Evaluation of factors affecting epidermal growth factor receptor tyrosine kinase inhibitor-induced hepatotoxicity in Japanese patients with non-small cell lung cancer: a two-center retrospective study.

BACKGROUND: Gefitinib and erlotinib, are epidermal growth factor receptor tyrosine kinase inhibitors, and are currently recommended for non-small cell lung cancer stage IV in the elderly and in patients with decreased performance status in the Japanese Lung Cancer Society Guideline, but they occasionally caused severe hepatotoxicity requiring postponement or modification of treatment. However, little is known about the risk factors for hepatotoxicity in patients receiving gefitinib and erlotinib. In this study, we investigated the factors influencing hepatotoxicity in Japanese non-small cell lung cancer (NSCLC) patients treated with gefitinib or erlotinib monotherapy. METHODS: Japanese patients with NSCLC who started gefitinib or erlotinib monotherapy from January 2005 to December 2017 at Kanazawa University Hospital or Kanazawa Medical University Hospital were included in this study. Factors affecting hepatotoxicity were retrospectively investigated by multiple logistic regression analysis. RESULTS: A total of 102 patients who received gefitinib and 95 patients who received erlotinib were included in the analysis. In the gefitinib group, a body mass index (BMI) ≥ 25 was associated with an increased risk of hepatotoxicity (OR = 4.571, 95% CI = 1.486-14.056, P = 0.008). In the erlotinib group, concomitant use of acid-suppressing medications (AS), namely proton pump inhibitors or histamine-2 receptor antagonists, was associated with a reduced risk of hepatotoxicity (OR = 0.341, 95% CI = 0.129-0.900, P = 0.030). CONCLUSIONS: BMI ≥ 25 in patients treated with gefitinib increased the risk of hepatotoxicity. In contrast, AS combination with erlotinib reduced the risk of hepatotoxicity. Thus, because different factors influence the risk of hepatotoxicity, monitoring for adverse events should take into account patient background factors and concomitant medications.

The East-West late lumen loss study: Comparison of angiographic late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: Regulatory decisions approving new coronary drug-eluting stent (DES) require mechanistic observations of angiographic late lumen loss (LLL). Patient safety and device approval times could be enhanced if angiographic follow-up data were found to be generalizable across jurisdictions and geographies. The objectives were to assess the comparability of in-segment LLL in Eastern and Western DES populations using the world's largest compilation of follow-up quantitative coronary angiography data. METHODS: Data from 4 manufacturers involving 29 DES clinical trials in Eastern and Western hemispheres were compiled. "East" and "West" cohorts were defined by trial location. Independent core laboratories quantified in-segment LLL for all studies. East and West were compared before and after adjustment for clinical and anatomic covariates known to correlate with LLL via conditioning on propensity score quintiles. An international panel of experts and regulators prospectively established a clinically meaningful difference between East and West mean in-segment LLL of ±0.40 mm. RESULTS: The data set comprised 2,047 East and 4,456 West patients. Unadjusted mean ± SD for West and East in-segment LLL (mm) was 0.25 ± 0.46 and 0.12 ± 0.42, respectively (difference 0.13 mm; 95% CI 0.11-0.16). Propensity score-adjusted in-segment LLL East and West least squares means were 0.11 and 0.26 mm, respectively (difference 0.15 mm; 95% CI 0.13-0.18). CONCLUSIONS: In the world's largest compilation of DES protocol 8- to 13-month angiographic follow-up data, clinically meaningful comparability of in-segment LLL by independent core laboratory quantitative coronary angiography in East and West cohorts was demonstrated in both unadjusted and adjusted comparisons. These findings suggest that DES LLL, once characterized, could be generalized across regulatory jurisdictions over the course of global registration efforts.

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes.

To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts.

BACKGROUND: The contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation. OBJECTIVE: The East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up. METHODS: Data from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements. CONCLUSION: Documentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs.

