The photo-regulation of transgene expression is one effective approach in mammalian synthetic biology due to its high spatial and temporal resolution. While DNAs are mainly used as vectors, modified ...RNAs (modRNAs) are also useful for medical applications of synthetic biology, because they can avoid insertional mutagenesis and immunogenicity. However, the optogenetic control of modRNA-delivered transgenes is much more difficult than that of DNA-delivered transgenes. Here, we develop two types of photo-controllable translational activation systems that are compatible with modRNAs. One is composed of a heterodimerization domain-fused split translational activator protein and a photocaged heterodimerizer. The other is composed of a destabilizing domain-fused translational activator protein and a photocaged stabilizer. The destabilized type can be used for not only translational activation but also translational repression of the modRNAs. These photo-controllable translation systems will expand the application of mammalian synthetic biology research.
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•Two photo-controllable translational activators for synthetic mRNAs are developed•One is a split translational activator that is reconstituted by light•The other is a destabilized translational activator that is stabilized by light•The destabilized type enables both translational activation and repression
Nakanishi et al. develop photo-controllable translational regulation systems for synthetic mRNAs containing modified nucleosides. These systems are composed of photocaged ligands, ligand-responsive domain-fused translational regulatory proteins, and target synthetic mRNAs containing a protein binding motif. They enable light-inducible translational activation or repression of the target mRNAs in mammalian cells.
Background
Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred ...in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients.
Methods
Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed.
Results
The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (
p
= 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (
p
< 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (
p
= 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14–0.99;
p
= 0.047).
Conclusion
Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient’s RFS while omitting immediate CLND had no significant negative influence on it.
The efficacy and safety of nivolumab + ipilimumab combination therapy were retrospectively examined in Japanese patients with unresectable advanced melanoma in clinical practice. Fifty‐seven patients ...with advanced melanoma received the nivolumab + ipilimumab combination therapy. The primary site was cutaneous, mucosal, uveal and unknown in 35, 16, two and four patients, respectively. The overall response rate was 26.3%, with complete response observed in two (3.5%) patients, partial response in 13 (22.8%), stable disease in 12 (21.1%) and progressive disease in 30 (52.6%). The response rate in the treatment‐naive and prior systemic therapy group was 40.7% and 13.3%, respectively. For those treated with a single immune checkpoint inhibitor followed by the nivolumab + ipilimumab combination therapy as second‐line therapy after disease progression, the response rate was 18.8%. Median progression‐free survival (PFS) and overall survival (OS) in all patients was 3.3 and 14 months, respectively. Median PFS in the treatment‐naive and prior systemic therapy groups was 13 and 2 months, respectively. Median OS was unreached in the treatment‐naive group and was 6.3 months in prior systemic therapy groups. There was no significant difference in PFS and OS for non‐acral, acral and mucosal melanoma. Adverse events occurred in 86% of patients; 56.1% were grade 3 or worse. The response rate in an actual clinical setting, including the prior systemic therapy group, was lower than that in the global study and the Japanese phase II study. However, in the treatment‐naive group, the rate was equivalent to that in the Japanese phase II study. PFS and OS in the treatment‐naive group were comparable with those in the global study and Japanese phase II study, suggesting that the treatment was effective. The proportion of grade 3 and 4 immune‐related adverse events was as high as that in the global study and Japanese phase II study.
Invasive extramammary Paget's disease may cause lymph node and distant metastases. Complete lymph node dissection is generally performed for extramammary Paget's disease presenting with lymph node ...metastases. Patients with extramammary Paget's disease and multiple lymph node metastases typically have poor prognoses, and there is no effective postoperative treatment to prevent recurrence or further metastases in such patients to date. This study aimed to evaluate the efficacy of postoperative radiotherapy in patients with extramammary Paget's disease and multiple lymph node metastases. We enrolled 26 patients with extramammary Paget's disease with ≥3 lymph node metastases who were treated at the National Cancer Center Hospital in Japan between January 2000 and June 2021. The patients were divided into those who underwent complete lymph node dissection only or with postoperative radiotherapy. We evaluated recurrence‐free survival, distant metastasis‐free survival, and overall survival outcomes with Kaplan–Meier curves. Among the 26 enrolled patients, 16 underwent complete lymph node dissection only and 10 underwent complete lymph node dissection with postoperative radiotherapy. The median follow‐up period was 16 months. The 5‐year recurrence‐free, distant metastasis‐free, and overall survival values were 47.3%, 63.0%, and 90% in those with complete lymph node dissection and postoperative radiotherapy, while these outcomes were all 0% (p = 0.001, 0.004, and 0.009, respectively) in those with only complete lymph node dissection. Thus, survival was significantly prolonged with postoperative radiotherapy. Additional postoperative radiotherapy may substantially improve the prognoses of patients with extramammary Paget's disease and ≥3 lymph node metastases, and undergoing curative surgery.
The most common adverse event of epidermal growth factor receptor inhibitors, used to treat colorectal, non‐small cell lung, and head and neck cancers, is acneiform eruption, with a profound effect ...on treatment continuation. Prolonged acneiform eruptions treated with topical corticosteroids, a standard management, may be associated with secondary bacterial infections, thus there is a need for new treatments. We conducted a multicenter, phase II trial to evaluate the efficacy and safety of topical benzoyl peroxide for epidermal growth factor receptor inhibitor‐induced prolonged acneiform eruptions. Patients with colorectal, non‐small lung cell, and head and neck cancers who received epidermal growth factor receptor inhibitors for >10 weeks and had persistent acneiform eruptions were eligible. Topical benzoyl peroxide was applied to the affected area of the face once daily for 8 weeks; a clinical evaluation was performed every 2 weeks. The primary endpoint was a change in acneiform eruption severity evaluated between disease onset and end of the treatment period. The quality of life of patients was assessed using the Dermatology Life Quality Index. Of the 14 enrolled patients, 11 completed the trial. The protocol‐specified grade of acneiform eruptions from baseline to week 8 improved from 2.0 to 1.0 (P < 0.01). The dermatology life quality index score from baseline to week 8 improved from 3.0 to 1.0 point (P < 0.01). No patient experienced severe adverse events. Overall, topical benzoyl peroxide may be effective for treating and managing prolonged acneiform eruptions induced by epidermal growth factor receptor inhibitors.
Extramammary Paget’s disease (EMPD) often invades the dermis and metastasizes to the lymph nodes. Patients with EMPD associated with lymph node metastases have poor prognosis; to date, effective ...treatment has not yet been established. Lymph node dissection, aiming to control the local disease, is a standard form of management for EMPD patients with lymph node metastases (LNM). We investigated the clinical and pathological features, treatment strategies and prognostic factors of patients with metastatic EMPD who underwent lymph node dissection. We retrospectively evaluated 38 cases of extramammary Paget’s disease with lymph node metastasis over 10 years. All patients underwent wide resection of the primary lesion and lymph node dissection. Univariate analysis revealed the number of metastatic nodes and lymphadenopathy as prognostic factors. In multivariate analysis, the number of metastatic lymph nodes retained statistical significance (hazard ratio, 35.3; 95% confidence interval, 3.23–387.0; P = 0.003). The 5‐year survival rate was 100% and 19.1% in patients with two or less LNM and with three or more LNM, respectively. In patients with three or more LNM, the 5‐year survival rate after adjuvant radiation therapy was better than that after surgery alone (75% vs 0%). In conclusion, patients with two or less LNM can be expected to have long‐term survival with lymph node dissection only, while patients with three or more LNM may require adjuvant radiation therapy to improve prognosis. These results suggest that lymph node dissection may be a strategy to treat EMPD with regional LNM.
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