Saturday, December 7, 2019

BRAF/MEK combo's for melanoma analyzed ~


About half of melanoma patients are BRAF positive.  A strange delineation that I tried to explain in 2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!  Only melanoma peeps who are BRAF positive will gain an effect from the BRAF/MEK combo (targeted therapy).  Since 2010, ratties have taught us much about how targeted therapy works and should be used.  Back in the day, we didn't realize that combining a BRAF inhibitor with a MEK inhibitor led to fewer side effects and greater efficacy.  Or that alternate dosing could help avoid resistance.  Or how best to handle side effects.  Now there are many combo's available for use as targeted therapy.  But, as no direct comparison studies have been made - what combo is best?  Now, there's this:

Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma.  Hamid, Cowey, Offner, et al.  Cancers (Basel). 2019 Oct 24.

No head-to-head studies exist comparing BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) combination treatments for BRAF-mutant melanoma. A side-by-side analysis of randomized phase III trials is presented that evaluated dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. The baseline characteristics, efficacy, and safety were compared: COMBI-v (dabrafenib/trametinib versus vemurafenib); coBRIM (vemurafenib/cobimetinib versus vemurafenib); and COLUMBUS (encorafenib/binimetinib versus encorafenib and vemurafenib). Vemurafenib was the control arm in all studies. The data sources included literature databases, European public assessment reports, U.S. Food and Drug Administration review documents, and prescribing information. The baseline characteristics were similar, except for coBRIM, which had a higher proportion of patients with elevated lactate dehydrogenase (LDH) levels. The median progression-free survival (PFS) and overall response rate (ORR) were similar across the trials, although numerically higher values were observed with encorafenib/binimetinib. In contrast, the median overall survival (OS) was numerically longer with encorafenib/binimetinib (33.6 months) compared to dabrafenib/trametinib (25.6 months) and vemurafenib/cobimetinib (22.3 months). Among vemurafenib arms, PFS, ORR, and OS were similar, despite variations in the baseline LDH. Each combination displayed a unique safety profile, with higher incidences of pyrexia with dabrafenib/trametinib and photosensitivity reactions with vemurafenib/cobimetinib. This analysis of BRAFi/MEKi combinations for BRAF-mutant melanoma, while limited as not a direct head-to-head clinical trial, highlights the differences in tolerability and efficacy that may be useful for therapeutic decision making.

So, there you have Hamid's take on comparing three of the BRAF/MEK combo's.  Their conclusions were pretty similar to my own in this post from 2018:  Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

Then, there's this:

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.  Holbrook, Lutzky, Davies, et al. Cancer. 2019 Oct 28.
Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.  A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates; the clinical benefit rate; the time to response; the duration of response; and safety.

A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.

Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

Okay.  Good.  But, I don't find these results that "new".  Small numbers were evaluated and we already knew BRAF/MEK worked in the brains of folks with BRAF positive melanoma.  To me, the best "news" of the article is that even those previously treated with BRAF/MEK were able to gain a response.  

Finally, there's this:

Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma.  Ribas, Daud, Pavlick, et al.  Clin Cancer Red. 2019 Nov 15. 


To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.

This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF V600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7).

Median OS was 31.8 months in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.

A subset of patients with advanced BRAF V600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Again.  Nothing really new here.  As I noted at the start, we have known for years now that folks treated with a BRAF/MEK combo do better than those treated with BRAFi alone.  The best take away from this, is the fact that given targeted therapy is known to have responses that are less durable than those for responders to immunotherapy - overall survival plateaued at 39% at 4 and 5 years out.  Something amazing ratties like Dick K (aka Richard K - thanks to spam blockers) have been demonstrating for some time.  NOTE:  For additional comparison, this post includes a report on the 5 year outcomes for the Dabrafenib/Tramedtinib combo:   Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

Hang tough ratties.  You save us all! - c

Wednesday, December 4, 2019

NSAID's and cancer (Colon and melanoma specifically!) ~


Much has been written in the literature regarding NSAID use and melanoma. NSAID's are drugs like aspirin, ibuprofen, naproxen, and lots of prescription ones, that block COX enzymes.  Enzymes that produce prostaglandins which lead to inflammation, pain and fever when left to do their own thing.  By blocking the enzyme, NSAID's reduce the prostaglandins and the unpleasantness they cause.  I first reported on them in 2012!  Here is a break down of how they might work in melanoma world from 2015:  An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!! 
Here are a zillion additional reports:  NSAID's - do they help or not? 
Basically, the data (and reports) cover:
"YES!!!  NSAID's make immunotherapy work better!"   "NSAID's increase survival in melanoma patients."  "No, NSAID's make no difference."

Though these drugs are not to be trifled with despite being accessible over the counter, most data says at worst they "do no harm".  Given the aches and pains immunotherapy causes, I've long said you would be hard pressed to find a patient on immunotherapy who did NOT partake in the use of NSAID's!!  I know I certainly took my share of advil during my treatment!!!  Now, there's this:

The Impact of Nonsteroidal Anti-Inflammatory Drugs, Beta Blockers, and Metformin on the Efficacy of Anti-PD-1 Therapy in Advanced Melanoma.  Wang, McQuade, Rai, et al.  Oncologist.  2019 Nov 29.

