More evidence that Vitamin D matters for melanoma and cancer patients generally!

Not news, really.  Here are a zillion related posts!!!
2014:  Vitamin D and Melanoma 
2016:  Vit D and melanoma - Part 2 
Jan 2017:  Vitamin D - low levels associated with a worse prognosis in melanoma...again... 
June 2017:  Vitamin D and melanoma - folks with higher levesl do better - again!!! 
September 2017:  Vitamin D and melanoma

Now this:

Circulating 25-hydroxyvitamin D up to 3 decades prior to diagnosis in relation to overall and organ-specific cancer survival.  Weinstein, Mondul, Yu, et al.  Eur J Epidemiol. 2018 Aug 2.

While vitamin D has been associated with improved overall cancer survival in some investigations, few have prospectively evaluated organ-specific survival. We examined the accepted biomarker of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], and cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Of 4616 cancer cases with measured serum 25(OH)D, 2884 died of their cancer during 28 years of follow-up and 1732 survived or died of other causes. Proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between pre-diagnostic 25(OH)D and overall and site-specific survival. Serum 25(OH)D was significantly lower among cases who subsequently died from their malignancy compared with those who did not (medians 34.7 vs. 36.5 nmol/L, respectively). Higher 25(OH)D was associated with lower overall cancer mortality. Higher 25(OH)D was related to lower mortality from the following site-specific malignancies: prostate, kidney, and melanoma, but increased mortality from lung cancer. Improved survival was also suggested for head and neck, gastric, pancreatic, and liver cancers, though not statistically significantly, and case numbers for the latter two organ sites were small. Higher 25(OH)D status years prior to diagnosis was related to improved survival for overall and some site-specific cancers, associations that should be examined in other prospective populations that include women and other racial-ethnic groups.

For what it's worth.  - c

More shoo shoo! Or...intestinal flora and melanoma

I've posted on all things dietetic and the flora in our gut in particular for YEARS!!!  Here was my latest round-up just this January:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

I do recommend healthy eating and exercise.  I do take 2000 iu of vitamin D daily.  I do eat lots of foods with active cultures in them - yogurt, kefir, sauerkraut, etc. I eat them because I like them and we have learned that cooties in our gut are important whether they really do anything when we take anti-PD-1 and deal with melanoma or not.  I wish that making immunotherapy effective for everyone who takes it were as simple as a diet change.  However, as I've noted in prior posts...this pendulum continues to swing back and forth and the data is far from conclusive.

Now, there's this ~

The gut microbiota and immune checkpoint inhibitors. Humphries and Daud.Hum Vaccin Immunother. 2018 Mar 1.

Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses. It is unclear whether the inconsistencies are due to differential approaches in study design (pre-clinical or clinical subjects, anti-CTLA-4 Ab or anti-PD-1 Ab), experimental methods and measurements (metagenomics sequencing and clustering variations) or subject population dynamics (differential cancer types and baseline characteristics). Moreover, we note studies regarding particular bacterial commensals and autoimmune diseases, which challenge findings from these investigations. We conclude that with the current research, clinical investigators can appreciate the critical role of gut microbiota in mediating immunostimulant response. However, prospective research exploring the biochemical mechanisms which commensal bacteria communicate with each other and the immune system is imperative to understand how they can be adjusted properly for higher immunotherapy response.

For what it's worth.  Hang tough.  Be well. - c

Vitamin D and melanoma

We've long known that higher vitamin D levels provide a better prognosis in melanoma.  Here is a link (with others within) discussing Vitamin D:  Vitamin D and melanoma - folks with higher levesl do better - again!!!

Now there is this ~

On the role of classical and novel forms of vitamin D in melanoma progression and management. Slominski, Brozyna, Skobowiat, et al. J Steroid Biochem Mol Biol. 2017 Jul 1.

Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH)₂D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors α and γ, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy.

