Takotsubo Syndrome in Older Men　- Clinical Characteristics Differ by Sex and Age.

Background: Takotsubo syndrome (TTS) in male patients is under-studied, particularly in the older population. Methods and Results: From 226 patients with TTS, 44 older male patients (prevalence rate: 19.5%, age: median 77 years) were compared with 182 older female patients (prevalence rate: 80.5%, age: median 80 years). Emotional triggers of TTS were less frequent (2% vs. 19%; P=0.007), whereas physical triggers were more frequent (75% vs. 58%; P=0.040) in older men than in women. Among physical triggers, serious respiratory infection was more common in older men than in women. As initial clues to the diagnosis, ECG T-wave inversion was more frequent (48% vs. 29%; P=0.018) and chest pain and/or dyspnea were less common (23% vs. 38%; P=0.050) in older men than in women. In total, 14 patients (6%) had cardiogenic shock and 41 (18%) had severe heart failure as complications, although there were no significant differences in the frequency of these complications between older men and women. Although cardiac death occurred in 3 female patients (1%) and noncardiac death in 3 male and 5 female patients (4%), there were no significant differences in death rate between older men and women. Conclusions: Emotional triggers of TTS were extremely infrequent whereas physical triggers were common in older men. Although severe heart failure was common, there were no significant differences in the frequency of complications and in-hospital deaths between older men and women.

Central amygdala is related to the reduction of aggressive behavior by monosodium glutamate ingestion during the period of development in an ADHD model rat.

Introduction: Monosodium glutamate (MSG), an umami substance, stimulates the gut-brain axis communication via gut umami receptors and the subsequent vagus nerves. However, the brain mechanism underlying the effect of MSG ingestion during the developmental period on aggression has not yet been clarified. We first tried to establish new experimental conditions to be more appropriate for detailed analysis of the brain, and then investigated the effects of MSG ingestion on aggressive behavior during the developmental stage of an ADHD rat model. Methods: Long-Evans, WKY/Izm, SHR/Izm, and SHR-SP/Ezo were individually housed from postnatal day 25 for 5 weeks. Post-weaning social isolation (PWSI) was given to escalate aggressive behavior. The resident-intruder test, that is conducted during the subjective night, was used for a detailed analysis of aggression, including the frequency, duration, and latency of anogenital sniffing, aggressive grooming, and attack behavior. Immunohistochemistry of c-Fos expression was conducted in all strains to predict potential aggression-related brain areas. Finally, the most aggressive strain, SHR/Izm, a known model of attention-deficit hyperactivity disorder (ADHD), was used to investigate the effect of MSG ingestion (60 mM solution) on aggression, followed by c-Fos immunostaining in aggression-related areas. Bilateral subdiaphragmatic vagotomy was performed to verify the importance of gut-brain interactions in the effect of MSG. Results: The resident intruder test revealed that SHR/Izm rats were the most aggressive among the four strains for all aggression parameters tested. SHR/Izm rats also showed the highest number of c-Fos + cells in aggression-related brain areas, including the central amygdala (CeA). MSG ingestion significantly decreased the frequency and duration of aggressive grooming and attack behavior and increased the latency of attack behavior. Furthermore, MSG administration successfully increased c-Fos positive cell number in the intermediate nucleus of the solitary tract (iNTS), a terminal of the gastrointestinal sensory afferent fiber of the vagus nerve, and modulated c-Fos positive cells in the CeA. Interestingly, vagotomy diminished the MSG effects on aggression and c-Fos expression in the iNTS and CeA. Conclusion: MSG ingestion decreased PWSI-induced aggression in SHR/Izm, which was mediated by the vagus nerve related to the stimulation of iNTS and modulation of CeA activity.

Phototoxicity avoidance is a potential therapeutic approach for retinal dystrophy caused by EYS dysfunction.

Inherited retinal dystrophies (IRDs) are progressive diseases leading to vision loss. Mutation in the eyes shut homolog (EYS) gene is one of the most frequent causes of IRD. However, the mechanism of photoreceptor cell degeneration by mutant EYS has not been fully elucidated. Here, we generated retinal organoids from induced pluripotent stem cells (iPSCs) derived from patients with EYS-associated retinal dystrophy (EYS-RD). In photoreceptor cells of RD organoids, both EYS and G protein-coupled receptor kinase 7 (GRK7), one of the proteins handling phototoxicity, were not in the outer segment, where they are physiologically present. Furthermore, photoreceptor cells in RD organoids were vulnerable to light stimuli, and especially to blue light. Mislocalization of GRK7, which was also observed in eys-knockout zebrafish, was reversed by delivering control EYS into photoreceptor cells of RD organoids. These findings suggest that avoiding phototoxicity would be a potential therapeutic approach for EYS-RD.