Anti-programmed cell death protein-1 (anti-PD-1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti-PD-1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti-PD-1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)-2 inhibitors (2%), and non-ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression-free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti-PD-1 therapy. Larger and more systematic analysis is required to confirm these findings.

Given my current condition, it is pertinent that my 2015 report started with this quote:
 "NSAID's, including aspirin, decrease the incidence and mortality from colon cancer in humans by 45% to 50%."  DuBois, Cancer Research, 56(4), 1996.

Now, there's this - The Association between NSAID use and Colorectal Cancer Mortality: Results from the Women's Health Initiative

Which notes:  "Randomized trial evidence demonstrates that non-steroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC). We examined the association between NSAID use and CRC mortality among 160,143 post-menopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Overall, NSAID use at baseline was not associated with CRC mortality. However, women who reported NSAID use at both baseline and year-three experienced reductions in CRC mortality compared to non-users.  Results suggest that NSAID use is associated with lower CRC mortality among post-menopausal women who use these medications more consistently over time. Our results support prolonged NSAID use in post-menopausal women for the prevention of poor CRC outcomes."

I have discussed all of this with my various docs.  They didn't have too much to say or contribute on the subject one way or another.  However, I was given their blessing to start an aspirin regimen of one baby aspirin (81mg) per day.  So, I did!  For what it's worth! - c

Saturday, November 30, 2019

Thankful ~ for you...


This season, this crazy world, this strange body I inhabit~  Nature's beauty, the joy of family, the sharing of small but essential human pleasures with so many who have graced my life~  All bring me here~

I am so grateful for my dear ones.  You have stood by me, despite the pain and worry I bring you, sharing humor, compassion, courage, hugs, kind words, sweet gestures.  Tokens of the human spirit that allow me to survive my worries and hardship.  It pains me more than any physical trial I have experienced to see the hurt my condition can bring to YOUR eyes.  When earlier this year, I heard this wrenchingly beautiful song,  it seemed to express perfectly my perception of how so many of you must have felt on my behalf.

Please give it a listen:  Soon You'll Get Better - Taylor Swift/Dixie Chicks

The buttons of my coat were tangled in my hair
In doctor's-office-lighting, I didn't tell you I was scared
That was the first time we were there
Holy orange bottles, each night I pray to you
Desperate people find faith, so now I pray to Jesus too
And I say to you
Ooh-ah, soon you'll get better, Ooh-ah, soon you'll get better
Ooh-ah, you'll get better soon, 'Cause you have to
I know delusion when I see it in the mirror
You like the nicer nurses, you make the best of a bad deal
I just pretend it isn't real
I'll paint the kitchen neon, I'll brighten up the sky
I know I'll never get it, there's not a day that I won't try
And I'll say to you
Ooh-ah, soon you'll get better, Ooh-ah, soon you'll get better
Ooh-ah, you'll get better soon, 'Cause you have to...
I am sorry for the pain and distress I know I cause.  But, I am ever so thankful for the laughter, love and comfort each of you share so generously with me, my dear peeps.  You've entered my life as childhood friends, coworkers, neighbors, melanoma peeps, family - from every corner of the crazy, crooked, structure that is my life.  You keep me strong.  You have given me more than I can ever repay.  I know I've been blessed.  And I am thankful ~ for you. 

Much love, les

Wednesday, November 20, 2019

A melanoma/GCC update ~ OR ~ If at all possible, don't let anyone take a hole punch to your lily!


Note to self:  Perhaps getting a labial biopsy, second shingrix injection, and a recheck with blood work at the oncologist's office all in one day is not the smartest move following a 3 day migraine!  But, what the heck?  I figure there's no need to let misery and time spent in waiting rooms poison more days than I can help!

Yep.  A labial biopsy is what you think it is.  (Labia minora to be anatomically correct - hoo hoo, monkey, pocket book [There's a really funny story re: B's lack of comprehension when a mother regaled him with the problems her daughter was having with HER pocket book!!!], fanny, nether regions, muffin, etc - to be more colloquial!)  And it ain't fun.  Not that anyone would suspect otherwise!  But, to back up a few steps, we'll cut to the chase first:

Currently, I am:

194 months (16 YEARS!!!!) post my original melanoma diagnosis in 2003 at the age of 39
114 months Stage IV (9 and 1/2 years!!!)
108 months NED (well....for melanoma at least)
106 months after starting nivo (Opdivo)
76 months (more than 6 years) AFTER my last nivo infusion in June 2013.

