Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis fact...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
BACKGROUND Radiation recall dermatitis has been defined as the "recalling" by skin of previous radiation exposure in response to the administration of certain response-inducing drugs. Although the phenomenon...BACKGROUND Radiation recall dermatitis has been defined as the "recalling" by skin of previous radiation exposure in response to the administration of certain response-inducing drugs. Although the phenomenon is relatively well known in the medical world,an exact cause has not been documented.CASE SUMMARY Here, we report the rare occurrence of radiation recall dermatitis after palliative radiotherapy for bone metastases in a metastatic melanoma patient treated with a combination of dabrafenib and trametinib.CONCLUSION We present a case of radiation recall dermatitis after completion of palliative radiotherapy while being treated with a combination of dabrafenib and trametinib. This is a very rare toxic event, and there is insufficient data to describe prevention strategies. Increased awareness and reporting of cases will help to better explain the association between targeted therapy and the radiation recall phenomenon.展开更多
BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a sub...BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor)for treating BRAF V600E-mutant ATC.However,reports on patients with ATC treated with this regimen following surgery are lacking.CASE SUMMARY We report the case of a 63-year-old female patient diagnosed with BRAF V600Emutant ATC.Following three surgeries—total thyroidectomy,total laryngectomy,and neck dissection—she was diagnosed with lung metastasis during follow-up.The metastatic ATC was successfully treated with dabrafenib and trametinib.The patient achieved a complete response at the 32-mo follow-up.CONCLUSION Adjuvant chemotherapy with dabrafenib plus trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.展开更多
A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete resp...A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.展开更多
The prognosis of patients with advanced melanoma is poor.The five-year recurrence rate is approximately 70%,whereas the overall survival rate is only 4%-10%.We report the case of a 61-year-old male patient with metast...The prognosis of patients with advanced melanoma is poor.The five-year recurrence rate is approximately 70%,whereas the overall survival rate is only 4%-10%.We report the case of a 61-year-old male patient with metastatic melanoma(B-Raft).The tumor load of the patient was significantly reduced after the application of dabrafenib plus trametinib(“DtT”)and radiotherapy.Further,it is suggested that medical staff should conduct a comprehensive analysis of the patient’s condition when dealing with adverse events(AEs)associated with such malignant tumors to provide evidence for adopting the appropriate targeted treatment or radiotherapy and nursing mode and achieve the best treatment effect.展开更多
BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects ha...BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects have been reported.We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment,thickened choroid,and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase(BRAF)mutant metastatic cutaneous melanoma.CASE SUMMARY A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes.Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber,mild vitritis,bullous multiple serous retinal detachments,and chorioretinal folds in both eyes.Treatment with dabrafenib and trametinib was suspended,and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule.One and a half months after the disease onset,ocular morphological and functional improvement was noted.Due to the metastatic melanoma dissemination,BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared,which later subsided after receiving oral corticosteroids.CONCLUSION Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis.Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients.Furthermore,appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.展开更多
