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
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 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 therapeutic efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors remained unsatisfactory due to the heterogeneity of tumor antigens and the immunosuppressive microenvironment.Low-glycosylated mucin ...The therapeutic efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors remained unsatisfactory due to the heterogeneity of tumor antigens and the immunosuppressive microenvironment.Low-glycosylated mucin 1(MUC1)was among the most promising tumor antigen targets for CAR-T cell treatment.However,the therapeutic efficacy of MUC1 CAR-T cell treatment varied substantially across different clinical trials.展开更多
鼠类肉瘤病毒癌基因同源物B(v-Rafmurine sarcoma viral oncogene homolog B,BRAF)是最重要的原癌基因之一,是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)/细胞外信号调节激酶(extracellular signalregulated kinase,E...鼠类肉瘤病毒癌基因同源物B(v-Rafmurine sarcoma viral oncogene homolog B,BRAF)是最重要的原癌基因之一,是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)/细胞外信号调节激酶(extracellular signalregulated kinase,ERK)信号通路的关键调节因子。BRAF突变在非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中的发生率为1.5%-5.5%,其中BRAF V600突变占所有BRAF突变的30%-50%,BRAF V600E是最常见的突变类型。目前,达拉非尼联合曲美替尼已被美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)、欧洲肿瘤内科学会(European Society of Medical Oncology,ESMO)、中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)等多个国内外指南推荐作为BRAF V600突变NSCLC的一线治疗选择。然而,针对BRAF非V600突变,目前尚无明确的靶向治疗推荐。尽管个案报道提示达拉非尼联合曲美替尼对部分BRAF非V600突变患者可能有效,但由于病例数量有限且缺乏大样本临床试验数据,其疗效和安全性仍需进一步验证。本文报道了1例经达拉非尼联合曲美替尼治疗有效的罕见BRAF插入缺失突变(BRAF p.L485_T488delinsF)的NSCLC病例,旨在提高临床医生对该类罕见突变病例的认识,并为未来治疗策略的探索提供参考。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
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.
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.
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.
基金supported by grants from National Key R&D Program of China(2022YFC3401001 and 2023YFE0204000)Key R&D Program of ZheJiang(2024C03160)+7 种基金the National Natural Science Foundation of China(82025026,82230091,81872144,82273204,81972471,and 82102865)Guangdong Basic and Applied Basic Research Foundation(2023A1515012412 and 2023A1515011214)Guangzhou Science and Technology Project(2023A03J0722,202206010078,and 202201020574)Guangdong-Dongguan Joint Fund of Guangdong Province(2023A1515140033)Sun Yat-Sen University Clinical Research 5010 Program(2018007 and SYS-5010-202409)Sun Yat-Sen Clinical Research Cultivating Program(SYS-C-201801)Guangdong Medical Science and Technology Program(A2020558)Tencent Charity Foundation(7670020025)。
文摘The therapeutic efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors remained unsatisfactory due to the heterogeneity of tumor antigens and the immunosuppressive microenvironment.Low-glycosylated mucin 1(MUC1)was among the most promising tumor antigen targets for CAR-T cell treatment.However,the therapeutic efficacy of MUC1 CAR-T cell treatment varied substantially across different clinical trials.
文摘目的分析达拉非尼联合曲美替尼治疗黑色素瘤致发热综合征的发生特点及规律,为临床安全用药提供参考。方法收集13例北京大学肿瘤医院(以下简称“某院”)应用达拉非尼联合曲美替尼方案治疗BRAF V600突变的黑色素瘤术后辅助或不可切除晚期患者的病例资料,同时检索从建库起至2024年6月30日中国知网、万方数据、Web of Science、Elsevier、PubMed数据库收载的相关个案报道,汇总相关数据进行分析。结果纳入分析的患者共33例,其中某院相关病例13例,国内外文献相关报道20例。男性18例,女性15例,年龄为35~77岁。首次中位发热时间16.5(1~240)d,3例患者发热后未进行处理自行好转,30例患者经中断药物治疗或非甾体抗炎药及类固醇处理后不再发热,随后20例患者以单药达拉非尼、达拉非尼联合曲美替尼原剂量或减量重启治疗,继续治疗后仍有18例患者再次出现发热。其中有20例患者经历2次及以上发热,3例患者因发生严重不良反应致永久停药。结论达拉非尼联合曲美替尼致首次发热的时间大多在用药后前30 d内(69.69%),60.60%患者经历2次及以上发热,本研究发现中断治疗、减少药物剂量、加用非甾体抗炎药或类固醇药物是改善发热综合征的关键管理策略。
文摘鼠类肉瘤病毒癌基因同源物B(v-Rafmurine sarcoma viral oncogene homolog B,BRAF)是最重要的原癌基因之一,是丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)/细胞外信号调节激酶(extracellular signalregulated kinase,ERK)信号通路的关键调节因子。BRAF突变在非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中的发生率为1.5%-5.5%,其中BRAF V600突变占所有BRAF突变的30%-50%,BRAF V600E是最常见的突变类型。目前,达拉非尼联合曲美替尼已被美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)、欧洲肿瘤内科学会(European Society of Medical Oncology,ESMO)、中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)等多个国内外指南推荐作为BRAF V600突变NSCLC的一线治疗选择。然而,针对BRAF非V600突变,目前尚无明确的靶向治疗推荐。尽管个案报道提示达拉非尼联合曲美替尼对部分BRAF非V600突变患者可能有效,但由于病例数量有限且缺乏大样本临床试验数据,其疗效和安全性仍需进一步验证。本文报道了1例经达拉非尼联合曲美替尼治疗有效的罕见BRAF插入缺失突变(BRAF p.L485_T488delinsF)的NSCLC病例,旨在提高临床医生对该类罕见突变病例的认识,并为未来治疗策略的探索提供参考。
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.