For what it's worth! - c

Everything Cures Melanoma....# 7

Yep, the list of melanoma cures (in a petri dish - for the most part) is long and varied!!!  The short list includes ~ coffee (multiple reports), tea, doxycycline, curcumin and curry (many reports), cimetadine, NSAID's, shiitake mushrooms, exercise, red wine, strawberry juice, snake venom, sephora root, glycoalkaloids (found in eggplants, potatoes, and tomatoes), dill and parsley extracts, wild olive leaves, emu oil, oyster extract, Brazilian lima beans, lichen, sandalwood, beta blockers, and vitamin D (there may actually be something to this one!!) ~ to name a few!!!  Here are links to the data:  Everything Cures Melanoma: Installment #6

But, there is still more!

Melanoma and brown seaweed: an integrative hypothesis.  Teas, Irhimeh.  J Apppl Phycol. 2017.  

Although relatively rare, melanoma accounts for 2 % of cancer diagnoses globally and accounts for about 1 % of all cancer deaths. Worldwide, the annual incidence of melanoma is 272,000 cases which vary hugely, ranging from Japan where it is incredibly infrequent, to Queensland, Australia, where it is nearly 100 times higher. Based on epidemiology and laboratory studies, there is compelling evidence suggesting that seaweed might be protective against different types of cancers such as breast cancer in seaweed consuming populations. By comparing countries where melanoma is more common with countries where it is infrequent, it is possible to construct a hypothesis for how consuming brown seaweeds which may hold clues to the differences in melanoma susceptibility between Japanese and Western nations. Unlike in these other countries, where melanoma incidence has increased dramatically over the last two decades, in Japan, rates have remained remarkably low and stable. There is limited evidence from clinical studies and animal models that have used whole seaweed or isolated fractions from seaweed and measured changes in biomarkers. They have demonstrated the effectiveness of seaweed at inhibiting melanoma development and progression. In this review, the various results will be described. Although there are several effective fractions, it is proposed that consuming whole seaweeds may hold additional benefits that could be lost by consuming only a single extract.

Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid. Su, Lin, Yu, et al. J Agric Food Chem. 2017 Jun 19.  

Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 ± 2.42 μM and 12.30 ± 1.67 μM after 24 h and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at S phase, along with the collapse of mitochondrial membrane potential (ΔΨm) and the accumulation of reactive oxygen species (ROS) level in cells but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor). Western blotting showed that the expressions of p53, cytochrome C, caspase-3 and PARP were up-regulated, the expression level of Bax/Bcl-2 ratio increased significantly. The 2527 significant differentially expressed genes were obtained by RNA-seq, which were assigned to 270 KEGG pathways. These results indicated that CM induced M14 cells apoptosis via the ROS triggered mitochondrial-associated pathways, which supports the potential application of CM for the therapy of melanoma cancer.

Young leaves of reed (Phragmites communis) suppress melanogenesis and oxidative stress in B16F10 melanoma cells. Sim, Ham, Lee. Biomed Pharmacother. 2017 Jun 16. 

This study investigated the effects young leaves of reed (Phragmites communis) water extract (YLR) on melanogenesis and oxidative stress using B16F10 cells. YLR decreased the intracellular melanin content, protein expression and enzyme activity of tyrosinase in a dose-dependent manner. YLR significantly decreased the gene and protein expression of melanogeneis-related proteins, such as microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein-1 and -2. In addition, YLR up-regulated the melanogenesis inhibitory proteins, extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), while it dose-dependently down-regulated p38 and cAMP response element-binding protein (CREB). Moreover, YLR significantly reduced H₂O₂-induced reactive oxygen species levels in B16F10 cells and showed antioxidant activity based on DPPH and ABTS free radical scavenging activity and SOD-like activity. These results suggest that YLR have anti-melanogensis properties that function through regulation of the CREB/MITF/tyrosinase pathway in B16F10 cells and antioxidant activity. Overall, these findings indicate that YLR has the potential for use in treatment of skin disorders and skin-whitening.

