Increased Creatine Phosphokinase Research Articles

Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease

AbstractHedgehog signaling plays a key role in tissue fibrosis, the pathological hallmark of chronic graft-versus-host disease (cGVHD). We conducted a phase 1 trial of sonidegib, a selective antagonist of the hedgehog coreceptor Smoothened, for the treatment of steroid-refractory cGVHD. After a 3+3 study design, sonidegib was administered for up to 12 cycles of 28 days each, using 3 doses: 200 mg/day (dose level 1), 400 mg/day (dose level 2), and 600 mg/day (dose level 3). Seventeen patients were enrolled. The median number of cycles completed was 6 (range, 0-12). There was only 1 dose-limiting toxicity (cohort 2, grade 3 creatine phosphokinase increase) observed. Immunohistochemical evaluation of skin biopsies revealed decreased protein expression of hedgehog signaling pathway molecules with sonidegib therapy. Clinically, 8 patients (47%) had a partial response in skin or sclerodermatous disease, 6 patients had no response, and 3 were not evaluable. Clinical responses were assessed by treating physicians and not by National Institutes of Health criteria. Overall, patients reported worsening of quality of life, which was more severe in clinical nonresponders. Accrual was terminated early as a result of the cumulative toxicity burden not attributed to sonidegib and patient decisions to stop taking sonidegib. We believe hedgehog signaling inhibition warrants further investigation in patients with cGVHD because of the association with clinical responses and immunohistochemical changes. This trial was registered at www.clinicaltrials.gov as #NCT02086513.

Brigatinib, a new treatment option in ALK-rearranged advanced non-small cell lung carcinoma

Anaplastic lymphoma kinase (ALK) rearrangement is a rare feature in advanced non-small cell lung cancer (NSCLC), occurring in around 5% of the patients (1). This oncogenic addiction is more frequent in no/light-smokers, in thyroid transcription factor-1 (TTF1)-positive adenocarcinoma, with cribriform architecture and ring cells (2). ALK rearrangement—most of the time a translocation with a partner gene—induces the formation of a fusion protein with oncogenic properties. The first targeted therapy developed for ALK -rearranged NSCLC was crizotinib, an ALK tyrosine kinase inhibitor (TKI). Crizotinib was proved to be superior to chemotherapy in first-line setting in ALK -rearranged NSCLC, with an overall response rate (ORR) of 74% and a progression-free survival (PFS) of 10.9 months (3). Crizotinib in first-line treatment is now widely used. Other ALK TKIs have been developed, as brigatinib. Results of the phase I-II trial published in 2016 showed in 79 advanced NSCLC patients treated with brigatinib an ORR at 75% [72% in previously crizotinib treated patients (n=71)] and a PFS (median) of 13.2 months (4). Safety profile showed specific lung toxicity, occurring at the beginning of the treatment (median 2 days) in 8% of the patients, with incidence increasing with the dose of brigatinib. The ALTA trial, published in May 2017 in Journal of Clinical Oncology by Kim et al . was a phase II trial that randomized patients with advanced ALK -rearranged NSCLC between 2 doses of brigatinib (90 mg daily and 90 mg daily for 7 days then 180 mg daily) (5). The primary endpoint was ORR, and no comparison between the 2 arms was pre-planned. Assuming an ORR ≥35% with a power of 90% and a bilateral alpha risk at 0.025, the study had to include 109 patients per arm. Patients should have an advanced ALK -rearranged NSCLC with progression with crizotinib and a performance status (PS) between 0 and 2. Brain metastases were allowed only if asymptomatic and with stable doses of steroid treatment. Two-hundred and twenty-two patients were randomized [112 patients arm A (90 mg) and 110 patients arm B (90 mg then 180 mg)]. Both arms were well-balanced, with a median age at 54 years, 57% of women, 31% of Asian, 60% of non-smokers, 97% of adenocarcinoma, 69% of brain metastases. ORR (investigator-assessed) was 45% in arm A and 54% in arm B, and disease-control rate was 82% (arm A) and 86% (arm B). Median time to response was 1.8 months (arm A) and 1.9 months (arm B), and duration of response was 13.8 months (arm A) and 11.8 months (arm B). Median PFS was 9.2 months (arm A) and 12.9 months (arm B). Post-hoc comparison between the 2 arms for PFS showed a clear benefit for arm B, with a hazard ratio (HR) at 0.55 [95% confidence interval (CI), 0.36–0.86]. One-year overall survival (OS) probability was 71% (arm A) and 80% (arm B). As shown in the phase I-II trial, brigatinib had intracranial efficacy. ORR for measurable brain metastases was 42% (arm A, n=26) and 67% (arm B, n=18). For active brain metastases (i.e., metastases without previous brain radiotherapy, or progression after brain radiotherapy), intracranial ORR was 42% (arm A, n=19) and 73% (arm B, n=15). Intracranial PFS (median) was 15.6 months (arm A) and 12.8 months (arm B), with a duration of intracranial response (median) not reached in both arms. In term of safety, no new signal was detected. In both arms, main toxicities (≥10% patients) were nausea (33%/40%), diarrhea (19%/38%), vomiting (24%/23%), headache (28%/27%), decrease appetite (22%/15%) and hypertension (11%/21%). Grade 3–4 toxicities were rare: hypertension (6%/6%), increased creatine phosphokinase (3%/9%) and rash (1%/3%), mainly. Pulmonary early toxicity occurred in 6% of patients (n=14), during the first 2 days of treatment (always at 90mg daily of brigatinib). Grade 3–5 pulmonary toxicities concerned 3% of patients (n=7). Half of the patients (n=7) had successfully continued brigatinib after suspension, whereas 7 patients stopped brigatinib definitely. One patient died from acute respiratory failure (<1%). Multivariate analysis showed that advanced age [odds ratio (OR) =2.10; 95% CI, 1.21–3.65] and time from last crizotinib dose to first brigatinib dose less than 7 days (OR =3.88; 95% CI, 1.10–13.68) were associated with early pulmonary toxicity. Seven percent (arm A) and 20% (arm B) patients had dose reduction, due to increase of creatine phosphokinase, pneumonitis and rash.

