"Artemisone is successfully encapsulated into the nano-vesicles with encapsulation efficiencies of 67±6% and 79±5%, and with average particle sizes being 211±10nm and 295±18nm respectively. The formulations displayed highly selective cytotoxicity towards the melanoma cells with negligible toxicity towards the normal skin cells. The artemisone-loaded nano-vesicles almost completely inhibited the melanoma cells compared to the free drug. The results overall suggest a potentially more useful therapeutic strategy that needs to be evaluated for the treatment of melanoma and other cancers."
Article - Berberine Inhibits Human Melanoma A375.S2 Cell Migration and Invasion via Affecting the FAK, uPA, and NF-κB Signaling Pathways and Inhibits PLX4032 Resistant A375.S2 Cell Migration In Vitro.
"The results showed that treatment with berberine resulted in a reduction in the phosphorylation of PI3K/AKT, ERK, and GSK3β. Taken together, the results suggested that berberine inhibits melanin synthesis and tyrosinase activity by downregulating the expression of MITF and tyrosinase."
'Over the past few years, several reports have demonstrated that Coptidis Rhizoma water extracts (CR) or its major active chemical component, berberine, has anticancer activities in various types of cancer, including melanoma. However, their underlying mechanisms have not been well understood. In the present study, we determined that CR suppressed melanoma cell viability, which was mainly mediated through apoptosis. In addition, the expression levels of anti-apoptotic proteins, BCL2A1, MCL1 and BCL-w, were strongly suppressed by CR treatment. Furthermore, multi-domain pro-apoptotic proteins BAX and BAK were activated by CR treatment and were also required for the CR-induced apoptosis. Collectively, CR or some formulations containing CR, may be effective safe treatment strategies for human melanoma."
Study - Clinical and Prognostic Value of Tumor Volumetric Parameters in Melanoma Patients Undergoing 18 F-FDG-PET/CT: A Comparison With Serologic Markers of Tumor Burden and Inflammation
S100-EPISPOT: A New Tool to Detect Viable Circulating Melanoma Cells
"We developed a new EPithelial ImmunoSPOT (EPISPOT) assay to detect viable CMCs [circulating melanoma cells] based on their secretion of the S100 protein (S100-EPISPOT). Then, we compared the results obtained with the S100-EPISPOT assay and the CellSearch® CMC kit using blood samples from a homogeneous population of patients with metastatic melanoma. We found that S100-EPISPOT sensitivity was significantly higher than that of CellSearch®. Specifically, the percentage of patients with ≥2 CMCs was significantly higher using S100-EPISPOT than CellSearch® (48% and 21%, respectively; p = 0.0114).
Study - Standardized Cannabis sativa extract attenuates tau and stathmin gene expression in the melanoma cell line.
Case study - Case Report of Extended Survival and Quality of Life in a Melanoma Patient with Multiple Brain Metastases and Review of Literature
The patient was 10+ years cancer free at the writing of the article in 2017. She was still running marathons and made a perfect score on a quality of life/brain cognition test in November 2017.
Case Report - Metastatic Malignant Melanoma Mimicking Mammary Mass: A Rare Presentation
"We present a case of 50-year-old female patient, who underwent wide local excision and split skin grafting for MM right leg. She did not undergo any adjuvant therapy and one year later presented to us with a solitary lump occupying the upper inner quadrant of the right breast. The breast lump turned out to be metastatic deposit from MM based on the presence of melanin in cells on fine needle aspiration cytology (FNAC). Therefore, breast lump in perimenopausal is not always a primary malignancy, and differential diagnosis should also include metastatic tumors."
"Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype...Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments."
"The aims of this review are to: provide an overview of the key early immune checkpoint inhibitor trials involving drugs targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in multiple disease types; provide an overview of emerging therapies aimed at these targets; and provide a detailed exploration of the status of immune checkpoint inhibitors in breast cancer."