I am also:  
14 months post my diagnosis of adenocarcinoma ex-goblet cell carcinoid (GCC) and the removal of my appendix containing its 10.5 cm tumor, my ascending colon including ileocecal valve, gall bladder and ovaries
11 months post completion of 3 months adjuvant CAPOX chemo for same

I have been lucky (and simultaneously seriously peeved) to have seen a zillion doctors over these past 16 years! Oncologists, radiologists, multiple surgeons, dermatologists.  Oddly enough, despite the relatively rare (only once or twice a year) migraine previously mentioned and asthma since childhood - shockingly improved once done with lung surgeries and immunotherapy!!!! - I am the healthiest person with two deadly diseases that you will ever meet!!!  And, though I HATE being the patient, I am a very good one.  I had annual pap-smears well into my 40's (ALL completely NORMAL!!!) and even got my first recommended mammogram (though as a forever member of the itty bitties, the necessity eludes me especially given the incredible number of chest CT scans I've been exposed to) which was also completely normal.  My cholesterol and lipid levels make some I could mention quite jealous.  BUT, our medical system in the states requires a PCP (primary care provider) and mine, though mostly in name only to be honest, retired last year.  So B and my local onc got a bee in their bonnets that it was time for me to have a real physical by a real doctor.  Good Grief! Luckily, I found a very bright, attentive, if a tad anal, physician who didn't run screaming from the room nor allow her eyes to glaze over when faced with my history.  She seemed more knowledgeable about post chemo symptoms than my onc and was optimistic that my neuropathies were likely to continue to improve.  However, she was intent on a COMPLETE tune up and eval, so that's what I've been doing!  Bone density - done and fabulous.  Mammogram - completed and normal.  (Seriously, is it really necessary to advise a person whose boobie is stuck in a vice, to:  "Hold still.  Don't move."????  Awwe, man!  I was just about to walk away!)  Flu and both doses of shingrix vaccine (to prevent shingles) duly attained.  And though I REALLY didn't want one, a visit to a gyn was the only thing I needed.  But, NOT for the pap-smear.  Which yes, I got, and was NORMAL!

There were two actual issues.  Ever since my ovaries were summarily yanked in September of 2018, I have not had one night that didn't include several episodes of extreme hot flashes with the feeling of smothering, followed by profuse sweating, often soaking the bed linens, followed by being freezing cold. Not very conducive to rest!  Surely, I thought, over time, these symptoms would improve.  Lord knows, I am far from the only woman on the planet to experience them.  However, over a year in, they had not.  Hormone replacement therapy is one of many things in the medical world that swings on a pendulum - ricocheting from "the best thing ever" to "risky and contraindicated".  My research indicated that it should pose no increased risk given my melanoma and GCC history and no undue issues otherwise as I am not a smoker or infirm - but what do I know?  My PCP wouldn't touch the issue, leaving it up to the gyn.  I can assure you, if men endured menopause we would know a lot more about it!!!

Issue number two.  Remember my bungie work-out adventure?  Perhaps I didn't share that here.  Anyhow, late in the summer Rose and I joined my dear Ashia for a Bungie Workout!  A strange event during which you are placed in a harness attached to a bungie cord from the ceiling and you proceed to do a workout while so tethered!  It was fun!  It was also a bit rough on the nether regions as my harness was too large and loose, causing a fair amount of chafing and soreness to that area.  When the soreness continued, I gave the area a close inspection and noted some very dark purple/black splotches to the labia on one side.  Hmmm....  I decided they were bruises and gave them some time.  They did not improve - nor worsen - though the soreness went away.  After a few weeks I confessed the situation to B.  He put on his brave face.  The one that he uses to try to cover the, "Oh, F$@K!" expression.  Still, our research indicated that I had something called vaginal melanosis.  A fairly common condition that most women don't even know they have.  Often occurs along with vitiligo - oddly enough - which I have everywhere, including that area.  And as the lesions remained unchanged, were not terribly discrete in their blotchy splotches, were never raised, painful, itchy, bleeding - or anything else - and my melanoma had been cutaneous rather than mucosal - we figured it was okay.  But again, what did we know?  We figured a biopsy would be in order.  UGGGGHHHHHHH!

So, yes indeed.  My unhappy ass was off to the gyn.  A limp sort of fellow, who doesn't pay attention to much, ordered and completed all the testing previously noted.  Stated that he felt the lesions were melanosis and nothing to worry about were it not for my melanoma history.  A biopsy would be in order which given his lack of concern would be completed on my recheck for the hormone replacement therapy he thought would have no ill effects and perhaps some positive ones.  Last week I returned.  The hormones have worked well and I can sleep through the night again!  A biopsy was completed.  If at all possible, don't let anyone take a hole punch to your lily!  Yes, a punch biopsy, the size of a typical pencil eraser, was taken from an anatomic location that is not very thick in the first place and then rather than place a stitch to stop the bleeding, silver nitrate was applied.  This is a chemical placed on the head of a stick, making it look a lot like a match, that can be used to sizzle off overgrown tissue and yes, stop bleeding.  But you have to realize, as a provider dabbing said stick around, that everything you 'dab' is going to turn black and slough off!!!  Should men really be allowed to function as OB/GYN's?  I have mixed feelings about that, but to continue...  Healing has been more difficult than after having either of my babies.  Yes, all the tissue to which silver nitrate was applied - ....  Well, I'll spare you the gory details, but suffice it to say that what was a punch, turned into a doughnut hole, then a tear, then a mess, and now a healing hound's ear that did not come out of the fight with the coon as well as he had hoped!

Still, all's well that ends well, right?  The biopsy was negative for melanoma and consistent with the changes of melanosis.  I did have a moment of pause, when on receipt of the path report I noted the pathologist was the same one who had failed to accurately diagnose my original melanoma back in 2003!  What tangled webs we weave!!!  The proteins (CA19-9, CA125, and CEA) my oncologist follows via blood draws in an attempt to determine any progression of my GCC were all normal.  I will have a recheck with her in March after a colonoscopy and CT's of chest, abdomen and pelvis.  Maybe I can get all those done in one day!!!

