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The gastric [H.sup.+], [K.sup.+]-ATPase of the parietal cell is responsible for acid secretion in the stomach and is the main target in the pharmacological treatment of acid-related diseases. Omeprazole and other benzimidazole drugs, although having delayed efficacy if taken orally, have high success rates in the treatment of peptic ulcer disease. Potassium competitive acid blockers (P-CAB) compete with K+ for binding to the [H.sup.+], [K.sup.+]-ATPase and thereby they inhibit acid secretion. In this study, the in vitro properties of AZD0865, a reversible [H.sup.+], [K.sup.+]-ATPase inhibitor of gastric acid secretion, are described. We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand-dissected rat gastric glands. Glands were stimulated with histamine (100 [micro]M) and exposed to a bicarbonate- and [Na.sup.+]-free perfusate to induce an acid load. [H.sup.+], [K.sup.+]-ATPase inhibition was determined by calculating phi recovery (dpH/dT) in the presence of omeprazole (10-200 [micro]M) or AZD0865 (0.01-100 [micro]M). The efficacies of both drugs were compared. Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100-fold lower dose than omeprazole (1 [micro]M AZD0865 vs. 100 [micro]M omeprazole). This study demonstrates that AZD0865 is a potent, fast-acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore, these data strongly suggest that AZD0865 has great potential as a fast-acting, low-dose inhibitor of acid secretion. potassium competitive acid blockers; gastric acid secretion; pH measurements; gastroesophageal reflux disease

The gastric H+,K+-ATPase of the parietal cell is responsible for acid secretion in the stomach and is the main target in the pharmacological treatment of acid-related diseases. Omeprazole and other benzimidazole drugs, although having delayed efficacy if taken orally, have high success rates in the treatment of peptic ulcer disease. Potassium competitive acid blockers (P-CAB) compete with K+ for binding to the H+,K+-ATPase and thereby they inhibit acid secretion. In this study, the in vitro properties of AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion, are described. We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand-dissected rat gastric glands. Glands were stimulated with histamine (100 µM) and exposed to a bicarbonate- and Na+-free perfusate to induce an acid load. H+,K+-ATPase inhibition was determined by calculating pHi recovery (dpH/dT) in the presence of omeprazole (10-200 µM) or AZD0865 (0.01-100 µM). The efficacies of both drugs were compared. Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100-fold lower dose than omeprazole (1 µM AZD0865 vs. 100 µM omeprazole). This study demonstrates that AZD0865 is a potent, fast-acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore, these data strongly suggest that AZD0865 has great potential as a fast-acting, low-dose inhibitor of acid secretion. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) dysfunction is recognized as a cardinal prognostic marker in systolic heart failure patients. Conflicting data exist on the interaction of RV function and left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT). This prospective monocentric trial was set up to assess the predictive value of baseline RV function and corresponding RV-pulmonary artery (PA) coupling on LV reverse remodeling after CRT., Methods: 110 patients with a CRT indication were prospectively enrolled. RV function and RV-PA interaction were analyzed at baseline using echocardiographic and invasive pressure-volume loop catheter approach. The primary endpoint was reverse LV remodeling (CRT-responder) defined as a reduction in LV end-systolic volume of ≥15% at 6 months., Results: Responders had higher RV-PA coupling ratios (single-beat end-systolic elastance/PA elastance: Ees/Ea) at baseline, which corresponded to smaller RVs with better ejection fraction and lower afterload. After multivariate adjustment, the baseline Ees/Ea remained