Elevation of end-tidal CO2 during exercise is attenuated in patients with cardiac amyloidosis.

Reduced exercise tolerance is one of the hallmarks of patients with cardiac amyloidosis (CA), but detailed biological responses during exercise were not investigated. The purpose of this study was to compare the cardiopulmonary exercise test (CPX) parameters between CA patients and propensity-matched heart failure patients. This was a single-center, retrospective, observational study of patients diagnosed with CA. The control group was extracted by propensity score matching from patients who underwent CPX for chronic heart failure during the same period. Clinical data including assessment of biological responses during CPX were compared between the patients with CA (CA group, n = 16) and the control group (non-CA group, n = 16). Echocardiography suggested more impaired diastolic function in the CA group than in the non-CA group. There was no significant difference between groups in the fraction of end-tidal carbon dioxide (FETCO2) at rest. However, the difference between the FETCO2 at rest and the FETCO2 at the respiratory compensation point (ΔFETCO2) was significantly smaller in the CA group than in the non-CA group (0.40% ± 0.37% vs. 0.82% ± 0.33%; p = 0.002). Only in the CA group, there was a significant negative correlation between the ΔFETCO2 and the E/e' ratio on echocardiography (r = - 0.521; p = 0.039) and the serum high-sensitivity troponin T concentration (r = - 0.501; p = 0.048). In conclusion, patients with CA may find it difficult to increase cardiac output during exercise due to severe diastolic dysfunction.

Social anxiety disorder in adolescents who stutter: A risk for school refusal.

BACKGROUND: Stuttering is a childhood-onset fluency disorder. Part of the counseling for middle and high school students with persistent stuttering is related to school refusal. Anxiety disorders are known to contribute to school refusal. However, it is not known whether social anxiety disorder (SAD) is a factor in school refusal among adolescents who stutter. METHODS: In our first study, we examined the relationship between school refusal and SAD in 84 middle and high school students who stutter; 26% of the 84 students were in the school refusal group and the remaining 74% were in the school attendance group. The second study examined whether SAD was associated with 10 factors related to speech and stuttering frequency using the Japanese version of the Liebowitz Social Anxiety Scale for Children and Adolescents to determine the presence of SAD. Of the 84 students in the first study, 40 participated in the second study. RESULTS: The school refusal group of adolescents who stutter had significantly higher rates of SAD than the school attendance group. Fifty percent of adolescents who stutter met the criteria for SAD. Moreover, adolescents who stutter with SAD had significantly higher scores on the items "When speaking in public, do you experience tremors in your limbs?" and "After you stutter, do you have negative thoughts about yourself?" than the adolescents who stutter without SAD. CONCLUSIONS: When examining adolescents who stutter, checking for comorbid SAD may lead to better support. Moreover, noticing their repetitive negative thinking, nervousness, and trembling during speech may help to resolve SAD.

[A Case of Breast Cancer Recurrence Responding to Trastuzumab Deruxtecan for Increased Cervical Lymph Node Metastasis during Anti-HER2 Therapy].

A 65-year-old woman underwent breast-conserving surgery for right breast cancer 12 years ago. The primary lesion was ER-positive, PgR-negative, presenting no amplification of the HER2 gene, and endocrine therapy was continued. After 10 years postoperation, duodenal stenosis due to peritoneal metastasis was noted, and the positive conversion of the HER2 expression was confirmed in peritoneal metastasis. Peritoneal lesions could be reduced by chemotherapies combined with trastuzumab and pertuzumab; however, hoarseness due to cervical lymph node metastasis appeared. Administration of T- DXd was initiated. After 4 cycles of T-DXd, her cervical lymph nodes shrank, and hoarseness improved. Because of its high drug-to-antibody ratio and the bystander effect, T-DXd was considered effective even in metastatic lesions presenting tumor heterogeneity or low HER2 expression.

Awareness of stuttering in Japanese children aged 3-7 years.