Symptomatic arterial hypertension associated with primary hyperaldosteronism

Objective.Primary hyperaldosteronism (PGA) (Conn’s syndrome) is a relatively rare phenomenon in therapeutic practice, occurring in 4,7–9%. In resistant hypertension (HTN) the rate of PGA achieves 10–20%. Often it results from the aldosterone-producing adrenal tumors and manifests by symptomatic HTN, neuromuscular, and renal symptoms. We present the cases of successful verification and surgical treatment of PGA. HTN patients and patients with rhabdomyolysis symptoms (increased creatine phosphokinase or lactate dehydrogenase) require further examination to exclude PGA.

Effects of a New Nutraceutical Formulation (Berberine, Red Yeast Rice and Chitosan) on Non-HDL Cholesterol Levels in Individuals with Dyslipidemia: Results from a Randomized, Double Blind, Placebo-Controlled Study.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m2) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (−30 ± 20 mg/dL; p = 0.012), LDL cholesterol (−31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (−14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention.

Daboia (Vipera) palaestinae envenomation in horses: Clinical and hematological signs, risk factors for mortality and construction of a novel severity scoring system

Daboia palaestinae is the most common venomous snake in Israel and an important cause of envenomations in humans and animals. Although specific antivenom is produced from horses, little documentation exists regarding the characteristics of envenomed horses. This survey was constructed to describe the clinical, hematological and biochemical characteristics of D. palaestinae envenomation in horses, to identify risk factors for fatality and to construct a prognostic snakebite severity scale (SSS) to be used by veterinarians in the field. Data regarding 123 equine snakebite cases were collected over four years. Clinical signs most frequently described were local swelling (100%), tachycardia (67%), increased respiratory effort (62%), bite marks (44%) and reduced appetite (50%). Blood samples were collected at initial presentation from 23 of these horses. Hematological and biochemical abnormalities described in the majority of the sampled cases included leukocytosis (52%), neutrophilia (78%), increased creatine phosphokinase (77%), hypoproteinemia (50%), decreased total carbon dioxide (54%), and hyperphosphatemia (54%). The overall case fatality rate was 20.3% (25/123 horses). Risk factors associated with increased mortality (P < 0.05) were body weight below 200 kg, hind limb envenomation, severity of local swelling, mental status, respiratory effort, bleeding disorders, dehydration, basophilia, monocytosis, bilirubinemia, hypocalcemia and hyperphosphatemia. These risk factors were used to construct an SSS adapted for the assessment of envenomed horses in the field, consisting of seven dichotomous parameters. A cutoff value of 1.5 predicted mortality with 95% sensitivity and 68% specificity. In the future, this tool could assist clinicians with case management and communication with owners.

