Diagnostic Pathway From Incidental Mass to Metastatic Melanoma: Role of Multimodal Imaging and Medical Therapy.

We present a case of detection of a right atrial mass during surveillance echocardiography, mimicking myxoma. Cardiac magnetic resonance and computed tomography revealed infiltration into the pericardium, suggesting malignancy. Abdominal computed tomography showed multiple liver masses that were histologically positive for metastatic amelanotic melanoma. Under immunotherapy adequate remission was achieved.

Phoenix atherectomy for patients with peripheral artery disease.

BACKGROUND: Endovascular atherectomy enables minimally invasive plaque removal in peripheral artery disease (PAD). AIMS: We aimed to evaluate the safety and the long-term effectiveness of the Phoenix atherectomy for the treatment of complex and calcified lesions in PAD patients. METHODS: Consecutive all-comer patients with PAD underwent the Phoenix atherectomy. Device safety in terms of perforation and distal embolisation were evaluated. Lesion calcifications were categorised by the Peripheral Arterial Calcium Scoring System (PACSS) and lesion complexity was assessed by the Transatlantic Inter-Society Consensus (TASC). Clinically driven target lesion revascularisation (TLR) was assessed. RESULTS: A total of 558 lesions were treated in 402 consecutive patients. Clinical follow-up was available at 15.7±10.2 months for 365 (91%) patients. Of 402 patients, 135 (33.6%) had claudication, 37 (9.2%) had ischaemic rest pain and 230 (57%) exhibited ischaemic ulcerations. Lesions were mostly identified in the femoropopliteal segments (55%), followed by below-the-knee (BTK) segments (32%). Complex TASC C/D lesions and moderate to severe calcifications (PACSS score ≥2) were present in 331 (82%) and 323 (80%) patients, respectively. The mean lesion length was 20.6±14.3 cm. Five (1%) perforations and 10 (2%) asymptomatic embolisations occurred. Bail-out stenting was performed in 4%, 16% and 3% of patients with common femoral artery, femoropopliteal and BTK lesions, respectively. During follow-up, 5 (3.9%) patients with claudication and 52 (21.9%) patients with critical limb-threatening ischaemia (CLTI) died (hazard ratio [HR] 3.7; p<0.001). Freedom from TLR was 87.5% (112 of 128) in patients with claudication and 82.3% (195 of 237) in patients with CLTI, respectively (HR 1.8; p=0.03). CONCLUSIONS: The Phoenix atherectomy can be safely performed in patients with complex lesions with a relatively low rate of bail-out stenting and clinically acceptable TLR rates. GERMAN CLINICAL TRIALS REGISTER: DRKS00016708.

Clinical safety of low-dose anticoagulation with fondaparinux in patients undergoing peripheral endovascular treatment due to critical limb-threatening ischaemia - a pilot study.

AIMS: To evaluate the safety and effectiveness of fondaparinux in addition to dual antiplatelet therapy (DAPT) in patients with critical limb-threatening ischaemia (CLTI). METHODS: Fondaparinux (2.5 mg/d) was administered for 1-4 weeks after endovascular procedures together with DAPT (fondaparinux arm). Patients who received standard DAPT were retrospectively matched and generated the control arm. Demographic, angiographic and follow-up data, including (i) clinically relevant bleeding and (ii) target vessel revascularisation or major amputation after 12 months was analysed. RESULTS: Twenty-four patients (78.7 ± 6.9 years, 14 [58%] female, 4 TASC B, 10 TASC C and 10 TASC D lesions, total lesion length = 210 ± 98 mm, mean Rutherford class = 4.7 ± 0.6) received fondaparinux (over a period of 22 ± 9 d, range 7-28 d) and DAPT versus 24 control patients who received standard DAPT (78.3 ± 8.4 years, 14 [58%] female, 4 TASC B, 8 TASC C and 12 TASC D lesions, total lesion length = 204 ± 73 mm, mean Rutherford class = 4.6 ± 0.6). During follow-up, 3(13%) patients in the fondaparinux arm exhibited significant bleeding versus 5 (21%) in the control arm (p = ns). Four (17%) patients of the fondaparinux arm underwent target vessel revascularisation or major amputation versus 6 (25%) in the control group (p = ns). CONCLUSIONS: Adding fondaparinux to DAPT does not seem to result in excess of clinically relevant bleeding. Our preliminary data suggest that prospective studies are now warranted in larger patient cohorts. GERMAN CLINICAL TRIALS REGISTER: DRKS00015856.