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Japan (JSTP), Europe (ESTP), Great Britain (BSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The primary purpose of this publication is to provide a standardized nomenclature for characterizing lesions observed in the cardiovascular (CV) system of rats and mice commonly used in drug or chemical safety assessment. The standardized nomenclature presented in this document is also available electronically for society members on the internet (http://goreni.org). Accurate and precise morphologic descriptions of changes in the CV system are important for understanding the mechanisms and pathogenesis of those changes, differentiation of natural and induced injuries and their ultimate functional consequence. Challenges in nomenclature are associated with lesions or pathologic processes that may present as a temporal or pathogenic spectrum or when natural and induced injuries share indistinguishable features. Specific nomenclature recommendations are offered to provide a consistent approach.

Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop.

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.

Development and application of a loop-mediated isothermal amplification assay for rapid detection of Pythium helicoides.

Root rot of poinsettia, caused by Pythium helicoides at high temperatures in hydroponic cultures, has become a serious problem in many parts of the world. We have developed a species-specific, loop-mediated isothermal amplification (LAMP) assay for the rapid diagnosis of this pathogen. The primers were designed using the ribosomal DNA internal transcribed spacer sequence. Primer specificity was established using 40 Pythium species including P. helicoides, 11 Phytophthora species, and eight other soil-borne pathogens. A sensitivity test was carried out using genomic DNA extracted from P. helicoides, and the detection limit was c. 100 fg which is comparable to that of the polymerase chain reaction (PCR). In addition, we tested the ease of pathogen detection in poinsettia roots. The LAMP results were consistent with those from the conventional plating method and showed more sensitivity than the PCR results. Consequently, the LAMP method developed in this study is effective for the rapid and easy detection of P. helicoides.

Symptomatic and morphological differences between choroidal excavations.

PURPOSE: The purpose of this report is to describe the morphological and clinical features of two patients with focal choroidal excavation in an attempt to understand more about this rare condition. CASE REPORT: Spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography, and indocyanine green angiography were used to assess the morphological characteristics of the patients' choroidal excavations. Both patients showed the following features on SD-OCT: (1) the retinal pigment epithelium band and inner/outer segment junction followed the contour of the choroidal excavation, which involved the outer nuclear layers up to the outer limiting membrane; (2) the sclerochoroidal junction was smooth and undisturbed, but large choroidal vessels were present beneath each excavation. The patient with metamorphopsia showed separation between the photoreceptor outer segment and the retinal pigment epithelium as well as disturbance of the inner/outer segment junction on SD-OCT volume scans and hyperfluorescence and hypofluorescence in the foveal region on indocyanine green angiography. CONCLUSIONS: Symptomatic and morphological differences between focal choroidal excavations suggested anatomical alterations between the photoreceptor tips and the retinal pigment epithelium or location of choroidal excavation as the cause of metamorphopsia. We speculate that the pathogenesis of focal choroidal excavation involves outward traction on the macula caused by choroidal vascular abnormalities because of embryonic developmental failure of the choroid.

Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats.

Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manual counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats.

Salivary mucocele in a laboratory beagle.

The histologic characteristics of a salivary mucocele in a beagle used in a toxicity study are described in this report. A pale yellowish cyst under the mandibular skin containing frothy mucus was observed at necropsy. Microscopically, numerous villous projections arose from the internal surface of the cyst and were lined by stratified epithelial-like macrophages, which were immunopositive for macrophage scavenger receptor A. A ruptured sublingual interlobar duct connected to the lumen was observed near the cyst. Luminal amorphous material showed a positive reaction with Alcian blue and periodic acid-Schiff staining as did mucin in the sublingual gland. Ultrastructurally, the epithelial-like macrophages had numerous vacuoles containing electron-lucent material, which was presumed to be lysosomal in origin, and had pseudopods on their cell surfaces interdigitating with those on the adjacent cells. This case report helps to understand the diversity of the background findings in beagles used in toxicity studies.

Randomized comparison of the Nobori Biolimus A9-eluting coronary stent with the Taxus Liberté paclitaxel-eluting coronary stent in patients with stenosis in native coronary arteries: the NOBORI 1 trial--Phase 2.