Human iPSC-derived renal collecting duct organoid model cystogenesis in ADPKD.

In autosomal dominant polycystic kidney disease (ADPKD), renal cyst lesions predominantly arise from collecting ducts (CDs). However, relevant CD cyst models using human cells are lacking. Although previous reports have generated in vitro renal tubule cyst models from human induced pluripotent stem cells (hiPSCs), therapeutic drug candidates for ADPKD have not been identified. Here, by establishing expansion cultures of hiPSC-derived ureteric bud tip cells, an embryonic precursor that gives rise to CDs, we succeed in advancing the developmental stage of CD organoids and show that all CD organoids derived from PKD1-/- hiPSCs spontaneously develop multiple cysts, clarifying the initiation mechanisms of cystogenesis. Moreover, we identify retinoic acid receptor (RAR) agonists as candidate drugs that suppress in vitro cystogenesis and confirm the therapeutic effects on an ADPKD mouse model in vivo. Therefore, our in vitro CD cyst model contributes to understanding disease mechanisms and drug discovery for ADPKD.

Intracardiac Thrombosis and Systemic Embolism in a Patient with Cardiac Amyloidosis in Sinus Rhythm.

Intracardiac thrombosis formation in patients in sinus rhythm is a rare phenomenon. An 84-year-old woman was admitted because of worsening dyspnea on exertion. An electrocardiogram showed sinus rhythm, left atrial overload, marked left axis deviation, low voltage, and poor r-wave progression in leads V1-4. An echocardiogram showed relatively preserved left ventricular ejection fraction with minimal wall thickening. Her serum level of B-type natriuretic peptide (931 pg/mL) was markedly elevated and a diagnosis of worsening heart failure was made. During the course of treatment for heart failure, she was complicated by acute abdominal aortic thromboembolism together with left atrial thrombus. An emergency abdominal aortic thrombectomy was followed by the removal of a left atrial thrombus 2 days later. Left ventricular biopsy performed during the surgery revealed amyloid deposits in the myocardial interstitium. Immunohistochemical study confirmed the diagnosis of transthyretin cardiac amyloidosis. It is postulated that the risk of intracardiac thrombosis and systemic embolism is increased even in sinus rhythm in patients with cardiac amyloidosis.

Unilateral Pulmonary Edema in Patients With Acute Mitral Regurgitation Caused by Chordal Rupture.

Background: Cardiogenic unilateral pulmonary edema (UPE) has been reported as an unusual condition and to occur in association with severe mitral regurgitation (MR). However, the prevalence of UPE in patients with severe MR remains unknown. Methods and Results: Among 143 consecutive patients with chordal rupture and significant MR, 38 patients with acute severe MR were studied. The prevalence of UPE was 50% (19 patients); all these patients had right-sided UPE. Eight (21%) patients had bilateral pulmonary edema (BPE). All 8 patients with BPE and 18 of 19 patients with UPE had chordal rupture of the posterior leaflet. All patients with UPE and BPE had severe MR with similar left atrial size. Chest radiographs taken ≤48 h from symptom onset diagnosed UPE in 15 of 19 (79%) patients and BPE in 3 of 8 (38%) patients (P=0.037). Chest radiographs taken >48 h from symptom onset diagnosed UPE in 4 (21%) patients and BPE in 5 (62%) patients (P=0.037). Conclusions: The prevalence of UPE was estimated as 50%; it was most frequently right sided and almost always associated with chordal rupture of the posterior leaflet. UPE is not rare, but common, particularly shortly after the development of acute severe MR caused by chordal rupture.

Acute Left Circumflex Coronary Artery Occlusion　- Diagnostic Problems of Initial Electrocardiographic Changes.