Safety, effectiveness and mid-term follow-up in 136 consecutive patients with moderate to severely calcified lesions undergoing phoenix atherectomy.

To investigate the safety and effectiveness of the Phoenix atherectomy device for the treatment of complex and calcified lesions in patients with peripheral artery disease (PAD). 136 consecutive all-comer patients with chronic PAD underwent Phoenix atherectomy. Safety in terms of vessel injury and embolism, efficacy and clinical success in terms of ≥ 1Rutherford class (RF) improvement during follow-up were systematically analyzed. Lesion calcification was categorized by the Peripheral Arterial Calcium Scoring System (PACSS), whereas lesion complexity was classified by the Transatlantic Inter-Society Consensus (TASC). 151 lesions were treated in 136 consecutive patients. Clinical follow-up was available at 10.3 ± 4.2 months in 132 (97%) patients. 55 patients (40%) had intermittent claudication, 16 (12%) rest pain and 65 (48%) had ischemic ulcerations (mean RF class = 4.2 ± 1.1). 15 (11%) patients had TASC B lesions, whereas the majority 72 (53%) and 49 (36%) exhibited TASC C and D lesions, respectively. Mean PACSS score was 3.3 ± 0.9. Mean lesion length was 106 ± 92 mm. Atherectomy was combined with drug-coated balloon (DCB) in 129 (95%) patients. Nine (6.6%) patients with infra-inguinal lesions received stents. Technical and procedural success were recorded in 102 (75%) and 135 (99%), respectively. Perforation was noticed in 2 (1%), whereas asymptomatic embolism occurred in 6 (4%) patients. Clinical success was present in 54 (100%) patients with claudication and in 65 of 78 (83%) patients with critical limb ischemia (CLI). Atherectomy in combination with DCB angioplasty can be safely performed in patients with complex, calcified peripheral lesions with a relatively low rate of bail-out stenting and promising clinical mid-term results.German Clinical Trials Register: DRKS00016708.

Comparison of ante-versus retrograde access for the endovascular treatment of long and calcified, de novo femoropopliteal occlusive lesions.

To compare antegrade versus retrograde recanalization, in terms of procedural time, radiation and contrast agent exposure, number and total length of implanted stents and procedural complications, in long and calcified, de novo femoropopliteal occlusions. We performed retrospective matching of prospectively acquired data by lesion length, occlusion length and lesion calcification by the peripheral arterial calcium scoring system (PACSS) score in patients who were referred for endovascular treatment due to symptomatic peripheral artery disease (PAD). Forty-two consecutive patients with antegrade and 23 patients with retrograde after failed antegrade recanalization were identified (mean lesion length = 32.1 ± 6.9 cm; mean occlusion length = 24.6 ± 7.7 cm; PACSS score = 3.25 ± 0.91). 23% of the patients had intermittent claudication, whereas 77% exhibited critical limb ischemia (CLI). Patients who underwent retrograde versus antegrade recanalization required a significantly lower number of stents (0.9 ± 1.0 versus 1.8 ± 1.4, p = 0.01) and a lower total stent length (6.8 ± 8.5 cm versus 11.7 ± 9.9 cm, p < 0.05) in the interest of more extensive coverage of the lesions using drug coated balloons (DCB) (28.5 ± 12.0 cm versus 18.2 ± 16.0 cm, p = 0.01). No re-entry device was required with the retrograde versus 9 of 42 (21%) with the antegrade recanalization group (p = 0.02). The rate of complications due to retrograde puncture was low (one patient with hematoma and one with distal pseudoaneurysm, both managed conservatively). In long and calcified femoropopliteal occlusions, the retrograde approach is associated with a lower number of re-entry devices and stents and with more extensive lesion coverage with DCB, in the interest of costs and possibly long-term patency.German Clinical Trials Register: DRKS00015277.

