Systemic therapy for Asian patients with advanced BRAF V600-mutant melanoma in a real-world setting: A multi-center retrospective study in Japan (B-CHECK-RWD study).

BACKGROUND: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. METHODS: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. RESULTS: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. CONCLUSIONS: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

Palmitoylation-Dependent Small-Molecule Fluorescent Probes for Live-Cell Golgi Imaging.

Small-molecule fluorescent probes enabling visualization of the Golgi apparatus in living cells are essential tools for studying Golgi-associated biological processes and diseases. So far, several fluorescent Golgi stains have been developed by linking ceramide lipids to fluorophores. However, ceramide-based probes suffer from cumbersome staining procedures and low Golgi specificity. Here, we introduce fluorescent Golgi-staining probes based on the tri-N-methylated myristoyl-Gly-Cys (myrGC3Me) motif. The cell-permeable myrGC3Me motif localizes to the Golgi membrane upon S-palmitoylation. By modularly conjugating the myrGC3Me motif to fluorophores, we developed blue, green, and red fluorescent Golgi probes, all of which allowed simple and rapid staining of the Golgi in living cells with high specificity and no cytotoxicity. The probe was also applicable to the visualization of dynamic changes of the Golgi morphology induced by drug treatments and during cell division. The present work provides an entirely new series of live-cell Golgi probes useful for cell biological and diagnostic applications.

Treatment outcomes and prognostic factors in 47 patients with primary anorectal malignant melanoma in the immune therapy era.

PURPOSE: Primary anorectal melanoma (ARM) accounts for approximately 1.2% of all melanomas and 16.5% of all mucosal melanomas. ARM is associated with the shortest interval to disease progression and the highest rate of metastasis; however, optimal therapeutic strategies for ARM remain controversial. This study aimed to assess the ideal surgical intervention for ARM and to determine the effect of immune checkpoint inhibitors (ICI). METHODS: We included 47 patients with ARM treated at the National Cancer Center Hospital in Japan from 2011 to 2020. We performed a survival analysis for each of these groups: (i) patients with ARM (n = 47); (ii) operable non-stage IV cases at initial presentation (n = 35); and (iii) stage IV cases (n = 32). RESULTS: The 5-year overall survival (OS) was 53.6%, and the median OS was 78.7 months in patients with ARM. No statistically significant difference in 5-year OS was found between rectal and anal sites (50.9% vs. 56.7%). In the non-stage IV subgroup, the type of surgery (abdominoperineal resection or wide local excision) did not correlate with OS (HR 1.85; 95% CI 0.46-7.5; p = 0.39). In the stage IV subgroup, the 2-year OS of the ICI treatment group was 61.4%, whereas that of the dacarbazine regimen group was 0% (p = 0.048). CONCLUSION: Our ARM prognosis was better than that of previous studies. Our findings suggest that the availability of ICI therapy may improve survival in patients with advanced ARM. However, further research is warranted to identify both the clinical and molecular predictors of response to improve patient selection.

Type 1 diabetes associated with immune checkpoint inhibitors for malignant melanoma: A case report and review of 8 cases.

Advanced malignant melanoma (MM) is treated with immune checkpoint inhibitor (ICI) therapy, which often results in several immune-related adverse events. Fulminant type 1 diabetes mellitus (T1DM) is a rare, rapidly progressive, life-threatening disease. Here, we summarize 8 cases of MM with ICI-induced T1DM and describe one case that developed fulminant T1DM due to nivolumab therapy. We retrospectively reviewed patients treated with ICI from 2014 to 2021 at our hospital. The clinical features and risk factors of ICI-induced T1DM were discussed. ICIs were administered to 426 MM patients at our hospital. Among these, nivolumab was administered in 5 cases, pembrolizumab in 1 case, and the combination of nivolumab and ipilimumab in 2 cases. The frequency of ICI-associated T1DM was 1.88%. The mean glycated hemoglobin level at T1DM onset was 8.0 ± 1.0%. Of the patients, 75% were diagnosed with fulminant T1DM, 62.5% developed diabetic ketoacidosis, and 25% had glutamic acid decarboxylase (GAD) antibodies (an early predictive marker for T1DM). The mean interval between the first ICI administration and T1DM development was 201 ± 187 days. The mean duration of resumption was 13 ± 7 days. We should monitor for T1DM development following treatment with ICIs. ICI can be continued to be used to treat MM if insulin therapy successfully controls T1DM. A 67-year-old patient who received adjuvant nivolumab therapy developed fulminant T1DM and thyrotoxicosis 57 days later and tested positive for GAD antibodies. Subsequently, he developed hypophysitis and an isolated adrenocorticotropin deficiency. He continued receiving nivolumab along with self-injected insulin without developing recurrence.

Postoperative radiation therapy improves prognoses in extramammary Paget's disease presenting with multiple lymph node metastases.

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.

Post-Immunotherapy Robotic-Assisted Resection for Primary Anorectal Melanoma: A Case Report.

Anorectal malignant melanoma (AMM) is a rare and aggressive neoplasm. Here, we report a case of AMM that was treated with robotic-assisted abdominoperineal resection (APR) after immunotherapy. A 68-year-old Japanese woman presented at our hospital because of diagnosis AMM. Computed tomography revealed a mass in the lower anorectal region and enlarged perirectal lymph nodes, but showed no evidence of distant metastases. We determined that radical resection would be difficult; therefore, the patient received immunotherapy with pembrolizumab for nine cycles. The size of pararectal lymph nodes was reduced, and the patient subsequently underwent robot-assisted APR and lymph node dissection. Histopathological examination showed spindle-shaped atypical melanocytes with acidophilic changes indicative of tumor cell necrosis in the rectal mucosa. We found no viable tumor cells in all 48 lymph nodes that were resected, and resection margins were tumor free. The patient was able to complete 15 cycles of adjuvant immunotherapy with pembrolizumab and remained relapse free at the 2-year postoperative follow-up. The present case showed that combination of complete surgical resection and immunotherapy is expected to improve outcomes in AMM patients if immunotherapy is effective.

Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.

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.

Efficacy and safety of topical benzoyl peroxide for prolonged acneiform eruptions induced by cetuximab and panitumumab: A multicenter, phase II trial.

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.

Light-controllable RNA-protein devices for translational regulation of synthetic mRNAs in mammalian cells.

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.

Real-world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma.

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.

Outcomes of lymph node dissection in the treatment of extramammary Paget's disease: A single-institution study.

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.

Efficacy of oral retinoids for keratoacanthoma centrifugum marginatum.

Keratoacanthoma centrifugum marginatum (KCM) is a rare variant of keratoacanthoma. This condition is difficult to diagnose because of its large size and expansive nature and may be diagnosed as a malignant tumor. There are various treatments such as surgery and oral retinoids; however, limited studies have verified their effectiveness. Here, we report a case of KCM on the anterior chest of a 50-year-old woman and evaluate the efficacy of oral retinoids. In this case, oral retinoids were highly effective for KCM treatment. A total of 55 cases of KCM, including 54 previously reported cases, were reviewed, and their clinical characteristics and treatment were examined. In this report, 14 of 16 patients were effectively treated with oral retinoids, resulting in a treatment rate of 87.5%. Furthermore, even low-to-medium doses were sufficient for treatment and prevention. KCM can be misdiagnosed as a malignant disease based on its clinical features. Due to its large size and expansive nature, a wide excision may be performed; however, because oral retinoids have a very high response rate, an accurate diagnosis will help avoid an unnecessary wide excision.