Background: Acute coronary syndrome (ACS) with occlusion of the left circumflex coronary artery (LCX) poses diagnostic problems that may lead to a delay in reperfusion. Methods and Results: From a group of 1,269 consecutive patients with ACS, 138 patients with ACS due to LCX occlusion were analyzed for clinical, electrocardiographic, and angiographic presentations, as well as door-to-balloon (DTB) time. Electrocardiographic changes were classified into 4 patterns: ST-segment elevation in inferior/lateral leads (ST-E); ST-segment depression in V1-V4 (ST-D); no significant ST changes (No-ST); and others. The No-ST group was associated with a longer DTB time (P<0.0001) compared with the ST-E and ST-D groups. Compared with the No-ST and ST-E groups, the ST-D group presented with a more advanced Killip class (P=0.003), greater peak creatine phosphokinase (P=0.007) and peak creatine kinase-MB (P=0.006), more frequent proximal LCX occlusion (P=0.007), and worse 1-year outcomes (P=0.0034). Conclusions: One-third of ACS patients with LCX occlusion showed no ST-segment changes, resulting in significantly longer DTB time. Improving diagnostic accuracy is challenging but critical to avoid delayed reperfusion in these patients without electrocardiographic changes.

Paraganglioma of the urinary bladder initially diagnosed as gastrointestinal stromal tumor requiring combined resection of the rectum: a case report.

BACKGROUND: Paraganglioma of the urinary bladder (Pub) is rare and presents with clinical symptoms caused by catecholamine production and release. The typical symptoms of Pub are hypertension, macroscopic hematuria, and a hypertensive crisis during micturition. The average size of detected Pubs is approximately 3 cm. Herein, we report a case of a large Pub in which the symptoms were masked by oral medication, precise preoperative diagnosis was difficult, and intraoperative confirmation of tumoral adhesion to the rectum resulted in hypertensive attacks during surgery. CASE PRESENTATION: A 64-year-old Japanese male with a history of hypertension and arrhythmia controlled with oral medication presented with a large tumor in the pelvic region, detected on examination for weight loss, with no clinical symptoms. Computed tomography and magnetic resonance imaging revealed a tumor measuring 77 mm in diameter in the posterior wall of the urinary bladder. The border with the rectum was unclear, and the tumor showed heterogeneous enhancement in the solid part with an enhancing hypodense lesion. Cystoscopy revealed compression of the bladder trigone by external masses; however, no tumor was visible in the lumen. Endoscopic ultrasonography-guided fine-needle aspiration revealed CD34-positive spindle-shaped cells in the fibrous tissue, suggestive of a mesenchymal neoplasm. The tumor was suspected to be a gastrointestinal stromal tumor, and surgery was performed. After laparotomy, we suspected that the tumor had invaded the rectum, and total cystectomy and anterior resection of the rectum were performed. Histologically, the tumor cells had granular or clear amphophilic cytoplasm with an oval nucleus and nests of cells delimited by connective tissue and vascular septations. Immunohistochemically, the tumor was positive for chromogranin A, CD56, and synaptophysin, and a diagnosis of paraganglioma of the urinary bladder was confirmed. There was no tumor recurrence at the 7-month follow-up. CONCLUSION: This case highlights the importance of careful examination of pelvic tumors, including endocrine testing, for detecting paraganglioma of the urinary bladder in patients with a history of hypertension or arrhythmia.

Takotsubo Syndrome in Octogenarians and Nonagenarians.

Background: Takotsubo syndrome (TTS) in the very elderly is poorly understood. We sought to clarify the characteristics of octogenarians and nonagenarians with TTS. Methods and Results: From 148 patients with TTS who underwent coronary angiography, 68 very elderly patients aged ≥80 years (octogenarians/nonagenarians) were compared with 80 younger patients aged ≤79 years. Emotional triggers of TTS were less frequent (7% vs. 19%; P=0.043), whereas physical triggers were more frequent (69% vs. 46%; P=0.005), in octogenarians/nonagenarians than in patients aged ≤79 years. As initial clues to the diagnosis, electrocardiogram changes were more frequent (71% vs. 46%; P=0.003) and chest pain and/or dyspnea were less common (25% vs. 51%; P=0.001) in octogenarians/nonagenarians than in patients aged ≤79 years. Twenty-nine patients had acute heart failure (AHF) as a complication. AHF was more frequently found in octogenarians/nonagenarians than in patients aged ≤79 years (29% vs. 11%, respectively; P=0.006). Cardiac death occurred in 2 octogenarians/nonagenarians; non-cardiac death occurred in 3 octogenarians/nonagenarians and in 2 patients aged ≤79 years. Conclusions: Emotional triggers of TTS were infrequent in octogenarians/nonagenarians with TTS. AHF was common and there was significant in-hospital all-cause mortality among octogenarians/nonagenarians.

