Mast cells and basophils share some functions in common and are generally associated with T helper 2 (Th2) immune responses, but taking basophils as surrogate cells for mast cell research or vice ...versa for several decades is problematic. Thus far, their in vitro functions have been well studied, but their in vivo functions remained poorly understood. New research tools for their functional analysis in vivo have revealed previously unrecognized roles for mast cells and basophils in several skin disorders. Newly developed mast cell‐deficient mice provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. In addition, studies using basophil‐deficient mice have revealed that basophils were responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Moreover, human basophils infiltrate different skin lesions and have been implicated in the pathogenesis of skin diseases ranging from atopic dermatitis to autoimmune diseases. In this review, we will discuss the recent advances related to mast cells and basophils in human and murine cutaneous immune responses.
Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of ...anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.
We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan–Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.
In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group 6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).
Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.
•Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma.•We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody.•Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients.•Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma.
Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs) generated by ionizing radiation (IR) and anti-cancer drugs. Therefore, inhibiting the activity of ...proteins involved in this pathway is a promising way of sensitizing cancer cells to both radiotherapy and chemotherapy. In this study, we developed an assay for evaluating NHEJ activity against DSBs in chromosomal DNA in human cells to identify the chromatin modification/remodeling proteins involved in NHEJ. We showed that ablating the activity of the homologous histone acetyltransferases, CBP and p300, using inhibitors or small interfering RNAs-suppressed NHEJ. Ablation of CBP or p300 impaired IR-induced DSB repair and sensitized lung cancer cells to IR and the anti-cancer drug, etoposide, which induces DSBs that are repaired by NHEJ. The CBP/p300 proteins were recruited to sites of DSBs and their ablation suppressed acetylation of lysine 18 within histone H3, and lysines 5, 8, 12, and 16 within histone H4, at the DSB sites. This then suppressed the recruitment of KU70 and KU80, both key proteins for NHEJ, to the DSB sites. Ablation of CBP/p300 also impaired the recruitment of BRM, a catalytic subunit of the SWI/SNF complex involved in chromatin remodeling at DSB sites. These results indicate that CBP and p300 function as histone H3 and H4 acetyltransferases at DSB sites in NHEJ and facilitate chromatin relaxation. Therefore, inhibition CBP and p300 activity may sensitize cancer cells to radiotherapy and chemotherapy.
Nivolumab has shown promising early results in patients with advanced malignancies, including melanoma and lung cancer, with generally manageable side effects. On the other hand, recent studies ...showed that the immune activation caused by PD-1 blockade might promote severe autoimmune toxicity. Herein, we report a case of idiopathic thrombocytopenic purpura during nivolumab therapy.
Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies ...suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients.
We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4.
Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001).
First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.
•Anti-PD-1 plus anti-CTLA-4 antibody therapy (PD1 + CTLA4) is an option for patients with advanced mucosal melanoma (MCM).•Data on the efficacy of PD1 + CTLA4 compared with PD-1 monotherapy (PD1) for MCM, however, are limited.•We retrospectively analyzed data from 329 Japanese patients with advanced MCM treated with PD1 or PD1 + CTLA4.•No significant differences in objective response rate, progression-free survival, or overall survival were observed.•Immune-related adverse events resulting in treatment cessation were higher in the PD1 + CTLA4 group.
Summary
Background
Taxanes are the current first‐line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or ...comorbidity. However, no effective second‐line therapy for such patients has been established.
Methods
We designed a single‐arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m−2 on days 1 and 8 in a 21‐day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression‐free survival (PFS) and toxicity assessment.
Results
We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference.
Conclusions
ERB showed a promising RR and is a potential candidate for second‐line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients.
What is already known about this topic?
Taxanes are the current first‐line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity.
No effective therapy for taxane‐resistant CAS has been established thus far.
Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes.
What does this study add?
In our single‐arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression‐free survival were 8·6 and 3·0 months, respectively.
Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively.
Although 16 grade 3/4 severe adverse events occurred, all patients recovered.
Eribulin showed a promising response rate and is a potential candidate for second‐line treatment in CAS after taxane treatment.
Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797–798.
What is already known about this topic?
Taxanes are the current first‐line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity.
No effective therapy for taxane‐resistant CAS has been established thus far.
Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes.
What does this study add?
In our single‐arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression‐free survival were 8·6 and 3·0 months, respectively.
Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively.
Although 16 grade 3/4 severe adverse events occurred, all patients recovered.
Eribulin showed a promising response rate and is a potential candidate for second‐line treatment in CAS after taxane treatment.
Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797–798.
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