous flow provided by these collaterals and the simultaneous haemodynamic status are what determine the clinical diversity of anomalous left coronary artery from the pulmonary artery.
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http://dx.doi.org/10.1017/S1047951119003299DOI Listing
March 2020

Reply to correspondence article, correspondence on "Significance of automated external defibrillator in identifying lethal ventricular arrhythmias".

Eur J Pediatr 2019 12;178(12):1919-1920

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE, 19803, USA.

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http://dx.doi.org/10.1007/s00431-019-03494-6DOI Listing
December 2019

Bacteremia caused by Slackia exigua: A report of two cases and literature review.

J Infect Chemother 2020 Jan 9;26(1):119-123. Epub 2019 Jul 9.

Department of Clinical Infectious Diseases, Toyama University Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address:

Slackia exigua is an obligate anaerobic coccobacillus associated with dental infection, but rarely causes extraoral infection. We report two cases of monomicrobial bacteremia caused by S. exigua isolated from two institutions. The first case involved community-acquired bacteremia associated with pleural empyema in a 69-year-old man. The second case involved hospital-acquired bacteremia secondary to postoperative intra-abdominal abscess in a 73-year-old man with primary intestinal diffuse large B-cell lymphoma. S. exigua was finally identified by 16S ribosomal RNA gene sequencing analyses in both cases. In the first case, our attempts to identify the organism using commercial identification kits for anaerobes resulted in inaccurate identification as Gemella morbillorum. However, S. exigua was promptly identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in the second case. The epidemiology and clinical characteristics of S. exigua extraoral infection remain unclear because of the limitations in accurate identification and because only 19 cases of extraoral S. exigua infection have been reported previously, including four cases of bacteremia. Physicians should focus on this species, which can cause community-acquired infections and spread via various routes even in patients with no comorbidities. Further studies are needed to clarify the clinical characteristics of extraoral S. exigua infections.
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http://dx.doi.org/10.1016/j.jiac.2019.06.006DOI Listing
January 2020

Significance of automated external defibrillator in identifying lethal ventricular arrhythmias.

Eur J Pediatr 2019 Sep 11;178(9):1333-1342. Epub 2019 Jul 11.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE, 19803, USA.

Automated electrical defibrillator (AED) is critical in saving children who develop unexpected cardiac arrest (CA), but its diagnostic capacity is not fully acknowledged. Retrospective cohort study of patients with aborted sudden cardiac death (SCD) was performed. Twenty-five patients (14 males) aged 1.3 to 17.5 years who presented with CA survived with prompt cardiopulmonary resuscitation. Eighteen patients had no prior cardiac diagnosis. Cardiac arrest occurred in 10 patients with more than moderate exercise, in 7 with light exercise, and in 8 at rest (including one during sleep). Twenty-two patients were resuscitated with AED, all of which were recognized as a shockable cardiac rhythm. Thorough investigations revealed 6 ion channelopathies (4 catecholaminergic polymorphic ventricular tachycardia, one long QT syndrome, and one Brugada syndrome), 5 congenital heart disease (including 2 with coronary artery obstruction), 6 cardiomyopathies, 2 myocarditis, and 2 miscellaneous. Four patients had no identifiable heart disease. In 5 patients, the downloaded AED-recorded rhythm strip delineated the underlying arrhythmias and their responses to electrical shocks. Four patients who presented with generalized seizure at rest were initially managed for seizure disorder until AED recording identified lethal ventricular arrhythmias.Conclusions: AED reliably identifies the underlying lethal ventricular arrhythmias in addition to aborting SCD. What is Known: • Although infrequent in children, sudden cardiac death (SCD) is often an unexpected and tragic event. The etiology is diverse and sometimes remains unknown despite extensive investigations. • Automated external defibrillator (AED) is both therapeutic in aborting SCD and diagnostic in identifying the underlying lethal ventricular arrhythmias. However, the diagnostic aspect of AED is under-acknowledged by most medical providers. What is New: • Four of 25 patients (16%) were initially managed for possible seizure disorders until AED recording identified lethal ventricular arrhythmia. • The AED recording of the lethal arrhythmia during cardiopulmonary resuscitation (CPR) should always be obtained as it plays a crucial role in the decision-making process before ICD implantation. All medical providers should become familiar with downloading cardiac rhythm strips from AED when requested.
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http://dx.doi.org/10.1007/s00431-019-03421-9DOI Listing
September 2019

Identifying Subclinical Coronary Abnormalities and Silent Myocardial Ischemia After Arterial Switch Operation.