Successful endovascular treatment in patients with acute thromboembolic ischemia of the lower limb including the crural arteries.

AIM: To examine the efficacy and safety of the 6 French (6F) Rotarex®S catheter system in patients with acute limb ischemia (ALI) involving thromboembolic occlusion of the proximal and mid-crural vessels. METHODS: The files of patients in our department with ALI between 2015 and 2017 were examined. In seven patients, the Rotarex®S catheter was used in the proximal segment of the crural arteries. Data related to the clinical examination, Doppler sonography, angiography and follow-up from these patients were further used for analysis. RESULTS: Two patients (29%) had thrombotic occlusion of the common femoral artery, and the remaining five exhibited thrombosis of the superficial femoral artery and popliteal artery. Mechanical thrombectomy was performed in all cases using a 6F Rotarex®S catheter. Additional Rotarex®S catheter thrombectomy due to remaining thrombus formation with no reflow was performed in the anterior tibial artery in two of seven cases (29%), in the tibiofibular tract and posterior tibial artery in two of seven cases (29%) and in the tibiofibular tract and fibular artery in the remaining three of seven cases (43%). Ischemic symptoms resolved promptly in all, and none of the patients experienced a procedural complication, such as crural vessel dissection, perforation or thrombus embolization. CONCLUSION: Mechanical debulking using the 6F Rotarex®S catheter system may be a safe and effective treatment option in case of thrombotic or thromboembolic occlusion of the proximal and mid-portion of crural arteries.

Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.

BACKGROUND & AIMS: There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. METHODS: Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4years, with suppressed HBV DNA for ≥3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. RESULTS: Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was -0.59log10IU/ml (range -4.49 to 0.02log10IU/ml) vs. 0.21log10IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA <2,000IU/ml. There were no unexpected safety issues identified with stopping TDF therapy. CONCLUSIONS: This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA <2,000IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance. Clinical trial number: NCT01320943.

Successful carbon dioxide angiography guided endovascular thrombectomy of the superficial femoral artery in a young patient with critical limb ischemia.

Currently, the treatment of thromboembolic ischemia of the lower extremities includes percutaneous rotational thrombectomy and aspiration devices. However, the standard approach for endovascular treatment requires the administration of iodine contrast agents, which is problematic in patients with pre-existing renal disease and diabetes. Herein, we describe a case of a CO2 angiography guided endovascular thrombectomy of the superficial femoral artery (SFA) in a young patient with critical limb ischemia. Mechanical thrombectomy using the Rotarex system, catheter aided aspiration and subsequent stent placement in the SFA was entirely guided using CO2 angiography.

Successful recanalization of long femoro-crural occlusive disease after failed bypass surgery.

Patients with critical limb ischemia necessitate immediate intervention to restore blood flow to the affected limb. Endovascular procedures are currently preferred for these patients. We describe the case of an 80-year-old female patient who presented to our department with ischemic rest pain and ulceration of the left limb. The patient had history of left femoral popliteal bypass surgery, femoral thromboendarterectomy and patch angioplasty of the same limb 2 years ago. Doppler sonography and magnetic resonance angiography revealed an occlusion of the left superficial femoral artery (SFA) and popliteal artery and of all three infra-popliteal arteries. Due to severe comorbidities, the patient was scheduled for a digital subtraction angiography. An antegrade approach was first attempted, however the occlusion could not be passed. After revision of the angiography acquisition, a stent was identified at the level of the mid SFA, which was subsequently directly punctured, facilitating the retrograde crossing of the occlusion. Thereafter, balloon angioplasty was performed in the SFA, popliteal artery and posterior tibial artery. The result was considered suboptimal, but due to the large amount of contrast agent used, a second angiography was planned in 4 wk. In the second session, drug coated balloons were used to optimize treatment of the SFA, combined with recanalization of the left fibular artery, to optimize outflow. The post-procedural course was uneventful. Ischemic pain resolved completely after the procedure and at 8 wk of follow-up and the foot ulceration completely healed.