A polymethoxyflavone mixture extracted from orange peels, mainly containing nobiletin, 3,3',4',5,6,7,8-heptamethoxyflavone and tangeretin, suppresses melanogenesis through the acidification of cell organelles, including melanosomes. Yoshizaki, Hashizume, Masaki.  J Dermatol Sci. 2017 Jun 10.

Skin color is determined by melanin contents and its distribution. Melanin is synthesized in melanosomes of melanocytes, catalyzed by tyrosinase, melanogenic enzymes. Regarding the process of melanin synthesis, melanosomal pH is considered to play an important role, because it has been reported to differ between Caucasian and Black melanocytes.
Although polymethoxyflavone (PMF) has many beneficial effects, it has not been reported which PMF suppresses melanogenesis. In this study, we identified the mechanism underlying the effect of PMF on melanogenesis METHODS: We determined the effects of a PMF mixture extracted from orange peels on melanogenesis, on tyrosinase expression, on the localization of tyrosinase and on the acidification of organelles, including melanosomes, in HM3KO human melanoma cells. RESULTS TREATMENT: with the PMF mixture elicited the suppression of melanogenesis, the degradation of tyrosinase in lysosomes and the mislocalization of tyrosinase associated with the acidification of intracellular organelles, including melanosomes. The neutralization of cell organelle pH by ammonium chloride restored melanogenesis and the correct localization of tyrosinase to melanosomes, which had been suppressed by the PMF mixture.  These results suggest that the PMF mixture suppresses the localization of tyrosinase to melanosomes and consequently inhibits melanogenesis due to the acidification of cell organelles, including melanosomes.

Bioactivities of ethanol extract from the Antarctic freshwater microalga, Chloromonas sp. Suh, Yang, Lee, et al. Int J Med Sci. 2017 Apr 28.  

Cancer is the principal cause of human death and occurs through highly complex processes that involve the multiple coordinated mechanisms of tumorigenesis. A number of studies have indicated that the microalgae extracts showed anticancer activity in a variety of human cancer cells and can provide a new insight in the development of novel anti-cancer therapy. Here, in order to investigate molecular mechanisms of anticancer activity in the Antarctic freshwater microalga, Chloromonas sp., we prepared ethanol extract of Chloromonas sp. (ETCH) and performed several in vitro assays using human normal keratinocyte (HaCaT) and different types of cancer cells including cervical, melanoma, and breast cancer cells (HeLa, A375 and Hs578T, respectively). We revealed that ETCH had the antioxidant capacity, and caused significant cell growth inhibition and apoptosis of cancer cells in a dose-dependent manner, whereas it showed no anti-proliferation to normal cells. In addition, ETCH had a significant inhibitory effect on cell invasion without the cytotoxic effect. Furthermore, ETCH-induced apoptosis was mediated by increase in pro-apoptotic proteins including cleaved caspase-3 and p53, and by decrease in anti-apoptotic protein, Bcl-2 in ETCH-treated cancer cells. Taken together, this work firstly explored the antioxidant and anticancer activities of an Antarctic freshwater microalga, and ETCH could be a potential therapeutic candidate in the treatment of human cancer.

Anti-Metastatic Effect of Semi-Purified Nuphar Lutea Leaf Extracts. Ozer, Fishman, Eilam, et al.  J Cancer. 2017 May 12.  

Nuphar lutea L. SM., leaf and rhizome extracts (NUP), contain nupharidines as active components. Nupharidines belong to the sesquiterpene lactones class of a naturally occurring plant terpenoids. This family of compounds has gained considerable interest for treating infection, inflammation and cancer. NF-κB is a central, downstream regulator of inflammation, cell proliferation and apoptosis. In our previous work we demonstrated strong inhibition of NF-κB activity and induction of apoptosis by NUP. In addition, NUP exhibited anti-inflammatory properties and partial protection from LPS-induced septic shock by modulating ERK pathway and cytokine secretion in macrophages. In the present study, we examined the effect of NUP in a B16 melanoma experimental murine lung metastasis model and its ability to affect the ERK and NF-κB pathways in variety of cell lines. We showed that NUP and cisplatin combined treatment was synergistic and reduced the lung metastatic load. In addition NUP treatment inhibited TNFα-induced IκBα degradation and NF- κB nuclear translocation. We also observed that NUP induced ERK activation. Furthermore, ERK inhibition prevented NF-κB inactivation by NUP. Overall, our work implies that co-administration of NF-κB inhibitors such as NUP, with standard anti-cancer drugs, may act as "sensitizers" for more effective chemotherapy.

