Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.

Background: Liver resection is the only curative therapeutic option for intrahepatic cholangiocarcinoma (ICC), but the approach to recurrent ICC is controversial. This study analysed the outcome of liver resection in patients with recurrent ICC. Methods: Demographic, radiological, clinical, operative, surgical pathological and follow-up data for all patients with a final surgical pathological diagnosis of ICC treated in a tertiary referral centre between 2001 and 2015 were collected retrospectively and analysed. Results: A total of 190 patients had liver resection for primary ICC. The 1-, 3- and 5-year overall survival (OS) rates were 74·8, 56·6 and 37·9 per cent respectively. Independent determinants of OS were age 65 years or above (hazard ratio (HR) 2·18, 95 per cent c.i. 1·18 to 4·0; P = 0·012), median tumour diameter 5 cm or greater (HR 2·87, 1·37 to 6·00; P = 0·005), preoperative biliary drainage (HR 2·65, 1·13 to 6·20; P = 0·025) and local R1-2 status (HR 1·90, 1·02 to 3·53; P = 0·043). Recurrence was documented in 87 patients (45·8 per cent). The mean(s.d.) survival time after recurrence was 16(17) months. Independent determinants of recurrence were median tumour diameter 5 cm or more (HR 1·71, 1·09 to 2·68; P = 0·020), high-grade (G3-4) tumour (HR 1·63, 1·04 to 2·55; P = 0·034) and local R1 status (HR 1·70, 1·09 to 2·65; P = 0·020). Repeat resection with curative intent was performed in 25 patients for recurrent ICC, achieving a mean survival of 25 (95 per cent c.i. 16 to 34) months after the diagnosis of recurrence. Patients deemed to have unresectable disease after recurrence received chemotherapy or chemoradiotherapy alone, and had significantly poorer survival. Conclusion: Patients with recurrent ICC may benefit from repeat surgical resection.

Antecedentes: La resección hepática es la única opción terapéutica curativa para el colangiocarcinoma intrahepático (intrahepatic colangiocarcinoma, iCCA), pero el enfoque terapéutico de la recidiva del iCCA es controvertido. En este estudio se analizaron los resultados de la resección hepática en pacientes con recidiva de un iCCA. Métodos: Se recopilaron de forma retrospectiva y se analizaron los datos demográficos, radiológicos, clínicos, quirúrgicos, de anatomía patológica y de seguimiento de todos los pacientes con diagnóstico anatomopatológico definitivo de iCCA en un centro de referencia terciario entre 2001 y 2015. Resultados: En total, 190 pacientes se sometieron a resección hepática por iCCA primario. La supervivencia global (overall survival, OS) a 1, 3 y 5 años fue del 75%, 57% y 38%, respectivamente. La edad de ≥ 65 años (cociente de riesgos instantáneos, hazard ratio, HR 2,2, i.c. del 95% 1,2­4,0, P = 0,012), la mediana del diámetro del tumor ≥ 5 cm (HR 2,9, i.c. del 95% 1,4­6,0, P = 0,005), el drenaje biliar preoperatorio (HR 2,6, i.c. del 95% 1,3­6,2, P = 0.025) y el estado local R1/2 (HR 1,9, i.c. del 95% 1,0­3,5, P = 0,043) fueron factores pronósticos independientes de la OS. La recidiva se documentó en 87 (45,8%) pacientes. El tiempo medio de supervivencia después de la recidiva fue de 16 ± 2 meses. Los factores pronósticos independientes de recidiva fueron la mediana del diámetro del tumor ≥ 5 cm (HR 1,7, i.c. del 95% 1,1­2,7, P = 0,020), el tumor de alto grado (G3­G4) (HR 1,6, i.c. del 95% 1,0­2,5, P = 0,034) y el estado local R1 (HR 1,7, i.c. del 95% 1,1­2,6, P = 0,020). La resección repetida con intención curativa se realizó en 25 pacientes con iCCA recidivado, con una supervivencia media de 25 meses (i.c. del 95% 16­34 meses) tras el diagnóstico de recidiva. Los pacientes que se consideraron no resecables después de la recidiva se sometieron a quimioterapia o quimiorradioterapia y presentaron una supervivencia significativamente peor. Conclusión: Los pacientes con recidiva de un iCCA pueden beneficiarse de la resección quirúrgica repetida.

