• Genomics & Informatics
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• 제19권1호
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• pp.2.1-2.10
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• 2021

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

• Korean Journal of Radiology
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• 제22권4호
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• pp.584-595
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• 2021

Objective: Immune checkpoint inhibitor (ICI) therapy has shown activity against melanoma brain metastases. Recently, promising results have also been reported for ICI combination therapy and ICI combined with radiotherapy. We aimed to evaluate radiologic response and adverse event rates of these therapeutic options by a systematic review and meta-analysis. Materials and Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed up to October 12, 2019 and included studies evaluating the intracranial objective response rates (ORRs) and/or disease control rates (DCRs) of ICI with or without radiotherapy for treating melanoma brain metastases. We also evaluated safety-associated outcomes. Results: Eleven studies with 14 cohorts (3 with ICI combination therapy; 5 with ICI combined with radiotherapy; 6 with ICI monotherapy) were included. ICI combination therapy {pooled ORR, 53% (95% confidence interval [CI], 44-61%); DCR, 57% (95% CI, 49-66%)} and ICI combined with radiotherapy (pooled ORR, 42% [95% CI, 31-54%]; DCR, 85% [95% CI, 63-95%]) showed higher local efficacy compared to ICI monotherapy (pooled ORR, 15% [95% CI, 11-20%]; DCR, 26% [95% CI, 21-32%]). The grade 3 or 4 adverse event rate was significantly higher with ICI combination therapy (60%; 95% CI, 52-67%) compared to ICI monotherapy (11%; 95% CI, 8-17%) and ICI combined with radiotherapy (4%; 95% CI, 1-19%). Grade 3 or 4 central nervous system (CNS)-related adverse event rates were not different (9% in ICI combination therapy; 8% in ICI combined with radiotherapy; 5% in ICI monotherapy). Conclusion: ICI combination therapy or ICI combined with radiotherapy showed better local efficacy than ICI monotherapy for treating melanoma brain metastasis. The grade 3 or 4 adverse event rate was highest with ICI combination therapy, and the CNS-related grade 3 or 4 event rate was similar. Prospective trials will be necessary to compare the efficacy of ICI combination therapy and ICI combined with radiotherapy.

• Journal of Korean Neurosurgical Society
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• 제54권2호
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• pp.107-111
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• 2013

Objective : We investigated the effectiveness of stereotactic gamma knife Radiosurgery (GKR) for radioresistant brain metastases with the impact upon histology. Methods : Between April 2004 and May 2011, a total of 23 patients underwent GKR for 67 metastatic brain tumors from 12 renal cell cancers, 5 sarcomas and 6 melanomas. The mean age was 56 years (range, 18 to 79 years). Most of the patients were classified as the Radiation Therapy Oncology Group recursive partitioning analysis class II (91.3%). The synchronous metastasis was found in 6 patients (26.1%) and metachronous metastasis in 17 patients (73.9%). We analyzed the local control rate, intracranial progression-free survival (PFS) and overall survival (OS). Results : The mean tumor volume for GKR was 2.24 cc and the mean prescription dose was 19.4 Gy (range, 10 to 24) to the tumor margin. Out of metachronous metastases, the median duration to intracranial metastasis was 3.3 years in renal cell cancer (RCC), 2.4 years in melanoma and 1.1 years in sarcoma (p=0.012). The total local control rate was 89.6% during the mean 12.4 months follow-up. The six-month and one-year local control rate was 90.2% and 83% respectively. Depending on the pathology, the control rate of RCC was 95.7%, sarcoma 91.3% and melanoma 80.5% during the follow-up. The common cause of local failure was the tumor bleeding in melanoma. The median PFS and OS were 5.2 and 8.4 months in RCC patients, 6.5 and 9.8 months in sarcoma, and 3.8 and 5.1 months in melanoma. Conclusion : The GKR can be one of the effective management options for the intracranial metastatic tumors from the radioresistant tumors. The melanoma showed a poor local control rate compared to other pathologies because of the hemorrhage.

