Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

Optimization of adipose tissue-derived mesenchymal stromal cells transplantation for bone marrow repopulation following irradiation.

BACKGROUND: Bone marrow (BM) suppression is one of the most common side effects of radiotherapy and the primary cause of death following exposure to irradiation. Despite concerted efforts, there is no definitive treatment method available. Recent studies have reported using mesenchymal stromal cells (MSCs), but their therapeutic effects are contested. AIM: We administered and examined the effects of various amounts of adipose-derived MSCs (ADSCs) in mice with radiation-induced BM suppression. METHODS: Mice were divided into three groups: Normal control group, irradiated (RT) group, and stem cell-treated group following whole-body irradiation (WBI). Mouse ADSCs (mADSCs) were transplanted into the peritoneal cavity either once or three times at 5 × 105 cells/200 µL. The white blood cell count and the levels of, plasma cytokines, BM mRNA, and BM surface markers were compared between the three groups. Human BM-derived CD34+ hematopoietic progenitor cells were co-cultured with human ADSCs (hADSCs) or incubated in the presence of hADSCs conditioned media to investigate the effect on human cells in vitro. RESULTS: The survival rate of mice that received one transplant of mADSCs was higher than that of mice that received three transplants. Multiple transplantations of ADSCs delayed the repopulation of BM hematopoietic stem cells. Anti-inflammatory effects and M2 polarization by intraperitoneal ADSCs might suppress erythropoiesis and induce myelopoiesis in sub-lethally RT mice. CONCLUSION: The results suggested that an optimal amount of MSCs could improve survival rates post-WBI.

A multicenter, randomized, and double-blind phase IV clinical trial to compare the efficacy and safety of fixed-dose combinations of amlodipine orotate/valsartan 5/160 mg versus valsartan/hydrochlorothiazide 160/12.5 mg in patients with essential hypertension uncontrolled by valsartan 160 mg monotherapy.

BACKGROUND: To determine whether the effectiveness and safety of fixed-dose combinations (FDCs) of amlodipine orotate/valsartan (AML/VAL) 5/160 mg are noninferior to those of valsartan/hydrochlorothiazide (VAL/HCTZ) 160/12.5 mg in hypertensive patients with inadequate response to valsartan 160 mg monotherapy. METHODS: This 8-week, active-controlled, parallel-group, fixed-dose, multicenter, double-blind randomized controlled, and noninferiority trial was conducted at 17 cardiovascular centers in the Republic of Korea. Eligible patients had mean sitting diastolic blood pressure (msDBP) ≥90 mm Hg despite monotherapy with valsartan 160 mg for 4 weeks. Patients were randomly assigned to treatment with AML/VAL 5/160 mg FDC (AML/VAL) group or VAL/HCTZ 160/12.5 mg FDC (VAL/HCTZ) group once daily for 8 weeks. A total of 238 patients were enrolled (AML/VAL group, n = 121; VAL/HCTZ group, n = 117), of whom 228 completed the study. RESULTS: At 8 weeks after randomization, msDBP was significantly decreased in both groups (-9.44 ±â€Š0.69 mm Hg in the AML/VAL group and -7.47 ±â€Š0.71 mm Hg in the VAL/HCTZ group, both P < .001 vs baseline). Between group difference was -1.96 ±â€Š1.00 mm Hg, indicating that AML/VAL 5/160 mg FDC was not inferior to VAL/HCTZ 160/12.5 mg FDC at primary efficacy endpoint. Control rate of BP defined as the percentage of patients achieving mean sitting SBP (msSBP) <140 mm Hg or msDBP <90 mm Hg (target BP) from baseline to week 8 was significantly higher in the AML/VAL group than that in the VAL/HCTZ group (84.3% [n = 102] in the AML/VAL group vs 71.3% [n = 82] in the VAL/HCTZ group, P = .016). At 8 weeks after randomization, mean uric acid level was significantly increased in the VAL/HCTZ group compared to that at baseline (0.64 ±â€Š0.08 mg/dL; P < .001). However, it was slightly decreased from baseline in the AML/VAL group (-0.12 ±â€Š0.08 mg/dL; P = .085). The intergroup difference was significant (P < .001). CONCLUSION: The effectiveness and safety AML/VAL 5/160 mg FDC are noninferior to those of VAL/HCTZ 160/12.5 mg FDC in patients with hypertension inadequately controlled by valsartan 160 mg monotherapy.