An automatable platform for genotoxicity testing of nanomaterials based on the fluorometric γ-H2AX assay reveals no genotoxicity of properly surface-shielded cadmium-based quantum dots.

The large number of nanomaterial-based applications emerging in the materials and life sciences and the foreseeable increasing use of these materials require methods that evaluate and characterize the toxic potential of these nanomaterials to keep safety risks to people and environment as low as possible. As nanomaterial toxicity is influenced by a variety of parameters like size, shape, chemical composition, and surface chemistry, high throughput screening (HTS) platforms are recommended for assessing cytotoxicity. Such platforms are not yet available for genotoxicity testing. Here, we present first results obtained for application-relevant nanomaterials using an automatable genotoxicity platform that relies on the quantification of the phosphorylated histone H2AX (γ-H2AX) for detecting DNA double strand breaks (DSBs) and the automated microscope system AKLIDES® for measuring integral fluorescence intensities at different excitation wavelengths. This platform is used to test the genotoxic potential of 30 nm-sized citrate-stabilized gold nanoparticles (Au-NPs) as well as micellar encapsulated iron oxide nanoparticles (FeOx-NPs) and different cadmium (Cd)-based semiconductor quantum dots (QDs), thereby also searching for positive and negative controls as reference materials. In addition, the influence of the QD shell composition on the genotoxic potential of these Cd-based QDs was studied, using CdSe cores as well as CdSe/CdS core/shell and CdSe/CdS/ZnS core/shell/shell QDs. Our results clearly revealed the genotoxicity of the Au-NPs and its absence in the FeOx-NPs. The genotoxicity of the Cd-QDs correlates with the shielding of their Cd-containing core, with the core/shell/shell architecture preventing genotoxicity risks. The fact that none of these nanomaterials showed cytotoxicity at the chosen particle concentrations in a conventional cell viability assay underlines the importance of genotoxicity studies to assess the hazardous potential of nanomaterials.

[Identical oncological results with lower perioperative morbidity after laparoscopic liver resection : Results of a matched pair analysis]. / Identische onkologische Ergebnisse bei niedrigerer perioperativer Morbidität nach laparoskopischer Leberresektion : Ergebnisse einer Matched-Pair-Analyse.

BACKGROUND: Laparoscopic liver resection belongs to the standard repertoire in hepatobiliary surgery. The advantages and disadvantages are still the subject of controversial discussion. OBJECTIVE: The aim of the study was to compare the perioperative and long-term outcomes of laparoscopic and open liver resections. MATERIAL AND METHODS: All patients who underwent liver resection in the Department of Surgery at the certified liver center of the  municipal hospital Karlsruhe were analyzed. From a total of 268 hepatic resections 65 laparoscopic liver resections were identified and matched 1:1 with 65 open resections, based primarily on the extent of the resection and secondarily on diagnosis, age and gender of the patients. The demographic data, comorbidities, perioperative and long-term outcomes were compared. RESULTS: Both groups had comparable demographic parameters and comorbidities. Operation time, duration of intensive care stay and percentage of negative resection margins were comparable in both groups. The 30-day mortality was 0% and 90-day mortality 1.5% in both groups. The laparoscopic group showed lower intraoperative and postoperative transfusion rates (p < 0.001), shorter hospital stay (p < 0.001) and lower overall morbidity (p < 0.001). The 1-, 3- and 5-year overall and tumor-free survival of patients with colorectal liver metastases was comparable (p = 0.984; p = 0.947). The same applied for patients with hepatocellular carcinomas (p = 0.803; p = 0.935). CONCLUSION: Laparoscopic liver resections have identical long-term outcomes with lower overall morbidity. Laparoscopic liver resections offer advantages regarding transfusion rates, length of hospital stay and postoperative complications.