Influence of SLCO1B1 polymorphisms on atorvastatin efficacy and safety in Macedonian subjects.

Atorvastatin, as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a widely prescribed medication for the treatment of dyslipidemia. However, despite its clinical efficacy in reducing major cardiovascular events, a wide inter-individual variability in its response exists. Several studies in this area point to the effect of polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the multiple organic anion-transporting polypeptide 1B1 (OATP1B1) involved in hepatic uptake of atorvastatin. Hence, the aim of this study was to analyze the association between the SLCO1B1 c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G polymorphisms and lipid-lowering effect and safety of atorvastatin. A hundred and fifty six patients with hyperlipidemia IIa and IIb, all of Macedonian origin, were included in the study receiving atorvastatin 20 - 80 mg/day for 3 months. SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped using the TaqMan allelic discrimination assay. As parameters of atorvastatin response, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A (ApoAI), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, using standard laboratory methods, at baseline and after 3 months of treatment. No statistically significant association between the different SLCO1B1 SNPs and atorvastatin response was observed. However, the carriers of c.521CC manifested a lower decrease in plasma levels of TG, TC, LDL-C and Lp(a), with percentage difference being 16%, 7%, 29% and 149%, respectively, compared to the carriers of c.521TT variant. Lower increase in HDL-C (271%) and ApoAI (293%) and higher increase in CPK (69%) in c.521CC carriers were also observed, confirming the lower OATP1B1 activity in carriers of the variant c.521 C allele. Similar results were obtained when a comparison between the percentage of biochemical parameter change was made between *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers. The lack of a statistically significant association between the SLCO1B1 polymorphism and atorvastatin response can be explained dominantly by the low number of individuals homozygous for the rare c.521C variant allele. Despite this limitation, the study offers valuable information on the influence of the genetic determinant SLCO1B1 on atorvastatin response in the Macedonian population.

Minimally invasive surgery for resection of ossification of the ligamentum flavum in the thoracic spine.

IntroductionThoracic ossification of the ligamentum flavum (TOLF) is a common cause of progressive thoracic myelopathy. Surgical decompression is commonly used to treat TOLF.AimTo evaluate the clinical outcomes of microsurgical decompression of TOLF via a paraspinal approach, using a percutaneous tubular retractor system.Material and methodsFirst, three-dimensional (3D) image reconstruction and printed models were made from thin computed tomography scans for each patient. Then, 3D computer-assisted virtual surgery was performed using the 3D reconstruction to calculate the precise location and sizes of the bone window and the angle of insertion of the percutaneous tubular retractor system. In total, 13 patients underwent the surgery through the percutaneous micro channel unilateral vertebral approach under electrophysiological monitoring. Five days after the surgery, increased creatine phosphokinase levels returned to preoperative levels. The Japanese Orthopedic Association (JOA) score was improved and computed tomography reconstruction and magnetic resonance imaging of the thoracic spine showed that decompression was achieved without injuries to the spinal cord or nerve root. The stability of the spine was not affected, nor were any deformities of the spine detected. Finally, nerve functional recovery was achieved with minimal injury to the paraspinal muscle, articulum, spinous process and ligament.ResultsThe mean operative time was 98.23 ±19.10 min, and mean blood loss was 19.77 ±5.97 ml. At a mean follow-up of 13.3 months (median: 12 months), the mean JOA score was 7.54 ±1.13 at the final follow-up, yielding a mean RR of 49.10 ±15.71%. Using The recovery rate, 7 (53.85%) patients had good outcomes, 5 (38.46%) patients had a fair outcome, and 1 (7.69%) patient had poor outcomes, indicating significant improvement by the final follow-up examination (p < 0.05).ConclusionsThe 3D printed patient model-based microsurgical resection of TOLF via the paraspinal approach can achieve decompression of the spinal canal with minimal complications, faster recovery and improved stability of the vertebral body.

Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial

There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. Array BioPharma and Novartis Pharmaceuticals Corporation.

Unveiling the Metabolic Changes on Muscle Cell Metabolism Underlying p-Phenylenediamine Toxicity.

Rhabdomyolysis is a disorder characterized by acute damage of the sarcolemma of the skeletal muscle leading to release of potentially toxic muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobulin, and is frequently accompanied by myoglobinuria. In the present work, we evaluated the toxicity of p-phenylenediamine (PPD), a main component of hair dyes which is reported to induce rhabdomyolysis. We studied the metabolic effect of this compound in vivo with Wistar rats and in vitro with C2C12 muscle cells. To this aim we have combined multi-omic experimental measurements with computational approaches using model-driven methods. The integrative study presented here has unveiled the metabolic disorders associated to PPD exposure that may underlay the aberrant metabolism observed in rhabdomyolys disease. Animals treated with lower doses of PPD (10 and 20 mg/kg) showed depressed activity and myoglobinuria after 10 h of treatment. We measured the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) in rats after 24, 48, and 72 h of PPD exposure. At all times, treatment with PPD at higher doses (40 and 60 mg/kg) showed an increase of AST and ALT, and also an increase of lactate dehydrogenase (LDH) and CK after 24 h. Blood packed cell volume and hemoglobin levels, as well as organs weight at 48 and 72 h, were also measured. No significant differences were observed in these parameters under any condition. PPD induce cell cycle arrest in S phase and apoptosis (40% or early apoptotic cells) on mus musculus mouse C2C12 cells after 24 h of treatment. Incubation of mus musculus mouse C2C12 cells with [1,2-13C2]-glucose during 24 h, subsequent quantification of 13C isotopologues distribution in key metabolites of glucose metabolic network and a computational fluxomic analysis using in-house developed software (Isodyn) showed that PPD is inhibiting glycolysis, non-oxidative pentose phosphate pathway, glycogen turnover, and ATPAse reaction leading to a reduction in ATP synthesis. These findings unveil the glucose metabolism collapse, which is consistent with a decrease in cell viability observed in PPD-treated C2C12 cells and with the myoglubinuria and other effects observed in Wistar Rats treated with PPD. These findings shed new light on muscle dysfunction associated to PPD exposure, opening new avenues for cost-effective therapies in Rhabdomyolysis disease.

Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system.

Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried. From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.

CLINICAL AND LABORATORY ANALYSIS OF LETHAL CASES OF SEVERE INFLUENZA A(H1N1) PDM 2009 DURING THE EPIDEMIC 2015/2016 IN ST. PETERSBURG

The purpose of our study was to investigate the characteristics of severe form of influenza A (H1N1) pdm 2009 with a fatal outcome, given the comorbidities. Materials and methods. Medical histories of 105 people who died in hospitals of St. Petersburg for the period of the epidemic of 2015/16 served as material for analysis. The lethality caused by the pandemic virus type A/ H1N1 / 2009 pdm was higher in males. Most of the patients had concomitant chronic diseases in the anamnesis. Obesity was observed in 44.8% (47/105) of patients, diabetes mellitus — 28.5% (30/105), isolated heart disease — 19.0% (20/ 105), combined pathology — 48.6% (51/105). In the first biochemical analysis of blood, creatine phosphokinase, lactate dehydrogenase were increased, total protein and prothrombin consumption index were reduced. The patient's death occurred after 5 days of illness in 88.6% cases, in 11.4% — up to 5 days of illness (inclusive). The analysis of fatal cases up to 5 days of a disease and death from complications (2—4 week) didn't find significant differences in the character and frequency of comorbidity. Specific antiviral therapy has been assigned to all patients, but 48 hours later. Bilateral subtotal viral and bacterial pneumonia was identified on the section, in the majority of cases, in 70.5% with hemorrhagic component. 30% patients had cerebral oedema, 41% patients had severe toxic parenchymatouse degeneration of miocardium, liver and kidneys. The pathology of the cardiovascular system, diabetes and obesity worsen the prognosis of the disease. Increased creatine phosphokinase, lactate dehydrogenase, and reduced total protein and prothrombin consumption index can be considered as markers of severe influenza. The ineffectiveness of antiviral therapy due to its late appointment, thus timely initiation of etiotropic treatment is very impotent.

