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
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF...BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.展开更多
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.
基金Supported by the Henan Department of Science and Technology,China,No.162102310317
文摘BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
文摘Binimetinib是Array BioPharma开发的丝裂原活化细胞外信号调节蛋白激酶(mitogen-activated extracellular signal regulated kinase,MEK)1/2抑制剂,2018年6月在美国获批上市。本品联合康奈非尼用于治疗具有BRAF V600E或V600K突变的不可切除或转移性黑色素瘤患者。2018年7月后,欧盟、澳大利亚、瑞士和日本也提交了binimetinib和康奈非尼组合用于治疗BRAF突变阳性晚期黑色素瘤的登记申请。Binimetinib可抑制MEK和细胞外信号调节蛋白激酶(extracellular regulated protein kinases,ERK)磷酸化,从而抑制肿瘤生长,对于BRAF、NRAS和KRAS基因突变的肿瘤尤其有效。目前世界各地正在进行binimetinib对于转移性结直肠癌、非小细胞肺癌、晚期胆道癌、神经纤维瘤等治疗的临床试验。本文以binimetinib为关键词进行文献检索,并对其药理作用、药动学、临床评价、用法用量、安全性和药物相互作用等进行综述。