BACKGROUND: Boey et al. (2009) devised a questionnaire for measuring children's awareness of stuttering and showed that even very young children were often aware of their stuttering. There has been no replication of studies using Boey et al.'s parent-reported questionnaire. The aim of this study was to test whether using Boey et al.'s seven questions, developed for a Dutch speaking population could be effective for measuring the awareness of stuttering in Japanese children. METHODS: Participants were 54 children who stutter (CWS) aged 3-7 years. Parents answered seven questions about their child's awareness of stuttering according to the questions developed Boey et al. RESULTS: Parental-reported observations of the child responses citing at least one awareness incident were 76%. The percentage of stuttering children with awareness of their own speech difficulties, according to chronological age, were as follows: 70% at age 3 years; 67% at age 4 years; 75% at age 5 years; 81% at age 6 years; and 90% at age 7 years. CONCLUSIONS: We found that even at age 3 years, many CWS were already aware of their stuttering. The similarity of the data with the seminal study by Boey et al. suggests that the question-based assessment is reproducible even in a country with a different spoken language. The seven questions in Boey et al. are useful for evaluating whether children's awareness of stuttering could contribute to a clinical decision as well as stuttering severity.

Soluble urokinase-type plasminogen activator receptor represents exercise tolerance and predicts adverse cardiac events in patients with heart failure.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a membrane-binding protein that is released into the blood stream by immune activation. Recent reports suggest that circulating suPAR levels are associated with adverse cardiovascular outcomes. Exercise tolerance is an independent predictor of prognosis in patients with heart failure (HF); however, the relationship between serum suPAR level and exercise tolerance is unclear. We prospectively enrolled 94 patients who were hospitalized for worsening of HF. All patients underwent a symptom-limited cardiopulmonary exercise test to evaluate exercise tolerance. The median value of serum suPAR was 4848 pg/ml. During follow up, 44 patients (47%) were admitted for all-cause mortality and re-hospitalization for HF. Median serum suPAR was significantly higher in the patients with cardiac events than in the patients with non-event group. Patients were divided into two groups according to circulating suPAR levels. Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly higher in the high suPAR group (log-rank p = 0.023). Multivariate analysis revealed that suPAR was independently correlated with the parameters of exercise tolerance such as anaerobic threshold (p = 0.007) and peak oxygen uptake (p = 0.005). suPAR levels predicted adverse cardiac events and independently correlated with the parameters of exercise tolerance. suPAR could be a useful surrogate biomarker of exercise tolerance in patients with HF.

Total synthesis of agalloside, isolated from Aquilaria agallocha, by the 5-O-glycosylation of flavan.

Agalloside (1) is a neural stem cell differentiation activator isolated from Aquilaria agallocha by our group using Hes1 immobilized beads. We conducted the first total synthesis of agalloside (1) via the 5-O-glycosylation of flavan 25 using glycosyl fluoride 20 in the presence of BF3·Et2O. Subsequent oxidation with DDQ to flavanone 2 and deprotection successively provided agalloside (1). This synthetic strategy holds promise for use in the synthesis of 5-O-glycosylated flavonoids. The synthesized agalloside (1) accelerated neural stem cell differentiation, which is a result comparable to that for the naturally occurring compound 1.

[A Case of Drug-Induced Lung Injury Associated with Paclitaxel plus Bevacizumab Therapy].

A 61-year old woman with recurrent breast cancer received combined treatment with paclitaxel (PTX) and bevacizumab (BV) as the third-line chemotherapy. During the administration of PTX in the 3 courses of chemotherapy, she suddenly developed respiratory failure, and both chest X-ray and CT revealed bilateral pulmonary infiltrates. Symptoms and radiographic findings responded dramatically to steroid pulse therapy. The history of onset and laboratory data showed no evidence of infection; therefore, we made a diagnosis of acute lung injury induced by the chemotherapy. It should be noted that lung injury may be induced by both PTX and BV, and is one of the important adverse events despite the low frequency of occurrence.

[Breast Cancer Patient with Bone Metastases Who Was Able to Return Home without Using Opioids after Administration of Strontium-89 Chloride].