Gross tumor volume dependency on phase sorting methods of four-dimensional computed tomography images for lung cancer.

PURPOSE: To see the gross tumor volume (GTV) dependency according to the phase selection and reconstruction methods, we measured and analyzed the changes of tumor volume and motion at each phase in 20 cases with lung cancer patients who underwent image-guided radiotherapy. MATERIALS AND METHODS: We retrospectively analyzed four-dimensional computed tomography (4D-CT) images in 20 cases of 19 patients who underwent image-guided radiotherapy. The 4D-CT images were reconstructed by the maximum intensity projection (MIP) and the minimum intensity projection (Min-IP) method after sorting phase as 40%-60%, 30%-70%, and 0%-90%. We analyzed the relationship between the range of motion and the change of GTV according to the reconstruction method. RESULTS: The motion ranges of GTVs are statistically significant only for the tumor motion in craniocaudal direction. The discrepancies of GTV volume and motion between MIP and Min-IP increased rapidly as the wider ranges of duty cycles are selected. CONCLUSION: As narrow as possible duty cycle such as 40%-60% and MIP reconstruction was suitable for lung cancer if the respiration was stable. Selecting the reconstruction methods and duty cycle is important for small size and for large motion range tumors.

Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention.

BACKGROUND: There are no previous data on serial changes in neutrophil gelatinase-associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. MATERIALS AND METHODS: We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. RESULTS: The mean pre-NGAL and post-NGAL levels were 109.2±76.1 and 93.3±83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. CONCLUSION: In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome.

A case of a resected benign myxoma-like hemorrhagic cyst, which later recurred as undifferentiated pleomorphic sarcoma in the left atrium.

RATIONALE: An intracardiac cystic mass is a rare type of mass found in the left atrium. The differential diagnosis of an intracardiac cystic mass includes hydatid cysts, bronchogenic cysts, intracardiac varices, and hemorrhages in some tumor types, including myxoma. PATIENT CONCERNS: We present the case of a 68-year-old woman who presented with episodic dyspnea. DIAGNOSES-INTERVENTIONS-OUTCOMES: Transthoracic echocardiography (TTE) revealed the presence of a left atrial mass mimicking myxoma. However, in postoperative findings, it was determined that the mass was actually a hemorrhagic cyst. Eighteen months later, the patient presented with recurrent exertional dyspnea and TTE revealed the recurrence of a left atrial mass. Computed tomography showed that the mass extended into the right atrium, inferior vena cava, and coronary sinus. After re-operation, the final histological diagnosis was determined to be an undifferentiated pleomorphic sarcoma in the left atrium. LESSONS: An intracardiac hemorrhagic cyst was suspected during the operation of a benign-looking LA mass. As such, we recommend that other rare etiologies be considered and more biopsies be performed when possible.

miRNA polymorphisms (miR­146a, miR­149, miR­196a2 and miR­499) are associated with the risk of coronary artery disease.