"The therapeutic landscape in melanoma is evolving rapidly. In this podcast, Dr Jonathan Lim (a member of the ESMO Young Oncologists Committee) interviews Dr Teresa Amaral (the current chair of the ESMO Young Oncologists Committee and an expert in melanoma) for an update on the current practice and advances in adjuvant and neoadjuvant therapies in melanoma. Dr Amaral summarises key practicechanging studies which have established the current recommendations in this field, including CheckMate 238, KEYNOTE 054, COMBI-AD, Combi-Neo, NeoCombi and opACIN-neo. We also deliberated on the toxicity profile of these therapies, and currently available evidence of neoadjuvant versus adjuvant therapies. Finally, we addressed how COVID-19 has affected the delivery of adjuvant and neoadjuvant therapies in patients with melanoma."
Melanoma patients who followed a modified Gerson Therapy had exceedingly better 5-year survival rates than those studied elsewhere.
"Results: Of 14 patients with stages I and II (localized) melanoma, 100% survived for 5 years, compared with 79% of 15,798 reported by Balch. Of 17 with stage IIIA (regionally metastasized) melanoma, 82% were alive at 5 years, in contrast to 39% of 103 from Fachklinik Hornheide. Of 33 with combined stages IIIA + IIIB (regionally metastasized) melanoma, 70% lived 5 years, compared with 41% of 134 from Fachklinik Hornheide. We propose a new stage division: IVA (distant lymph, skin, and subcutaneous tissue metastases), and IVB (visceral metastases). Of 18 with stage IVA melanoma, 39% were alive at 5 years, compared with only 6% of 194 from the Eastern Cooperative Oncology Group. Survival impact was not assessed for stage IVB. Male and female survival rates were identical for stages I-IIIB, but stage IVA women had a strong survival advantage.
The 5-year survival rates reported here are considerably higher than those reported elsewhere. Stage IIIA/B males had exceptionally high survival rates compared with those reported by other centers."
Study - Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling
"Our findings suggest a “mutation-specific” function in which BRAF V600E upregulates HMGCL, leading to increased intracellular levels of acetoacetate that specifically promote BRAF V600E binding to MEK1 and subsequent MEK1 phosphorylation (Figure 7H)."
Study - Prevention of dietary fat-fueled ketogenesis attenuates BRAF V600E tumor growth
"Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice."
Study - Recurrent Loss of STING Signaling in Melanoma Correlates With Susceptibility to Viral Oncolysis
My (Bailey's) take: After DNA is damaged in cells some DNA is released into the cytoplasm, activating an immune response including the production of cytokines. STING regulates cytokine production and "extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity." In many melanomas STING is suppressed, preventing a full immune response to DNA damage and allowing viruses to take advantage of the cells. In some cases such as in the use of Imlygic, this is advantageous in enabling viral therapies to work. However at the same time it presumably makes a person vulnerable to pathogenic viruses.
"The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1. Cancer Res; 76(22); 6747-59. ©2016 AACR."
Melatonin helps reduce damage caused by UVB exposure!
Melatonin and Its Metabolites Ameliorate UVR-Induced Mitochondrial Oxidative Stress in Human MNT-1 Melanoma Cells.
"In conclusion, Mel, 6(OH)Mel and 5-MT protect MNT-1 cells, which express melatonin receptors (MT1 and MT2) against UVB-induced oxidative stress and mitochondrial dysfunction, including the uncoupling of oxidative phosphorylation."
Study - Daphnane diterpenes inhibit the metastatic potential of B16F10 murine melanoma cells in vitro and in vivo
"Here, we show that daphnane diterpenes type of compounds can prevent melanoma metastasis by inhibiting metastasis-associated matrix metalloproteinases expression without cytotoxicity."
What are daphnane diterpenes? They are molecular structures from the Diarthron vesiculosum seed:
Eat organically grown foods!