Outcomes and Costs of Treating Hepatitis C Patients in the Era of First Generation Protease Inhibitors - Results from the PAN Study.

1 OBJECTIVE: Chronic hepatitis C virus infections (HCV) cause a significant public health burden. Introduction of telaprevir (TVR) and boceprevir (BOC) has increased sustained virologic response rates (SVR) in genotype 1 patients but were accompanied by higher treatment costs and more side effects. Aim of the study was to assess outcomes and costs of treating HCV with TVR or BOC in routine care. 2 MATERIAL AND METHODS: Data was obtained from a non-interventional study. This analysis relates on a subset of 1,786 patients for whom resource utilisation was documented. Sociodemografic and clinical parameters as well as resource utilisation were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. 3 RESULTS: Mean age of patients was 49.2 years, 58.6% were male. In treatment-naive patients SVR-rates of 62.2% and 55.7% for TVR and BOC were observed (prior relapser: 68.5% for TVR and 63.5% for BOC; prior non-responder: 45.6% for TVR and 39.1% for BOC). Treatment costs are dominated by costs for pharmaceuticals and range between €39,081 and €53,491. We calculated average costs per SVR of €81,347 (TVR) and €70,163 (BOC) in treatment-naive patients (prior relapser: 78,089 €/SVR for TVR and 82,077 €/SVR for BOC; prior non-responder: 116,509 €/SVR for TVR and 110,156 €/SVR for BOC). Quality of life data showed a considerable decrease during treatment. 4 CONCLUSION: Our study is one of few investigating both, outcomes and costs, of treating HCV in a real-life setting. Data can serve as a reference in the discussion of increasing costs in recently introduced agents.

Effectiveness and Safety of Tenofovir Disoproxil Fumarate in Chronic Hepatitis B: A 3-Year Prospective Field Practice Study in Germany.

BACKGROUND AND AIMS: Multiple clinical trials have demonstrated the efficacy and safety of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB). However, long-term efficacy and safety data for TDF in real-life clinical practice are limited. METHODS: Prospective German field practice study in CHB-mono-infected patients. Patients were TDF-naïve but could have been treated previously with other HBV antivirals. RESULTS: Efficacy analysis included 400 patients; 301 (75 %) completed 36 months of TDF treatment. Both treatment-naïve and treatment-experienced patients showed a rapid decline in HBV DNA within 3 months of TDF initiation. After 36 months, HBV DNA < 69 IU/mL was achieved by 91 % of treatment-naïve patients (90 and 92 % in hepatitis B "e" antigen [HBeAg]-positive and [HBeAg]-negative, respectively) and 96 % of treatment-experienced patients (93 and 97 %, respectively). Three patients experienced virologic breakthrough, all with reported non-compliance. Overall, 5.7 % HBeAg-positive and 2.2 % HBeAg-negative patients lost hepatitis B surface antigen. Safety data were consistent with the known TDF safety profile; the most commonly reported adverse events possibly related to TDF were fatigue (2.0 %) and headache (2.0 %). Few patients (1.3 %) experienced renal-related adverse reactions. Creatinine clearance remained relatively stable over time; patients responded favorably where TDF was dose adjusted per label for decreased creatinine clearance. CONCLUSIONS: TDF showed a favorable tolerability profile and induced rapid and sustained suppression of HBV DNA in patients with CHB treated for up to 3 years in routine clinical practice, irrespective of treatment history. Efficacy and safety in this heterogeneous patient population were consistent with data from clinical trials.