Small non­coding microRNAs (miRNAs) are not only important for heart and vascular development but are also important in cardiovascular pathophysiology and diseases, such as ischemia and atherosclerosis­related diseases. However, the effect of miR­146a, miR­149, miR­196a2 and miR­499 polymorphisms on coronary artery disease (CAD) susceptibility remain unknown. The aim of the present study was to examine the genotype frequencies of miR­146a, miR­149, miR­196a2 and miR­499 polymorphisms in patients with CAD, and assess their clinical applications for diagnosing and monitoring CAD. Using polymerase chain reaction­amplified DNA, microRNA polymorphisms were analyzed in 522 patients with CAD and 535 control subjects. The miR­149 rs2292832 C>T and miR­196a2 rs11614913 T>C polymorphisms were shown to be significantly associated with CAD prevalence. In subgroup analyses according to disease severity, the miR­146a rs2910164GG genotype was significantly associated with CAD risk in the stent ≥2 group. In addition, miR­146aG/­149T/­196a2C/­499 G allele combination was significantly associated with CAD prevalence (G­T­C­G and G­C­C­G of miR­146a/­149/­196a2/­499). The combination genotypes of miR­146aGG/149TC+CC and miR­149CC/196a2TC were significantly associated with CAD incidence. In subgroup analyses, miR­146a rs2910164 C>G increased the risk of developing CAD in non­smoking, hypertensive and nondiabetic subgroups. Furthermore, miR­149 rs2292832 C>T and miR­196a2 rs11614913 T>C was shown to increase CAD risk in females and patients aged >63 years old. The miR­149T allele, miR­196a2C allele and miR­146aG/­149T/­196a2C/­499 G allele combination were associated with CAD pathogenesis. The combined effects of environmental factor and genotype combination of miRNA polymorphisms may contribute to CAD prevalence.

Prognostic value of preoperative N-terminal pro-brain natriuretic peptide in non-cardiac surgery of elderly patients with normal left ventricular systolic function.

AIM: We investigated the prognostic value of preoperative N-terminal pro-brain natriuretic peptide (NT-proBNP) in non-cardiac surgery in elderly patients who showed normal left ventricular function on preoperative echocardiography. METHODS: We analyzed 1459 patients aged older than 70 years who had consulted a cardiologist for the evaluation of cardiovascular risk for non-cardiac surgery. Of the 721 patients who simultaneously underwent echocardiography and NT-proBNP assessments, 506 who showed normal left ventricular systolic function were included. The predictive power of NT-proBNP for the risk of major adverse cardiac and cerebrovascular events (MACCE) was evaluated. RESULTS: MACCE occurred in 40 (7.9%) of the 506 patients, and the median value of NT-proBNP was higher in patients with complications than in those without (MACCE group: 1700.5 pg/mL vs non MACCE group: 206.35 pg/mL; P < 0.001). The area under the receiver operating characteristic curve was 0.804 (P < 0.001), with an optimal cut-off of 425.3 pg/mL. Multivariate analysis showed that increased NT-proBNP (>425.3 pg/mL; odds ratio 6.381; P < 0.001) was the only independent risk factor for the prediction of MACCE. CONCLUSIONS: In elderly patients who showed normal left ventricular systolic function on echocardiography, measurement of preoperative NT-proBNP concentration might be a useful test for predicting the occurrence of MACCE after non-cardiac surgery. Geriatr Gerontol Int 2016; 16: 1109-1116.

Comparison between audio-only and audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy.

PURPOSE: To compare audio-only biofeedback to conventional audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy, limiting damage to healthy surrounding tissues caused by organ movement. MATERIALS AND METHODS: Six healthy volunteers were assisted by audiovisual or audio-only biofeedback systems to regulate their respirations. Volunteers breathed through a mask developed for this study by following computer-generated guiding curves displayed on a screen, combined with instructional sounds. They then performed breathing following instructional sounds only. The guiding signals and the volunteers' respiratory signals were logged at 20 samples per second. RESULTS: The standard deviations between the guiding and respiratory curves for the audiovisual and audio-only biofeedback systems were 21.55% and 23.19%, respectively; the average correlation coefficients were 0.9778 and 0.9756, respectively. The regularities between audiovisual and audio-only biofeedback for six volunteers' respirations were same statistically from the paired t-test. CONCLUSION: The difference between the audiovisual and audio-only biofeedback methods was not significant. Audio-only biofeedback has many advantages, as patients do not require a mask and can quickly adapt to this method in the clinic.

Association of insulin resistance and coronary artery remodeling: an intravascular ultrasound study.

