it is known that vemurafenib quickly shrinks metastatic lesions . however , once a tumor is drug resistant , the metastatic lesions quickly become larger again . brain metastasis is frequently observed in patients with metastatic melanoma . in a phase iii trial of vemurafenib , therefore , it is not known whether vemurafenib is truly effective when treating brain metastasis . however , some studies have reported that brain metastasis responds to vemurafenib . unfortunately , it does not become clear in those reports whether vemurafenib is spontaneously effective against both brain and other metastases . here a total of 9 patients with braf mutation have been treated with vemurafenib at our institution . the other three patients were also categorized as partial response before brain metastasis occurred . in all of them , brain metastasis was suddenly detected on magnetic resonance imaging ( mri ) . patient 1 is a 43-year - old female with lung metastasis when she started vemurafenib therapy . 1a , b ) . however , 3 months after starting the vemurafenib therapy , brain metastasis was visible on mri ( ldh was 161 , fig . cyberknife treatment was performed , but the brain metastasis enlarged gradually ( ldh was 244 , fig . patient 2 was a 53-year - old male with lung and liver metastasis when he started vemurafenib therapy . . the brain metastasis could not be controlled , and the ldh level promptly increased to 5,665 . despite treatment , the patient eventually died 3 months later due to brain metastasis . patient 3 is a 75-year - old male with lung and liver metastasis when he started vemurafenib therapy . 1 g ) , whereas the patient 's other metastatic lesions appeared to be reduced on computed tomography . it is known that melanoma cells develop drug resistance within a few months and that the progression of acquired drug resistance induces the amplification of melanoma cells . on the other hand , vemurafenib has a high molecular weight ; therefore , it can not easily cross the blood - brain barrier . in addition , the primary and metastatic melanoma lesions were sometimes heterogeneous . based on these facts , some oncologists might conclude that our patients developed brain metastasis due to a braf mutation or the administered drug 's inability to cross the blood - brain barrier . however , we speculate that our patients tumors acquired drug resistance against vemurafenib since their metastatic lesions kept growing despite the patients being on vemurafenib . it is well known that acquired drug resistance induces mapk reactivation based on the activation of secondary mutations in nras , mek , and others . unfortunately , we could not investigate any other mutations in our patients . when treating patients with brain metastasis , it is important to monitor ldh fluctuation . even if a metastatic lesion other than brain metastasis is well controlled , it is possible that the ldh level may gradually increase , and brain metastasis might suddenly occur , as in patients 1 and 3 . when the ldh level increases , it is difficult to control brain metastasis , even with cyberknife treatment . patient 2 had a high ldh level , and the tumor activity was very aggressive . however , even when the ldh level is normal , it is necessary to carefully monitor tumor activity . to our knowledge , no reports of brain metastasis occurring suddenly during vemurafenib treatment have been published . we believe that this report is relevant for patients with malignant melanoma harboring the braf mutation and being on vemurafenib therapy .
vemurafenib is an inhibitor of the braf mutation and has been approved by the food and drug administration as a treatment option for patients with unresectable melanoma without brain metastasis . in the literature , vemurafenib has been reported to be also effective against brain metastasis . 
 we encountered 3 cases with brain metastasis on vemurafenib therapy . in these cases , vemurafenib was clinically effective against metastatic lesions other than those in the brain . 
 the brain lesions developed after the metastatic lesion had occurred . 
 therefore , we assume that the melanomas of the patients acquired resistance against vemurafenib . 
 the brain metastases were treated with the cyberknife . 
 patients 1 and 2 without ldh elevation are still alive , but patient 3 with abnormal ldh elevation died despite the treatment . 
 we need to carefully follow patients on vemurafenib therapy because brain metastasis can suddenly occur even if the metastatic lesion has decreased clinically . 
 the therapeutic effect of vemurafenib against brain metastasis is poor in cases with ldh elevation .