This study showed that thicker melanomas, whether spread to nearby lymph nodes or not, are associated with a lower chance of survival. Overall survival was the same in a group with melanoma thicknesses greater than 4mm with no node metastases and those with melanoma thicknesses less than 4mm with metastases in the nodes. Significant associations with poor survival in the thick melanomas without node involvement included higher age, higher thickness category, ulceration and male gender. (So if you're younger, have a thinner melanoma, no ulceration and are female your chance of survival increases.)If you have any suspicious spots on your skin don't wait to get them checked out!! 📷 <3 (Not shared with the intent of scaring anyone, just for info on prevention.)
Our results showed that exposure to quercetin resulted in inhibition of proliferation of melanoma cells, induction of cell apoptosis, and suppression of migratory and invasive properties. Mechanistic study indicated that quercetin inhibited the activation of STAT3 signaling by interfering with STAT3 phosphorylation, and reducing STAT3 nuclear localization. This inhibited STAT3 transcription activity and down-regulated STAT3 targeted genes Mcl-1, MMP-2, MMP-9 and VEGF, which are involved in cell growth, migration and invasion. Importantly, overexpression of constitutively active STAT3 partially rescued the growth inhibiting effects induced by quercetin. Furthermore, quercetin suppressed A375 tumor growth and STAT3 activities in xenografted mice model, and inhibited murine B16F10 cells lung metastasis in an animal model.
Case report - An interesting case of possible abscopal effect in malignant melanoma. (1975)
The patient experienced remission from late stage melanoma after having a wide excision, lymphangiogram and radiation to his inguinal (groin) region. However, unfortunately he had a sudden severe rectal hemorrhage after one year (I suspect it's likely due to the radiation) and passed away. I'm sharing this to suggest that the abscopal effect of radiation to one area of cancer leading to complete remission from other, distant metastases is an interesting effect to keep in mind when considering treatment options, depending on the area to be radiated (the area of digestive tract seems to be extremely problematic from what I have observed and researched) especially when natural methods have not been successful.
"The natural history of malignant melanoma is notoriously unpredictable. Although long term survival is not uncommon, lymph node involvement lowers the five yr survival rate to about 5%. It is generally accepted that radiation has no place in the treatment of metastases despite occasional reports of temporary tumor regression. In these cases the response to irradiation occurred in the treated area and simultaneous regression of distant untreated metastases has never been reported. Such behavior has been given the term 'abscopal effect'. It occurs not uncommonly in leukaemia but is extremely rare in other tumors and the case reported is therefore of interest. The patient was a 28 yr old male, who had had a melanoma on the lateral side of the right knee for many years. A wide excision of the melanoma with a skin graft was performed. A lymphangiogram carried out on the right leg showed extensive involvement of the glands in the right inguinal region, with abnormal lymphatic channels in the pelvis. There was failure to fill the right lumbar chain, with deviation of the contrast into the grossly abnormal left lumbar chain. The patient was treated with a full course of fast neutrons (1,440 rad in 12 fractions over 35 days) to the right inguinal region. The upper medial limit of the field was the inferior border of the right sacroiliac joint. A repeat lymphangiogram showed a remarkable regression from the initial very abnormal picture and nine mth after treatment was started, the lymphangiogram was normal. At laparotomy no metastases were found, either in the iliac or para aortic nodes. He remained clinically free of disease during one year when a sudden severe rectal haemorrhage resulted in his death. At post mortem there was no evidence of residual metastatic melanoma." Accessed 11/12/19 on ResearchGate.net
Study - Synergistic Cytotoxicity of Radiation and Oncolytic Lister Strain Vaccinia in (V600D/E)BRAF Mutant Melanoma Depends on JNK and TNF-α Signaling
"Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo... Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors."
I found this interesting study which suggested that melanoma staging can be done during surgery using injections of the GLV-1h68 virus which travels to metastases in lymph nodes and is picked up using noninvasive bioluminescence imaging and fluorescence imaging.