Effects of micro-plastic particles on paraquat toxicity to common carp (Cyprinus carpio): biochemical changes

In this study, we investigated the possible effects of paraquat and micro-plastics on blood biochemical parameters in common carp (Cyprinus carpio). We exposed C. carpio for 21 days to sublethal concentrations of paraquat (0.2 and 0.4 mg L−1) and micro-plastics (1 and 2 mg L−1), alone or in combination. Blood biochemical analysis indicated that exposure to 0.4 mg L−1 paraquat and mixture of paraquat and micro-plastics was followed by an increase in aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatine phosphokinase (CPK) activities and glucose levels. The activity of ALP and CPK showed a significant increase in fish treated with 2 mg L−1 micro-plastics. No significant changes were observed in glucose level, AST, ALT, and LDH activities in fish exposed to micro-plastics. Exposure to paraquat and/or micro-plastics resulted in a significant decrease in total protein, globulin, cholesterol, and triglyceride levels and γ-glutamyl transferase activity. When fish were exposed to paraquat or paraquat and micro-plastics, alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities increased significantly compared to the control group. Treating fishes with a mixture of paraquat and 2 mg L−1 micro-plastics caused a significant increase in albumin levels. However, a significant decrease in the albumin level was observed after exposure to paraquat or micro-plastics. Creatinine levels increased after exposure to paraquat and/or micro-plastics. The results indicate that increased doses of micro-plastics in water significantly increased toxic effects of paraquat in fish. Finally, these data support the hypothesis that changes in blood biochemical parameters were induced by exposure to paraquat and/or micro-plastics.

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib.

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ©2016 AACR.

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Merck KGaA, Darmstadt, Germany.

Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. F Hoffmann-La Roche-Genentech.

Post-ride inflammatory markers in endurance horses

ABSTRACT: The acute phase reaction occurs in response to diseases, surgical trauma and can happen after strenuous exercise, like long distance events. This study aimed to evaluate the Serum Amyloid A (SAA), pro-inflammatory interleukins (IL-1β and TNFα) and creatine phosphokinase (CK) after free speed races like physical stress markers in endurance horses. Blood of 21 trained horses that competed in tests of 80, 120 and 160km, was taken before and after race. There was a significant increase in CK and SAA after the race in all horses, as well as the anti-inflammatory interleukin IL-10. But when results were compared between the groups, only the SAA was different, being higher in 160km horses. There was no change in pro-inflammatory interleukins IL-1β and TNFα before and after the event; however, the TNFα was higher in 160km horses after the race. Based on data obtained in this study it was concluded that stress is more dependent on the distance than speed imposed and that SAA is a good marker of physical effort, since it is accompanied by other markers well established as CK. Interleukins are not a good markers since they did not change significantly.

The combination of nutraceutical and simvastatin enhances the effect of simvastatin alone in normalising lipid profile without side effects in patients with ischemic heart disease

Backgroundhyperlipidemia is one of the most important cardiovascular risk factors. Statins at high doses are commonly prescribed to lower LDL-cholesterol, but are often poorly tolerated. In particular, muscle pain and increase of creatine phosphokinase are frequent side effects. The purpose of this study was to assess whether the addition of a nutraceutical to simvastatin may result in the achievement of the therapeutic target (LDL-cholesterol less than 70mg/dL) without side effects in patients with ischemic heart disease. MethodsSixty-four patients with ischemic heart disease treated with simvastatin 20mg who had not achieved the therapeutic target were enrolled. Patients were randomised 1:1. Patients of group A (n=32) were given simvastatin 40mg per day and patients of group B (n=32) were given simvastatin 20mg plus 2 tablets of a nutraceutical composed of bergamot, phytosterols, artichoke, vitamin C. ResultsAfter 3months, patients in both groups showed a significant reduction from baseline in total cholesterol, LDL-c and tryglicerides. However, in group A, 4 patients reported myalgia (9,7%) with an increase in creatine phosphokinase; whereas no adverse events occurred in group B. ConclusionsThe association of a nutraceutical and simvastatin 20mg may be a valid therapeutic option for the treatment of hyperlipidemia in patients with ischemic heart disease intolerant to statin at high doses, in the absence of side effects. Further studies are needed to clarify the mechanisms of action of nutraceuticals.