Pediatr Cardiol 2019 Jun 9;40(5):901-908. Epub 2019 Mar 9.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE, 19803, USA.

The incidence of late coronary complications is reported around 8% after arterial switch operation (ASO) for d-transposition of the great arteries, but the affected patients are usually asymptomatic. Exercise stress test (EST) and myocardial perfusion imaging (MPI) are common non-invasive modalities to screen for silent myocardial ischemia, but their diagnostic reliability in children after ASO is unclear. We retrospectively reviewed asymptomatic patients following ASO with EST, MPI, and coronary imaging studies (CIS) and examined the reliability of each test in identifying abnormal coronary lesions responsible for myocardial ischemia. Thirty-seven asymptomatic patients (24 males; ages 12.7 ± 3.7 years) had EST, in which 27 and 33 patients also underwent MPI and CIS, respectively. Exercise capacity was comparable to the age- and sex-matched 37 controls. In seven patients with angiographically proven moderate to severe coronary abnormalities, only two patients had positive EST and/or MPI, and five patients were negative including one patient who later developed exercise-induced cardiac arrest due to severe proximal left coronary artery stenosis. Two patients with positive EST or MPI showed no corresponding coronary abnormalities by CIS. Occurrence of acquired late coronary abnormalities did not correlate with the original coronary anatomy or initial surgical procedures. There is no single reliable method to identify the risk of myocardial ischemia after ASO. Although CIS are regarded as a gold standard, multidisciplinary studies are essential to risk-stratify the potential life-threatening coronary lesions after ASO in children.
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http://dx.doi.org/10.1007/s00246-019-02085-4DOI Listing
June 2019

A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations.

Lung Cancer 2018 12 13;126:41-47. Epub 2018 Oct 13.

Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objective: The efficacy and safety of afatinib in elderly patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have not been evaluated. This study aimed to assess the efficacy and safety of afatinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.

Materials And Methods: We prospectively assessed the clinical effects of afatinib as a first-line treatment for elderly (age ≥70 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially administered afatinib (30 mg/day).

Results: Between May 2014 and August 2017, 40 patients (13 men, 27 women) with adenocarcinoma were included in our analysis. The median age was 77 years (range, 70-85 years). The dose was reduced in 19 patients. The objective overall response and disease control rates were 72.5% and 100%, respectively, and the median progression-free survival and overall survival were 12.9 months and not reached, respectively. Common adverse events (AEs) included diarrhea, rash/acne, and anemia. Major grade 3 or higher toxicities included diarrhea (12.5%), mucositis (7.5%), and pneumonitis (7.5%). Afatinib treatment was discontinued in 8 patients owing to AEs of elevated amylase (n = 1), liver dysfunction (n = 1), rash/acne (n = 1), nail change (n = 1), anorexia (n = 2), pneumonitis (n = 2), and diarrhea (n = 2). Two patients died due to treatment-related pneumonitis.

Conclusions: This is the first study that verified the efficacy and feasibility of first-line chemotherapy with afatinib at 30 mg/day in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. First-line afatinib of 30 mg/day could be a treatment option in this patient population.
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http://dx.doi.org/10.1016/j.lungcan.2018.10.014DOI Listing
December 2018

Chest tightness is relieved with the use of asthma drugs except bronchodilators.

J Asthma 2019 Nov 14;56(11):1182-1192. Epub 2018 Nov 14.

The Department of Thoracic Surgery, Toyama Prefectural Central Hospital , Toyama , Japan.