A 46-year-old woman underwent mastectomy for right inflammatory breast cancer.Three years later, she was diagnosed with multiple bone metastases and was treated with systemic chemotherapy and zoledronic acid.Six years after the mastectomy, she complained of severe sacral pain, and 40 Gy external radiotherapy was applied to the sacral metastases.Oxycodone was also administered, but dose escalation was difficult because of severe nausea and fatigue.A bone scan showed increased uptake of Tc99m in an area consistent with the painful regions, and an injection of 89SrCl2 was administered.Five weeks after the injection, her severe pain was relieved and she was able to discontinue the use of opioids completely.She successfully lived at home for 100 days without using opioids.In this case, radionuclide therapy with 89SrCl2 led to remarkable pain relief with an improvement in the quality of life of the patient.

[A case report of recurrent small bowel adenocarcinoma successfully treated with monoclonal antibody against EGFR and S-1].

A man in 30s was admitted to our hospital with a complaint of abdominal and back pain. Abdominal CT scan showed a large mass and double balloon endoscopy detected a tumor of the jejunum. The pathological diagnosis of biopsy samples was poorly differentiated adenocarcinoma. After radical resection, adjuvant chemotherapy with mFOLFOX6 was administered, however, a recurrent lesion developed. Although the lesion was successfully removed again, it did not react to the combination therapy with irinotecan and cisplatin. Because the tumor showed a high percentage of epidermal growth factor receptor (EGFR) expression and also had a wild-type KRAS status, a therapeutic strategy targeting EGFR was selected. The patient started on panitumumab associated with S-1 and obtained a complete response on CT 6 weeks later. Small bowel adenocarcinoma is an aggressive malignancy with a poor prognosis and little information about its definitive chemotherapy. Analysis of molecular characterization, an increase in reported experience, and prospective trials are needed to improve a prognosis.

[Efficacy and safety of low-dose matrix-type transdermal fentanyl applied for opioid initiation].

Minimum-size matrix-type transdermal fentanyl(TDF)(Durotep®MTPatch 2.1mg), with a dose equivalent to half of a minimum-size conventional-type TDF(Durotep Patch 2.5mg), was newly produced. Now, the use of minimum-size matrix-type TDF at the early stage of opioid initiation has become possible. For several reasons, we sometimes encounter clinical cases where clinicians are inclined to use the minimum-size matrix-type TDF first without prior use of other opioids. In order to evaluate the efficacy and safety of minimum-size matrix-type TDF, we analyzed 49 patients, retrospectively for whom minimum-size matrix-type TDF was initiated. We used the Wong-Baker faces pain rating scale to assess the effect of matrix-type TDF. The rate of effective and ineffective cases were 55% and 37%, respectively, and 8% of cases could not be evaluated. The frequency of side effects such as nausea, somnolence, sense of fatigue and constipation was 20%, 16%, 4% and 2%, respectively. However, respiration depression was not documented at all. The score of the palliative prognostic index was significantly higher in ineffective cases compared with effective cases. Patients who were judged ineffective tended to have poor prognoses. One of the reasons matrix-type TDF was thought to be ineffective in such patients was that a rapid increase of the dose according to dynamic changes of symptoms was difficult. These findings suggest that we can use a matrix-type TDF as opioid initiation relatively safely, but in cases with poor prognoses, we should use it under appropriate and sufficient rescue setting only when other opioids cannot be prescribed.

Thigh Intramuscular Fat on Prognosis of Patients With Nonischemic Cardiomyopathy.