Serum muscle-derived enzymes response during show jumping competition in horse.

Aim:The effect of two jumping competitions, performed in two consecutive weekends, on serum creatine phosphokinase (CPK), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), urea, creatinine (CREA) concentrations were evaluated in 12 healthy jumper horses.Materials and Methods:Blood sampling was performed before the 1st day of competition (T0), at the end of each show (J1, J2), on the day after the competition (T1); the same sampling plan was followed during the second weekend (J3, J4 and T2).Results:One-way repeated measures analysis of variance showed an increase in CPK at J1 and J2 respect to T0 and at J3 and J4 respect to all other time points (p<0.05). LDH activity showed an increase at J2 respect to T0, at J3 respect to T0, J1, J2 and at J4 respect to all other time points (p<0.05). AST values increased at J1 and J2 respect to T0 (p<0.05). A significant increase of CREA was found at J3 respect to T0, T1 and J1 and at J4 respect to all other time points (p<0.05). A decrease in serum urea levels was found at J1 respect to T0, at J2 and J4 respect to T0 and T1; at T2 respect to T0 (p<0.05). A positive correlation between urea/CPK (p=0.0042, r2=0.030), LDH/CPK (p<0.0001, r2=0.535), CREA/LDH (p<0.0001, r2=0.263), CREA/CPK (p<0.0001, r2=0.496) was observed.Conclusion:Our results suggest that 5 days recovery period between the two consecutive competition weekends is insufficient to allow muscle recovery and avoid potential additional stress. The findings obtained in this study improve the knowledge about metabolic changes occurring in athlete horse during the competition to identify muscle alterations following show jumping competitions.

Changes of Cardiac Biomarkers after High-intensity Exercise in Male and Female Elite Athletes of Dragon Boating

This study investigated the effects of three sport-specific high-intensity training units on cardiac biomarker alteration in elite athletes of dragon boating. Thirty six male (age 33 ± 9) and twenty nine female (age 31 ± 8) elite athletes, members of the German national team, were examined in their final training camp preparing for world championship. At two time points blood panels (pre-training and one hour post-training) were collected and concentrations of high sensitive troponin T, N-terminal pro brain natriuretic peptide (NT-pro BNP), creatine phosphokinase (CPK), MB-creatine kinase (CKMB) and myoglobin were assessed. After exercise, serum levels of NT-pro BNP, CPK, myoglobin and CKMB increased significantly (P < 0.01 for each) with only few values exceeding the upper reference limits. High sensitive troponin T remained below the limit of detection both before and after exercise in all athletes. Significant gender-related differences were found with a higher increase of NT-pro BNP levels in female athletes (P < 0.01) compared to males. In contrast, male athletes displayed a significant higher increase of CPK (P < 0.01) and myoglobin (P < 0.01) compared to female athletes. In conclusion, three high-intensity training units did not lead to elevated high sensitive troponin T concentrations in elite athletes of dragon boating but to significant increases of NT-pro BNP, CPK and myoglobin levels. This suggests that high-intensity training units do not lead to a cardiac injury in these athletes.