Many patients with a chief complaint of chest tightness are examined in medical facilities, and a lack of diagnosis is not uncommon. We have reported that these patients often include those with chest tightness relieved with bronchodilator use (CTRB) and those with chest tightness relieved with the use of asthma drugs except bronchodilators (CTRAEB). The purpose of this study was to demonstrate the clinical characteristics of the patients with CTRAEB and compare them with data from patients with CTRB. Patients with CTRB ( = 13) and CTRAEB ( = 7) underwent a bronchodilator test, assessments of airway responsiveness to methacholine, bronchial biopsy, and bronchial lavage under fiberoptic bronchoscopy before receiving treatment. In all, 10 healthy subjects, 11 bronchial biopsy control patients, and 10 asthmatic patients were recruited for comparison. Inhalation of a short-acting ß-agonist (SABA) increased the forced expiratory volume in one second (FEV) by 5.1% ± 4.0% in patients with CTRB and by 1.3% ± 3.5% in patients with CTRAEB, and the difference was statistically significant ( = 0.0449). The bronchial biopsy specimens from the patients with CTRB and CTRAEB exhibited significant increases in T cells ( < .05) compared with those of the control subjects. The bronchial responsiveness to methacholine was increased in only a minor portion of patients with CTRB and CTRAEB. We hypothesized that the clinical condition of patients with CTRAEB involves chest tightness arising from inflammation alone, and this chest tightness is mostly associated with airway T cells, without constriction of the airways. There is little to distinguish CTRAEB from CTRB aside from the response to bronchodilator treatment. This clinical trial is registered at www.umin.ac.jp (UMIN13994, 13998, and 16741).
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http://dx.doi.org/10.1080/02770903.2018.1531999DOI Listing
November 2019

SEMA4A promotes eosinophil survival and contributes to eosinophil-mediated allergic diseases.

Allergol Int 2019 Apr 19;68(2):274-276. Epub 2018 Oct 19.

Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka, Japan; Integrated Frontier Research for Medical Science Division, The Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka, Japan.

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http://dx.doi.org/10.1016/j.alit.2018.10.001DOI Listing
April 2019

Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity.

Int Immunol 2019 02;31(1):33-40

Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis (CRS) that is characterized by intractable nasal polyp formation. Eosinophil-derived neurotoxin (EDN) is an eosinophil granule protein that is closely related to allergic inflammation, but the pathological implications of EDN in ECRS remain unknown. In this study, we evaluated the function of EDN in ECRS pathogenesis and assessed its potential as a disease activity marker. Serum EDN levels were significantly higher in patients with ECRS than in those with other nasal and paranasal diseases, and were positively correlated with clinical disease activity. Production of EDN from isolated human eosinophils was induced by stimulation with IL-5 in vitro. Human nasal epithelial cells were stimulated with EDN, and the resultant changes in gene expression were detected by RNA sequencing. Pathway analysis revealed that the major canonical pathway affected by EDN stimulation was 'regulation of the epithelial-mesenchymal transition pathway'; the only gene in this pathway to be up-regulated was matrix metalloproteinase 9 (MMP-9). Consistent with this, immunostaining analysis revealed intense staining of both EDN and MMP-9 in nasal polyps from patients with ECRS. In conclusion, our data demonstrate that serum EDN level is a useful marker for the evaluation of ECRS severity. Furthermore, EDN induces production of MMP-9 from the nasal epithelium, which may be involved in the pathogenesis of ECRS.
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http://dx.doi.org/10.1093/intimm/dxy061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364622PMC
February 2019

Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions.

Authors:
Takeshi Tsuda

Int J Mol Sci 2018 Sep 17;19(9). Epub 2018 Sep 17.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, USA.

Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell⁻matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial⁻mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases.
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http://dx.doi.org/10.3390/ijms19092787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163299PMC
September 2018

Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB.

J Immunol 2018 06 23;200(11):3790-3800. Epub 2018 Apr 23.

Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan;

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid-sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.
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http://dx.doi.org/10.4049/jimmunol.1701283DOI Listing
June 2018

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype.