Skeletal muscle atrophy is an independent prognostic predictor for patients with chronic heart failure, and the concept of sarcopenia is drawing attention. Furthermore, the importance of not only muscle mass but also ectopic fat has been pointed out. However, there is a lack of consensus on the implications of ectopic fat for the prognosis in patients with nonischemic cardiomyopathy. We investigated whether ectopic fat in the thigh affects the prognosis of nonischemic cardiomyopathy. This prospective study recruited 145 patients diagnosed with nonischemic cardiomyopathy between September 2017 and January 2020. Finally, 93 patients with a reduced ejection fraction were enrolled. The clinical end points were cardiovascular death or unexpected rehospitalization because of a cardiac event. Using computed tomography, the percentage of intramuscular fat (%IMF) in the thigh was measured in all patients. Patients were divided into 2 groups based on the median %IMF. The results of Spearman's correlation coefficient analysis revealed a correlation among %IMF and peak oxygen uptake (Spearman r = -0.221, p = 0.036). Kaplan-Meier analysis results showed significantly higher risk of adverse events in the high %IMF group (log-rank p = 0.013). Multivariate Cox regression analysis results revealed the %IMF as an independent factor for adverse events (hazard ratio 1.361; 95% confidence interval 1.043 to 1.745; p = 0.018). In conclusion, %IMF may have adverse consequences such as increased cardiac events in patients with nonischemic cardiomyopathy with a reduced ejection fraction.

Epicardial adipose tissue volume is an independent predictor of left ventricular reverse remodeling in patients with non-ischemic cardiomyopathy.

BACKGROUND: In some patients with non-ischemic cardiomyopathy, left ventricular (LV) contraction is improved by optimal medical therapy, leading to LV reverse remodeling (RR). Patients with heart failure with improved ejection fraction and LVRR have a good prognosis, but the factors that predict RR are not fully understood. The relationship between body composition and cardiovascular disease has been reported. The present study aimed to assess the clinical predictors of LVRR in association with body composition. METHODS: We recruited patients who were diagnosed with non-ischemic cardiomyopathy between September 2017 and January 2020. Finally, 89 patients with a reduced LV ejection fraction were enrolled in this prospective study. Body composition, including ectopic fat, was measured in all patients using computed tomography. Echocardiography was performed 6 months after enrollment to evaluate LVRR. RESULTS: LVRR was observed in 39 patients (43.8%) after 6 months. In terms of the demographic findings, epicardial adipose tissue volume was greater in the LVRR group than in the non-LVRR group (135.2 cm3 [SD 128.4 cm3] vs. 88.9 cm3 [SD 54.6 cm3]; p = 0.040). The Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly less frequent in the LVRR group than in the non-LVRR group (log-rank test, p = 0.013). The multivariate logistic regression analysis identified epicardial adipose tissue volume as an independent predictor of LVRR (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 1.001-1.01; p = 0.036). CONCLUSION: Epicardial adipose tissue volume is an independent predictor of LVRR in patients with non-ischemic cardiomyopathy.

Increased oxidative stress during exercise predicts poor prognosis in patients with acute decompensated heart failure.

AIMS: Oxidative stress plays an important role in the development and progression of heart failure (HF). Although exercise and oxidative stress are closely related, the effect of acute exercise on reactive oxygen species production and the fluctuation on prognosis are unclear. METHODS AND RESULTS: We enrolled 94 patients who were hospitalized for worsening HF (mean age 68.0 ± 14.5 years old, 63.8% male). The changes in diacron-reactive oxygen metabolites (d-ROM) values, a marker of oxidative stress, before and after a cardiopulmonary exercise test were considered as Δd-ROM. The mean follow-up period was 24 ± 13 months, during which 15 patients had all-cause death or left ventricular assist system implantation. Kaplan-Meier analysis demonstrated that all-cause death or left ventricular assist system implantation was significantly higher in the Δd-ROM-positive group than in the Δd-ROM-negative group (log-rank P = 0.047). Elevated Δd-ROM levels were associated with increased mortality risk. Multivariate analysis adjusted for body mass index and peak oxygen uptake revealed that Δd-ROM was an independent prognostic factor of adverse events (Tertile 3 vs. 1; hazard ratio: 4.57; 95% confidence interval: 1.21-29.77; P = 0.022). CONCLUSIONS: Patients with HF who underwent a cardiopulmonary exercise test and had an increased oxidative stress marker level had a poor prognosis. The appropriate exercise intensity could be determined by evaluating the changes in oxidative stress status in response to acute exercise in patients with HF.