So, there you go.  A day (weeks, months, years - if we're lucky) in the life of a cancer patient.

Today the crystal clear blue sky is a perfect canvas for the red and gold trees.  Temperatures have warmed a bit.  Think I'll go for a run.  Me and my lily should be up to it!

Just keeping it real.  Thankful for my days and more importantly, for each of you.  Love, les.

Saturday, November 16, 2019

Everything cures melanoma, installment #11!!!!


It's been a while since my last update on these "crazy" items, extracts, etc. that can kill/cure melanoma!!!  Yep, I've been cataloging all these CURES for years:  Everything Cures Melanoma - Installment #10  I see all sorts of strange reports like these all the time, but the last two additions pushed me over the edge. So, here's my latest collection:

Anti-tumor and anti-metastasis activities of honey bee larvae powder by suppressing the expression of EZH2. Kageyama, Li, Sun, et al.  Biomed Pharmacother. 2018 Jun 12.

Honey bee larvae products have been widely used as traditional daily supplements and complementary medicine for health promotion. However, there is little scientific evidence about their bioactivities. This study was designed to examine the anti-tumor and anti-metastasis effects of honey bee larvae powder (HLP) and explore the underlying mechanism. A subcutaneous transplantation model (murine breast cancer cell 4T1-LUC) and lung metastasis model (murine melanoma cell B16-F10) were established to evaluate the anti-tumor and anti-metastasis effects of HLP. Honey bee larvae powder extract (HLE) was obtained by 70% ethanol extraction, and its chemical composition was determined according to physiochemical methods. Cell Counting Kit-8 assay was performed to test the cytotoxicity of HLE, and qRT-PCR assays were conducted to examine the mRNA levels of tumor marker EZH2 in HLE-treated tumor cells. In vivo xenograft tumor assays in BALB/c mice revealed dose-dependent suppression of tumor growth and lung metastasis showing an inhibition rate of 37.5% and 70.4% at 6 g/kg HLP-administered group with no toxicity to the animals. In vitro studies indicated that HLE showed no cytotoxicity to cancer cells at doses up to 1000 μg/mL, however, it significantly decreased EZH2 mRNA levels in HLE (1000 μg/mL)-treated B10-F10 cells (28.49%) and 4T1-LUC cells (26.75%). Further studies to elucidate the mechanisms involved and to isolate the active components of honey bee larva may provide more valuable information for its development and application in cancer treatment.
6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells. Venturelli, Niessner, Sinnberg, et al.Cell Physiol Biochem. 2018 Nov 20.

Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs).  We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells.
In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells.  The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.


Botanical Therapeutics: Phytochemical Screening and Biological Assessment of Chamomile, Parsley and Celery Extracts against A375 Human Melanoma and Dendritic Cells. Danciu, Zupko, Bor, et al. Int J Mol Sci. 2018 Nov 16.

Chamomile, parsley, and celery represent major botanical sources of apigenin, a well-known flavone with chemopreventive properties. The aim of this study was to assess the phytochemical composition, antioxidant, and anti-inflammatory potential of methanol extracts obtained from chamomile, parsley, and celery collected from Romania, as well as the biological activity against A375 human melanoma and human dendritic cells. Results have shown that all three extracts are rich in polyphenolic compounds and flavonoids, and they generate a radical scavenger capacity, iron chelation potential, as well as lipoxygenase inhibition capacity. Chamomile and celery extracts present weak antiproliferative and pro-apoptotic properties in the set experimental conditions, while parsley extract draws out significant pro-apoptotic potential against A375 human melanoma cells. Parsley and chamomile extracts affected the fibroblast-like morphology of the screened tumor cell line. On the other hand, chamomile and celery extracts abrogated the expansion of LPS-activated dendritic cells, while the metabolic activity was attenuated by stimulation with celery extract; chamomile and parsley extracts had no effect upon this parameter. Chamomile and parsley extracts incubation with naive dendritic cells did not trigger cytokine secretion (TNF-alpha, IL-6, IL-10), but celery extract stimulation significantly reduced the anti-inflammatory, cytokine IL-10.

Anti-cancer effect of dung beetle gludosaminoglucans on melanoma.  Ahn, Kim, Kim, et al. BMC Cancer. 2019 Jan 5.