J Cardiovasc Dev Dis 2017 Sep 8;4(3). Epub 2017 Sep 8.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, 1600 Rockland Rd, DE 19803, USA.

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts.
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http://dx.doi.org/10.3390/jcdd4030014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715712PMC
September 2017

Transient Ischemic Attack and Ischemic Stroke in Danon Disease with Formation of Left Ventricular Apical Thrombus despite Normal Systolic Function.

Case Rep Pediatr 2017 20;2017:6576382. Epub 2017 Sep 20.

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.

Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal systolic function. This unexpected LV apical thrombus may be associated with a wide spectrum of neurological deficits ranging from TIA to ischemic stroke in Danon disease. Possibility of cerebral ischemic events should be suspected in Danon disease when presenting with neurological deficits even with normal systolic function. Careful assessment for LV apical thrombus is warranted in such cases.
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http://dx.doi.org/10.1155/2017/6576382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632496PMC
September 2017

Clinical Manifestations and Overall Management Strategies for Duchenne Muscular Dystrophy.

Authors:
Takeshi Tsuda

Methods Mol Biol 2018 ;1687:19-28

Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE, 19803, USA.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that causes progressive weakness and wasting of skeletal muscular and myocardium in boys due to mutation of dystrophin. The structural integrity of each individual skeletal and cardiac myocyte is significantly compromised upon physical stress due to the absence of dystrophin. The progressive destruction of systemic musculature and myocardium causes affected patients to develop multiple organ disabilities, including loss of ambulation, physical immobility, neuromuscular scoliosis, joint contracture, restrictive lung disease, obstructive sleep apnea, and cardiomyopathy. There are some central nervous system-related medical problems, as dystrophin is also expressed in the neuronal tissues. Although principal management is to mainly delay the pathological process, an enhanced understanding of underlying pathological processes has significantly improved quality of life and longevity for DMD patients. Future research in novel molecular approach is warranted to answer unanswered questions.
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http://dx.doi.org/10.1007/978-1-4939-7374-3_2DOI Listing
June 2018

Development of quality metrics for ambulatory pediatric cardiology: Transposition of the great arteries after arterial switch operation.

Congenit Heart Dis 2018 Jan 2;13(1):52-58. Epub 2017 Oct 2.

Department of Pediatrics/Division of Pediatric Cardiology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

Objective: To develop quality metrics (QMs) for the ambulatory care of patients with transposition of the great arteries following arterial switch operation (TGA/ASO).

Design: Under the auspices of the American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Steering committee, the TGA/ASO team generated candidate QMs related to TGA/ASO ambulatory care. Candidate QMs were submitted to the ACPC Steering Committee and were reviewed for validity and feasibility using individual expert panel member scoring according to the RAND-UCLA methodology. QMs were then made available for review by the entire ACC ACPC during an "open comment period." Final approval of each QM was provided by a vote of the ACC ACPC Council.

Patients: Patients with TGA who had undergone an ASO were included. Patients with complex transposition were excluded.

Results: Twelve candidate QMs were generated. Seven metrics passed the RAND-UCLA process. Four passed the "open comment period" and were ultimately approved by the Council. These included: (1) at least 1 echocardiogram performed during the first year of life reporting on the function, aortic dimension, degree of neoaortic valve insufficiency, the patency of the systemic and pulmonary outflows, the patency of the branch pulmonary arteries and coronary arteries, (2) neurodevelopmental (ND) assessment after ASO; (3) lipid profile by age 11 years; and (4) documentation of a transition of care plan to an adult congenital heart disease (CHD) provider by 18 years of age.

Conclusions: Application of the RAND-UCLA methodology and linkage of this methodology to the ACPC approval process led to successful generation of 4 QMs relevant to the care of TGA/ASO pediatric patients in the ambulatory setting. These metrics have now been incorporated into the ACPC Quality Network providing guidance for the care of TGA/ASO patients across 30 CHD centers.
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http://dx.doi.org/10.1111/chd.12540DOI Listing
January 2018