Microbiology and resistance in first episodes of spontaneous bacterial peritonitis: implications for management and prognosis.

PURPOSE: International guidelines for antibiotic treatment of spontaneous bacterial peritonitis (SBP) are based on studies conducted decades ago and do not reflect regional differences of bacterial epidemiology. METHODS: We retrospectively analyzed epidemiology of agents, antibiotic resistance patterns, and survival in liver cirrhosis patients with their first episode of SBP during the years 2007-2013. RESULTS: Of the 311 patients included, 114 patients had a positive ascites culture, and 197 had an ascitic neutrophil count >250 µL. Gram-positive bacteria (47.8%) were more frequently found than Gram-negatives (44.9%), fungi in 7.2%. Enterobacter spp. (40.6%), Enterococcus spp. (26.1%), and Staphylcoccus spp. (13.8%) were the most frequently isolated agents. Third-generation cephalosporins covered 70.2% of non-nosocomial and 56.3% of nosocomial-acquired SBP cases.When SBP was diagnosed by a positive ascitic culture, survival was highly significantly reduced (mean: 13.9 ± 2.9 months; 95% confidence interval [CI]: 8.1-19.8) compared with culture-negative SBP patients (mean: 44.1 ± 5.4 months; 95% CI: 33.4-54.9; P = 0.000). Along with model of end-stage liver disease score and intensive care unit contact, a positive ascites culture remained an independent risk factor associated with poor survival (odds ratio: 1.49; 95% CI: 1.09-2.03) in multivariate analysis; piperacillin/tazobactam proved to be an adequate antibiotic for nosocomial and non-nosocomial SBP in 85.1% and 92.5%, respectively. SBP infection with Enterococcus spp. was associated with poor patient survival (P = 0.048). CONCLUSIONS: Third-generation cephalosporins have poor microbial coverage for treatment of SBP. Current guidelines need to adapt for the emerging number of Gram-positive infectious agents in SBP patients.

Early virological response may predict treatment response in sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center "real-life" cohort.

BACKGROUND: The combination of sofosbuvir (SOF), ribavirin (RBV) and peg-interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a "real-life" cohort. METHODS: We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV. RESULTS: The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74% (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79% (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92% (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80% (n = 4). Of all 26 patients with a relapse in our cohort, 69% (n = 18) of these patients presented with liver cirrhosis and 58% (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels ≥ 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30% (n = 17/56, p < 0.0001) of cases and treatment response was even lower with SVR 12 of 25% (n = 5/20, p = 0.0016) in the subgroup of patients with cirrhosis. CONCLUSION: We observed a high rate of SVR 12 with SOF-based treatment regimes, however probably due to the high number of patients with liver cirrhosis and prior treatment experience, treatment response rates were lower than in previously published trials. In genotype 1 patients the analysis of early virological response may predict treatment response in SOF-based combination therapies.

Survival in patients with colorectal cancer diagnosed by screening colonoscopy.

BACKGROUND: In Germany, screening colonoscopy was first established in 2002 as part of the national cancer screening program. OBJECTIVE: To evaluate whether colorectal cancer (CRC) survival differs when CRC is diagnosed by screening colonoscopy (S-CRC) versus diagnostic colonoscopy (D-CRC). DESIGN: Long-term, retrospective, multicenter, observational study. SETTING: Study centers: 10 private gastroenterology practices in Germany. PATIENTS: A total of 60 patients diagnosed with CRC during screening colonoscopy and 252 patients during diagnostic colonoscopy in 2002, 2003, and 2004. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Survival of patients up to December 2013. RESULTS: Mean (± standard deviation [SD]) follow-up time was 81.0 (± 40.1) months. Union Internationale Contre le Cancer (UICC) stages I and II were found more often in S-CRC (81.6%) compared with D-CRC (59.9%; P < .002). Kaplan-Meier analysis showed significantly reduced overall survival for patients with D-CRC (mean [± SD] 86.9 [± 3.0] months; 95% confidence interval [CI], 81.0-92.8) compared with S-CRC (mean [± SD] 107.1 [± 4.9] months; 95% CI, 97.4-116.9; P = .003). When deaths not related to CRC were excluded, survival was still shorter for D-CRC patients (mean [± SD] 89.4 [± 3.0] months; 95% CI, 83.5-95.4) compared with S-CRC (mean [± SD] 109.6 [± 4.7] months; 95% CI, 100.2-119.0; P = .004). LIMITATIONS: Retrospective study design. CONCLUSION: In this long-term, retrospective study, patients with CRC diagnosed during screening colonoscopy lived significantly longer when compared with patients with CRC diagnosed during diagnostic colonoscopy.