Dung beetle glycosaminoglycan is known to possess anti-aging activities. However, its anti-cancer mechanisms are not fully elucidated yet. The objective of this study was to evaluate the anti-cancer effect of insect-derived polymer dung beetle glycosaminoglycan (GAG) after intraperitoneally injecting it to melanoma mice induced by B16F10 cells.  To determine molecular mechanism involved in the anti-cancer effect of dung beetle GAG, its origin N-glycan under 3KD Dalton was assayed for melanoma cell cytotoxicity. Quantitative comparisons of adhesive molecule on extracellular matrix and activities of tissue inhibitor of metalloprotease 2 (TIMP-2) were also investigated. In vivo anti-cancer effect of dung beetle GAG on solid tumor size, survival time and gene-expression profiles was also assayed using B10F10 melanoma mice model. Mice with induced melanoma were then treated with Catharsius molossus (dung beetle) GAG (CaG) at 5 mg/kg for 8 weeks to investigate its anti-cancer effects compared to bumblebee (Bombus ignitus) queen glycosaminoglycan (IQG) and Huechys sanguinea glycosaminoglycan (HEG).  These N-glycans derived from these GAG were composed of many linear heparinoid polysaccharides, polymers with hexose and N-acetylhexose. Adminstration with these GAGs increased survival time and decreased melanoma sizes in mice, in accordance with their inhibitory effects on cell growth ratio of melanoma B16F10. In addition, treatment with N-glycans derived from theses glycosaminoglycan increased activities of TIMP-2 in HMVEC cells pretreated with TNF-alpha and in melanoma cells, suggesting that they had anti-inflammatory and anticancer activities. In DNA microarray results, compared to control, CaG treated mouse group showed upregulation of 192 genes including collagen,typeI,alpha1 (Col1a1), consistent with the highly increased in vitro extracellular matrix (ECM) adhesion on collagen 1 and up-regulation of heparanase (Hpse). After treatment with CaG, a total of 152 genes were down-regulated, including nuclear RNA export factor (Nxf3) and hyaluronan proteoglycan link protein1.  Glycosaminoglycan, CaG can strengthen ECM by increasing activity of TIMP-2 and adhesion activity on collagen known to inhibit changes of ECM, leading to tumor cell invasion and progression.

Inositol hexaphosphate plus inositol induced complete remission in stage IV melanoma: a case report. Khurana, Baldeo, Joseph. Melanoma Res. 2019 Jan 5.

Inositol hexaphosphate (IP6) also called phytic acid is a polyphosphorylated carbohydrate naturally found in cereals, nuts, grains, and high-fiber-containing foods. It has been shown to inhibit the growth of many different tumor cell lines both in vitro and in vivo like colon, pancreas, liver, prostate, and even melanoma. Vitamin B inositol is a precursor of IP6 and another naturally occurring compound with anticancer properties. We present a case report of a patient with metastatic melanoma who declined traditional therapy and opted to try over the counter supplement IP6+inositol instead. To our surprise, the patient achieved a complete remission and remains in remission 3 years later. On the basis of this case and previous preclinical studies, we believe further research is indicated in exploring antiproliferative and potential immune stimulating effects of IP6+inositol in patients with metastatic melanoma.

Anti-melanization effects and inhibitory kinetics of tyrosinase of bird's nest fern (Asplenium australasicum) frond extracts on melanoma and human skin. Zend and Lai. J Biosci Bioeng. 2019 Jan 10.

Some bioactive properties of p-coumaric acid and fucose-rich polysaccharide in skin health have been studied, including melanogenesis inhibition of the phenolic acid and growth inhibitory effects of the polysaccharide on melanoma. The dermatological benefits of bird's nest fern extracts (BNFE), containing both substantial fucose-rich polysaccharide and p-coumaric acid, like promoting collagen production and growth of fibroblast cell and further improving the elasticity and dryness of human skins have been demonstrated in our previous study. Besides, the anti-melanization effects of various BNFE on B16-F10 melanoma and human skin were first studied here. The promising extracts revealed that the main phenolic acid, p-coumaric acid, in BNFE resulted in suppression against tyrosinase activity from melanogenesis. The inhibitory kinetics on the diphenolase activity indicated that AE40 was a noncompetitive inhibitor of mushroom tyrosinase. On the other hand, the fucose-rich mucilage of BNFE showed pronouncedly suppressing effect on B16-F10 melanoma viability. Clinical trial was performed by recruiting 46 female volunteers and the results indicated that the lotions with 1% of BNFE was non-irritant and reduced effectively the pigmentation on human skin after 7-14 days of continuous application. It was suggested that the fucose-rich mucilage and p-coumaric acid in BNFE may have potential for nutricosmetics and phytotherapy applications as a natural hypopigmenting agent.

Uncovering the anti-proliferation mechanism and bioactive compounds in red kidney bean coat against B16-F10 melanoma cells by metabolomics and network pharmacology analysis.  Nie, Huang, Wu, et al. Food Funct. 2019 Jan 30.

In this study, coat (RKBC) and kernel (RKBK) extracts of red kidney bean were prepared, and their chemical compositions and potential anti-cancer activity against B16-F10 cells were evaluated. Then the anti-proliferation mechanisms of the active RKBC extract were investigated by flow cytometry analysis, cellular metabolomics, network pharmacology and western blotting. The RKBC extract inhibited B16-F10 cell proliferation and migration in a dose-dependent manner. Further analysis showed that RKBC induced G1 and G2/M phase arrest, and triggered apoptosis and vacuolization. Mechanistically, RKBC significantly increased the cellular content of cGMP, decreased the levels of AKT1/2/3 and cleaved-MMP2, and up-regulated the expression of Bcl-xl. Besides, network pharmacology revealed that RKBC potentially influenced the cell cycle via the regulation of CDK2 and CDK4. Finally, quercetin might serve as the major active component in the RKBC extract. In conclusion, our study showed the potential of the RKBC extract for the prevention or treatment of melanoma.