Study - Real-time Intraoperative Detection of Melanoma Lymph Node Metastases Using Recombinant Vaccinia Virus GLV-1h68 in an Immunocompetent Animal Model
"The UK MelFO study seems to support the notion that a reduced stage-adjusted follow-up schedule is an appropriate and safe approach for AJCC stages 1B to 2C melanoma patients after staging with sentinel biopsy in terms of QoL, patient satisfaction, and disease safety at 3 years. We anticipate reporting the final outcome of the study at the end of 2020, with the data from the Netherlands and the UK combined to ensure adequate power to detect any difference in recurrence rates, thereby dispelling any lingering concerns about patient safety with a reduced follow-up regimen."
Study - Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls
"Results: Recreational sun exposure was a risk factor for melanoma on the trunk (pOR ¼ 1.7; 95% CI: 1.4–2.2) and limbs (pOR ¼ 1.4; 95% CI: 1.1–1.7), but not head and neck (pOR ¼ 1.1; 95% CI: 0.8–1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR ¼ 1.7; 95% CI: 1.0–3.0). Total sun exposure was
associated with increased risk of melanoma on the limbs at low latitudes (pOR ¼ 1.5; 95% CI: 1.0–2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3–1.7), 1.5 (95% CI: 1.3–1.7) and 1.4 (95% CI: 1.1–1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR ¼ 4.0; 95% CI: 1.7–9.1) and limbs (pOR ¼ 4.0; 95% CI: 1.9–8.4)."
"Conclusion: Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes."
Review - Sun Exposure and Skin Cancer, and the Puzzle of Cutaneous Melanoma: A Perspective on Fears Et Al. Mathematical Models of Age and Ultraviolet Effects on the Incidence of Skin Cancer Among Whites in the United States.
"In this perspective paper, we put this novel hypothesis into the context of knowledge at the time, and describe subsequent epidemiological and molecular research into melanoma that elaborated the intermittent exposure hypothesis and ultimately replaced it with a dual pathway hypothesis. Our present understanding is of two distinct biological pathways by which cutaneous melanoma might develop; a nevus prone pathway initiated by early sun exposure and promoted by intermittent sun exposure or possibly host factors; and a chronic sun exposure pathway in sun sensitive people who progressively accumulate sun exposure to the sites of future melanomas."
Study - Correlates Between Host and Viral Transcriptional Program Associated with Different Oncolytic Vaccinia Virus Isolates
People who have immunity to smallpox may not experience the same benefit when injected with the virus systemically; however, further research was being done on whether other routes of administration would help make it more effective:
"The results demonstrate a probable correlation between viral replication, early gene expression, and the respective host response, and thus a possible involvement of human host factors in viral early replication. The characterization of human target genes that influence viral replication could help answer the question of host cell permissiveness to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome... Despite the remarkable progress in oncolytic VACV-therapy, pre-existing immunity in smallpox vaccinated subjects is still a concern since neutralizing antibodies could limit the efficacy of the therapy. A preformed protection against poxviruses is particularly problematic for systemic treatment. Current research targeting this issue has focused on alternative routes of vaccine delivery (i.e., intratumoral), temporary immunosuppression, and immune evasion via carrier cell delivery (Guo et al., 2010) as well as dose escalation."
Study - Engineered oncolytic viruses to treat melanoma: where are we now and what comes next?
"Expert opinion: Engineered and naturally oncolytic viruses have demonstrable local and systemic efficacy as immunotherapies in cancer. T-VEC leads the way with improved survival outcomes for unresectable, stage IIIB-IVM1a melanoma as a monotherapy, and is demonstrating superior results in combination with systemic checkpoint inhibitors. Additional viral vectors show acceptable safety profiles and varying degrees of efficacy in targeting melanoma. The indications for use of oncolytic viruses will expand as their efficacy and appropriate usage is better understood in coming years."
Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma
Study - Talimogene Laherparepvec (T-VEC) for the Treatment of Advanced Melanoma
"Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that TVEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has now been assessed in Phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival compared to granulocyte-macrophage colony-stimulating factor. Despite these promising results, responses have been uncommon in patients with visceral metastases. TVEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity. In this review, we discuss the preclinical rationale, the clinical experience, and future directions for T-VEC in advanced melanoma."