Clinicopathological Analysis of 17 Surgically Resected Pulmonary Pleomorphic Carcinoma Cases.

OBJECTIVES: To determine the outcomes and prognostic factors associated with pulmonary resection of pulmonary pleomorphic carcinoma (PPC). METHODS: During 2008-2017, 17 patients underwent pulmonary resection for primary PPC at the Saitama Cancer Center, Japan. We investigated clinicopathological characteristics and outcomes of these cases. Overall survival (OS) and disease-free survival (DFS) rates were determined using Kaplan-Meier method and compared using log-rank test. Univariate analysis was performed to identify prognostic factors. RESULTS: The 5-year OS and DFS rates were 27.2% and 51.0%, respectively. The median follow-up period was 30.8±24.9 (3.6-92.8) months after pulmonary resections. Patients with disease-free interval (DFI) <1 year of resection had poorer prognosis than those without (p = 0.001). Patients with N2 status and adenocarcinoma components had significantly poorer disease-free prognosis than their counterparts (p = 0.021 and p = 0.019, respectively). Univariate analysis revealed that DFI <1 year was an unfavorable prognostic factor for OS (p = 0.005); N2 pathological status and presence of adenocarcinoma components were unfavorable prognostic factors for DFS (p = 0.038 and p = 0.036, respectively). CONCLUSION: PPC patients with an adenocarcinoma component and N2 pathological status may have an earlier relapse and poorer prognosis than their counterparts. Further assessment of cases may help clarify the predictors of PPC.

Sclerosing thymoma followed up for eight years as mediastinal goiter: A case report.

INTRODUCTION: Sclerosing thymoma (ST) is an extremely rare disease with less than 20 cases ever been described. Here, we present a case of sclerosing thymoma that was followed up as mediastinal goiter for eight years. PRESENTATION OF CASE: A 77-year-old man was presented with a superior mediastinal tumor. The patient was asymptomatic and not affected by myasthenia gravis. Computed tomography showed a well-defined superior mediastinal tumor whose size had regressed over time. Ultrasonography-guided core-needle biopsy revealed type B1 to B2 thymoma, and total-thymectomy was performed. Histopathologically, most of the tumor showed hyalinization and sclerosis, and slight signs of type AB thymoma were found at the tumor's periphery. The patient was diagnosed with ST. No evidence of recurrence was observed 12 months following surgery. DISCUSSION: Since sclerosing thymoma is mostly composed of fibrous tissue, small specimens such as needle biopsies do not contain tumor cell nests and are difficult to confirm. Complete resection is currently the most common treatment for ST. Spontaneous regression of ST has been reported; however, the mechanisms involved have not yet been elucidated. CONCLUSION: This rare case of sclerosing thymoma is an unusual case since it has follow up information for an eight year period due to the misdiagnosis of goiter. The follow up visits showed significant regression of the tumor over the eight year period without treatment; however, the etiology of sclerosis and regression remain unknown. The patient was treated by thymectomy with no recurrence after 12 months.

Mixed squamous cell and glandular papilloma of the lung-A case report and literature review in Japan.

INTRODUCTION: Mixed squamous cell and glandular papilloma (MSGP) of the lung is rare neoplasm, only 19 cases previously reported in Japan. MSGP is one of three separate categories of solitary endobronchial papillomas, which account for less than 0.5 % of all lung tumors. MSGP is rarest of the three. We present a rare case of MSGP and review the literature in Japan. PRESENTATION OF CASE: A 49-year-old man presented with a nodulous shadow in the right lower lung field identified on a chest X-ray performed for back pain. Computed tomography demonstrated a well-circumscribed, 9-mm mass in the S8 segment of the right lower lung lobe. Positron emission tomography showed accumulation of 18F-fluorodeoxyglucose in the tumor with a standardized uptake value of 2.29. Following thoracoscopic partial resection, adenocarcinoma was diagnosed by frozen section, and radical segmentectomy of S8 was performed. The final diagnosis was mixed squamous cell and glandular papilloma. The patient had an uncomplicated postoperative course and remains asymptomatic 3 years after the procedure. DISCUSSION: The etiology and pathological characteristics of MSGP remain unclear. There has been no report of recurrence in MSGP cases treated with complete resection; thus, limited resection that preserves pulmonary function is desirable. Further data including new cases are required. CONCLUSION: We present a rare case of mixed squamous cell and glandular papilloma (MSGP) of the lung and review the literature in Japan. Limited resection that preserves pulmonary function, while ensuring complete resection, is desirable. Further investigations with new cases are required.