Effect of Sucrier Banana Peel Extracts on Inhibition of Melanogenesis through the ERK Signaling Pathway.  Phacharapiyangkul, Thirapanmethee, Sa-Ngiamsuntorn, et al.  Int J Med Sci. 2019 Apr 25.

Hyperpigmentation is a type of pigmentary disorder induced by overexpression of melanin content activated severe esthetic problems as melasma, freckle, ephelides, lentigo and other forms on human skin. Several whitening agents have restricted use because of their side effects or stability such as kojic acid, ascorbic acid and hydroquinone can act as cytotoxic substance which associated to dermatitis and skin cancer. To find for the safe substance, this study aimed to find for the ability of several components in Sucrier banana peel (SBP) extracts to inhibit melanogenesis process through p38 signaling pathway in B16F10 mouse melanoma cells. Tyrosinase activity and the cellular melanin content were dose dependent manner decreasing after SBP treatment. Furthermore, SBP decreased the expression of melanogenesis relate protein as microphthalmia-associated transcription factor (MITF) and tyrosinase protein after 24 hours incubation with α-melanocyte stimulating hormones (MSH) stimulating. The findings demonstrated that SBP contained an effective agent for hyperpigmentation inhibitor through p38 signaling pathways without any effect to ERK pathway, and subsequent down-regulate MITF expression and tyrosinase enzyme family production.

Bullfrog oil (Rana catesbeiana Shaw) induces apoptosis, in A2058 human melanoma cells by mitochondrial dysfunction triggered by oxidative stress.  Amaral-Machado, Oliveira, Alencar, et al. Biomed Pharmacother. 2019 Jun 13 

Bullfrog oil, an animal oil extracted from the adipose tissue of Rana catesbeiana Shaw, showed promising cytotoxic activity against melanoma cells and, therefore, has the potential to become a pharmaceutical active compound. However, there is a lack of information regarding the pathways involved in its pharmacological activity. Thus, the aim of this study was to investigate and elucidate the cytotoxic effect of this oil against A2058 human melanoma cells. The cytotoxic potential was evaluated by the MTT assay, the cell cycle analysis and the cell death assay. In addition, the apoptotic potential was investigated by (i) the DNA fragmentation using propidium iodide staining analysis, (ii) the evaluation of mitochondrial membrane potential and (iii) the determination of intracellular Reactive Oxygen Species (ROS) level. The results showed that the bullfrog oil was able to promote a time-dependent cytotoxic effect, decreasing cell viability to 38% after 72 h of treatment without affecting the cell cycle. Additionally, the bullfrog oil induced the apoptosis in A2058 cells, increasing up to 50 ± 13% of the intracellular ROS level, maintaining the DNA integrity and promoting an approximate decrease of 35 ± 5% in the mitochondrial membrane potential. It can be concluded that the in vitro cytotoxic effect of the bullfrog oil in A2058 human melanoma cells is mediated by oxidative stress that induces mitochondrial dysfunction, triggering the apoptosis. These unprecedented results highlight the pharmacological potential of bullfrog oil and provide important information to support studies on the development of new pharmaceutical products for complementary and alternative treatments for melanoma.

Citrus unshiu peel suppress the metastatic potential of murine melanoma B16F10 cells in vitro and in vivo.  Choi, Lee, Hwang, et al.  Phytother Res. 2019 Sep 4. 

The peel of Citrus unshiu Marcow. fruits (CU) has long been used as a traditional medicine that has therapeutic effects against pathogenic diseases, including asthma, vomiting, dyspepsia, blood circulation disorders, and various types of cancer. In this study, we investigated the effect of CU peel on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells, and in B16F10 cells inoculated-C57BL/6 mice. Our results show that ethanol extracts of CU (EECU) inhibited cell growth and increased the apoptotic cells in B16F10 cells. EECU also stimulated the induction of mitochondria-mediated intrinsic pathway, with reduced mitochondrial membrane potential and increased generation of intracellular reactive oxygen species. Furthermore, EECU suppressed the migration, invasion, and colony formation of B16F10 cells. In addition, the oral administration of EECU reduced serum lactate dehydrogenase activity without weight loss, hepatotoxicity, nor nephrotoxicity in B16F10 cell-inoculated mice. Moreover, EECU markedly suppressed lung hypertrophy, the number and expression of metastatic tumor nodules, and the expression of inflammatory tumor necrosis factor-alpha in lung tissue. In conclusion, our findings suggest that the inhibitory effect of EECU on the metastasis of melanoma indicates that it may be regarded as a potential therapeutic herbal drug for melanoma.

Kunitz type protease inhibitor from the canine tapeworm as a potential therapeutic for melanoma.  Ranasinghe, Rivera, Boyle, et al. Sci Rep. 2019 Nov 7. 

Modulating the tumor microenvironment to promote an effective immune response is critical in managing any type of tumor. Melanoma is an aggressive skin cancer and the incidence rate is increasing worldwide. Potent protease inhibitors have recently been extensively researched as potential therapeutic agents against various cancers. EgKI-1 is a potent Kunitz type protease inhibitor identified from the canine tapeworm Echinococcus granulosus that has shown anti-cancer activities in vivo. In this study we show that EgKI-1 significantly reduced the growth of melanoma in the B16-F0 mouse model and was not toxic to normal surrounding tissue. Moreover, EgKI-1 treatment significantly reduced survivin expression levels and increased the CD8+ T cell population in draining axillary lymph nodes. Therefore, EgKI-1 potentially reduces tumor growth by inducing apoptosis and modulating the tumor microenvironment, and has potential for development as an intra-lesional treatment for melanoma.

Cyclic analogues of horseshoe crab peptide tachyplesin I with anticancer and cell penetrating properties.  Vernen, Craik, Lawrence, et al.  ACS Chem Biol.  2019 Nov 12.

Tachyplesin-I (TI) is a host defense peptide from the horseshoe crab Tachypleus tridentatus that has outstanding potential as an anticancer therapeutic lead. Backbone cyclized TI (cTI) has similar anticancer properties to TI, but has higher stability and lower hemolytic activity. We designed and synthesized cTI analogues to further improve anticancer potential and investigated structure-activity relationships based on peptide-membrane interactions, cellular uptake and anticancer activity. The membrane-binding affinity and cytotoxic activity of cTI were found to be highly dependent on peptide hydrophobicity and charge. We describe two analogues with increased selectivity toward melanoma cells and one analogue with ability to enter cells with high efficacy and low toxicity. Overall, the structure-activity relationship study shows that cTI can be developed as a membrane-active antimelanoma lead, or be employed as a cell penetrating peptide scaffold that can target and enter cells without damaging their integrity.

Honey bee babies, celery, parsley, fern, bull frog oil, banana peel, bean skin, dog worm, horseshoe crab goo cocktail with a twist of unshiu along with a beer chaser and dung beetle poo poo platter, anyone?  Hey, if they can make it work in real live ratties, I'll sign up!!!

Have a great weekend guys!   - c

Thursday, November 14, 2019

Do pesticides, herbicides or hormonal replacement contribute to melanoma?


The short answer?  No.  Yes.  No.  Here's the deal:

The association between pesticide use and cutaneous melanoma: a systematic review and meta-analysis. Stanganelli, De Felici, Madnel, et al.  J Eur Acad Dermatol Venereol. 2019 Sep 21.

The incidence of cutaneous melanoma (CM), the deadliest form of skin cancer, has gradually increased in the last decades among populations of European origin. Epidemiological studies suggested that farmers and agricultural workers are at an increased risk of CM because they were exposed to pesticides. However, little is known about the relationship between pesticides and CM.  To investigate the association between exposure to pesticides and CM by systematically reviewing the literature. Secondary aim was to determine the categories of pesticides mainly involved in CM development.

A systematic review of the literature was performed up to September 2018 using Medline, Embase and Web of Science. Studies assessing CM risk in licensed pesticide applicators were considered. Priory criteria were established to select independent studies and risk estimates; random effect models, taking into account heterogeneity, were applied. A pooled risk estimate for CM was calculated for the use of each type of pesticide and type of exposure. Between-study and estimates heterogeneity was assessed and publication bias investigated.

A total of 9 studies (2 case-controls and 7 cohorts) comprising 184389 unique subjects were included. The summary relative risks for the categories "herbicides - ever exposure", "insecticides - ever exposure", "any pesticide - ever exposure" and "any pesticide - high exposure" resulted 1.85, 1.57, 1.31 and 2.17, respectively. Herbicides and insecticides had no between-study heterogeneity, while a significant heterogeneity was detected for the high exposure to any pesticide. No indication for publication bias was found.

Individuals exposed to herbicides are at an increased risk of CM. Future properly designed observational studies are required to confirm this finding.

So, basically - YES!!!  The pesticide issue is a little unclear, but folks exposed to herbicides (like Round Up, etc.) ARE at increased risk for cutaneous melanoma.

Now this:

Premenopausal Use of Progestogens and Cutaneous Melanoma Risk: A French Prospective Cohort Study.  Cervenka, Rahmoun, Mahamat-Saleh et al.  Am J Epidemiol. 2019 Oct 29. 

The influence of sex hormones on melanoma risk has been suggested, but the influence of premenopausal use of progestogens on this cancer has never been investigated. E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) is a prospective cohort of 98,995 French women aged 40-65 years at inclusion. We used Cox models adjusted for age and melanoma risk factors. Over 1992-2008, 540 melanoma cases were ascertained among 79,558 women. We found a modest association between self-reported progestogen use and melanoma risk  which was reduced after adjustment for melanoma risk factors. There was no heterogeneity across types of progestogens, and use of multiple progestogens was positively associated with melanoma risk. Among users, we found no relation with duration of progestogen use, age at start and last use, and time since first and last use. Although our results did not show evidence of a confounding effect of sun exposure, progestogen users had lower levels of residential sun exposure and were more likely to report sunscreen use, suggesting specific sun exposure profiles in users. Our findings do not support a strong influence of progestogens on melanoma risk. Further research is needed to confirm these results.

Exogenous Hormone Use and Cutaneous Melanoma Risk in Women: The European Prospective Investigation Into Cancer and Nutrition.  Cervenka, Al Rahmoun, Mahamat-Saleh, et al. Int J Cancer. 2019 Sep 10. 

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires.  Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, where of 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk, with no detected heterogeneity across countries. This risk increased linearly with duration of use. Among postmenopausal women, ever use of MHT was associated with a non-significant increase in melanoma risk overall, which was heterogeneous across countries. Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.

So, basically, though some self-reported answers on questionnaires demonstrated vague associations between oral contraceptive use and melanoma, overall, there was no significant increased risk for the development of melanoma and postmenopausal hormone replacement. 

Then, there's this, added 12/7/2019:

Hormone replacement therapy and the risk of melanoma in post-menopausal women.  Hicks, Kristensen, Pedersen, et al.  Hum Reprod.  2019 Dec 5

Is hormone replacement therapy (HRT) associated with an increased risk of melanoma skin cancer or prognostic outcomes amongst post-menopausal women?  Whilst we found evidence of an association with melanoma risk, the lack of dose-response and associations observed with recent use, localised disease and intravaginal oestrogens suggests this is a non-causal association.  Evidence on HRT and melanoma risk remains inconclusive, with studies providing conflicting results. Furthermore, evidence on melanoma survival is sparse, with only one previous study reporting protective associations with HRT use, likely attributable to immortal time bias.

We conducted a nation-wide population-based case-control study and a retrospective cohort study utilising the Danish healthcare registries. Case-control analyses included 8279 women aged 45-85 with a first-ever diagnosis of malignant melanoma between 2000 and 2015, matched by age and calendar time to 165 580 population controls. A cohort of 6575 patients with a diagnosis of primary malignant melanoma between 2000 and 2013 and followed through 2015 was examined to determine if HRT use had an impact on melanoma survival outcomes.

Based on prescriptions dispensed since 1995, ever-use of HRT was defined as having filled at least one prescription for HRT prior to the index date. In total, 2629 cases (31.8%) and 47 026 controls (28.4%) used HRT.

High use of HRT was associated with an OR of 1.21  for melanoma risk, with no evidence of a dose-response pattern. Results were most pronounced amongst recent high users, for localised disease and for intravaginal oestrogen therapy. Compared with non-use, there was no evidence of an association for secondary melanoma for post-diagnostic new-use or continuous HRT use. Similar associations were observed for all-cause mortality.

Despite the large sample size and the use of robust population-based registries with almost complete coverage, we lacked information on some important confounders including sun exposure.

Whilst we cannot rule out an association between HRT use and melanoma risk, the associations observed are also compatible with increased healthcare utilisation and thus increased melanoma detection amongst HRT users. No association between HRT use and melanoma survival outcomes was observed. This should provide some reassurance to patients and clinicians, particularly concerning the use of HRT in patients with a history of melanoma.

There is obviously much we do not understand about melanoma period.  We certainly lack a clear understanding regarding the implications of being female and the role pregnancy plays in melanoma:  Women and melanoma risk  These studies add to a start.  The more you know. - c

Tuesday, November 12, 2019

Leptomeningeal melanoma and brain mets - a relationship?


As I've said many times, "Melanoma sucks great big green stinky hairy wizard balls!!!" (An expansion of the sentiment first expressed by dear Ruthie!) BUT...leptomeningeal disease sucks even more.  Here is an article posted earlier this year with additional links within:  Leptomeningeal disease and melanoma Now, there's this:

High-resolution MRI demonstrates that more than ninety percent of small intracranial melanoma metastases develop in close relationship to the leptomeninges.  Lasocki, Khoo, Lau, et al.  Neuro Oncol. 2019 Sep 9. 

Despite classic teaching that intracranial metastases typically arise at the grey-white matter junction, small intracranial melanoma metastases (IMM) are frequently observed at the interface between the cortex and leptomeninges (i.e. "corticomeningeal interface"), suggesting possible leptomeningeal origin.

MRI brain examinations of melanoma patients treated at a specialist oncology centre from July 2015 to June 2017 were retrospectively reviewed. The MRI examination on which IMM were first visible was identified, utilising 1mm volumetric post-contrast imaging prior to local therapy. Individual metastases (up to 10 per patient) were assessed for the presence of leptomeningeal contact, as well as their number, size and morphology. Lesions greater than/= to 10mm in long axis were excluded, in order to examine early metastatic disease.

75 patients had evidence of IMM. 15 patients had only lesion(s) measuring greater than/= to10mm at diagnosis, leaving 60 patients. 192 individual metastases were examined (median 2 per patient, interquartile range 1-4), 174 (91%) demonstrating leptomeningeal contact. A nodular morphology was observed in 154 of 192 (82%), 32 (17%) were ovoid but elongated along the cortex, and 6 (3%) were linear. Only three patients (5%) also exhibited a 'classic' linear leptomeningeal disease appearance.

Most IMM measuring between 2 and 9mm in diameter are corticomeningeal nodules. These data raise the hypothesis that deeper parenchymal extension of IMM occurs secondarily. If the leptomeninges provide a preferential site for establishment of IMM, further investigation of the underlying biology of this phenomenon may provide opportunities for novel therapeutic strategies for patients with IMM.

For what it's worth.  The more we can learn about how to deal with this most unfortunate of evolutions in melanoma, the better.  And as always, still holding dear Rob and his precious Adriana in my heart. ~ c