The Genomic Landscape of Melanoma and Its Therapeutic Implications.

Melanoma is one of the most aggressive malignancies of the skin. The genetic composition of melanoma is complex and varies among different subtypes. With the aid of recent technologies such as next generation sequencing and single-cell sequencing, our understanding of the genomic landscape of melanoma and its tumor microenvironment has become increasingly clear. These advances may provide explanation to the heterogenic treatment outcomes of melanoma patients under current therapeutic guidelines and provide further insights to the development of potential new therapeutic targets. Here, we provide a comprehensive review on the genetics related to melanoma tumorigenesis, metastasis, and prognosis. We also review the genetics affecting the melanoma tumor microenvironment and its relation to tumor progression and treatment.

TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway.

INTRODUCTION: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. OBJECTIVES: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. METHODS: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. RESULTS: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. CONCLUSIONS: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.

Electronic brachytherapy for non-melanoma skin cancer in Asians: Experience from a Taiwan medical center.

BACKGROUND/PURPOSE: High-dose-rate (HDR) electronic brachytherapy (EBT) has been shown to be effective for non-melanoma skin cancer (NMSC) in Caucasian patients. However, its efficacy remains unknown in Asian patients. To analyze the clinical outcome of HDR EBT for NMSC in a Taiwanese medical center. METHODS: Medical records over a 5-year period between January 2015 to December 2019 were retrospectively analyzed. RESULTS: Forty-seven patients with 54 NMSC including 42 basal cell carcinomas (BCCs) and 12 squamous cell carcinomas (SCCs) were treated with HDR EBT. The average age was 73.8 years. The mean radiation dose was 45.3 Gy (40-80 Gy). Mean follow-up duration was 33.1 months. Adequate local control was achieved in 50 lesions (92.6%). Grade 1 acute skin toxicity was noted in 63.0% of lesions, while no tumors had Grade 4 acute toxicity. No ulceration was observed six months after completion of treatment. At the last follow-up visit, all lesions were rated to have "fair" to "excellent" cosmetic outcomes. CONCLUSION: HDR EBT provides adequate clinical outcomes and cosmetic results for NMSC in Asian patients. Further investigation of the dosage guidelines is needed for Asian patients with NMSC.

Osteoprotegerin and osteopontin levels, but not gene polymorphisms, predict mortality in cardiovascular diseases.

Aim: This study aims to investigate whether osteoprotegerin (OPG) or osteopontin (OPN) single nucleotide polymorphisms (SNPs) will predict survival. Materials & methods: This study enrolled 617 participants undergoing health examination, 536 coronary artery disease (CAD) patients and 86 peripheral artery disease (PAD) patients. Genotypes of OPG SNP rs2073618 and OPN SNP rs11730582 were determined. OPG and OPN levels were measured. Results: In both CAD and PAD populations, high OPG and OPN levels were strong predictors of all-cause death. The OPG rs2073618 CC genotype and the OPN rs11730582 TT genotype did not predict mortality. Conclusion: High OPG and high OPN levels, but not OPG rs2073618 CC genotype or OPN rs11730582 TT genotype, were strong predictors of mortality in both CAD and PAD patients.

Secondary basal cell carcinoma of scalp after radiotherapy: A case report.

RATIONALE: Radiotherapy (RT) is widely used for both malignant and benign tumors in order to reduce the risk of recurrence, to promote tumor control, and to improve survival. However, there have been studies reported that RT is also a risk factor of secondary cancer. Very few cases of secondary malignancy after RT to high grade brain cancer have been reported due to short survival of this disease, and most RT-induced malignancies presented with sarcomatous histology. Here we present a patient with basal cell carcinoma (BCC) 14 years after RT to his brain. PATIENT CONCERNS: A 28-year-old man without any underlying disease had suffered from left side weakness and clonic-tonic seizures for 12 days. DIAGNOSES: His brain images showed a tumor in the right frontal lobe. The pathologic report confirmed anaplastic astrocytoma (WHO Grade III). INTERVENTIONS: After craniotomy and tumor biopsy, RT was delivered. Fourteen years later, a gray-colored skin papule was noted in the previously irradiated area. The scalp biopsy revealed BCC. The scalp BCC was adequately resected. He then suffered from brain tumor recurrence and received further craniotomy for three times combined with chemotherapy with temozolomide. OUTCOMES: After treatment, follow-up brain images showed that the disease was under control. There was no neurological sequela. For scalp BCC, no skin tumor recurrence has been noted to date after the resection 14 years after initial RT. He has survived for more than 26 years since his initial diagnosis of anaplastic astrocytoma, and more than 12 years from the diagnosis of scalp BCC. LESSONS: Notwithstanding the risk of radiation-induced skin cancer, RT contributed to this patient's survival. The possible late adverse events should be informed to the patients.

Visual Subfield Progression in Glaucoma Subtypes.

PURPOSE: To investigate visual field progression pattern and factors associated with progression in patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and chronic angle-closure glaucoma (CACG). METHODS: The raw data of the 30-2 Humphrey Field Analyzer from glaucoma patients with definite visual field progression were processed with pointwise linear regression (PLR) analysis. The rate of change of retinal threshold sensitivity in the ten glaucoma hemifield test (GHT) zones, the upper and the lower hemifields, and the whole field was evaluated and was correlated with patients' basic demographic data. RESULTS: An average follow-up of 6.94 ± 2.69 years that showed the rate of change of visual field threshold sensitivity was correlated with the peak posttreatment intraocular pressure (IOP) and the long-term IOP fluctuations in all GHT zones except in the inferior arcuate area. The baseline IOP, the trough posttreatment IOP, the refractive status, and the CCT were not correlated with VF progression. CONCLUSION: The rate of visual field progression was correlated with the peak posttreatment IOP and the long-term IOP fluctuation but with subfield differences.