an independent predictor for LV response (OR 14.0 [1.5-130.8], p = 0.021). Normal coupling (Ees/Ea ≥ 1) was associated with higher responder rates (RR) (86%). Progressive uncoupling was associated with lower LV-RR (Ees/Ea ≤ 1-0.5: 57%, and Ees/Ea < 0.5: 32%, p < 0.001), corresponded with higher degrees of LV impairment and severity of mitral regurgitation, and was independently associated with an adverse outcome., Conclusions: A higher baseline RV-PA coupling, reflecting a lower degree of LV-induced pulmonary hypertension and secondary RV-dysfunction, is associated with an improved LV-reverse remodeling and is independently associated with better prognosis. The value of RV-PA ratio as potential guide for CRT patient selection warrants further investigation. Clinical Trial Registration - URL: http://www.drks.de. Unique Identifier: DRKS00011133., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to evaluate the efficacy, safety and predictive factors of RFA of primary and secondary lung malignancies., Patients and Methods: 79 patients with 129 primary and secondary lung malignancies were enrolled in a retrospective study. We treated 74 pulmonary metastases of colorectal cancer, 13 malignant melanoma lesions, 13 renal cancer metastases, 5 primary lung malignancies and 24 tumors of other different entities. All patients were considered to be unsuitable candidates for surgery, radiotherapy or chemotherapy. The primary endpoint was local tumor control, secondary endpoints were overall survival, safety and predictive factors, e.g. distance to pleura, vessels and bronchi., Results: The median tumor size was 1.2 cm (0.5-3.0 cm). After a median follow-up of 14 months (3-81 months), the LTC was 85.3 %. There were 34 lesions (26.4%) with complete remission, 48 (37.2 %) partial remission, 28 (21.7%) stable disease and 19 lesions (14.7%) with progressive disease. We evaluated an OS of 27 months. Pneumothorax in 19 cases (14.7%) and pleural effusion in 2 cases (1.6 %) were the leading complications (CTCAE, 5 grade III adverse events). The only significant influence regarding the outcome after RFA was the initial tumor size ( p = 0.01). Distance to vessel, bronchi, and pleura showed no significant effect ( p = 0.81; p = 0.82; p = 0.80)., Competing Interests: CONFLICTS OF INTEREST None.

Background: Cardiac magnetic resonance imaging (cMRI) has become the non-invasive reference standard for the evaluation of cardiac function and viability. The introduction of open, high-field, 1.0T (HFO) MR scanners offers advantages for examinations of obese, claustrophobic and paediatric patients.The aim of our study was to compare standard cMRI sequences from an HFO scanner and those from a cylindrical, 1.5T MR system., Material/method: Fifteen volunteers underwent cMRI both in an open HFO and in a cylindrical MR system. The protocol consisted of cine and unenhanced tissue sequences. The signal-to-noise ratio (SNR) for each sequence and blood-myocardium contrast for the cine sequences were assessed. Image quality and artefacts were rated. The location and number of non-diagnostic segments was determined. Volunteers' tolerance to examinations in both scanners was investigated., Results: SNR was significantly lower in the HFO scanner (all p<0.001). However, the contrast of the cine sequence was significantly higher in the HFO platform compared to the 1.5T MR scanner (0.685±0.41 vs. 0.611±0.54; p<0.001). Image quality was comparable for all sequences (all p>0.05). Overall, only few non-diagnostic myocardial segments were recorded: 6/960 (0.6%) by the HFO and 17/960 (1.8%) segments by the cylindrical system. The volunteers expressed a preference for the open MR system (p<0.01)., Conclusions: Standard cardiac MRI sequences in an HFO platform offer a high image quality that is comparable to the quality of images acquired in a cylindrical 1.5T MR scanner. An open scanner design may potentially improve tolerance of cardiac MRI and therefore allow to examine an even broader patient spectrum.