Organizing Pneumonia as the First Presentation in a Patient with Takayasu Arteritis: A Report of Rare Complication.

A 48-year-old woman without any medical history visited an outpatient clinic with a chief complaint of cough persisting for more than 1 year and was diagnosed with organizing pneumonia. Computed tomography showed wall thickening with luminal stenosis of the main branch vessels of the aorta, and a detailed examination including fluorodeoxyglucose-positron emission tomography revealed Takayasu arteritis. There have been some reports of combined organizing pneumonia in similar vasculitis cases, but Takayasu arteritis and organizing pneumonia have not been reported to be associated. This case can be referred to when considering the association of lung lesions with Takayasu arteritis.

[Role of palliative chemotherapy and shift from anticancer therapy to palliative care in patients with advanced or recurrent breast cancer].

We examined the role of palliative chemotherapy and the shift from anticancer therapy to palliative care in 30 patients who had died of advanced or recurrent breast cancer. Patients who received more than four chemotherapy regimens had a longer survival and started analgesics later than those who received less than three regimens. In addition, median survival time was prolonged in patients treated with both anthracycline- and taxane-containing regimens. Presence of bone metastases did not influence survival time, but extended the period of last hospitalization. In the average process of advanced or recurrent breast cancer, use of analgesics was started on the 500 th day and the last hospitalization was on the 760 th day from the diagnosis. Last chemotherapy was performed 29 days before death, and the median survival length was 811 days. Patients were treated as outpatients in 94% of the period from their recurrence until death. Therefore, it is especially important to support outpatients physically and mentally from the early stage of recurrence.

Total synthesis of lindbladione, a Hes1 dimerization inhibitor and neural stem cell activator isolated from Lindbladia tubulina.

Lindbladione (1) is a neural stem cell differentiation activator isolated from Lindbladia tubulina by our group. Hes1 dimerization inhibitory activity of lindbladione (1) was discovered using our original fluorescent Hes1 dimer microplate assay. We also found that lindbladione (1) accelerates the differentiation of neural stem cells. We conducted the first total synthesis of lindbladione (1) via Heck reaction of 1-hexene-3-one 7 with iodinated naphthoquinone 12, which was provided by Friedel-Crafts acylation followed by Claisen condensation, in the presence of Pd (II) acetate. Careful deprotection of the benzyl groups of 13 successively provided lindbladione (1). Synthesized lindbladione (1) exhibited potent Hes1 dimer inhibition (IC50 of 2.7 µM) in our previously developed fluorescent Hes1 dimer microplate assay. Synthesized lindbladione (1) also accelerated the differentiation of C17.2 mouse neural stem cells into neurons dose dependently, increasing the number of neurons by 59% (2.5 µM) and 112% (10 µM) compared to the control. These activities are comparable to those of naturally occurring lindbladione (1) isolated from L. tublina.

Pulmonary Artery Sarcoma Diagnosed Using an Endovascular Catheter Forceps Biopsy.

We herein report a case of pulmonary artery sarcoma (PAS) in a 64-year-old woman. She was admitted to our hospital because of massive genital bleeding from endometrial cancer. Contrast-enhanced computed tomography (CT) revealed a left pulmonary artery mass and deep vein thrombosis. She underwent anticoagulant therapy for one year. However, the mass lesion gradually expanded. 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT showed a positive uptake of FDG by the mass. An endovascular catheter biopsy was performed for the differentiation of endometrial cancer metastasis or primary sarcoma. The biopsy specimen tissue comprised spindle-shaped cells. Thus, the patient was diagnosed with PAS.

Successful catheter ablation improves exercise tolerance in persistent atrial fibrillation patients, especially those with reduced ventricular contraction, preserved atrial function, or a high CHADS2 score.