• 보험의학회지
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• 제25권
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• pp.63-77
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• 2006

국내 CI보험에서 정의한 '중대한 암'이란 용어는 의학적인 '암'의 정의보다는 다소 보험적인 의미를 가진 암으로 정의되고 있다. 따라서 의학적으로 정의된 암과 다른 보험적인 의미에서 암을 정의함에 따라 의료인이나 일반인이 생각하고 있는 암의 정의와 다른 개념의 차이로 보험사와 계약자간의 Medical Underwriting에서 많은 문제점이 있을 것으로 판단되었다. 이처럼 CI보험에서 정의한 '중대한 암'의 정의가 의학적 정의된 '암'과의 차이로 보험사와 계약자간의 분쟁의 소지가 될 수 있는 '중대한 암'의 Medical Underwriting의 제한적 요소로는 제I항의 정의에서 1) '암'과 '중대한 암'의 정의에 차이에 따른 보험사, 계약자, 의료인의 입장에서 본 제한적 요소 2) "악성신생물분류표"가 가지는 의미에 관한 제한적 요소 3) '중대한 암'과 '고액치료비 암'의 용어에 대한 제한적 요소를 고찰하였다. 제II항의 정의에서는 1) 암성의 변화에 따른 제한적요소 2)악성병변 부위가 국한된 경우 병리조직검사에서 악성으로 나타나지 않은 경우의 제한적 요소 3) 병원간 병리조직 검사결과의 차이에 따른 제한적 요소에 관해 고찰하였다. 제III항의 정의에서는 1) 하위조항이 상위조항에 위배되는 경우의 제한적 요소 2) 임상적 악성에 대한 제한적 요소를 고찰하였다. 그 외에도 '중대한 암'에서 제외되는 암으로 1)악성흑색종에서 침범정도가 낮은 경우 2) 초기전립샘 암 3) HIV에 관련된 악성종양 4) 악성흑색종을 제외한 모든 피부암들에 대한 제한적인 요소 5) 양성종양,전암병소,상피내암,경계성종양 등이 임상적으로 '중대한 암'으로 인정되는 경우와 진단서 작성에서의 제한적 요소를 고찰하여 '중대한 암'에 대한 Medical Underwriting의 문제점을 파악하였다.

• 대한의생명과학회지
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• 제25권3호
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• pp.201-210
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• 2019

The oncolytic viruses selectively infect and destroy cancer cells, not harming normal cells. The cancer cell materials released by oncolysis, like tumor antigens, stimulate host antitumor immune responses, which is a long-lasting antitumor immunity removing cancer cells in remote parts of the body by a systemic response. Oncolytic viruses armed with transgenes such as cytokines or other immune stimulating factors enhance the immune responses. The first oncolytic virus approved by US-FDA is $Imlygic^{(R)}$ targeting for melanoma. The oncolytic virus is considered as a revolutionary immunotherapy for tumors together with immune checkpoint inhibitors. A variety of oncolytic viruses are under research in the treatment of kidney cancer, liver cancer, breast cancer, and many others solid tumors. Clinical trials have shown promising results in different types of cancers. Here, we present a brief introduction of various aspects of oncolytic virus, and a review of the current status of oncolytic virus therapy development.

• BMB Reports
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• 제51권11호
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• pp.572-577
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• 2018

Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma-binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy.