Background and Purpose: To evaluate the reconstruction accuracy of brachytherapy (BT) applicators tips in vitro and in vivo in MRI-guided (192)Ir-high-dose-rate (HDR)-BT of inoperable liver tumors., Materials and Methods: Reconstruction accuracy of plastic BT applicators, visualized by nitinol inserts, was assessed in MRI phantom measurements and in MRI (192)Ir-HDR-BT treatment planning datasets of 45 patients employing CT co-registration and vector decomposition. Conspicuity, short-term dislocation, and reconstruction errors were assessed in the clinical data. The clinical effect of applicator reconstruction accuracy was determined in follow-up MRI data., Results: Applicator reconstruction accuracy was 1.6±0.5 mm in the phantom measurements. In the clinical MRI datasets applicator conspicuity was rated good/optimal in ⩾72% of cases. 16/129 applicators showed not time dependent deviation in between MRI/CT acquisition (p>0.1). Reconstruction accuracy was 5.5±2.8 mm, and the average image co-registration error was 3.1±0.9 mm. Vector decomposition revealed no preferred direction of reconstruction errors. In the follow-up data deviation of planned dose distribution and irradiation effect was 6.9±3.3 mm matching the mean co-registration error (6.5±2.5 mm; p>0.1)., Conclusion: Applicator reconstruction accuracy in vitro conforms to AAPM TG 56 standard. Nitinol-inserts are feasible for applicator visualization and yield good conspicuity in MRI treatment planning data. No preferred direction of reconstruction errors were found in vivo., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To assess safety and efficacy of irreversible electroporation (IRE) of lung malignancies., Materials and Methods: Patients with primary and secondary lung malignancies and preserved lung function were included in this prospective single arm trial. Primary and secondary endpoints were safety and efficacy. Recruitment goal was 36 subjects in 2 centers. Patients underwent IRE under general anesthesia with probe placement performed in Fluoroscopy-CT. The IRE system employed was NanoKnife® (Angiodynamics). System settings for the ablation procedure followed the manufacturer's recommendations. The Mann-Whitney U test was used to evaluate the correlation of nine technical parameters with local tumor control. Median follow up was 12 months., Results: The expected efficacy was not met at interim analysis and the trial was stopped prematurely after inclusion of 23 patients (13/10 between both centers). The dominant tumor entity was colorectal (n = 13). The median tumor diameter was 16 mm (8-27 mm). Pneumothoraces were observed in 11 of 23 patients with chest tubes required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. 14/23 showed progressive disease (61 %). Stable disease was found in 1 (4 %), partial remission in 1 (4 %) and complete remission in 7 (30 %) patients. The relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p < 0.05). Needle tract seeding was found in three cases (13 %)., Conclusions: IRE is not effective for the treatment of lung malignancies. We hypothesize that the energy deposition with current IRE probes is highly sensitive to air exposure.

Objectives: The aims of our study were (1) to assess the feasibility, effectiveness, and safety of exclusively magnetic resonance (MR)-guided freehand percutaneous abscesses drainage using a 1.0-T open MR scanner and (2) to evaluate the optimal method to visualize drainage catheters in situ., Material and Methods: In vitro studies in a dedicated MR gelatin phantom were performed to assess visualization of 8 different sizes of drainage catheters after instillation of sole 0.9% sodium chloride (NaCl) and diluted (1.0%) or concentrated (12.0%) gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) using a T1-weighted (T1w) 2-dimensional fast field echo (FFE) and a T2-weighted single-shot (ssh) turbo spin-echo (TSE) fast dynamic sequence. The catheter artifacts were evaluated with regard to the contrast-to-noise ratio (CNR), the artifact width using the full width at half-maximum (FWHM) method, and the artifact intensity, being the product of the CNR and the FWHM. We used the general linear model procedure as the global test and the Tukey studentized range test for post hoc analysis. In vivo MR-guided freehand drainage was prospectively performed in patients with increased systemic inflammation markers and abdominal, retroperitoneal, and pelvic abscess collections. This study had been approved by the institutional review board. All patients provided written informed consent. Technical success was the primary efficacy variable. The secondary efficacy variables were visibility of the puncture needle and drainage catheter artifact, using a qualitative 5-point rating scale, intervention and procedure time, and rate of postinterventional complications., Results: The FWHM, the CNR, and the artifact intensity of the drainage catheters filled with 0.9% NaCl or diluted or concentrated Gd-DTPA