Antiproliferative and proapoptotic activities of anthocyanin and anthocyanidin extracts from blueberry fruits on B16-F10 melanoma cells. Wang, Liu, XU, Liu.Food Nutr Res. 2017 Jun 19.  

Background: Anthocyanins have been proven to affect multiple cancer-associated processes in different cancer cell lines. However, relatively few studies have investigated the effects of blueberry anthocyanins on metastatic melanoma. Thus, this study focuses on evaluating the chemopreventive potential of blueberry anthocyanins and their aglycones (anthocyanidins) in B16-F10 melanoma cells. Methods: Blueberry anthocyanin and anthocyanidin extracts were prepared mainly by combined chromatography techniques. Their antiproliferative and proapoptotic effects on B16-F10 cells were evaluated by MTT assay, calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) staining, and flow cytometry of the cell cycle and apoptosis. Results: The MTT and calcein-AM/PI staining results showed that both anthocyanin (purity of 62.5%) and anthocyanidin (75.1%) extracts could significantly inhibit the viability and proliferation of B16-F10 cells in a dose-dependent manner, while anthocyanidin extracts exhibited significantly higher (p < 0.05) cytotoxicity than anthocyanin extracts. Furthermore, anthocyanin and anthocyanidin extracts blocked cell cycle procession at the G0/G1 phase below 400 and 200 μg/mL, and induced early apoptosis below 400 and 300 μg/mL, respectively. Conclusions: These data suggest that both anthocyanin and anthocyanidin extracts inhibit the proliferation and trigger the apoptosis of B16-F10 cells, and anthocyanidin extracts may be a more promising candidate in preventing metastatic melanoma than anthocyanin extracts.

Hmmm, brown seaweed, cashew nut SHELL liquid, leaves of young (NOT old!!!) reeds, orange peels, microalga (Is there macro-algae????) from fresh water in the Antartic, lutea leaves, and blueberries!!!  Sounds like yuppie compost!  Hey, whatever works!

For what it's worth! - c

Vitamin D and melanoma - folks with higher levesl do better - again!!!

Vitamin D and vitamin D levels of melanoma patients have long been discussed.  Here is a link to a couple of prior posts:  Vitamin D - low levels associated with a worse prognosis in melanoma...again...

Now there's this:

High serum vitamin D level correlates with better prognostic indicators in primary melanoma: A pilot study. Lim, Shayan, and Varigos. Australas J Dermatol. 2017 Mar 23.

Sunlight is a major risk factor for cutaneous melanoma. However, its interaction with melanoma is complex. In particular, vitamin D is a UVB-derived hormone that has been shown to have anti-cancer effects. In this retrospective pilot study we sought to determine an association between the clinicopathological features of melanoma and the patients' corresponding serum vitamin D level.

In total, 109 primary melanomas diagnosed between 2001 and 2013 were retrospectively identified from our institutional database with a corresponding 25-hydroxyvitamin D3 level estimated within 6 months of diagnosis. Tumour, clinical (age, sex, tumour location) and pathological (thickness, mitosis, ulceration, Clark level, subtype, metastatic status) parameters were correlated with vitamin D. 

Vitamin D level was inversely associated with Breslow thickness as a dichotomous, categorical and continuous variable. The association remained significant when controlled for patient's age and sex. Vitamin D was higher in non-ulcerated tumours compared with ulcerated tumours and in tumours with mitotic rate less than 1/mm² compared with greater than/= to 1/mm². A significant association was found between vitamin D level and tumour histological subtype. On subgroup analysis, significant associations were found between superficial spreading melanoma (SSM) and nodular melanoma, and SSM and acral lentiginous melanoma.  

