Case Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib.

Cardiac arrest occurred in an 85-year-old female administered osimertinib for advanced lung cancer expressing epidermal growth factor receptor (EGFR) mutations. Electrocardiogram (ECG) recorded at recurrence of spontaneous circulation showed sinus rhythm associated with mild QT prolongation (QTc = 455 ms) to which silent myocardial ischemia and coadministration of itraconazole and herbal drug causing hypokalemia (2.1 mEq/L) may have contributed. Discontinuation of osimertinib, itraconazole and herbal drug, potassium supplementation and percutaneous coronary intervention alleviated QT prolongation (QTc = 432 ms). Osimertinib is the third-generation tyrosine kinase inhibitor lengthening QT interval, and careful monitoring of ECG, serum potassium and drugs coadministered during chemotherapy including osimertinib are highly required.

Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex: A case report.

RATIONALE: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. PATIENT CONCERNS: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. DIAGNOSIS: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. INTERVENTIONS: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. OUTCOMES: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. LESSONS: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

Cardiac metastasis of squamous cell carcinoma of the thyroid gland with severe disseminated intravascular coagulation: A case report.

Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.

Retrospective analysis of cardiovascular diseases related to chemotherapies for advanced solid tumor patients.

Appropriate management of cardiovascular diseases (CVDs) related to chemotherapy for solid tumors is important for safe oncologic treatment. However, prediction of the onset and progression of CVDs has not generally been established in Japan. We carried out a retrospective analysis of advanced or recurrent solid tumor patients who received chemotherapies in a single institution. Patient characteristics, chemotherapy regimens, adverse events, CVDs before chemotherapy, and diagnosis of CVDs in association with chemotherapy were assessed. During the period from April 2006 to March 2012, 394 patients were examined. Cardiac diseases (CDs), hypertension (HT), or arterial thrombosis or venous thromboembolism were prevalent in 37 (9.4%), 22 (5.6%), five (1.3%), and 14 (3.5%) cases, respectively. HT (14.5%) and venous thrombosis (5.8%) were frequent in patients who received bevacizumab-containing chemotherapy. Four cases with left ventricular dysfunction experienced a decrease of ejection fraction and early filling/atrial filling (E/A) and E/A tended to decrease before ejection fraction. Ninety (62.1%) of 145 cases showed an increase in the D-dimer (DD) level before chemotherapy, and a further increase in DD level was found when venous thrombosis occurred. Relative risks of the disease progression of HT, CD, and thromboembolism because of chemotherapy were 1.3, 1.9, and 3.6, respectively. A decrease in E/A and an increase in DD were suggested to be valuable for early diagnosis of the respective onsets of left ventricular dysfunction and venous thrombosis related to chemotherapy. We conclude that patients with previous CD tend to have disease progression of CD during chemotherapy.

Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report.

In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. Subsequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.

Impaired deformability of circulating erythrocytes obtained from nondiabetic hypertensive patients: investigation by a nickel mesh filtration technique.

INTRODUCTION: Hypertension is associated with microcirculatory disturbance, and erythrocyte deformability is a major determinant of the microcirculation. However, impairment of erythrocyte deformability in hypertensive patients in relation to antihypertensive treatment is unclear. The present study aimed to investigate this impairment in hypertensive patients under treatment using a highly sensitive and quantitative nickel mesh filtration technique. METHODS: Deformability was evaluated by filterability, defined as the flow rate of a hematocrit-adjusted erythrocyte suspension relative to that of saline under a specific filtration pressure in a pressure-flow curve obtained by continuous filtration. Baseline characteristics of hypertensive patients (n = 101) and age-matched normotensive subjects (n = 14) were obtained from medical records, and diabetic patients were excluded. RESULTS: Erythrocyte deformability in the hypertensive group was significantly (p = 0.010) lower (87.8 ± 2.2 %) than that of the normotensive group (89.4 ± 1.7 %) and inversely proportional (r = -0.303, p = 0.002) to the mean blood pressure (BP) measured on blood sampling for the filtration study. Stepwise multiple regression analysis demonstrated that this impairment was mostly attributable to the mean BP (p = 0.001), whereas current smoking and episodes of stroke or coronary artery disease were not contributors. DISCUSSION: These findings indicate that erythrocyte deformability is impaired in the hypertensive patients, which depends on the current BP control rather than target organ damage.

Successful chemoradiotherapy for undifferentiated malignant neoplasm arising from the left pulmonary artery.

Undifferentiated malignant neoplasms, which occur primarily in the pulmonary artery, are extremely rare and associated with poor outcomes as there is no effective therapy. A 67-year-old woman visited our hospital with complaints of dry cough and dyspnea on exertion. A contrast-enhanced chest computed tomography revealed an intravascular tumor obstructing the left pulmonary artery and a pedunculated lesion extending to the main and right pulmonary artery. Multiple metastases in the lung, bones and bilateral adrenal glands were identified by fluorodeoxyglucose-positron emission tomography. A small sample was obtained by catheter aspiration biopsy of the intravascular tumor, and examination revealed undifferentiated small atypical cells. The tumor was diagnosed as an undifferentiated neoplasm arising from the pulmonary artery based on immunohistochemical findings, including the absence of expressions of organ-specific markers. Systemic chemotherapy (paclitaxel and carboplatin) and concurrent radiation were performed as treatment for the primary tumor. Marked shrinkage of the intravascular tumor was achieved, and no serious adverse events were observed during therapy. Chemotherapy was continued for 5 months, but the patient died because of tumor progression 9 months after the initial diagnosis. Chemoradiotherapy has efficacy against undifferentiated neoplasm of the pulmonary artery.