BACKGROUND: The newly developed Nobori coronary stent coated with a bioresorbable polymer, polylactic acid, and the antiproliferative agent Biolimus A9 has the potential to reduce restenosis by suppressing neointima formation. METHODS AND RESULTS: We conducted a randomized (2:1), controlled trial comparing the Biolimus A9-eluting stent Nobori and the paclitaxel-eluting stent Taxus Liberté, in 243 patients (153 Nobori and 90 Taxus) at 29 centers in Europe, Asia, and Australia. Patients with previously untreated lesions in up to 2 native coronary arteries were considered for enrollment. The primary end point was in-stent late loss at 9 months, whereas secondary end points included other quantitative coronary angiography parameters, such as in-segment late loss and the rate of restenosis as well as key intravascular ultrasound parameters. Clinical secondary end points were stent thrombosis and composite of major adverse cardiac events comprising death, myocardial infarction, and target vessel revascularization. At 9 months, the in-stent late loss was significantly lower in the Nobori group compared with the Taxus group (0.11+/-0.30 mm versus 0.32+/-0.50 mm) reaching both the primary hypothesis of noninferiority of Nobori stent versus Taxus Liberté stent (P<0.001) and the secondary hypothesis of superiority (P=0.001). This finding was confirmed by a significant reduction in binary restenosis from 6.2% in Taxus to 0.7% in Nobori (P=0.02) and neointimal volume obstruction, detected by intravascular ultrasound, from 5.5+/-7.2% in Taxus to 1.8+/-5.2% in Nobori (P=0.01). The major adverse cardiac events rate was 4.6% in the Nobori and 5.6% in the Taxus cohort of patients. The stent thrombosis rate was 0% in the Nobori arm and 4.4% in the Taxus arm. CONCLUSIONS: The NOBORI 1 clinical trial confirmed its primary hypothesis--noninferiority of the Nobori Biolimus A9-eluting stent versus the Taxus Liberté stent in reducing neointimal proliferation. Both stents showed a low major adverse cardiac events rate in the studied population.

Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs.

High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.

Randomised comparison of Nobori, biolimus A9-eluting coronary stent with a Taxus(R), paclitaxel-eluting coronary stent in patients with stenosis in native coronary arteries: the Nobori 1 trial.

BACKGROUND: We studied the Nobori coronary stent coated with a bioabsorbable polymer and the anti-proliferative agent Biolimus A9 which may reduce neointimal formation. METHODS AND RESULTS: Patients undergoing percutaneous coronary intervention for de novo lesions in up to two native coronary arteries, in 29 centres across Europe, Asia and Australia were randomly (2:1) assigned to receive the Biolimus A9 eluting stent Nobori (85 patients) or paclitaxel eluting stent Taxus(R) (35 patients). The two groups were well matched in baseline characteristics. The primary end point of non-inferiority for in-stent late loss of Nobori stent versus Taxus(R) stent, at 9 months, was reached with the values of 0.15+/-0.27 mm with Nobori stent and 0.32+/-0.33 mm with Taxus(R) stent (p=0.006). Neointimal volume obstruction was 2.2+/-6.0% and 8.9+/-9.2% for Nobori and Taxus(R) stent respectively (p=0.017). The rates of death, myocardial infarction and any target vessel revascularisation at 9 months were 0%, 4.7%, and 7.1% respectively for Nobori stent, and 0%, 8.6% and 14.3% respectively for Taxus(R) stent. Clinically-driven target lesion revascularisation rate was 0% for Nobori stent and 2.9% for Taxus(R) stent. Stent thrombosis rates at 9 months were 0% in both groups. CONCLUSIONS: In this trial the Nobori Biolimus A9 eluting stent proved to be safe and effective in reducing neointimal proliferation. The long term safety remains to be confirmed during the extended follow-up period of 5 years.

A novel ultra-thin bare metal stent (BMS): results from a worldwide registry.