• Archives of Plastic Surgery
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• 제36권4호
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• pp.411-416
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• 2009

Purpose: Malignant melanoma is recognized as the most serious skin cancer. We examined anatomical distribution and 5 - year survival rate of each stage of malignant melanoma on lower leg. Methods: We retrospectively analyzed the medical records of 91 patients(46 males and 45 females) with malignant melanoma on lower leg from 1985 to 2008. Age, sex, anatomical distribution and 5 - year survival rates of each stage of malignant melanoma on lower leg were investigated. Also, 5 - year survival rates of each stage and invasion depth of malignant melanoma on heel pad were investigated. Results: On lower leg, most frequently 32 cases(35.1%) occurred on heel pad, 27 cases(29.7%) occurred on dorsum of foot, 18 cases(19.8%) in toe and 14 cases(15.4%) on others in lower leg. We used the excision margin as 3 ~ 5 cm. After wide excision, in stage III, IV, the patients underwent the immunologic / chemo - therapy. The incidences of each stage were 22 cases(24.2%) in stage I, 47(51.6%) in II, 17(18.7%) in III and 5(5.5%) in IV. The 5 - year survival rates of each stage were 85%, 53.2%, 47.1% and 40%. On heel pad, the incidences of each stage were 5 cases(15.6%) in stage I, 19 cases(59.4%) in II, 7 cases(21.9%) in III and 1 case(3.1%) in IV. The 5 - year survival rates of each stage were 80%, 63.2%, 42.9% and 100%. On heel pad, incidence of local recurrence was 2 and 5 - year survival rate of this case was 100%. And systemic recurrence was 9 and 5 - year survival rate of this case was 55.6%. Conclusion: The 5 - year survival rate of malignant melanoma on heel pad was higher than previous study. To maintain the weight - bearing function of foot, we recommend the active reconstructive surgery for heel pad reconstruction after wide excision of heel pad malignant melanoma.

• Asian Pacific Journal of Cancer Prevention
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• 제16권6호
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• pp.2581-2581
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• 2015

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.210.2-210.2
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• 2003

Cornis fructus were extracted by successive extractions and then fractionated with chloroform extract to get active fractions. This study was performed to determine the cytotoxic effect of chloroform extract from Cornis fructus on NIH 3T3 fibroblasts and cancer cell lines using MTT assay. All extracts did not exhibit cytotoxicity in HIH 3T3 fibroblasts. Chloroform extract exhibited antitumor activity in A549, MDA-MB-123, B16 melanoma and SNU-C4 cells. Futher fractionation with chloroform extract was performed to obtain effective fractions. (omitted)

• 대한본초학회지
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• 제28권3호
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• pp.69-74
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• 2013

Objectives : Since hypopigmentation is known to increase the risk of skin cancer, melanogenesis in the skin needs to be regulated. Here, we evaluated the melanogenesis stimulatory effects of a modified Goagium herbal remedy (HR) and HR+ox bile (Bos taurus domesticus) extract (OBE) to address hypopigmentation disorders. Methods : B16F10 melanoma cells were treated with different dosages of HR and HR+OBE for 24 to 48 h after 1 h of 10 nM ${\alpha}$-melanocyte stimulating hormone (${\alpha}$-MSH). After the treatment, cell viability, tyrosinase activity, melanin synthesis and the expression of genes related to melanin synthesis were measured and the regulation of the ${\alpha}$-MSH signalling through cAMP responding element binding protein (CREB) was determined. Results : HR and HR+OBE with the ranges of $15{\sim}100{\mu}g/mL$ did not affect cell viability in melanoma cells. The 1 h treatment of HR+OBE (50 and $100{\mu}g/mL$) potentiated the phosphorylation of CREB by enhancing ${\alpha}$-MSH signaling and its 24 h treatment increased CREB expression. Consistent with CREB potentiation, their treatment for 24 h, the expression of microphthalmia-associated transcription factor (MIFT), tyrosinase, tyrosinase related protein (TRP)-1 and TRP-2 were increased in realtime PCR. Ultimately, the 48 h treatment of HR+OBE (50 and $100{\mu}g/mL$) increased tyrosniase activity and melanin contents in the melanoma cells in comparison to the control. Conclusions : HR+OBE (50 and $100{\mu}g/mL$) increases melanin synthesis in B16F10 melanoma cells via the stimulation of tyrosinase activity and expression of MIFT, tyrosinase, TRP-1 and TRP-2. HR+OBE can be used as the a possible treatment for hypopigmentation of the skin.