[Standards for treatment in forensic committment according to § 63 and § 64 of the German criminal code : Interdisciplinary task force of the DGPPN]. / Standards für die Behandlung im Maßregelvollzug nach §§ 63 und 64 StGB : Interdisziplinäre Task-Force der DGPPN.

People who have been convicted of a crime due to a severe mental disorder and continue to be dangerous as a result of this disorder may be placed in a forensic psychiatric facility for improvement and safeguarding according to § 63 and § 64 of the German Criminal Code (StGB). In Germany, approximately 9000 patients are treated in clinics for forensic psychiatry and psychotherapy on the basis of § 63 of the StGB and in withdrawal centers on the basis of § 64 StGB. The laws for treatment of patients in forensic commitment are passed by the individual States, with the result that even the basic conditions differ in the individual States. While minimum requirements have already been published for the preparation of expert opinions on liability and legal prognosis, consensus standards for the treatment in forensic psychiatry have not yet been published. Against this background, in 2014 the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology (DGPPN) commissioned an interdisciplinary task force to develop professional standards for treatment in forensic psychiatry. Legal, ethical, structural, therapeutic and prognostic standards for forensic psychiatric treatment should be described according to the current state of science. After 3 years of work the results of the interdisciplinary working group were presented in early 2017 and approved by the board of the DGPPN. The standards for the treatment in the forensic psychiatric commitment aim to initiate a discussion in order to standardize the treatment conditions and to establish evidence-based recommendations.

Transcutaneous sacral nerve stimulation for intraoperative verification of internal anal sphincter innervation.

BACKGROUND: The current standard for pelvic intraoperative neuromonitoring (pIONM) is based on intermittent direct nerve stimulation. This study investigated the potential use of transcutaneous sacral nerve stimulation for non-invasive verification of pelvic autonomic nerves. METHODS: A consecutive series of six pigs underwent low anterior rectal resection. For transcutaneous sacral nerve stimulation, an array of ten electrodes (cathodes) was placed over the sacral foramina (S2 to S4). Anodes were applied on the back, right and left thigh, lower abdomen, and intra-anally. Stimulation using the novel method and current standard were performed at different phases of the experiments under electromyography of the autonomic innervated internal anal sphincter (IAS). KEY RESULTS: Transcutaneous stimulation induced increase of IAS activity could be observed in each animal under specific cathode-anode configurations. Out of 300 tested configurations, 18 exhibited a change in the IAS activity correlated with intentional autonomic nerve damage. The damage resulted in a significant decrease of the relative area under the curve of the IAS frequency spectrum (P<.001). Comparison of the IAS spectra under transcutaneous and direct stimulation revealed no significant difference (after rectal resection: median 5.99 µV•Hz vs 7.78 µV•Hz, P=.12; after intentional nerve damage: median -0.27 µV•Hz vs 3.35 µV•Hz, P=.29). CONCLUSIONS AND INFERENCES: Non-invasive selective transcutaneous sacral nerve stimulation could be used for verification of IAS innervation.

Long-term control of olfactory neuroblastoma in a dog treated with surgery and radiation therapy.

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the nasal cavity in dogs that is thought to arise from specialised sensory neuroendocrine olfactory cells derived from the neural crest. CASE REPORT: An 8-year-old dog was presented for reclusiveness and pacing. On CT and MRI, a contract-enhancing mass was disclosed within the rostral fossa, extending caudally from the cribriform plate into the left nasal sinus. Surgical excision was performed and the diagnosis was histological grade III (Hyams grading scheme) olfactory neuroblastoma. Based on human CT criteria this was high stage (modified Kadish stage C). Surgical excision was incomplete and was followed by curative-intent radiation therapy using a linear accelerator to a total dose of 48 Gy. CONCLUSION: The dog survived 20 months after diagnosis. Although olfactory neuroblastoma is a rare tumour in dogs, aggressive local therapy may allow for prolonged survival, even when the tumour is advanced.

Contrast-enhanced ultrasound (CEUS) prediction of focal liver lesions in patients after liver transplantation in comparison to histopathology results.

