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.

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.

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.

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.

1,2-Di(6-azulenyl)tetraphenylbenzenes and (6-azulenyl)pentaphenylbenzenes were synthesized by Diels-Alder reactions of di(6-azulenyl)acetylenes and 6-(phenylethynyl)azulenes with tetraphenylcyclopentadienone. Cobalt-mediated cyclooligomerization of mono- and di(6-azulenyl)acetylenes afforded 1,3,5- and 1,2,4-tri(6-azulenyl)benzene derivatives together with (eta(5)-cyclopentadienyl)[tetra- and di(6-azulenyl)cyclobutadiene]cobalt complexes. The redox behavior of these novel (6-azulenyl)benzene derivatives and [tetra- and di(6-azulenyl)cyclobutadiene]cobalt complexes was examined by cyclic voltammetry (CV). Mono(6-azulenyl)benzenes exhibited a reduction wave upon CV. In contrast, 1,2-di(6-azulenyl)benzenes showed a two-step reduction wave at the similar potential region upon CV, which revealed the formation of a dianion stabilized by 6-azulenyl substituents under electrochemical reduction conditions. Three 6-azulenyl substituents on benzene in a 1,2,4 relationship also increased electron-accepting properties because of the formation of a closed-shell dianionic structure, whereas 1,3,5-tri(6-azulenyl)benzenes were reduced stepwise.

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BackgroundImmunotherapies that target immune-checkpoint molecules such PD-1 have helped to achieve durable responses in melanoma treatment. However, 25% of melanoma patients who showed objective responses to PD-1 blockade develop resistance and suffer from disease progression and ultimately death, which necessitates the identification of related resistance mechanisms.IL-34 is a cytokine that controls the biology of myeloid cell lineage through binding to CSF-1R. IL-34 is importantly involved in the pathogenesis of various diseases. In cancer, the expression of IL-34 has been suggested to associate with tumor growth, metastasis, angiogenesis, and therapeutic resistance such as in lung cancers and malignant pleural mesotheliomas. In this study, we evaluate the possible involvement of IL-34 in immunotherapeutic resistance.Case presentationMelanoma resection species were obtained from a patient who developed a refractory melanoma against immunotherapy with Nivolumab, and stained with anti-IL-34, anti-melanoma antigens and anti-CD163 antibody. Staining of these markers was compared between primary or metastatic refractory melanoma tissues. Immunohistochemistry staining of melanoma tissues showed an enhanced expression of IL-34 in metastatic refractory melanoma compared to primary melanoma tissues, which correlates with increased frequencies of CD163+ macrophages.ConclusionWe introduce for the first time a clinical case of a patient with metastatic refractory melanoma that acquired resistance to anti-PD-1 immunotherapy, showing an enhanced expression of IL-34 in refractory melanoma tissues.

Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.