increased according to the drainage catheter size in an almost linear fashion in both image weighting (all P ≤ 0.006; all R(2) ≥ 0.73). The T1w FFE sequence yielded the highest FWHM, CNR, and artifact intensity of all groups, using 12.0% Gd-DTPA instillation (all P < 0.001), and the least FWHM and artifact intensity, using 1.0% Gd-DTPA instillation (all P < 0.022; all P < 0.009). The T2w ssh TSE yielded higher FWHM, using 12.0% Gd-DTPA instillation, whereas the CNR was higher for 0.9% NaCl instillation (all P < 0.001). Magnetic-resonance-guided abscess drainage was performed in 22 patients with 24 abdominal, retroperitoneal, or pelvic abscess collections. The technical success rate of in vivo MR-guided freehand drainage was 100%. Visibility of the puncture needle was excellent (≥4.4 [0.5] points). Visibility of the drainage catheters was rated with 3.9 (0.9) and 4.5 (0.8) points using T2w ssh TSE with 0.9% NaCl and 12.0% Gd-DTPA instillation as well as 4.8 (0.5) and 4.2 (0.8) points using T1w FFE with 1.0% and 12.0% Gd-DTPA instillation, respectively. The procedure and intervention time was 52.4 (16.4) minutes (range, 28-78 minutes) and 27.4 (7.2) minutes (range, 17-40 minutes). Two minor and no major complications were recorded., Conclusions: Magnetic-resonance-guided freehand percutaneous abscesses drainage using fast dynamic sequences in an open 1-T MR scanner is feasible, effective, and safe. Visualization of drainage catheters can be facilitated by instillation of 0.9% NaCl or diluted or concentrated contrast media.

Aim: In combined positron emission tomography/computed tomography (PET/CT) of neuroendocrine neoplasms using (68)Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTATOC), partial volume effects (PVEs) may occur in smaller lesions. This study determined the lesional cutoff size for the occurrence of PVEs in a clinical setting., Methods: Retrospective assessment of 51 PET/CT examinations (16-slice PET/CT device) for malignant PET foci was carried out. In all foci, the maximal standardized uptake value (SUVmax) and maximal lesion diameter on axial CT was documented. Determined SUVmax and lesional sizes were correlated via LOESS regression. In the resulting curve, the cutoff point for SUVmax size dependency was determined visually and mathematically using 2 approximating straight lines., Results: In 45 patients, 313 of 413 PET foci found were malignant, measurable on CT and had a roughly spherical geometry (SUVmax: 2.5-103.3, mean ± SD 20.5 ± 15.18; CT diameter: 5-103 mm, mean ± SD 21.8 ± 13.1 mm). The cutoff lesional size for the occurrence of PVEs was 20.4 mm by the mathematical approach and 25 mm by visual assessment., Conclusion: In (68)Ga-DOTATOC imaging, the clinical lesional size threshold is far larger than expected from systemic resolution only. Thus, tracer uptake quantification is only acceptable in sufficiently large lesions., (Copyright © 2013 S. Karger AG, Basel.)

Unlabelled: The diagnostic value of neuroendocrine tumor (NET) imaging using PET with integrated CT is dependent on both components. This retrospective study assessed the value of the single CT phases of a triple-phase (early arterial, portal-venous inflow, and venous) CT protocol in comparison to (68)Ga-DOTATOC PET in a masked reading., Methods: (68)Ga-DOTATOC PET/CT examinations from 51 patients with known or suspected NET were included. Two readers assessed the data of PET and each of the 3 CT phases for NET lesions independently (using a 3-point score: 1 = benign, 2 = indeterminate, and 3 = malignant) and by consensus (using binary benign/malignant interpretation only). Only lesions within the field of the abdominal scan were evaluated. Clinical and imaging follow-up, histopathology (if available), and the decision of an interdisciplinary truth-panel served as a standard of reference. In addition to the calculation of standard statistical parameters (including general linear mixed models), interobserver reliability was estimated (Cohen's κ)., Results: Of 510 abdominal lesions observed, 354 were classified as malignant. Sensitivity was 77.1% for combined triple-phase CT, 53.4% for arterial CT, 66.1% for portal-venous CT, 66.9% for venous CT, and 72.8% for PET. The respective specificities were 85.3%, 92.9%, 92.3%, 89.7%, and 97.4%, and the respective accuracies were 79.6%, 65.5%, 74.1%, 73.9%, and 80.4%. Although arterial CT was found to be inferior to PET, portal-venous CT, and venous CT (P < 0.001), the differences between the other scans were not significant. Detection was exclusively by PET for 16.1% of lesions, by triple-phase CT for 20.3%, by arterial CT for 0.5%, by portal-venous CT for 3.9%, and by venous CT for 3.9%. Regarding interobserver reliability, the κ-value was 0.768 for PET, 0.391 for triple-phase CT, 0.577 for arterial CT, 0.583 for portal-venous CT, and 0.482 for venous CT., Conclusion: No CT phase can be omitted in NET imaging, and the triple-phase protocol continues to be strongly recommended also for PET/CT.