PURPOSE: To investigate the value of contrast-enhanced ultrasound (CEUS) in histologic prediction of focal liver lesions after liver transplantation. MATERIALS AND METHODS: 10 focal liver lesions in 10 patients after liver transplantation were scanned using CEUS and the CEUS results were compared with the histopathological results. RESULTS: Among 10 focal liver lesions, 7 proofed to be histopathological benign and 3 lesions proofed to be histopathological malignant. All lesions (100%) were correctly report as benign or malignant in the report of the CEUS examination. CONCLUSION: CEUS can be helpful in the differentiation of benign and malignant focal liver lesions in patients after liver transplantation and can be used in clinical management of focal liver lesions.

Inpatient treatment of patients with acute idiopathic peripheral facial palsy: A population-based healthcare research study.

OBJECTIVES: To determine the inpatient management for patients with acute idiopathic facial palsy (IFP) in Thuringia, Germany. DESIGN: Population-based study. SETTING: All inpatients with IFP in all hospitals with departments of otolaryngology and neurology in 2012, in the German federal state, Thuringia. MAIN OUTCOME MEASURES: Patients' characteristics and treatment were compared between departments, and the probability of recovery was tested. RESULTS: A total of 291 patients were mainly treated in departments of otolaryngology (55%) and neurology (36%). Corticosteroid treatment was the predominant therapy (84.5%). The probability to receive a facial nerve grading (odds ratio [OR=12.939; 95% confidence interval [CI]=3.599 to 46.516), gustatory testing (OR=6.878; CI=1.064 to 44.474) and audiometry (OR=32.505; CI=1.485 to 711.257) was significantly higher in otolaryngology departments, but lower for cranial CT (OR=0.192; CI=0.061 to 0.602), cerebrospinal fluid examination (OR=0.024; CI=0.006 to 0.102). A total of 131 patients (45%) showed a recovery to House-Brackmann grade≤II. A pathological stapedial reflex test (Hazard ratio [HR]=0.416; CI=0.180 to 0.959) was the only independent diagnostic predictor of worse outcome. Prednisolone dose >500 mg (HR=0.579; CI 0.400 to 0.838) and no adjuvant physiotherapy (HR=0.568; CI=0.407 to 0.794) were treatment-related predictors of worse outcome. CONCLUSIONS: Inpatient treatment of IFP seems to be highly variable in daily practice, partly depending on the treating discipline and despite the availability of evidence-based guidelines. The population-based recovery rate was worse than reported in clinical trials.

Malignancies after liver transplantation: Value of contrast-enhanced ultrasound (CEUS).

PURPOSE: To evaluate the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and computed tomography (CT) in the diagnosis of malignancies after liver transplantation. MATERIALS AND METHODS: A total of 23 patients with suspicious liver masses after liver transplantation with initial imaging series between September 2006 and September 2015 were statistically analysed. CEUS and CT were compared in their diagnosis of malignancy with CT being the gold standard. Out of 23 patients 9 patients showed malignant masses in CT, which could also be detected in 7 out 9 of cases using CEUS. RESULTS: CEUS showed a sensitivity of 77.8%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 87,5% in comparison with CT being the gold standard. In 2 cases CT showed a malignancy, contrary to the CEUS examination that was reported as normal. CONCLUSION: CEUS seems to be an alternative option for the evaluation of malignant masses in liver transplant patients. CEUS shows a high specificity and PPV in the detection of malignant liver masses.

Vascular complications in liver transplantation: Beneficial role of contrast-enhanced ultrasound (CEUS) in the postoperative phase.

PURPOSE: To compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and computed tomography (CT) in the diagnosis of vascular complications after liver transplantation in the postoperative phase. MATERIALS AND METHODS: A total of 60 patients with elevated liver function tests after liver transplantation with initial imaging studies between July 2005 and November 2015 were retrospectively analysed. CEUS and CT were compared in their diagnosis of vascular complications and CT was considered as the gold standard. Out of 60 patients 28 patients showed vascular complications in CT, which could also be detected in 25 out 28 of cases using CEUS. Diagnostic accuracy was tested by using the CT diagnosis as the gold standard. RESULTS: CEUS showed a sensitivity of 89.3%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 91,4% compared to CT as the gold standard. In 3 cases CT showed a vascular complication, whereas the CEUS examination was reported as normal. CONCLUSION: CEUS is a fast, non-ionizing imaging modality for the initial exclusion of vascular complications after liver transplantation. CEUS shows a high specificity and PPV in the detection of vascular complications. In unclear cases CT still is considered as the gold standard.