Phase 1 Study of a Hepcidin Antagonist, LY2787106, in Cancer-Associated Anemia

▪ BACKGROUNDHepcidin is a 25-amino-acid peptide that binds to ferroportin and causes internalization and degradation of the hepcidin-ferroportin complex, leading to decreased iron absorption and reduced iron export from reticuloendothelial cells. High hepcidin levels are found in cancer patients (pts) and implicated in anemia pathogenesis. It is hypothesized that neutralizing hepcidin with a monoclonal antibody (mAb) will prevent internalization of ferroportin, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow to support erythropoiesis. LY2787106 is a fully humanized mAb with high affinity for human hepcidin. This phase 1 study evaluated the safety, PK/PD, and efficacy (effects on serum iron panel [iron, ferritin, transferrin saturation (TSAT), soluble transferrin receptor, reticulocyte hemoglobin], reticulocytosis, and hemoglobin [Hb]) of LY2787106 in cancer pts with anemia. METHODSA 3+3 design was used in the dose-escalation phase to determine the recommended phase 2 dose of LY2787106. Eligible pts were ≥18 years old with previously treated metastatic/incurable nonmyeloid cancer, Hb <11 g/dL, serum hepcidin ≥5 ng/mL, and ECOG performance status ≤2. The primary objective of Part A was to assess the safety of LY2787106 over a range of doses (0.3-10 mg/kg IV every 3 weeks [Q3W]); the primary objective of Part B was to assess mean change in Hb from baseline to end of Cycle 4 following LY2787106 treatment (10 mg/kg IV weekly) with (Cohort B1) or without (Cohort B2) oral iron supplementation. RESULTSA total of 33 pts were enrolled (Part A, n=19; Part B, B1, n =7; B2, n=7). Overall, most pts had multiple myeloma (n=14 [42.4%]). Mean age was 65 years (range, 44-88 years). There were 20 females and 13 males. Patients had received a median of 4.5 prior oncology treatments. Mean (SD) Hb level at baseline was 9.2 (0.95) g/dL. The median number of cycles given and completed was 3. No DLTs were seen in Part A, so the MTD was not reached. Data from Part A showed that LY2787106 was well tolerated when given Q3W, had a short half-life (~7 days), and transiently increased serum iron. This supported more frequent weekly dosing in Part B. Treatment-emergent AEs related to LY2787106 occurred in 4 pts (12.1%): increased creatine phosphokinase (grade 2), cardiac failure (grade 3), QT prolongation (grade 1), and neutropenia (grade 2) (1 pt each). Eight pts generated antibodies to LY2787106, but none had hypersensitivity reactions. The LY2787106 PK profile was consistent with reported PK characteristics of a mAb; the profile included a small clearance of ~0.032 L/h associated with limited volume of distribution, resulting in a terminal half-life of ~7 days. LY2787106 PK was independent of time and dose and exposure linear in the 0.3-10 mg/kg dose range. PD data indicated that LY2787106 administration led to a mean maximum 3.48-fold increase (90% CI, 2.5-4.8) from baseline in serum iron at the highest dose (10 mg/kg) in Parts A and B. Serum iron increase was maximal ~24-48 hours post dose, but returned to baseline within a week after dosing. The increase in serum iron paralleled a transient increase in TSAT at dose levels of 1, 3, and 10 mg/kg. This translated to a transient increase in mean ratio of reticulocyte count relative to baseline at 2 weeks post dose in pts who received 10 mg/kg Q3W, but Hb levels remained relatively unchanged. In Part B, a ≥0.5 g/dL increase in Hb from baseline, albeit transient, was seen in 4 pts at Week 12 (2 pts each cohort). No consistent increase in reticulocytes or changes in iron profiles were seen in these pts. Factors that may have confounded the limited change in Hb and reticulocyte profiles included the myelosuppressive effects of chemotherapy concomitantly given during the study, comorbidities, and study-related blood draws. As expected, LY2787106 administration led to increased hepcidin concentrations secondary to hepcidin binding/neutralization by LY2787106 and hepcidin release in response to iron increase. CONCLUSIONSThis is the first clinical trial of a fully humanized mAb against hepcidin. LY2787106 was well tolerated in cancer pts with anemia. Targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization and reticulocyte count relative to baseline, thus supporting the role of hepcidin in iron regulation and anemia pathogenesis. DisclosuresVadhan-Raj:Eli Lilly & company: Research Funding. Goldman:Eli LIlly and Company: Research Funding. Slapak:Eli Lilly and Company: Employment. Tiu:Eli Lilly and Company: Employment. Wang:Eli Lilly and Company: Employment. Callies:Eli Lilly and Company: Employment. Cox:Eli Lilly and Company: Employment. Tuttle:Eli Lilly and Company: Employment. Lau:Eli Lilly and Company: Employment. Roeland:Cellceutix: Other: DSMB; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Helsinn: Membership on an entity's Board of Directors or advisory committees; Inform Genomics: Membership on an entity's Board of Directors or advisory committees; TEVA: Speakers Bureau.