BACKGROUND: It has been reported that rhythm control for persistent atrial fibrillation (per-AF) patients by catheter ablation improves their exercise tolerance, subjective symptoms, and quality of life (QoL). However, clinical factors that can predict future improvement of exercise capacity after successful catheter ablation in per-AF patients are unclear. METHODS: This study consisted of 62 patients (mean age 65.6 ±â€¯8.7 years, 77% males) with per-AF who underwent catheter ablation from June 2017 to May 2018. All patients were subjected to extended pulmonary vein isolation. Exercise tolerance was evaluated using a symptom-limited cardiopulmonary exercise test before and 3 months after catheter ablation. Primary endpoints were QoL measurements using an original questionnaire and functional assessments performed at 3 months. RESULTS: The questionnaire revealed significant improvement in QoL after catheter ablation (minimal metabolic equivalents occurring symptoms: from 5.48 ±â€¯1.14 to 5.64 ±â€¯1.06; p = 0.01). Endurance exercise characteristics improved significantly after catheter ablation, demonstrated by a shift in anaerobic threshold (from 13.3 ±â€¯3.0 to 15.2 ±â€¯3.3 ml/kg/min; p < 0.001), peak oxygen uptake (from 19.1 ±â€¯4.6 to 22.5 ±â€¯5.0 ml/kg/min; p < 0.001), and minute ventilation vs carbon dioxide production slope (from 28.3 ±â€¯6.1 to 25.7 ±â€¯3.8; p < 0.001). Multivariate Cox regression analysis revealed that a decreased left ventricular ejection fraction, high left atrial appendage velocity, and high CHADS2 score were identified as independent predictors of anaerobic threshold and a peak value of oxygen uptake with more than 20% improvement. CONCLUSIONS: Catheter ablation for per-AF patients improves QoL and exercise tolerance. The effect was especially remarkable in patients with reduced ventricular function, those who had a preserved atrial function, or those at high risk of thromboembolism.

[A case of recurrent endocrine cell carcinoma of the common bile duct successfully treated by hepatic artery infusion with CPT-11 and CDDP].

A 77-year-old woman underwent pancreatoduodenectomy with the diagnosis of biliary tract cancer. Postoperative immunohistochemical study showed endocrine cell carcinoma originating in the common bile duct. Systemic infusion of gemcitabine was started as adjuvant chemotherapy, however, 6 months after the operation, multiple liver and lymph node metastases were revealed by computed tomography. Then hepatic artery infusion with CPT-11 (40 mg/body) and CDDP (20 mg/body) were repeated every two weeks. Tumor markers normalized, and the size of both lymph nodes and liver tumors was remarkably decreased after 5 months. Endocrine cell carcinoma of the bile duct generally has a poor prognosis. This method could be a therapeutic option for recurrent endocrine cell carcinoma of the bile duct.

Protective role of interleukin-18 against Fas-mediated liver injury.

Interleukin (IL)-18 plays an important role in the pathogenesis of several liver diseases as well as Fas-mediated apoptosis. However, the effects of IL-18 on Fas-mediated liver injury have not been well elucidated. Therefore, we examined the effects of IL-18 on Fas-mediated apoptosis in in vitro and in vivo experiments. We found that recombinant IL-18 protected mouse hepatocellular carcinoma cell lines, BNL5, from Fas-mediated apoptosis in a dose-dependent manner with up-regulation of both nuclear factor (NF) kappaB and X-linked inhibitors of apoptosis (XIAP). IL-18 transgenic (Tg) mice were also protected from Fas-mediated liver injury and this was further confirmed by histological study and TUNEL staining. In IL-18 Tg mice, up-regulation of XIAP and down-regulation of caspase 3 were observed after injection of anti-Fas, which was consistent with the in vitro findings. These results suggest that IL-18 suppresses Fas-mediated apoptosis of hepatocytes by up-regulation of NFkappaB and XIAP, following inhibition of caspase-3 activity. This observation raises the possibility that IL-18 could be a therapeutic strategy for Fas-mediated liver injury as a negative regulator of XIAP.