Comparison of magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in the evaluation of unclear solid renal lesions.

PURPOSE: To compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI) in the evaluation of unclear renal lesions to the histopathological outcome. MATERIALS AND METHODS: A total of 36 patients with a single unclear solid renal lesion with initial imaging studies between 2005 and 2015 were included. CEUS and MRI were used for determining malignancy or benignancy and initial findings were correlated with the histopathological outcome. Out of the 36 renal masses a total of 28 lesions were malignant (77.8%) and 8 were found to be benign (22.2%). Diagnostic accuracy was testes by using the histopathological diagnosis as the gold standard. RESULTS: CEUS showed a sensitivity of 96.4%, a specificity of 100.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 88,9%. MRI showed a sensitivity of 96.4%, a specificity of 75.0%, a PPV of 93.1% and a NPV of 85.7%. Out of the 28 malignant lesions a total of 18 clear cell renal carcinomas, 6 papillary renal cell carcinomas and 4 other malignant lesions, e.g. metastases, were diagnosed. Out of the 8 benign lesions a total 3 angiomyolipomas, 2 oncocytomas, 1 benign renal cyst and 2 other benign lesions, e.g. renal adenomas were diagnosed. Using CEUS, 1 lesion was falsely identified as benign. Using MRI, 2 lesions were falsely identified as benign and 1 lesion was falsely identified as malignant. CONCLUSION: CEUS is an useful method which can be additionally used to clinically differentiate between malignant and benign renal lesions. CEUS shows a comparable sensitivity, specificity, PPV and NPV to MRI. In daily clinical routine, patients with contraindications for other imaging modalities can particularly benefit using this method.

A rare case of recurrent malignant triton tumor in a male with NF1: Case report and mini-review.

BACKGROUND: Malignant triton tumors (MTT) represent a rare subset of tumors with rhabdomyoblastic differentiation within the heterogeneous group of malignant peripheral nerve sheath tumors (MPNST). CASE PRESENTATION: Here, we report on a case of a 25 year-old male with a history of neurofibromatosis type I and MTT of the mediastinal wall who presented in our clinic with a pelvic tumor and multiple hypervascular mesenteric masses and underwent resection. Upon resection, histological findings revealed an MTT of the omentum and an atypical neurofibroma of the pelvis with focal transitions to a low-grade MPNST. The patient relapsed just one month later and died 3 months after the surgery. CONCLUSION: Clinically, MTTs are characterized as highly aggressive tumors that are fast-growing and prone to local recurrence and distant metastasis. To date, there is no treatment consensus available yet and many patients succumb to the disease shortly after diagnosis. This is because the pathogenesis of MTT remains unknown and patients with MTT are often diagnosed at a late stage of disease. Our case presents valuable teaching points in terms of providing a possible progression model based on the coexistence of a low-grade MPNST and MTT in the context of NF1 and an atypical neurofibroma in this patient. Close monitoring of patients with NF1 and atypical neurofibromas or MPNST might therefore help to diagnose MTT at an earlier stage.

A molecular view of the role of chirality in charge-driven polypeptide complexation.

Polyelectrolyte molecules of opposite charge are known to form stable complexes in solution. Depending on the system conditions, such complexes can be solid or liquid. The latter are known as complex coacervates, and they appear as a second liquid phase in equilibrium with a polymer-dilute aqueous phase. This work considers the complexation between poly(glutamic acid) and poly(lysine), which is of particular interest because it enables examination of the role of chirality in ionic complexation, without changes to the overall chemical composition. Systematic atomic-level simulations are carried out for chains of poly(glutamic acid) and poly(lysine) with varying combinations of chirality along the backbone. Achiral chains form unstructured complexes. In contrast, homochiral chains lead to formation of stable ß-sheets between molecules of opposite charge, and experiments indicate that ß-sheet formation is correlated with the formation of solid precipitates. Changes in chirality along the peptide backbone are found to cause "kinks" in the ß-sheets. These are energetically unfavorable and result in irregular structures that are more difficult to pack together. Taken together, these results provide new insights that may be of use for the development of simple yet strong bioinspired materials consisting of ß-rich domains and amorphous regions.