BACKGROUND: There are few studies that investigated the correlation between insulin resistance (IR) and the coronary artery remodeling. The aim of the study is to investigate the association of IR measured by homeostasis model assessment of insulin resistance (HOMA-IR) and coronary artery remodeling evaluated by intravascular ultrasound (IVUS). METHODS: A total of 298 consecutive patients who received percutaneous coronary interventions under IVUS guidance were retrospectively enrolled. The value of HOMA-IR more than 2.5 was considered as IR positive. Metabolic syndrome was classified according to NCEP ATP III guidelines. The remodeling index was defined as the ratio of the external elastic membrane (EEM) area at the lesion site to the EEM area at the proximal reference site. RESULTS: A total of 369 lesions were analyzed (161 lesions in HOMA-IR positive and 208 lesions in HOMA-IR negative). Remodeling index was significantly higher in the HOMA-IR positive group compared with the negative group (HOMA-IR positive vs. negative: 1.074 ± 0.109 vs. 1.042 ± 0.131, p = 0.013). There was a significant positive correlation between remodeling index and HOMA-IR (p = 0.010). Analysis of HOMA-IR according to remodeling groups showed increasing tendency of HOMA-IR, and it was statistically significant (p = 0.045). Multivariate analysis revealed that only HOMA-IR was an independent predictor of remodeling index (r = 0.166, p = 0.018). CONCLUSION: Increased IR estimated by HOMA-IR was significantly associated with a higher remodeling index and positive coronary artery remodeling.

Development of a 3D optical scanner for evaluating patient-specific dose distributions.

PURPOSE: This paper describes the hardware and software characteristics of a 3D optical scanner (P3DS) developed in-house. The P3DS consists of an LED light source, diffuse screen, step motor, CCD camera, and scanner management software with 3D reconstructed software. MATERIALS AND METHOD: We performed optical simulation, 2D and 3D reconstruction image testing, and pre-clinical testing for the P3DS. We developed the optical scanner with three key characteristics in mind. First, we developed a continuous scanning method to expand possible clinical applications. Second, we manufactured a collimator to improve image quality by reducing scattering from the light source. Third, we developed an optical scanner with changeable camera positioning to enable acquisition of optimal images according to the size of the gel dosimeter. RESULTS: We confirmed ray-tracing in P3DS with optic simulation and found that 2D projection and 3D reconstructed images were qualitatively similar to the phantom images. For pre-clinical tests, the dose distribution and profile showed good agreement among RTP, optical CT, and external beam radiotherapy film data for the axial and coronal views. The P3DS has shown that it can scan and reconstruct for evaluation of the gel dosimeter within 1 min. We confirmed that the P3DS system is a useful tool for the measurement of 3D dose distributions for 3D radiation therapy QA. Further experiments are needed to investigate quantitative analysis for 3D dose distribution.

Delayed embolisation of amplatzer ASD closure device caused partial obstruction of left ventricular outflow tract.

A 54-year-old male presented with symptoms of dyspnoea, and oedema of the lower extremities. Transthoracic echocardiography (TTE) revealed secondum-type atrial septal defect (ASD). He successfully received a 30-mm Amplatzer ASD closure device percutaneously. Echocardiography immediately after the procedure and the next day showed a well-positioned device. He was discharged the next day on 100 mg aspirin daily and warfarinisation due to atrial fibrillation. A month later, he revisited the hospital due to recurrence of dyspnoea and a grade 2 systolic murmur was heard on the left parasternal border. A chest X-ray showed abnormal location of the closure device and TTE revealed re-appearance of the ASD and an embolised Amplatzer device in the left ventricular outflow tract (LVOT) with partial obstruction. He requested surgery to remove the Amplatzer device and received an ASD patch repair, tricuspid valve repair and modified Maze operation concurrently. He is now in routine follow up without any other complications.

Development of a one-stop beam verification system using electronic portal imaging devices for routine quality assurance.

In this study, a computer-based system for routine quality assurance (QA) of a linear accelerator (linac) was developed by using the dosimetric properties of an amorphous silicon electronic portal imaging device (EPID). An acrylic template phantom was designed such that it could be placed on the EPID and be aligned with the light field of the collimator. After irradiation, portal images obtained from the EPID were transferred in DICOM format to a computer and analyzed using a program we developed. The symmetry, flatness, field size, and congruence of the light and radiation fields of the photon beams from the linac were verified simultaneously. To validate the QA system, the ion chamber and film (X-Omat V2; Kodak, New York, NY) measurements were compared with the EPID measurements obtained in this study. The EPID measurements agreed with the film measurements. Parameters for beams with energies of 6 MV and 15 MV were obtained daily for 1 month using this system. It was found that our QA tool using EPID could substitute for the film test, which is a time-consuming method for routine QA assessment.