To date three potential candidates for parietal cell basolateral Cl(-) entry have been described: the highly 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)-sensitive Cl(-)/HCO(3)(-) exchanger AE2, the HCO(3)(-) and lowly DIDS-sensitive SLC26A7 protein, and the Na(+)-2Cl(-)K(+) cotransporter (NKCC1). In this study we investigate the contribution of these pathways to secretagogue stimulated acid secretion. Individually hand-dissected rat gastric glands were microfluorimetrically monitored for Cl(-) influx and pH(i) changes. Transporter activity was determined by varying ion content and through the use of pharmacological inhibitors. Expression of SLC26A7 in rat parietal cells was shown by immunohistochemistry and Western blot. SLC26A7 was inhibited by 5-Nitro-2-(3-phenylpropyl-amino)benzoic acid (NPPB) (100 microM) in the Xenopus laevis oocyte expression system. Cl(-) influx in parietal cells was enhanced by histamine, depended partially on endogenous HCO(3)(-) synthesis and completely on extracellular Na(+). Removal and subsequent readdition of Cl(-) revealed a low and a high DIDS-sensitive HCO(3)(-) extrusion system contributing to Cl(-) uptake. At acidic pH(i), however, H(+) extrusion via the H(+),K(+)-ATPase depending on Cl(-) uptake was abolished only in the presence of 100 microM (NPPB) and at high (250 microM) DIDS concentration. There was no effect of the NKCC inhibitor bumetanide on stimulated H(+) extrusion. These results would be compatible with SLC26A7 as a Cl(-) uptake system under histamine stimulation.

Gastric acid secretion is regulated by a variety of stimuli, in particular histamine and acetyl choline. In addition, dietary factors such as the acute intake of a protein-rich diet and the subsequent increase in serum amino acids can stimulate gastric acid secretion only through partially characterized pathways. Recently, we described in mouse stomach parietal cells the expression of the system L heteromeric amino acid transporter comprised of the LAT2-4F2hc dimer. Here we address the potential role of the system L amino acid transporter in gastric acid secretion by parietal cells in freshly isolated rat gastric glands. RT-PCR, western blotting and immunohistochemistry confirmed the expression of 4F2-LAT2 amino acid transporters in rat parietal cells. In addition, mRNA was detected for the B(0)AT1, ASCT2, and ATB(0+) amino acid transporters. Intracellular pH measurements in parietal cells showed histamine-induced and omeprazole-sensitive H+-extrusion which was enhanced by about 50% in the presence of glutamine or cysteine (1 mM), two substrates of system L amino acid transporters. BCH, a non-metabolizable substrate and a competitive inhibitor of system L amino acid transport, abolished the stimulation of acid secretion by glutamine or cysteine suggesting that this stimulation required the uptake of amino acids by system L. In the absence of histamine glutamine also stimulated H+-extrusion, whereas glutamate did not. Also, phenylalanine was effective in stimulating H+/K+-ATPase activity. Glutamine did not increase intracellular Ca2+ levels indicating that it did not act via the recently described amino acid modulated Ca2+-sensing receptor. These data suggest a novel role for heterodimeric amino acid transporters and may elucidate a pathway by which protein-rich diets stimulate gastric acid secretion.