AIMS: To evaluate a new generation, thin strut, stainless steel Tsunami coronary stent in a contemporary percutaneous coronary intervention (PCI) practice across a wide geographical area. METHODS AND RESULTS: Patients (n=1,437) with single or multiple vessel coronary artery disease undergoing PCI in 82 sites in Europe, Asia, and Australia were enrolled in the MATSURI registry. Clinical follow-ups were scheduled at 1, 6 and 18 months. Primary endpoint was major adverse cardiac events (MACE) rate at 6 months. Diabetes was present in 25% of patients, 40% had unstable angina, 54% multivessel disease and 31% previously underwent PCI/CABG. Procedural success was achieved in 98.1% of patients. MACE rate was 1.8%, 7.3%, and 12.6% for 1, 6 and 18 month follow-up, respectively. At 6 months, the incidence of cardiac death, MI and TLR were 1%, 1.9% and 4.5% respectively, and confirmed stent thrombosis occurred in 0.2% of patients. Lower risk patients (43% of registry population) had six months MACE free survival of 96.7%. CONCLUSIONS: Based on the results of this large registry we can conclude that the Tsunami BMS combines excellent deliverability and safety for all, together with very low MACE rates for lower risk patients. Long term follow-up confirmed sustained clinical benefit.

Visual electrophysiological features of two naturally occurring mouse models with retinal dysfunction.

PURPOSE: We developed two strains of mouse with retinal dysfunction, named the ICR-derived retinal dysfunction (IRD)1 and IRD2, from one male ICR mouse with a retinal dysfunction but a normal fundus. The purpose of this study was to describe the features of retinal dysfunction in both mutant mice. METHODS: Scotopic and photopic electroretinograms (ERGs) were recorded from IRD1 and IRD2 mice at 1 month of age to evaluate retinal function, and then the structures of the retinas in both mutant mice were observed by light microscopy at 1 and 3 months of age. In a mating study, the inheritance pattern and the genetic relation of IRD1 and IRD2 mice were defined. RESULTS: At 1 month of age, IRD1 mice showed affected scotopic and photopic ERGs, and IRD2 mice exhibited normal photopic but affected scotopic ERGs. The retinal structures of both mutant mice remained normal even at 3 months of age. The IRD1, and IRD2 phenotypes showed an autosomal recessive pattern of inheritance and in the IRD1 backcross offspring some mice that had only cone dysfunction were seen in addition to normal, IRD1, and IRD2 phenotypes. All F1 (IRD1 x IRD2) offspring exhibited IRD2 phenotype, rod dysfunction. CONCLUSIONS: IRD1 and IRD2 mice had affected rod systems caused by a homozygous mutation in the same rod function-related gene, and additionally IDR1 mice had affected cone systems caused by a homozygous mutation in the cone function-related gene, without apparent anatomical abnormalities in the retinas of either mutant mice even at 3 months of age. We believe that these mice could be new spontaneous animal models for the study of human inherited retinal disorders.

Inhibition of growth plate angiogenesis and endochondral ossification with diminished expression of MMP-13 in hypertrophic chondrocytes in FGF-2-treated rats.

Fibroblast growth factors (FGFs)/fibroblast growth factor receptor-3 signaling interferes with endochondral bone growth. However, the exact mechanisms by which FGFs inhibit endochondral ossification remain to be elucidated. In the present study, we utilized immunohistochemical techniques to clarify the effects of FGF-2 on the proximal tibial growth plate cartilage, when injected systemically into growing rats. In the FGF-2-treated rats, the growth plate was obviously thickened and, in the lowermost part, the hypertrophic chondrocytes were flattened, with an irregular arrangement. The connection of the cartilage columns and trabecular bone was disrupted. FGF-2 treatment stimulated the proliferation of chondrocytes and permitted their differentiation, but inhibited vascular invasion and resorption of the cartilage matrix. Expression of matrix metalloproteinase-13 (MMP-13) was detected in the chondrocytes in the last row of the hypertrophic zone of the growth plate in control animals. The immunoreactivity of MMP-13 was diminished in the regions where endochondral ossification was disturbed in the FGF-2-treated rats. Because MMP-13 has potent proteolytic activity on cartilage components, the FGF-2 signal may inhibit angiogenesis and endochondral ossification of the growth plate by the suppression of MMP-13 expression in hypertrophic chondrocytes.