A high vitamin D status may benefit prognosis in patients diagnosed with primary melanoma. A prospective cohort analysis with a large sample and controlled for other vitamin D confounders would validate these findings.

And again....  Take that Vitamin D, folks!!! - c

Side effects of immunotherapy - Part 8

In the ongoing saga...see the previous post:  Side effects of immunotherapy - Part 7

New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma. Behling, Kaes, Munzel, et al. Melanoma Res. 2017 Apr;27.

There has been considerable progress in treating malignant melanoma over the last few years. The immune-checkpoint-inhibitors nivolumab and pembrolizumab have been approved by the Food and Drug Administration in 2014 for the therapy of metastatic melanoma. Anti-programmed cell death-1-blocking antibodies are known to cause immune-related adverse events. Physicians should be aware of common and rare side effects and pay attention to new ones. We therefore report a severe and life-threatening side effect of anti-programmed cell death-1 immunotherapy with nivolumab that has not been previously reported: the development of a third-degree atrioventricular block. After a second infusion with nivolumab, our patient developed a troponin I-positive and autoantibody-positive myositis and a few days later a new-onset third-degree atrioventricular block. This is most likely because of an autoimmune-induced myositis with a cardiac impairment in terms of a myocarditis, which led to an impairment of the conduction of cardiac electrical stimuli.

Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients. Nguyen, Kuo, Budiman, Christie. Melanoma Res. 2017 April.

Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients. One case is in an 81-year-old man and the second case in an 86-year-old woman, both with BRAF-negative metastatic melanoma receiving pembrolizumab. These two cases of ocular only associated myasthenic syndrome appeared 7 and 11 weeks after the initiation of pembrolizumab. We conclude that the condition is most likely associated with pembrolizumab as symptoms started after treatment with pembrolizumab, neither patient had other evidence of neurological cause for presentation, and symptoms also improved rapidly with administration of steroids. Both patients showed good oncological response to anti-PD1 treatment and one patient successfully continued to receive ongoing treatment with no further complications.

PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis. Wu, Hong, Zhang, et al. Lancet Oncol. 2017 Mar 3.

Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% for all-grade and 1.53% for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.

Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody secondary to pembrolizumab therapy. Brown, Hissaria, Hsieh, et al. J Neuroimmunol. 2017 Apr 15.

Immune checkpoint inhibitors such as Pembrolizumab are used to restore antitumour immune response. It is important to be vigilant of immune mediated adverse events related to such therapy. We report a case of autoimmune limbic encephalitis with Contactin-Associated Protein-like 2 (CASPR2) antibody secondary to Pembrolizumab therapy for metastatic melanoma.

Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Win, Thein, Qdaisat, and Yeung. Am J Emerg Med. 2017 Feb 27.

Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia.  A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia.  Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology.

Be safe.  Be aware.  Seek help if you think you need it!  Hang tough, ratties!  Hang tough!  - c

Vitamin D - low levels associated with a worse prognosis in melanoma...again...

These results are not exactly new.  Here are a couple of previous articles:  Vit D and melanoma - Part 2

Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma. Timerman, McEnery-Stonelake,...Hodi, et al. Oncotarget. 2016 Dec 28.

Vitamin D deficiency (less than or = to 20 ng/mL) is associated with an increased incidence and worse prognosis of various types of cancer including melanoma. A retrospective, single-center study of individuals diagnosed with melanoma from January 2007 through June 2013 who had a vitamin D (25(OH)D3) level measured within one year of diagnosis was performed to determine whether vitamin D deficiency and repletion are associated with melanoma outcome. A total of 409 individuals diagnosed with histopathology-confirmed melanoma who had an ever measured serum 25(OH)D3 level were identified. 252 individuals with a 25(OH)D3 level recorded within one year after diagnosis were included in the study and the individual and melanoma characteristics such as age, sex, Breslow thickness, ulceration, stage, mitotic rate, and LDH were obtained from the medical record. A worse melanoma prognosis was associated with vitamin D deficiency, higher stage, ulceration, and higher mitotic rate. In patients with stage IV metastatic melanoma, vitamin D deficiency was associated with significantly worse melanoma-specific mortality. Patients with metastatic melanoma who were initially vitamin D deficient and subsequently had a decrease or less than or = to 20 ng/mL increase in their 25(OH)D3 concentration had significantly worse outcomes compared to non-deficient patients who had a greater than 20 ng/mL increase. Our results suggest that initial vitamin D deficiency and insufficient repletion is associated with a worse prognosis in patients with metastatic melanoma.