Extracorporeal life support and plasmapheresis in a case of severe polyintoxication.

BACKGROUND: Resuscitation without return to spontaneous circulation in patients with suicidal ingestion of cardiotoxic drugs necessitates alternative bridging therapies for drug removal. OBJECTIVES: To show the effectiveness of emergency extracorporeal membrane oxygenation (ECMO) and plasmaspheresis in severe polyintoxication. CASE REPORT: A 21-year-old woman developed asystole after suicidal polyintoxication with 1.75 g carvedilol, 300 mg amlodipine, 6 g amitriptyline, 500 mg torsemide, 1.5 g ketoprofen, 28 g nicotinic acid, and 16 g gabapentin. After 3 h of cardiopulmonary resuscitation without return to spontaneous circulation, ECMO was used as a bridging therapy and a temporary pacemaker was inserted. Plasma peak levels were measured for amlodipine (29.3 µg/L), amitriptyline (1456 µg/L), carvedilol (585 µg/L), and gabapentin (126.8 mg/L). To facilitate drug removal, therapeutic plasma exchange was performed. The patient could be weaned from ECMO at day 4 and extubated on day 8 after admission without neurologic sequelae. CONCLUSION: ECMO and plasma exchange should be considered as a therapeutic option in selected patients under resuscitation without return to spontaneous circulation after severe intoxication.

Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.

BACKGROUND: Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway. METHODS: Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure. RESULTS: Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1ß (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome. CONCLUSIONS: Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.

Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy.

Drug interactions with immunosuppressive drugs are a major problem associated with protease inhibitor-based antiviral triple therapy for hepatitis C virus (HCV) reinfection after liver transplantation. In this retrospective cohort study, we analyzed biomarkers of the immunosuppressive effects of cyclosporine A (CSA) by quantifying nuclear factor of activated T cells (NFAT)-regulated gene expression during telaprevir (TVR) therapy in 5 liver transplant patients. Furthermore, dose adjustments and blood concentrations of CSA as well as the clinical course were analyzed. We observed a clear impact of TVR not only on doses and blood concentrations but also on the immunosuppressive effects of CSA. Despite apparently adequate CSA trough concentrations, the CSA peak concentration decreased to 68% (range = 44%-90%). This was associated with a 1.9-fold (1.6- to 4.1-fold) increase in the residual gene activity of NFAT-regulated genes, which indicated reduced immunosuppressive activity of CSA with TVR co-medication. The median dose of CSA was reduced to 25% (range = 16%-48%) and 31% (range = 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range = 31.0%-49.4%). We report excellent antiviral efficacy. At the end of the observation period, all patients were HCV RNA-negative (1 patient at 18 weeks, 1 patient at 12 weeks, and 3 patients at 4 weeks after the end of therapy). Safety was acceptable, with mild acute rejection and reactivation of cytomegalovirus being the most serious adverse events. One patient with histologically proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy. In conclusion, the immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CSA during antiviral therapy with TVR in our cohort of liver transplant patients. Thus, the immunosuppressive effects of CSA may be overestimated if one is looking only at trough concentrations during co-medication with protease inhibitors or other strong cytochrome P450 3A inhibitors. Immunomonitoring of NFAT-regulated gene expression could, therefore, help to prevent overimmunosuppression or underimmunosuppression.