A case of resected primary pulmonary pleomorphic carcinoma with long-term survival after multidisciplinary treatment.

BACKGROUND: Generally, primary pulmonary pleomorphic carcinoma is resistant to treatment and has a poor prognosis. We report a case of resected primary pulmonary pleomorphic carcinoma with long-term survival after multidisciplinary treatment. CASE PRESENTATION: A 74-year-old man with a history of emphysema, pneumoconiosis, and chronic bronchitis presented with left lung nodule and left adrenal tumor based on computed tomography. We suspected clinical T1bN0M1b, stage IVB lung cancer. Adrenalectomy of the left adrenal tumor yielded a definitive diagnosis of pleomorphic carcinoma. Chemotherapy was performed despite the spontaneous regression of lung lesions. Since lung lesions re-enlarged 11 months after adrenalectomy, the left lower lobe was partially resected followed by chemotherapy. The lung lesion was the primary lesion of the adrenal tumor. There was no recurrence 100 months after the lung resection. CONCLUSIONS: The patient experienced long-term survival after multidisciplinary treatment. Both multidisciplinary treatment and immunological mechanisms caused spontaneous regression of the primary lesion.

G-CSF-producing Undifferentiated Pleomorphic Sarcoma Adjacent to the Ascending Colon and in the Right Iliopsoas Muscle: A Case Report and Review of the Literature.

Undifferentiated pleomorphic sarcoma (UPS) is a soft tissue sarcoma, occurring most commonly on the lower extremities. We herein report a rare case of primary UPS adjacent to the ascending colon and in the right iliopsoas muscle. Computed tomography of the abdomen revealed large masses, and the patient experienced a high-grade fever, leukocytosis, elevated serum C-reactive protein level, and hematopoietic activation on 18F-fluorodeoxyglucose-positron emission tomography. This inflammatory reaction was caused by granulocyte colony-stimulating factor secreted by tumor cells. Surgical resection was performed, and the inflammatory reaction disappeared immediately. The patient received adjuvant chemotherapy and survived one year after the operation without evidence of recurrence.

Cancer of the mandibular gingiva metastasizing to the small intestine.

Head and neck cancer metastasizing to the small intestine is very rare. Here we report a case of cancer of the mandibular gingiva metastasizing to the small intestine. The patient was an 82-year-old man who had squamous cell carcinoma of the mandibular gingiva staged as T2N2bM0. Two months after surgery, he presented with lower abdominal pain accompanied by signs of peritoneal irritation. Urgent abdominal surgery was performed, during which a crater-shaped perforation was noted on the wall of the ileum. Microscopic findings at this site confirmed a diagnosis of metastatic squamous cell carcinoma in the small intestine from the mandibular gingiva. To our knowledge, this is the first case report of oral cancer metastasizing to the small intestine. If gastrointestinal symptoms appear in a patient with advanced oral cancer, a differential diagnosis of metastasis to the gastrointestinal tract should be kept in mind.

Radiotherapy for localized gastric mucosa-associated lymphoid tissue lymphoma: long-term outcomes over 10 years.

This study aimed to assess the long-term outcomes of radiotherapy in patients with localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Twenty-seven patients with Stage I gastric MALT lymphoma were treated with radiotherapy from 1999 to 2010. The median age was 65 years (range: 31-84). Fifteen patients were Helicobacter pylori-negative. Thirteen patients were treated with definitive radiotherapy alone. The other 14 patients who had refractory or residual disease following a prior treatment received salvage radiotherapy. The median dose of the radiotherapy was 30 Gy in 20 fractions (range: 30-39.5 Gy). The median follow-up period was 121 months (range: 8-176 months). The 5- and 10-year overall survival rates for all patients were 92% and 87%, respectively. No patients died from MALT lymphoma. Three patients died of other diseases at 8, 33 and 74 months after radiotherapy (myocardial infarction, pneumonia and hepatocellular carcinoma, respectively). No cases of local recurrence were observed during the follow-up period. There were no serious late gastric, liver or kidney complications during a median follow-up period of over 10 years. Two patients remain alive with distant metastases: a lung metastasis and an abdominal lymph node metastasis at 104 months and 21 months after radiotherapy, respectively. Excellent long-term local control was observed in patients with localized gastric MALT lymphoma after radiotherapy. However, lifelong follow-up should be conducted to detect cases of late recurrence, especially distant metastases.