Take that Vitamin D, folks!!! - c

A look at effect of routine meds used by patients when on ipi....

Effects of commonly used chronic medications on the outcomes of ipilimumab therapy in patients with metastatic melanoma.  Failing, Finnes, Kottschade, et al.  Melanoma Res. 2016 Sep.

Ipilimumab can induce long-term survival in 20% of patients with metastatic melanoma. Concurrent chronic medications may impact the patient's immune system, possess antimelanoma properties, and potentially affect clinical outcomes. This retrospective study sought to describe the efficacy and toxicity effects of 12 classes of chronic medications in metastatic melanoma patients treated with ipilimumab. A total of 159 adults who received ipilimumab for metastatic melanoma at Mayo Clinic (Rochester, Minnesota, USA) from 1 March 2011 through 31 December 2014 were included. Classes of chronic medications included statins, metformin, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, calcium channel blockers, aspirin, non-steroidal anti-inflammatory drugs, H1 and H2 receptor antagonists, proton pump inhibitors (PPIs), antidepressants, and vitamin D supplements. Of the 12 medication classes, only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab on the basis of a case-control analysis. Although not significant, PPI use also trended toward improved overall survival and progression-free survival on the basis of Kaplan-Meier and Cox proportional hazard modeling. No medication class was associated with an increased risk of grades 3-5 immune-related adverse events with ipilimumab on the basis of case-control analysis. In summary, patients on PPIs may be more likely to experience a partial response/complete response following ipilimumab therapy. Because of the small sample size and the retrospective nature of this work, these findings are only descriptive and further study should be carried out. Other classes of chronic medications did not produce statistically significant effects for any of the measured outcomes.

PPI's anyone????  Well, before you get too excited...  PPI's are protein pump inhibitors.  They decrease acid in the stomach and were the 9th most commonly prescribed drugs in 2015.  They include the drugs nexium, prilosec, and prevacid (along with some others).  By decreasing stomach acid, these drugs also decrease the ability of the body to absorb some vitamins and minerals, and kill bad bacteria, leading to untoward effects.  These drugs already carry warnings for several known risks, including C. difficile infections and chronic diarrhea, pneumonia, low magnesium levels (which can contribute to heart problems, muscle spasms, seizures and fractures).  Recent studies have also connected them with an increased risk for chronic kidney disease and dementia.  Hmmm....  What to do?  While the intel in the study above is interesting...we might best wait and see how all this plays out. 

Poor ratties. - c

Everything cures melanoma...redux....#5?????

Lord knows I have covered 'most' everything that folks have tested and came away saying would cure melanoma:  coffee, curcumin, strawberry extract, wine, doxycycline, beta blockers, snake venom, shitakes, eggplant, potatoes, tomatoes, cimetadine, NSAID's, Vitamin D, Vietnamese Sophora root, exercise, sandalwood...I did leave off sea urchin snot....just seemed a bridge too far!!!!  Here are those posts if you'd like to see the data for yourself:

From 2013:  Everything cures melanoma, so why do we have it?

Be Better in 2013: Jump up, jump around and get down!

2014: Red, red wine boosts radiation effect

Also from 2014:  For melanoma: eat that curry again we just don't know why!

2015: Everything kills melanoma: Take 4

Now we have these reports touting the benefits of dill and parsley, coffee and curcumin again, anti-cholesterol meds and stress control! Here you go:

Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity.  Semenov, Tsyganov, Semenova, et al.  J Nat Prod. 2016 Apr 21. 

