Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab.

Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.

In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.

Background It is unclear whether microneedle vaccinations of Japanese encephalitis virus can induce sufficient neutralising antibodies and reduce the amount of vaccine needed. We aimed to assess the safety and dose-sparing effect of a microneedle vaccine patch against Japanese encephalitis in healthy individuals who are naive to both the vaccine and natural infection. MethodsThe MNA-J study was a randomised, partly blinded, active-controlled, phase 1 clinical trial at Hokkaido University (Sapporo, Japan) that enrolled healthy adults aged 20-34 years with no history of Japanese encephalitis vaccination nor of infection as confirmed by seronegativity. We excluded individuals who had been infected with or vaccinated against Japanese encephalitis. Eligible participants were randomly assigned (1:1:1) to one of three groups to receive inactivated Japanese encephalitis vaccine administered twice, 3 weeks apart, by either 2•5 μg per injection by subcutaneous injection, 0•63 μg per patch by high-dose microneedle array (MNA-25%), or 0•25 μg per patch by low-dose microneedle array (MNA-10%). The randomisation sequence, using stratification by cohort and blocks of six, was computer-generated by a statistician who was unaware of group assignment. After administration, the remaining amount of unadministered vaccine was measured by ELISA and calculated as the delivered amount of vaccine. The primary outcome was the neutralising antibody titre at day 42 after first immunisation. Successful seroconversion was defined as post-vaccination titres of 1•3 (log 10 ) or higher in individuals whose pre-vaccination titres had been less than 1 (log 10 ). This study is registered with the Japan Registry of Clinical Trials (s011190004). FindingsBetween Aug 31 and Sept 2, 2019, 39 participants were enrolled and each was randomly assigned to a group (n=13 per group). No serious adverse events were observed. All participants in the microneedle array groups had a localised erythematous reaction. The amount of vaccine delivered by microneedle array to each participant was 0•63-1•15 μg (50-92%) of the full 1•26 μg for the MNA-25% group and 0•25-0•41 μg (51-84%) of the full 0•50 μg for the MNA-10% group. All participants demonstrated seroconversion at day 42, and the mean titres (log 10 ) were 2•55 for MNA-25%, 2•04 for MNA-10%, and 2•08 for subcutaneous injection.Interpretation A microneedle patch of the Japanese encephalitis vaccine is safe, well tolerated, and immunogenically effective. The dose-sparing effect suggests a significant potential to reduce the amount of immunogens needed. However, improved delivery is needed to make it more tolerable and user friendly.Funding FUJIFILM.

A series of poly(6-azulenylethynyl)benzenes substituted with n-hexyloxycarbonyl chains at 1,3-positions in azulene rings, i.e., hexakis-, 1,2,4,5-tetrakis-, 1,3,5-tris-, and 1,4-bis(6-azulenylethynyl)benzene derivatives 1, 2, 3, and 4b, have been prepared by a simple one-pot reaction involving repeated Pd-catalyzed alkynylation of halogenated arenes with substituted 6-ethynylazulene and/or ethynylated arenes with substituted 6-bromoazulene under Sonogashira-Hagihara conditions. The redox behavior of these novel poly(6-azulenylethynyl)benzene derivatives was examined by cyclic voltammetry (CV), which revealed the presumed multielectron redox properties. Compound 4b exhibited a one-step, two-electron reduction wave upon CV, which revealed the formation of the dianion stabilized by two 6-azulenylethynyl substituents under electrochemical reduction conditions. Four 6-azulenylethynyl substituents on a benzene ring in a 1,2,4,5 relationship increased the electron-accepting properties because of the formation of a stabilized closed-shell dianionic structure, whereas 3 was reduced at more negative reduction potentials. In contrast to the multistep redox behavior of 2, compound 1 was reduced in one step at -1.28 V upon CV. Compound 1 showed a wide temperature range of columnar mesophases (Col(ho) and Col(ro)) from 77.3 degrees C to the decomposition temperature at ca. 270 degrees C. Compounds 2, 3, and 4b exhibited columnar mesomorphism (Col(ro)) with crystalline polymorphs for 2, unusual triple-melting behavior for 3, and both double-melting behavior and columnar mesomorphism (Col(ho)) for 4b. Therefore, the investigated systems exemplify a new principle for multielectron redox behavior with liquid crystalline properties.