目的:分析达拉非尼联合曲美替尼治疗黑色素瘤致皮肤系统不良反应(ADR)的发生情况及临床特点,为临床安全用药提供参考。方法:检索Web of Science、PubMed、知网和万方数据库,收集国内外相关个案报道并进行分析总结。结果:共筛选出有效文...目的:分析达拉非尼联合曲美替尼治疗黑色素瘤致皮肤系统不良反应(ADR)的发生情况及临床特点,为临床安全用药提供参考。方法:检索Web of Science、PubMed、知网和万方数据库,收集国内外相关个案报道并进行分析总结。结果:共筛选出有效文献31篇,共38例次,患者年龄主要为31~80岁(89.47%);ADR多发生在用药后90 d内(60.52%);主要临床表现为痤疮样皮疹(18.42%)、肉芽肿性皮炎(13.16%)、脂膜炎(10.53%)、纹身并发症(10.53%)及结节性红斑病变(10.53%);34例患者皮肤ADR痊愈或好转,其中2例永久停用了达拉非尼与曲美替尼,10例继续联合治疗,12例暂停联合治疗,其中11例患者好转或痊愈后重启联合治疗。在重启或继续使用联合治疗的患者中,10例再次出现ADR。结论:本研究中,达拉非尼联合曲美替尼致皮肤系统ADR表现出不同的发生率和特征,且免疫治疗后进行靶向治疗可能增加严重皮肤ADR发生风险。临床在联合使用时应加强用药监测,及时发现ADR并采取适当的防治措施,同时严密监测重启或继续用药所致ADR,确保用药安全。展开更多
目的:系统评价达拉非尼联合曲美替尼治疗黑色素瘤致皮肤不良反应的发生率。方法:计算机检索PubMed、EMbase、Cochrane Library、Web of Science和中国知网、维普、万方、中国生物医学文献数据库,收集国内外公开发表的相关研究,检索时间...目的:系统评价达拉非尼联合曲美替尼治疗黑色素瘤致皮肤不良反应的发生率。方法:计算机检索PubMed、EMbase、Cochrane Library、Web of Science和中国知网、维普、万方、中国生物医学文献数据库,收集国内外公开发表的相关研究,检索时间为自建库至2020年12月。采用Stata 15.1软件计算皮肤不良反应的发生率,采用Rev Man 5.3软件评估所有等级皮肤不良反应的相对危险度(RR)。结果:共纳入10项研究,2623例患者。Meta分析结果显示:达拉非尼联合曲美替尼治疗黑色素瘤致所有等级皮肤不良反应的发生率为:皮疹22%[95%CI(0.19,0.26)]、瘙痒10%[95%CI(0.08,0.11)]、角化过度7%[95%CI(0.04,0.10)]、脱发5%[95%CI(0.04,0.07)]、皮肤乳头状瘤1%[95%CI(0.01,0.03)]、痤疮样皮炎10%[95%CI(0.06,0.14)]、皮肤鳞状细胞癌2%[95%CI(0.00,0.04)]、干性皮肤10%[95%CI(0.08,0.12)]和红斑11%[95%CI(0.09,0.13)];与单用BRAF抑制剂相比,达拉非尼联合曲美替尼降低了瘙痒、角化过度、脱发、皮肤乳头状瘤、皮肤鳞状细胞癌的发生率(P<0.05)。结论:达拉非尼联合曲美替尼治疗黑色素瘤患者常见的皮肤不良反应为皮疹;与单用BRAF抑制剂相比,联合用药显著降低了皮肤不良反应的发生。展开更多
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
文摘BACKGROUND Radiation recall dermatitis has been defined as the "recalling" by skin of previous radiation exposure in response to the administration of certain response-inducing drugs. Although the phenomenon is relatively well known in the medical world,an exact cause has not been documented.CASE SUMMARY Here, we report the rare occurrence of radiation recall dermatitis after palliative radiotherapy for bone metastases in a metastatic melanoma patient treated with a combination of dabrafenib and trametinib.CONCLUSION We present a case of radiation recall dermatitis after completion of palliative radiotherapy while being treated with a combination of dabrafenib and trametinib. This is a very rare toxic event, and there is insufficient data to describe prevention strategies. Increased awareness and reporting of cases will help to better explain the association between targeted therapy and the radiation recall phenomenon.
基金Supported by the 2023 Yeungnam University Research Grant.
文摘BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor)for treating BRAF V600E-mutant ATC.However,reports on patients with ATC treated with this regimen following surgery are lacking.CASE SUMMARY We report the case of a 63-year-old female patient diagnosed with BRAF V600Emutant ATC.Following three surgeries—total thyroidectomy,total laryngectomy,and neck dissection—she was diagnosed with lung metastasis during follow-up.The metastatic ATC was successfully treated with dabrafenib and trametinib.The patient achieved a complete response at the 32-mo follow-up.CONCLUSION Adjuvant chemotherapy with dabrafenib plus trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.
文摘A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published;therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.