Infective endocarditis caused by Listeria monocytogenes forming a pseudotumor.

A 73-year-old woman with breast cancer and metastasis under chemotherapy suffered from fever, pleural effusion and pericardial effusion. Despite the administration of treatment with cefozopran and prednisolone, the patient's fever relapsed. An electrocardiogram identified a new complete atrioventricular block and an echocardiogram revealed vegetation with an unusual pseudotumoral mass in the right atrium. Blood cultures grew Listeria monocytogenes. The patient was eventually diagnosed with right-sided infective endocarditis, which improved following the six-week administration of ampicillin and gentamicin. Homemade yoghurt was suspected to be the cause of infection in this case. Listeria endocarditis is rare; however, physicians should pay more attention to preventing this fatal disease in immunocompromised patients.

Short- and mid-term results of balloon angioplasty for renal artery fibromuscular dysplasia.

This study aimed to evaluate short- and mid-term outcomes of percutaneous transluminal renal artery angioplasty (PTRA) in patients with symptomatic renal artery stenosis caused by renal artery fibromuscular dysplasia (RAFMD). Retrospective analysis of 22 patients with RAFMD who were performed PTRA between 2006 and 2012. These patients underwent PTRA due to poorly controlled hypertension. Pre- and post-PTRA blood pressure (BP) measurements and renal function were evaluated. Freedom from events (restenosis, repeat intervention, renal failure, and recurrent hypertension) was investigated using life table analysis. Twenty-two patients (54.5% women, mean age 39.2 years) with 24 renal arteries underwent PTRA. The technical success rate was 100%. The mean systolic BP decreased from 155.9 ± 14.7 to 138.3 ± 9.41 mmHg (P = 0.00004), and the mean diastolic BP decreased from 99.0 ± 11.5 to 88.0 ± 7.19 mmHg (P = 0.0043). Rates of freedom from recurrent or worsening hypertension, defined by >140 mmHg systolic BP and >90 mmHg diastolic BP, were 89.4, 89.4, 81.3, and 71.1% at 1, 2, 3, and 4 years, respectively. Restenosis-free rates were 90.0, 83.6, 73.4, and 61.9%, respectively. No patient underwent repeat intervention and renal failure. PTRA is a durable modality for treating RAFMD with favorable short- and mid-term clinical outcomes.

Further assessment of atrial fibrillation as a risk factor for gastroesophageal reflux disease: a multicenter questionnaire survey.

OBJECTIVE: Although both atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) are common diseases, the relationship between these two conditions remains controversial, depending on the study design and type of AF. Therefore, we focused on the relationship between nonvalvular AF and GERD. METHODS: A total of 479 consecutive subjects (255 men and 224 women, mean age: 60.4 ± 12.8 years), including outpatients at several hospitals (n=201) and participants of an annual health screening program (n=278), were enrolled. Subjects with valvular AF, malignancy or dementia were excluded. The frequency scale for symptoms of GERD (F-scale) was applied after obtaining each patient's informed consent for screening symptomatic GERD with a total cutoff score of 8 points. The score on the questionnaire was correlated with the baseline characteristics extracted from the patients' medical records. RESULTS: The total F-scale scores were significantly higher in the older patients (≥ 60 years) than in the younger patients (<60 years) (p=0.017) and increased in the following order: permanent AF > paroxysmal AF > sinus rhythm (p=0.003). The incidence of GERD increased in the same order among the patients with the various heart rhythm classifications (p<0.001). Coronary heart disease, hypertension, diabetes and dyslipidemia were not correlated with the F-scale scores or incidence of GERD. The stepwise discriminant analyses demonstrated that nonvalvular AF alone was significantly associated with symptomatic GERD (Wilks' lambda=0.983, p=0.004). CONCLUSION: This multicenter study demonstrated that nonvalvular AF is significantly correlated with symptomatic GERD. This small sample survey warrants a future study of a large-scale cohort.

Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker⁺ cardiomyocytes in vivo.

BACKGROUND: Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS: Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP)-transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rγ(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor-derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin(-/low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin(-/low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair.

Impaired erythrocyte filterability of spontaneously hypertensive rats: investigation by nickel filtration technique.