[Methotrexate-associated photosensitization]. / Photosensibilisierung durch Methotrexat.

BACKGROUND: Methotrexate (MTX), alongside fumaric acid esters, is the most commonly used drug in the systemic therapy of psoriasis in Germany. It is sometimes used in combination with topical therapy and/or phototherapy due to synergistic effects. CASE REPORT: Here we describe a case of phototoxic dermatitis during treatment with MTX. Other cutaneous side effects of MTX include so-called UV recall, radiation recall, and skin tumor formation.

Population-based analysis of tonsil surgery and postoperative hemorrhage.

Although tonsil surgery is one of the most frequent otorhinolaryngological procedures, not many population-based regional or country-wide studies are published on the incidence of postoperative bleeding and its risk factors. 2,216 patients underwent tonsil surgery in 2012 in Thuringia, a federal state in Germany. Most frequent indications were recurrent tonsillitis (44 % of all cases), tonsillar abscess (27 %), and tonsillar hyperplasia (20 %). 29 % of the patients were <10 years of age. Most frequent methods of surgery were tonsillectomy (73 %) and tonsillotomy (19 %). 215 patients (10 %) had 221 events of a postoperative hemorrhage. Re-surgery for hemostasis was necessary in 137 patients (6 %). The interval to re-surgery was 4.4 ± 4.6 days. The re-surgery rate was 8, 0.2, and 15 % after tonsillectomy, tonsillotomy, and radical tonsillectomy, respectively. In cases of recurrent tonsillitis, male gender (p < 0.001), age >24.78 years (median; (p = 0.018), and waiving of perioperative antibiotics (p = 0.029) were independent factors associated with hemorrhage. In cases of tonsillar hyperplasia tonsillectomy instead of tonsillotomy, the only significant risk factor was postoperative hemorrhage (p = 0.005). The overall incidence of tonsillar surgery was 87.6/100,000. The highest incidence was seen for patients 3-4 years of age with 862.7/100,000. In children <10 years, the incidence was always higher for boys than for girls. Throughout all age groups, a reverse gender relation was only seen, if surgery was indicated for recurrent tonsillitis. We recommend establishing national guidelines for indication of tonsil surgery, especially of tonsillectomy, including recommendations for perioperative care to decrease variations in tonsil surgery rates and minimize postoperative complications.

High Resolution Imaging of Viscoelastic Properties of Intracranial Tumours by Multi-Frequency Magnetic Resonance Elastography.

PURPOSE: In recent years Magnetic Resonance Elastography (MRE) emerged into a clinically applicable imaging technique. It has been shown that MRE is capable of measuring global changes of the viscoelastic properties of cerebral tissue. The purpose of our study was to evaluate a spatially resolved three-dimensional multi-frequent MRE (3DMMRE) for assessment of the viscoelastic properties of intracranial tumours. METHODS: A total of 27 patients (63 ± 13 years) were included. All examinations were performed on a 3.0 T scanner, using a modified phase-contrast echo planar imaging sequence. We used 7 vibration frequencies in the low acoustic range with a temporal resolution of 8 dynamics per wave cycle. Post-processing included multi-frequency dual elasto-visco (MDEV) inversion to generate high-resolution maps of the magnitude |G*| and the phase angle φ of the complex valued shear modulus. RESULTS: The tumour entities included in this study were: glioblastoma (n = 11), anaplastic astrocytoma (n = 3), meningioma (n = 7), cerebral metastasis (n = 5) and intracerebral abscess formation (n = 1). Primary brain tumours and cerebral metastases were not distinguishable in terms of |G*| and φ. Glioblastoma presented the largest range of |G*| values and a trend was delineable that glioblastoma were slightly softer than WHO grade III tumours. In terms of φ, meningiomas were clearly distinguishable from all other entities. CONCLUSIONS: In this pilot study, while analysing the viscoelastic constants of various intracranial tumour entities with an improved spatial resolution, it was possible to characterize intracranial tumours by their mechanical properties. We were able to clearly delineate meningiomas from intraaxial tumours, while for the latter group an overlap remains in viscoelastic terms.

Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12 -receptor.

BACKGROUND: The G-protein-coupled P2Y12 -receptor plays a crucial role in platelet aggregation. Recently, ticagrelor was licensed as the first perorally active and reversible P2Y12 -receptor antagonist. OBJECTIVE: The present study investigated the site and the antagonistic mode of action of ticagrelor at wild-type or mutant human P2Y12 -receptors. METHODS: Recombinant wild-type or mutant human P2Y12 -receptors were stably expressed in Chinese hamster ovary Flp-In cells. Receptor function was assessed by quantification of ADP- and 2-methylthio-ADP-mediated inhibition of forskolin-induced cellular cAMP production either using a [(3) H]cAMP-radioaffinity assay or a cAMP response element-driven luciferase reporter gene assay. RESULTS: The natural agonist ADP inhibited forskolin-induced cAMP formation at the wild-type P2Y12 -receptor with a lower potency (EC50 209 nm) than the synthetic agonist 2-methylthio-ADP (EC50 1.0 nm). Ticagrelor shifted the concentration-response curves of both agonists in a parallel and surmountable manner to the right. Increasing concentrations of ticagrelor caused increasing shifts. Schild-plot analysis revealed pA2 values of 8.85 for ticagrelor against ADP, and 8.69 against 2-methylthio-ADP, and slopes of the regression lines not different from unity. In cells expressing a recombinant C194A(5.43) -mutant P2Y12 -receptor construct, ticagrelor lost antagonistic potency when tested against ADP or 2-methylthio-ADP. CONCLUSIONS: The experiments reveal a surmountable and competitive mode of antagonism of ticagrelor at P2Y12 -receptors activated by either the natural agonist ADP or the synthetic agonist 2-methylthio-ADP. Cys194(5.43) is likely to be involved in the interaction of ticagrelor with ADP and 2-methylthio-ADP. The data give new insights into the site and mode of action of ticagrelor at the human P2Y12 -receptor.

Short-term intravenous fish-oil emulsions in pediatric oncologic patients--effect on liver parameters.

Pediatric oncologic patients often need parenteral nutrition (PN) during chemotherapy. Long-term use of soybean-based lipid emulsions is associated with progressive liver disease and cholestasis, whereas fish-oil based emulsions have anticholestatic effects. We studied the potentially hepato-protective effects of short-term use of SMOF lipids in children undergoing chemotherapy. Fifteen pediatric oncologic patients treated with SMOF lipids were retrospectively analyzed in respect to bilirubin and liver parameters and compared to matched-controls who had received soybean-based fat emulsions. For statistics the time-points baseline, Day 14 of PN (PN14), and post (Day+7) were chosen. None of the study patients developed cholestasis. Within the SMOF-lipid group there were no differences in the laboratory parameters between baseline, PN14, and post. In the control group, gamma glutamyltransferase (γGT) levels increased during PN (baseline vs. PN14, 26.43 vs. 63.00 U/l, P < 0.05). Lactate dehydrogenase (LDH) levels showed a significantly different behavior in the 2 groups: In the SMOF lipids group, LDH decreased whereas it increased in the controls (-32.75 U/l vs. + 29.57 U/l, P < 0.05). An advantage of fish oil-based fat emulsions can be shown even after short-term PN. In children undergoing chemotherapy the use of soybean-based fat emulsions but not SMOF lipids led to increased γGT levels.

Dual regulation of ß2-adrenoceptor messenger RNA expression in human lung fibroblasts by ß2-cAMP signaling; delayed upregulated inhibitors oppose a rapid in onset, direct stimulation of gene expression.