文摘The prognosis of patients with advanced melanoma is poor.The five-year recurrence rate is approximately 70%,whereas the overall survival rate is only 4%-10%.We report the case of a 61-year-old male patient with metastatic melanoma(B-Raft).The tumor load of the patient was significantly reduced after the application of dabrafenib plus trametinib(“DtT”)and radiotherapy.Further,it is suggested that medical staff should conduct a comprehensive analysis of the patient’s condition when dealing with adverse events(AEs)associated with such malignant tumors to provide evidence for adopting the appropriate targeted treatment or radiotherapy and nursing mode and achieve the best treatment effect.
文摘BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma.In addition to systemic side effects,several usually mild ocular adverse effects have been reported.We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment,thickened choroid,and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase(BRAF)mutant metastatic cutaneous melanoma.CASE SUMMARY A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes.Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber,mild vitritis,bullous multiple serous retinal detachments,and chorioretinal folds in both eyes.Treatment with dabrafenib and trametinib was suspended,and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule.One and a half months after the disease onset,ocular morphological and functional improvement was noted.Due to the metastatic melanoma dissemination,BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared,which later subsided after receiving oral corticosteroids.CONCLUSION Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis.Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients.Furthermore,appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.
文摘目的:分析达拉非尼联合曲美替尼治疗黑色素瘤致皮肤系统不良反应(ADR)的发生情况及临床特点,为临床安全用药提供参考。方法:检索Web of Science、PubMed、知网和万方数据库,收集国内外相关个案报道并进行分析总结。结果:共筛选出有效文献31篇,共38例次,患者年龄主要为31~80岁(89.47%);ADR多发生在用药后90 d内(60.52%);主要临床表现为痤疮样皮疹(18.42%)、肉芽肿性皮炎(13.16%)、脂膜炎(10.53%)、纹身并发症(10.53%)及结节性红斑病变(10.53%);34例患者皮肤ADR痊愈或好转,其中2例永久停用了达拉非尼与曲美替尼,10例继续联合治疗,12例暂停联合治疗,其中11例患者好转或痊愈后重启联合治疗。在重启或继续使用联合治疗的患者中,10例再次出现ADR。结论:本研究中,达拉非尼联合曲美替尼致皮肤系统ADR表现出不同的发生率和特征,且免疫治疗后进行靶向治疗可能增加严重皮肤ADR发生风险。临床在联合使用时应加强用药监测,及时发现ADR并采取适当的防治措施,同时严密监测重启或继续用药所致ADR,确保用药安全。
文摘目的:系统评价达拉非尼联合曲美替尼治疗黑色素瘤致皮肤不良反应的发生率。方法:计算机检索PubMed、EMbase、Cochrane Library、Web of Science和中国知网、维普、万方、中国生物医学文献数据库,收集国内外公开发表的相关研究,检索时间为自建库至2020年12月。采用Stata 15.1软件计算皮肤不良反应的发生率,采用Rev Man 5.3软件评估所有等级皮肤不良反应的相对危险度(RR)。结果:共纳入10项研究,2623例患者。Meta分析结果显示:达拉非尼联合曲美替尼治疗黑色素瘤致所有等级皮肤不良反应的发生率为:皮疹22%[95%CI(0.19,0.26)]、瘙痒10%[95%CI(0.08,0.11)]、角化过度7%[95%CI(0.04,0.10)]、脱发5%[95%CI(0.04,0.07)]、皮肤乳头状瘤1%[95%CI(0.01,0.03)]、痤疮样皮炎10%[95%CI(0.06,0.14)]、皮肤鳞状细胞癌2%[95%CI(0.00,0.04)]、干性皮肤10%[95%CI(0.08,0.12)]和红斑11%[95%CI(0.09,0.13)];与单用BRAF抑制剂相比,达拉非尼联合曲美替尼降低了瘙痒、角化过度、脱发、皮肤乳头状瘤、皮肤鳞状细胞癌的发生率(P<0.05)。结论:达拉非尼联合曲美替尼治疗黑色素瘤患者常见的皮肤不良反应为皮疹;与单用BRAF抑制剂相比,联合用药显著降低了皮肤不良反应的发生。