BACKGROUND: Deformability of erythrocytes plays a key role in the impairment of the microcirculation in hypertension. However, erythrocyte deformability in spontaneously hypertensive rats (SHR) during development of hypertension has not been fully investigated so far. METHODS AND RESULTS: Erythrocyte filterability (whole cell deformability) was investigated in relation to blood pressure measured by the tail-cuff method in SHR and age-matched Wistar-Kyoto rats (WKY), using a highly sensitive and reproducible nickel mesh filtration technique. Impaired erythrocyte filterability was marked (37.0+/-17.5%) in prehypertensive young SHR (7 weeks of age) and sustained (51.6+/-13.3%) in hypertensive mature SHR (18 weeks of age), when compared with that of age-matched WKY (62.1+/-7.2% in 7 weeks of age, P<0.005, and 71.1+/-3.9% in 18 weeks of age, P<0.005, respectively). This impairment in SHR could not be explained by the mean corpuscular volume or mean corpuscular hemoglobin concentration of erythrocytes, but the erythrocyte count was significantly (P<0.005) greater in SHR than in the age-matched WKY. CONCLUSIONS: Although the precise mechanisms remain to be elucidated, markedly impaired erythrocyte filterability in SHR is considered to contribute to the development and maintenance of genetic hypertension. (Circ J 2010; 74: 129 - 136).

Case of atrial tachycardia originating from giant coronary sinus connected to persistent left superior vena cava: successful catheter ablation guided by noncontact mapping.

Radiofrequency (RF) catheter ablation is widely applied to tachyarrhythmia associated not only with structurally normal hearts but also with relatively mild cardiac anomalies. We present a case of 35 year-old female complaining of exercise-induced frequent palpitations caused by atrial tachycardia (AT) originating from giant coronary sinus (CS) connected to persistent left superior vena cava. AT was sensitive to intravenous ATP administration. Electrophysiological study partly using noncontact balloon of EnSite system clarified that two foci of AT were located at the orifice and the distal inner lumen of giant CS. After repetitive applications of RF energy to these origins, AT was not induced by drip infusion of isoproterenol. AT was not evoked by exercise without antiarrhythmic drugs 15 months after the RF ablation. This case indicates that RF ablation guided by noncontact mapping technique should be considered as a therapeutic regimen for AT associated with mild cardiac malformations.

SNPs in BRAP associated with risk of myocardial infarction in Asian populations.

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population. Here we identify BRAP (BRCA1-associated protein) as a galectin-2-binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 x 10(-18), OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 x 10(-6), 862 cases and 1,113 controls and P = 4.7 x 10(-3), 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-kappaB, a central mediator of inflammation.

Feasibility of the Inoue single-branched stent-graft implantation for thoracic aortic aneurysm or dissection involving the left subclavian artery: short- to medium-term results in 17 patients.

OBJECTIVE: This study assessed the short- to medium-term clinical results of the Inoue single-branched stent graft for repair of thoracic aortic aneurysms or dissections involving the left subclavian artery. METHODS: A retrospective review of experiences at two institutions was performed. We analyzed the data of consecutive 17 patients with thoracic aortic aneurysms or dissections who underwent endovascular repairs with the Inoue single-branched stent graft between July 1999 and April 2004. Complete baseline and follow-up data were available on all patients. The mean age was 71 +/- 9 years, and 13 of the patients (76%) were men. Eight patients (47%) were considered unfit for open surgery because of advanced age or the presence of comorbid diseases. RESULTS: The stent grafts were successfully delivered and deployed in all 17 patients. Periprocedural major complications, defined as those that caused any persistent disorder, occurred in one patient who developed spinal ischemia. A postoperative computed tomographic scan revealed three attachment site endoleaks; two endoleaks were from the proximal attachment sites and one endoleak was from the distal attachment site. The mean follow-up period was 26 months (range, 7 to 65 months). Two deaths occurred in the follow-up period from cerebral bleeding and pneumonia, both considered unrelated to the stent grafting. Two patients with attachment site endoleaks needed secondary stent-grafting; one patient required the implantation of a straight stent-graft in the distal attachment site and the other, the implantation of a double-branched stent-graft. Another patient with attachment site endoleak was considered very high-risk for open surgery or secondary stent grafting and did not undergo secondary intervention. The aneurysmal sac size of the patient has been stable for 28 months. The branched section of the stent graft was patent in all patients in the follow-up period. CONCLUSION: The results demonstrate the feasibility of the Inoue single-branched stent graft for thoracic aortic aneurysms or dissections involving the left subclavian artery.

Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro.

Myocardial infarction (MI) has become one of the leading causes of death in the world. Its pathogenesis includes chronic formation of plaque inside the vessel wall of the coronary artery and acute rupture of the artery, implicating a number of inflammation-mediating molecules, such as the cytokine lymphotoxin-alpha (LTA). Functional variations in LTA are associated with susceptibility to MI. Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family. Our case-control association study in a Japanese population showed that a single nucleotide polymorphism in LGALS2 encoding galectin-2 is significantly associated with susceptibility to MI. This genetic substitution affects the transcriptional level of galectin-2 in vitro, potentially leading to altered secretion of LTA, which would then affect the degree of inflammation; however, its relevance to other populations remains to be clarified. Smooth muscle cells and macrophages in the human atherosclerotic lesions expressed both galectin-2 and LTA. Our findings thus suggest a link between the LTA cascade and the pathogenesis of MI.