Based on their bronchodilatory effect, ß2-adrenoceptor agonists constitute essential elements in the treatment of bronchial asthma and COPD. As treatment with ß2-adrenoceptor agonists has been associated with worsening of airway hyper-reactivity, possibly because of loss of ß-adrenoceptor function, molecular mechanism of the regulation of ß2-adrenoceptor expression were studied. MRC-5 human lung fibroblasts were cultured in absence or presence of test substances followed by ß2-adrenoceptor messenger RNA (mRNA) determination by qPCR. After inhibition of mRNA synthesis by actinomycin D, ß2-adrenoceptor mRNA decreased with a half-life of 23 min, whereas inhibition of protein synthesis by cycloheximide caused an about 5- and 6-fold increase within 1.5 and 4 h, respectively. ß2-Adrenoceptor mRNA was increased by about 100 % after 1 h exposure to formoterol or olodaterol but decreased by about 60 % after 4 h agonist exposure. Both effects of ß2-adrenoceptor agonists were mimicked by forskolin, a direct activator of adenylyl cyclase and cholera toxin, which stimulates adenylyl cyclase by permanent activation of Gs. ß2-Adrenoceptor agonist-induced upregulation of ß2-adrenoceptor mRNA was blocked by the ß2-adrenoceptor antagonist ICI 118551 and prevented by actinomycin D, but not by cycloheximide. Moreover, in presence of cycloheximide, ß2-adrenoceptor agonist-induced reduction in ß2-adrenoceptor mRNA was converted into stimulation, resulting in a more than 10-fold increase. In conclusion, expression of ß2-adrenoceptors in human lung fibroblasts is highly regulated at transcriptional level. The ß2-adrenoceptor gene is under strong inhibitory control of short-living suppressor proteins. ß2-Adrenoceptor activation induces via adenylyl cyclase - cyclic adenosine monophosphate (cAMP) signaling a rapid in onset direct stimulation of the ß2-adrenoceptor gene transcription, an effect opposed by a delayed upregulation of inhibitory factors.

Efficacy, patient-reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for the reduction of unwanted submental fat: results from a phase III, randomized, placebo-controlled study.

BACKGROUND: Unwanted submental fat (SMF) may result in an unattractive chin profile and dissatisfaction with appearance. An approved and rigorously tested non-surgical method for SMF reduction is lacking. OBJECTIVE: To evaluate the efficacy and safety of ATX-101 for the pharmacological reduction of unwanted SMF in a phase III randomized, double-blind, placebo-controlled study. METHODS: Patients (n = 360) with moderate or severe SMF were randomized to receive ATX-101 1 or 2 mg/cm(2) or placebo injected into their SMF for up to four treatments ~28 days apart, with a 12-week follow-up. Coprimary efficacy endpoints were the proportions of treatment responders, defined as a ≥1-point reduction in SMF on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS), and those satisfied with their appearance in association with their face and chin after treatment on the Subject Self-Rating Scale (SSRS score ≥4). Secondary efficacy endpoints included a ≥1-point improvement in SMF on the Patient-Reported Submental Fat Rating Scale (PR-SMFRS) and changes in the Patient-Reported Submental Fat Impact Scale (PR-SMFIS). Additional patient-reported outcomes and changes in the Skin Laxity Rating Scale were recorded. Adverse events (AEs) and laboratory test results were monitored. RESULTS: Compared with placebo, a greater proportion of patients treated with ATX-101 1 and 2 mg/cm(2) showed a ≥1-point improvement in CR-SMFRS (58.3% and 62.3%, respectively, vs. 34.5% with placebo; P < 0.001) and patient satisfaction (SSRS score ≥4) with the appearance of their face and chin (68.3% and 64.8%, respectively, vs. 29.3%; P < 0.001). Patient-reported secondary efficacy endpoints showed significant improvements in SMF severity (PR-SMFRS; P = 0.009 for ATX-101 1 mg/cm(2) , P < 0.001 for ATX-101 2 mg/cm(2) vs. placebo) and emotions and perceived self-image (PR-SMFIS; P < 0.001). No overall worsening of skin laxity was observed. AEs were mostly transient, mild to moderate in intensity and localized to the treatment area. CONCLUSION: ATX-101 was effective and well tolerated, and may be an alternative to surgery for patients desiring improvement of their submental profile.