Guiding curve based on the normal breathing as monitored by thermocouple for regular breathing.

Adapting radiation fields to a moving target requires information continuously on the location of internal target by detecting it directly or indirectly. The aim of this study is to make the breathing regular effectively with minimizing stress to the patient. A system for regulating patient's breath consists of a respiratory monitoring mask (ReMM), a thermocouple module, a screen, inner earphones, and a personal computer. A ReMM with thermocouple was developed previously to measure the patient's respiration. A software was written in LabView 7.0 (National Instruments, TX), which acquires respiration signal and displays its pattern. Two curves are displayed on the screen: One is a curve indicating the patient's current breathing pattern; the other is a guiding curve, which is iterated with one period of the patient's normal breathing curve. The guiding curves were acquired for each volunteer before they breathed with guidance. Ten volunteers participated in this study to evaluate this system. A cycle of the representative guiding curve was acquired by monitoring each volunteer's free breathing with ReMM and was then generated iteratively. The regularity was compared between a free breath curve and a guided breath curve by measuring standard deviations of amplitudes and periods of two groups of breathing. When the breathing was guided, the standard deviation of amplitudes and periods on average were reduced from 0.0029 to 0.00139 (arbitrary units) and from 0.359 s to 0.202 s, respectively. And the correlation coefficients between breathing curves and guiding curves were greater than 0.99 for all volunteers. The regularity was improved statistically when the guiding curve was used.

Rectum dose analysis employing a multi-purpose brachytherapy phantom.

PURPOSE: It is difficult to reproduce a brachytherapy measurement because of changes in the rectal shape during inter-fraction. We constructed a multi-purpose brachytherapy phantom (MPBP) and reproduced the same conditions found in actual therapy. We further attempted to apply the measured optimal dose to reduce rectal complications. METHODS: A measured dose was administered at rectal reference point R1 using a diode detector in four patients who used a tandem and ovoid in brachytherapy for carcinoma of the cervix. A total number of 20 rectal dose measurements were performed five times per patient. In addition, discrepancies in the set-up of the diode detector were analyzed with each repetitive measurement. After reproducing the same conditions as found in actual therapy using a multi-function applicator (MFA) in the multi-purpose brachytherapy phantom constructed for this study, the dose was measured at reference points in the rectum using a thermoluminescence dosimeter (TLD). RESULTS: According to the discrepancies measured in the set-up using a diode detector, Patient 1 showed a maximum value of 11.25 +/- 0.95 mm in the Y direction, Patients 2 and 3 exhibited 9.90 +/- 2.40 mm and 20.85 +/- 4.50 mm in the Z direction, respectively. Patient 4 showed 19.15 +/- 3.33 mm in the Z direction. In addition, values of the mean dose according to the position of the diode detector were recorded as 122.82 +/- 7.96-323.78 +/- 11.16 cGy. In the measured results for TLD in an MPBP, relative error for Patients 1 and 4 at the rectal reference point R2 were a maximum of 8.6 and 7.7%, respectively. For Patients 2 and 3 they were 1.7 and 1.2%, respectively. Furthermore, the dose measured at point R1 and R2 exhibited values approximately 1.7-8.6% higher than the dose calculated in advance, excluding point R1 in Patient 2. The discrepancies in the set-up owing to repetitive measurements and alterations in dosage according to these changes were not analyzed. It was evident that the relative error between the calculated and measured value was within 15%, which was allowable according to the recommendations by the American Association of Physicists in Medicine (AAPM). CONCLUSIONS: The multi-purpose brachytherapy phantom constructed for this study successfully reproduced an optimal dose measured under the same conditions found in actual therapy in which the dose was precisely analyzed at a rectal reference point. In addition, these results were considered reliable and applicable for dose optimization before applying therapy using the measured data from the phantom in order to reduce rectal complications.