A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives 9 starting with readily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides 7 into the respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into the target series 9. The biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and an in vivo sea urchin embryo assay. Both screening platforms confirmed the antimitotic effect of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings, respectively, were less active than the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 μM concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule-destabilizing effect of isoflavones 9cg, 9cd, and 9cf.

Higher Caffeinated Coffee Intake Is Associated with Reduced Malignant Melanoma Risk:  A Meta-analysis study.  Liu, Shen, Shi, Cai, PLoS One.  2016 Jan 27.

Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM) risk.  Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015). Study-specific risk estimates were pooled under the random-effects model.  Two case-control studies (846 MM patients and 843 controls) and five cohort studies (including 844,246 participants and 5,737 MM cases) were identified. For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81 for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found. Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk.  This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings.


Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism.  Yang, Bai, Xiong, et al.  Nature. 2016 Mar 16. 

CD8⁺ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8⁺ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8⁺ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8⁺ but not CD4⁺ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8⁺ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8⁺ T cells were better than wild-type CD8⁺ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Curcumin:  A new candidate for melanoma therapy?  Mirzaei, Naseri, Reazee, et al.  Int J Can.  2016 Jun 9.  

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic, and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g. BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

Association of stress coping strategies with immunological parameters in Melanoma Patients.  Trapp, Trapp, Avian, et al.  Acta Derm Venereol. 2016 Jun 9.

In this exploratory case control study the association between stress coping strategies and lymphocyte subpopulations was calculated in 18 non-metastatic melanoma patients and 18 controls with benign skin diseases. Coping strategies were assessed using the German version of the stress-coping questionnaire (SVF 120). While in the control group patients showed significant negative correlations of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD45+ cells) with coping strategies that refer to defence, in melanoma patients significant positive correlations between lymphocyte subpopulations (CD3+, CD4+, CD19+, CD45+ cells) were found with regard to coping strategies that are characterized by diversion from stress and focusing on stress-compensating situations. The present data, in melanoma patients and controls, show contrary correlations between stress coping strategies and lymphocyte subpopulations. The interconnection between stress coping and immunologic alterations in malignant melanoma is a field deserving further multiprofessional investigation in order to provide new therapeutical approaches in the treatment and understanding of melanoma patients.

Supercritical Fluid Extract of Spent Coffee Grounds Attenuates Melanogenesis through Downregulation of the PKA, PI3K/Akt, and MAPK Signaling Pathways.  Huang, Wei, Siao, et al.  Evid Based Complement Alternat Med. June 2016.

The mode of action of spent coffee grounds supercritical fluid CO2 extract (SFE) in melanogenesis has never been reported. In the study, the spent coffee grounds were extracted by the supercritical fluid CO2 extraction method; the chemical constituents of the SFE were investigated by gas chromatography-mass spectrometry (GC-MS). The effects of the SFE and its major fatty acid components on melanogenesis were evaluated by mushroom tyrosinase activity assay and determination of intracellular tyrosinase activity and melanin content. The expression level of melanogenesis-related proteins was analyzed by western blotting assay. The results revealed that the SFE of spent coffee grounds (1-10 mg/mL) and its major fatty acids such as linoleic acid and oleic acid (6.25-50 μM) effectively suppressed melanogenesis in the B16F10 murine melanoma cells. Furthermore, the SFE decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). The SFE also decreased the protein expression levels of p-JNK, p-p38, p-ERK, and p-CREB. Our results revealed that the SFE of spent coffee grounds attenuated melanogenesis in B16F10 cells by downregulation of protein kinase A (PKA), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen-activated protein kinases (MAPK) signaling pathways, which may be due to linoleic acid and oleic acid.
 
While most of these...coffee, curcumin, and becoming a bit more zen most certainly....are likely to do no harm, do keep this word of warning in mind should you be determine to cure yourself:   Combining alternative and conventional treatments can be a risky business!

For what it's worth! - c