Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0–400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.     

Survival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers

Peptide‐based cancer vaccines are able to induce strong immune responses, but their clinical results are unsatisfactory. To determine clinically correlated peptides, we analyzed survival data from urological cancer patients treated by personalized peptide vaccination (PPV), in which different multiple peptides were used for individual patients based on human leukocyte antigen (HLA) type and pre‐existing immunity. Survival data were obtained from a database of 265 urological cancer patients treated in 5 clinical PPV trials comprising 154 patients with castration‐resistant prostate cancer (CRPC) and 111 patients with advanced urothelial cancer (UC). Expression of tumor‐associated antigens (TAA) was evaluated in 10 prostate cancer tissues, 4 metastatic lymph nodes from prostate cancer, and 10 UC tissues using immunohistochemical staining. Clinical efficacy of individual peptides for overall survival was evaluated by the Cox proportional hazards regression model. All TAA coding candidate peptides used in PPV treatment were expressed in tumor cells from prostate cancer and UC samples except for p56Lck in both, and prostate‐specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate‐specific membrane antigen (PSMA) in the UC samples. Patients with the following peptides had a significantly longer survival than patients without the peptides (hazard ratio <1.0, 95% confidence intervals <1.0 and P < .05): SART3‐109, PTHrP‐102, HNPRL‐140, SART3‐302 and Lck‐90 in CRPC patients, and EGF‐R‐800, Lck‐486, PSMA‐624, CypB‐129 and SART3‐734 in advanced UC patients, respectively. Correlated peptides selected using both survival data and pre‐existing immunity for PPV treatment may enhance the clinical benefits for urological cancer patients.     

Cardiac Rupture Complicating Hemorrhagic Infarction after Intracoronary Thrombolysis

An 80-year-old woman with acute myocardial infarct intracoronary thrombolysis by a large dose of urokinase four hours after the onset of chest pain. Despite the patient having no chest pain after intracoronary thrombolysis and her general condition being stable, she died suddenly on the 4th hospital day. Autopsy revealed hemopericardium due to cardiac rupture, which occurred at the center of the transmural hemorrhagic infarction of the anteroseptal wall. The massive hemorrhagic infarction was promoted by reperfusion from thrombolytic therapy. She had also classic risk factors for cardiac rupture, such as hypertension, senility, female gender, and first acute myocardial infarct. Therefore, the present case demonstrated that hemorrhagic infarction increased the incidence of cardiac rupture.     

Cerebro-spinal infarction caused by atheromatous emboli

Cholesterol embolization to the abdominal viscera is common, but rare in the central nervous system. Fourteen cases of atheromatous embolization to the central nervous system were morphologically investigated. Among the 800 consecutive autopsy cases, 38 cases had atheromatous emboli in various organs. Cerebro-spinal infarction caused by atheromatous emboli was found in 11 cases. Infarction rate (11/14) was relatively higher than in other organs and 5 of these cases were thought to be due to direct injury to the erosive surface of the aorta; cardiac catheterization (2 cases), intra-aortic balloon pumping (2 cases), and extra-anatomical bypass graft operation (1 case). These 14 patients consisted of elderly patients (70.1 +/- 6.3 years old) usually associated with hypertension (78.6%) and diabetes mellitus (42.8%). Anatomically, aortic aneurysms were seen in 10 cases (71.4%), in which aortic arch aneurysm was seen in 6 cases. Hence, aortic mechanical procedure is of great importance for denuding atheromatous materials from erosive atherosclerosis to the central nervous system.     

HETEROTOPIC BRAIN OF THE TONGUE

A 6-week-old male infant with lingual mass suffered from feeding difficulty and respiratory distress. Resected specimens revealed brain tissue composed of astroglia, oligodendroglia, ependyma, choroid plexus, neuronal cells, and primitive cells but no other elements suggestive of teratoma, therefore it was diagnosed as heterotopic brain of the tongue. ACTA PATHOL. JPN. 1397 -1402, 1986.     

Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method

One-step fluorescein-conjugated polyclonal antibody technique has shown that C-reactive protein (CRP) was located only extracellularly in human atherosclerotic lesions. In this report a more sensitive streptavidin-biotin technique was applied to detect the localization of CRP in human athere sclerotic lesions. lmmunohistochemical staining with polyclonal and monoclonal anti-human CRP antibodies both produced a brown color extracellularly in the necrotic lesions, and intracelluarly in CD68+ foam cells. The latter suggests an uptake of CRP-lipid complexes by macro-phages. The staining is human CRP-specific because it was eliminated by preabsorption of the monoclonal antibody with pure human CRP, or by substitution of the primary antibody with non-immune rabbit serum. By overlaid CRP-binding study, a positive stain was observed on intimal smooth muscle cells and foam cells, suggesting that they have CRP-binding sites unless the CRP-binding activity was generated de novo through the fixation procedure. Accordingly, it is hypothesized that CRP may facilitate the uptake of lipids by macrophages accumulating in atherosclerotic lesions. Further, CRP might participate in cytolysis, which enlarges the necrotic area, and/or in phagocytosis that scavenges the necrotic tissue.     

Immunization procedures for anti-idiotypic antibody induction in mice and rats

Anti-idiotypic antibodies (Ab2) mimicking antigens (Ags)-defined by antibodies (Ab1) directed to tumors or pathogens have elicited Ag-specific humoral, cellular and/or protective immunity in experimental animals and in humans. In immunizations of rodents with Ab1, factors such as animal species, form of Ab1 and choice of adjuvant are crucial for the successful induction of Ab2 as candidate vaccines against tumors and pathogens. Here we survey the outcome of 362 fusion events (each event representing one animal), using nine immunization schedules in mice and seven schedules in rats and including 10 different Ab1 directed against human tumor- and immunodeficiency virus (HIV-1)-associated Ags. Ab1 IgG or F(ab')2 were administered uncoupled or coupled to keyhole limpet hemocyanin (KLH). As adjuvants, complete and incomplete Freund's adjuvant (CFA/IFA), lipid A, aluminum hydroxide, TiterMax or vaccinia virus were used. In syngeneic immunizations with murine Ab1 in mice, F(ab')2 coupled to KLH and emulsified in CFA/IFA preferentially induced Ab2 mimicking tumor or HIV-1 associated epitopes. In xenogeneic immunizations with mouse Ab1 in rats, various forms of Ab1 and adjuvants successfully induced Ab2 mimicking tumor Ags.     

Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: A National Lung Cancer Roundtable best-practice guide

Advances in biomarker-driven therapies for patients with nonsmall cell lung cancer (NSCLC) both provide opportunities to improve the treatment (and thus outcomes) for patients and pose new challenges for equitable care delivery. Over the last decade, the continuing development of new biomarker-driven therapies and evolving indications for their use have intensified the importance of interdisciplinary communication and coordination for patients with or suspected to have lung cancer. Multidisciplinary teams are challenged with completing comprehensive and timely biomarker testing and navigating the constantly evolving evidence base for a complex and time-sensitive disease. This guide provides context for the current state of comprehensive biomarker testing for NSCLC, reviews how biomarker testing integrates within the diagnostic continuum for patients, and illustrates best practices and common pitfalls that influence the success and timeliness of biomarker testing using a series of case scenarios.     

Antitumor effect of afatinib,as a human epidermal growth factor receptor 2‐targeted therapy,in lung cancers harboring HER2 oncogene alterations

Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non‐small‐cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2‐targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)–HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS‐2B, ectopically overexpressing wild‐type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2‐altered NSCLC cells (H2170, Calu‐3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G₁ arrest and apoptotic cell death. In contrast, HER2‐ or EGFR‐non‐dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2‐altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2‐targeted therapy for NSCLC harboring HER2 amplification or mutations.