IL1RL1 single nucleotide polymorphism predicts sST2 level and mortality in coronary and peripheral artery disease.

BACKGROUND AND AIMS: There are many IL1RL1 single nucleotide polymorphisms (SNP) significantly associated with circulating sST2 concentration. Little is known about the effects of IL1RL1 SNP on the outcome of cardiovascular disease. The aim of this study is to investigate whether IL1RL1 SNP can predict mortality. METHODS: We enrolled 601 individuals receiving health examination, 532 patients with coronary artery disease (CAD), and 86 patients with peripheral artery disease (PAD). Genotyping for SNP rs950880 and rs13001325 was performed and sST2 level was measured. The primary endpoint was all-cause death. The secondary endpoints were cardiovascular death, myocardial infarction, hospitalization for heart failure, stroke, and amputation. RESULTS: Individuals having rs950880 AA genotype all had rs13001325 TT genotype and tended to have lower sST2 levels in all 3 populations. Kaplan-Meier survival curves showed that patients with high sST2 level and rs950880 AA genotype had the lowest survival rate in presence of CAD (p < 0.001) and PAD (p = 0.007). In multivariable Cox regression analysis, the independent predictors of all-cause death were rs950880 AA homozygote (p = 0.018), age (p = 0.002), log sST2 level (p = 0.014), and log GDF-15 level (p = 0.017) in CAD patients. The independent predictor of all-cause death was rs950880-AA homozygote (p = 0.019) in PAD patients. There was no significant difference in secondary endpoints between rs950880 AA homozygote and C allele carriers. CONCLUSIONS: Individuals having rs950880 AA genotype also have rs13001325 TT genotype and tend to have lower sST2 levels. The rs950880 AA homozygote is an independent predictor of all-cause mortality in CAD and PAD patients.

Association of ABCG2 rs2231142-A allele and serum uric acid levels in male and obese individuals in a Han Taiwanese population.

BACKGROUND/PURPOSE: Recent studies suggest that hyperuricemia is a potential risk factor for cardiovascular disease (CVD). Hyperuricemia is highly heritable and is associated with sex and body weight. Previous genome-wide association studies have found that the ABCG2 single nucleotide polymorphism (SNP) rs2231142 is an important genetic factor for increased uric acid (UA) levels, and the degree of association between rs2231142 and hyperuricemia is affected by both sex and ethnicity. This investigation aimed to analyze the association between ABCG2 polymorphisms and UA levels, as well as their interactions with sex and obesity in Taiwanese. METHODS: Two genetic polymorphisms around the ABCG2 gene were genotyped in 459 patients. RESULTS: After adjusting for clinical covariates, the rs2231142 SNP was found significantly associated with UA levels using a dominant inheritance model. Patients carrying the rs2231142-A allele had a higher frequency of hyperuricemia than those with the rs2231142-CC allele. Subgroup analysis revealed an association of rs2231142 with UA levels in male or obese patients, and there was no association in nonobese female patients. CONCLUSION: The rs2231142 SNP is associated with serum UA levels and hyperuricemia in Taiwanese patients and it occurs predominantly in male or obese patients. Hyperuricemia might be controlled differently by sex and obesity.

Immediate results and long-term cardiovascular outcomes of endovascular therapy in octogenarians and nonoctogenarians with peripheral arterial diseases.

PURPOSE: To investigate the clinical outcomes of endovascular therapy (EVT) in octogenarians and nonoctogenarians with peripheral arterial disease. METHODS: A retrospective analysis of 511 patients (654 affected legs) who underwent EVT between July 2005 and December 2013 was conducted in a prospectively maintained database. Immediate results and long-term vascular outcomes were analyzed and compared between octogenarians and nonoctogenarians. RESULTS: Octogenarians were more likely to be female and have atrial fibrillation (AF), whereas nonoctogenarians had higher rates of obesity, claudication, and medical comorbidities. There were no differences in the rates of EVT success, 30-day major adverse vascular events, and 6-month functional improvement between groups. Over the 10-year follow-up period, the rates of 3-year limb salvage, sustained clinical success, freedom from major cerebrovascular and cardiovascular events, and composite vascular events were similar between groups, but the survival rate was better in nonoctogenarians than in octogenarians (73% vs 63%, respectively, P=0.004). In Cox regression analysis, dependence on dialysis and AF were significant predictors of death (odds ratio [OR] 4.44 in dialyzed and 2.83 in AF patients), major cerebrovascular and cardiovascular events (OR 3.49 and 2.45), and composite vascular events (OR 3.14 and 2.25). CONCLUSION: EVT in octogenarians was feasible, without an increased risk of periprocedural complications. The rates of limb salvage, sustained clinical success, and long-term vascular events were comparable between groups. Dialysis dependence and AF are independent predictors for poor prognosis in patients with peripheral arterial disease. However, these observations require further confirmation in larger scale studies.

Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ±â€Š1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ±â€Š0.67 dB/y, inferior field -0.10 ±â€Š0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression.