Monday, April 30, 2018

Across Eight Aprils! Can you believe it????

Eight years ago today, I was in surgery having the right upper lobe of my lung removed three days after having radiation to my brain.  Such a crazy time.  Such a juxtaposition between what nature had wrought within me and the beauty she shares so abundantly every April here on the mountain.  When you pair that with my love for, Across Five Aprils, the story of a family during the American Civil War, so beautifully written by Irene Hunt, I find April particularly poignant and lovely.

My Aprils....

2017 ~ Across Seven Aprils
2016 ~ Spring Fling - Across Six Aprils
2015 ~ Across Five Aprils
2014 ~ Across Four Aprils....A melanoma perspective...
2013 ~ This year I didn't follow my usual look back...but wrote this instead:  UBUNTU - (oo-bun-too). I am, because we are.
2012 ~ Across Two Aprils
2011 ~ I fear I was too deep in the soup of my trial to look about me as much as I might have.  But on April 1, there was this:  A poem of comfort and sound advice for you... While on April 24, I reported on my most recent trip to Tampa:  More pie....well 3/4's at least!!!!
2010 ~ On this day, 8 years ago, there were these posts from my sweet girl:
Today is...a big day
Update on the surgery:
The Worst Part is Over
While on April 27, 2010, after application of my halo (Probably the only one I'll ever wear!!  HA!) while awaiting SRS...I wrote:  Brain Squeezers  Later that evening, there was this:  Home Again
I still like the essay written just before starting this blog:  Life

Yesterday, April did herself proud!  We had BIRD day!!!

I reveled in being present, listening to their busy twitter as I made a small rock wall around a flower bed, moved irises to new beds (I know!!!  I should have done that in the fall...but, it will all work out!!!), dug up some plants to share with a friend who has a new home, moved a few bluets from one creek to another, returned errant mint to its proper bed, and generally had a grand time playing in the dirt while enjoying nature's beauty.

We rounded out our evening at a vigil, sponsored by Chattanooga Students Leading Change who have been amazing in organizing rallies and our local  March for Our Lives, in honor of those who lost their lives to gun violence at a Waffle House in Nashville.

So, for just a moment ~ today ~ I look back.  I look back with great thanks and appreciation for those who cared for me and mine on that day 8 years ago and ever so many days since.  I look back on the beauty of yesterday and all the other Aprils I have been so generously blessed to enjoy. 

Most days, I look forward.  Today, I took care of my kiddos.  Helped a friend plant special flowers in her yard to commemorate a time of beauty and the pain of loss.  Each day I seek to contribute my bit, to strangers and dear ones alike, such that my presence on this spinning ball may be in some small way of value, if only for our brief moment.  But most of all, on days like today, I look to my love ~ B.  You have made, and continue to make, my Aprils possible.  With much love to you all ~ les

Sunday, April 29, 2018

Baseline tumor size and OS in melanoma patients treated with Keytruda

Not exactly news here, as we have long known that immunotherapy tends to be most effective in those with lower tumor burden...but still...

Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients With Melanoma Treated With Pembrolizumab. Joseph, Elassaiss-Schaap, Kefford, et al.  Clin Cancer Res. 2018 Apr 23.

To assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827).

BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations.

Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1-89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites). In univariate analyses, BTS below the median was associated with higher ORR (44% vs 23%) and improved OS. In multivariate analyses, BTS below the median remained an independent prognostic marker of OS but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1-positive tumors were independently associated with higher ORR and longer OS.

BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma.

Out of 655 patients these peeps treated with pembrolizumab (Keytruda), 583 of them had baseline measurable disease for which the BTS [baseline tumor size] was determined, a figure the researchers quantified by "adding the sum of the longest dimensions of all measurable baseline target lesions".  In those patients, when they looked at lower than average BTS alone, it was associated with higher overall response rates (44% vs 23%) and improved overall survival.  However, when other factor were included in the analysis, smaller BTS was still associated with improved overall survival, but not with overall response rate.

What tangled webs melanoma weaves.  Keep looking, researchers ~ keep looking.  We need to learn ALL the factors that facilitate a to attain an effective response for the melanoma peeps who don't happen to have them!!! - c

Friday, April 27, 2018

Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

I have been yelling about simple blood tests that give good information to melanoma patients for YEARS!!  I think my first post was in 2015.  Here is some of what I said and a link to that February post (with a zillion links within): "Yep.  It's me again, Margaret.  I'm still yelling about simple blood draws that can provide critical information related to the diagnosis of, feasibility of treatment for, response to treatment, and prognosis generally in melanoma patients!"  Simple blood tests that tell us how melanoma patients are responding to therapy and identify their disease in the first place....AGAIN!!!!

On a rather disheartening note ~ At a recent symposium for melanoma patients in Atlanta, facilitated by Northside and MRF, with "melanoma specialists" from Emory and Northside Hospital, I asked the panel what they were utilizing in regard to blood assays in diagnosing, monitoring, and implementing treatment for their patients.  They looked at me like deer in the headlights!!  One blathered on about it only being useful in regard to diagnosing BRAF status, not being "validated", blah, blah, blah. Seriously???  I call - B.S.!!!!  Some of these tests are not particularly special, like the NLR (neutrophil-to-lymphocyte ratio) for instance.  This is easily attained and computed via a simple CBC (complete blood count) drawn at every lab in this country a zillion times a day.  AND...we have looked at this data long enough to know that it is true!!!

Okay.  I'll quit yelling.  Now, there's this ~

Neutrophil-to-lymphocyte Ratio (NLR) as a predictor for recurrence in patients with stage III melanoma. Ma, Kuzman, Ray, et al.  Sci Rep. 2018 Mar 6. 

Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan-Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio greater than or = to 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma.

Liquid biopsy to monitor melanoma patients. Gaiser, von Bunoff, Gebhardt, Utikal. J Dtsch Dermatol Ges. 2018 Mar 7.

During the last six years, several innovative, systemic therapies for the treatment of metastatic malignant melanoma (MM) have emerged. Conventional chemotherapy has been superseded by novel first-line therapies, including systemic immunotherapies (anti-CTLA4 and anti-PD1; authorization of anti-PDL1 is anticipated) and therapies targeting specific mutations (BRAF, NRAS, and c-KIT). Thus, treating physicians are confronted with new challenges, such as stratifying patients for appropriate treatments and monitoring long-term responders for progression. Consequently, reliable methods for monitoring disease progression or treatment resistance are necessary. Localized and advanced cancers may generate circulating tumor cells and circulating tumor DNA (ctDNA) that can be detected and quantified from peripheral blood samples (liquid biopsy). For melanoma patients, liquid biopsy results may be useful as novel predictive biomarkers to guide therapeutic decisions, particularly in the context of mutation-based targeted therapies. The challenges of using liquid biopsy include strict criteria for the phenotypic nature of circulating MM cells or their fragments and the instability of ctDNA in blood. The limitations of liquid biopsy in routine diagnostic testing are discussed in this review.

Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy. Haselmann, Gebhardt, Brechtel, et al.Clin Chem. 2018 Feb 26. 

The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy.

In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy.

Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of BRAF mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase.

Blood-based testing compares favorably with standard-of-care tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.

Early evolution of BRAFV600 status in the blood of melanoma patients correlates with clinical outcome and identifies patients refractory to therapy. Gonzalez-Cao, Mayo de Las Casas, Jordana, et al. Melanoma Res. 2018 Feb 23.

Serial analysis of BRAF mutations in circulating-free DNA (cfDNA) could be of prognostic value in melanoma patients. We collected blood samples from 63 advanced BRAFV600E/K melanoma patients and determined BRAFV600E/K status in cfDNA using a quantitative 5'-nuclease PCR-based assay. Levels of BRAF mutation in pre-cfDNAs were associated significantly with tumour burden, progression-free survival and overall survival. Changes in BRAF status in cfDNA after initiation of treatment (early-cfDNA) had a significant correlation with outcome. In patients with persistent BRAF mutations (n=12), progression-free survival and overall survival were 3.5 months and 5.3 months compared with 16.6 months and 21.9 months in patients with BRAF negativization (n=16), and 15.1 months and NR in patients who maintained their initial negative status (n=12). The median duration of response in patients with radiological response, but persistence of BRAFV600 in early-cfDNA (n=5) was 4 months. Our study indicates that serial BRAF testing in the blood of advanced melanoma identifies patients refractory to therapy.

And these are just a handful of reports!!!   They don't even address other blood assays of which we know a great deal, including CD4+ T cells, microRNA, gene expressions, and circulating melanoma cells. I am just one little woman sitting in Chattanooga, TN!!  With melanoma.  Without a salary for this effort.  But with a computer and basic common sense!  You "melanoma experts" need to do better!!!  Get with the program.  These tests are available, have important implications for melanoma patients, and we need YOU to get on board and start incorporating them in your management of melanoma patients NOW!  Some folks don't have the luxury of waiting around for you to get off your hands!  Liquid blood assays WILL be utilized to diagnosis, monitor and evaluate melanoma patients for appropriate treatment choices!!  They are not likely to be the sole, end-all-be-all answer to all things melanoma, but will certainly be an essential component of basic care.  We need you peeps to make it so...SOONER...rather than later.  C'mon, man!!!!  (It's good that ratties have long tails!  We need them!) - c

Wednesday, April 25, 2018

Sew Chaotically! - New work-out top!!

You might remember:  Sew Chaotically! - Exercise tops for Roo - M7610

They were a hit, but she had requested that they be a bit longer and I wanted to add this little back detail with inspo from an Athleta top!!!  With some purple and black athletic mesh from Mood, I was ret tah go!!!!
I scooped out the neck by about an inch as I had done previously. Lengthened the entire top by about 2 inches and created a curved hem.  I serged the neckline, arm holes, and bottom after attaching one respective edge, but before attaching the final side or shoulder seam.  Finished the garment.  Folded all serged edges under, and top stitched them down with a small zig-zag.
For the straps in the back I cut a strip about 1.5 inches wide.  Folded both edges to the center, then folded that in half, with both raw edges now within the band, and top stitched it together with the same small zig zag.
She loved it!!!  She is a purple durple, after all!!
I think she rocked it!!! Sew chaotically!!! - les

Sunday, April 22, 2018

Odds and Ends ~ Melanoma in children and cancer trial access for people of color

Even the briefest look at the data makes it abundantly clear that no group is immune to melanoma.  While it does occur most in older, fair complected folks, it is still pretty indiscriminate.  It can affect the young and plenty of brown skinned peeps.   I wrote this in 2013:  Melanoma...a disease without discrimination!!!

Sadly, while melanoma (and other cancers) are equal opportunity offenders, people are not so egalitarian!!! Though this article is a bit old, it still tells an inadequately corrected truth, NY Times, December 2016, In Cancer Trials, Minorities Face Extra Hurdles.  The author notes that despite a 1993 law that requires research funded by the NIH to include sufficient numbers of women and minorities to determine whether the drugs tested would cause different outcomes in those groups, in 2015, minority enrollment in NIH clinical research was only 28% generally, and only 40% in Phase III trials.  The usual players in discrimination are involved here as well:  poverty, lower levels of education, and the fact that communities that fail to have a reasonable grocery store are unlikely to be the location for a major medical facility, all of which combine to diminish access to clinical trials.  And as if that isn't enough, the double whammy those issues create is a population at greater risk for poorly controlled concomitant disease processes (like diabetes) that can make them ineligible for trial participation if they even manage to get to the application process.

C'mon man!!!  We can do better.  We must do better!  People are people no matter how small!!!! And to that point....there's this ~, Pediatric News: Melanoma in young children may be biologically distinct from that in teens. April 2018.

Here, the author notes:  "Pediatric melanomas appear to be more progressive in adolescents than in young children, based on data from a retrospective study of 32 cases.
Few young children with melanoma die, despite a greater likelihood of thicker tumors, lymph node metastasis, and later diagnosis, which suggests that melanoma in young children may be biologically distinct from melanoma in adolescents, wrote Diana W. Bartenstein, of Harvard University Medical School, Boston, and her colleagues.
In a study published in Pediatric Dermatology, the researchers reviewed data from 12 children younger than 11 years and 20 adolescents aged 11-19 years diagnosed with melanoma who were seen at a single center between Jan. 1, 1995, and Dec. 21, 2016. The children ranged in age from 3.3 to 19.5 years.
Overall, significantly more children than adolescents had spitzoid melanoma (50% vs. 10%). In addition, children were more likely than adolescents to present with stage 3 or 4 cancer (58% vs. 25%) and with Clark level IV and V tumors (42% vs. 35%), although these differences were not significant. The median Breslow thickness of lesions was greater in children than in adolescents (3.5 mm vs. 1.5 mm) as was the median mitotic index and children were more likely than adolescents to have neural invasion, but these differences were not significant either.
During the study period of more than 20 years, none of the children younger than 11 years died, compared with four deaths in adolescents, a statistically significant difference. The follow-up for surviving individuals ranged from 9-37 months with a median of 44 months.  The study findings were limited by several factors including the small sample size and difficulty in assessing spitzoid tumors, the researchers noted.  However, 'these results support the hypothesis that melanoma in young children may be biologically distinct from melanoma in adults,' they said. 'Alternatively, melanoma sub-type may drive survival differences between children and adolescents.'”
So...all that is a bit...depressing, overwhelming, disheartening???  Well, yes.  BUT!!!  We CAN do better!  For some time I have felt that melanoma, as we currently know it, will be found to be different diseases or at least notably different in ways we will eventually understand.  I suspect that uveal, mucosal, and possibly pediatric/adolescent melanoma will be found to be quite different in some important ways from cutaneous melanoma.  Unfortunately, we are most certainly behind the curve here since for years and years, clinical trials have failed to allow participation of those with CNS involvement, ocular/uveal, or mucosal melanoma.  Most trials also require participants to be over 18 years of age as well, though there are separate studies available for children in some settings.  These points have conspired to create two circumstances:
1.  A set of untreated melanoma peeps in desperate need of care.
2.  A tremendous information gap about how these patients will respond to treatment.

In regard to medical care for minorities in this country, the data is sadly clear.  If you have brown skin in America you are less likely to attain the care you need, whether we are talking about care generally or cancer trials in particular.  To my credit, after a very brief sit-down in Dr. Weber's office at Moffitt Cancer Center, in Tampa ~ after a very long (months and months!!!) research process by a trained medical professional to even learn of the trial option in the first place, an incredibly long drive, through a snow storm, on Christmas day, that I was lucky to have the transportation option and money sufficient to indulge in what, at that moment, was a merely investigative journey (not to mention the financial and physical wherewithal to participate in the trial for over 2 1/2 years!!!) ~ I did ask Weber, "Do you note in your research papers, that your trial participants are predominantly wealthy white people?"  My B, aka Donkey most certainly on the Edge, almost passed out on the spot with some sort of heart attack.  Not that he didn't think this was a valid question.  But, because he didn't want me to piss off  the man who held the keys to the only possible treatment option I had.  Dr. Weber gave me a rather long look and replied, "No, but I probably should." 

Fixing these problems will not be easy.  They are old, ingrained and complex.  But that doesn't mean it can't be done.  I will keep working to find ways to make it better.  And you can bet...that until things are better....I won't quit yelling about them.  Wishing love, luck, and equality to you all. ~ les

Saturday, April 21, 2018

Everything Cures Melanoma - Installment #10

So....just to keep y'all up to date on the latest and greatest, I keep reporting all things (well...almost all....some things are just too far fetched to make even THIS list!!!) peeps are looking at to "Cure" melanoma.  Here's a link to the last installment:  Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)

Now, there's this.....

Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study. Sassi, Maatouk, El Gueder, et al. Chem Biol Interact. 2018 Jan 15.

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound which has many biological activities as an anticancer agent. The current report is aimed at finding out whether the antitumor potential of chrysin, evidenced in vitro and in vivo, is linked or not to its effect on immunological mechanisms of melanoma-bearing mice. Chrysin-treated B16F10 cells were analyzed for their metabolic rate and apoptotic potentials. In vivo, BALB/c mice received a subcutaneous injection of B16F10 melanoma cells prior to antitumor treatments with chrysin (50 mg/kg b.w) for 14 days and 21 days. The results showed that chrysin inhibited cancer cell growth at a dose-dependent manner by inducing apoptosis and cell cycle arrest at G2/M phase. Moreover, chrysin suppressed melanoma tumor growth at an average of 60% (after 14 days of treatment) and 71% (after 21 days of treatment) compared to the tumor-bearing group. Furthermore, chrysin treatment increased the cytotoxic activity of NK, CTL and macrophages. The findings showed that chrysin antitumor action on the murine melanoma model was very promising, suggesting that chrysin could be a potentially good candidate for future use in alternative anti-melanoma treatments.

So, at least in 70% of poor little mice given melanoma, chrysin, found in honey and most often extracted from blue passion flowers, melanoma tumor growth was suppressed after about a month of treatment.

Oridonin inhibits migration, invasion, adhesion and TGF-β1-induced epithelial-mesenchymal transition of melanoma cells by inhibiting the activity of PI3K/Akt/GSK-3β signaling pathway. Li, Wang, Shen, et al. Oncol Lett. 2018 Jan;15.

Epithelial-mesenchymal transition (EMT) has been reported to play pivotal roles in tumor invasion and metastasis. Inhibition of EMT may exert beneficial effects in regulating metastasis. Oridonin (ORI), an active diterpenoid compound isolated from Rabdosia rubescens, was found to be a potent anti-metastatic agent. However, the possible involvement of ORI in the EMT in malignant melanoma is unclear. The present study found that ORI inhibited cell migration, invasion, and adhesion in A375 and B16-F10 melanoma cells. The transforming growth factor-β1 (TGF-β1)-induced EMT was also inhibited in ORI-treated cells, as reflected in the upregulation of E-cadherin, and downregulation of vimentin and Snail. Similar results were observed in A375 and B16-F10 melanoma cells treated with ORI. Furthermore, pre-treatment with ORI blocked the TGF-β1-induced phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (Akt)/glycogen synthase kinase (GSK)-3β signaling pathway activation. These effects mimicked PI3 kinase inhibitor LY294002 treatment. ORI interfered with the PI3K/Akt/GSK-3β pathway, and reversed TGF-β1-induced EMT, which suppressed the invasion and metastasis of melanoma cells. Taken together, the present study demonstrated that ORI inhibits melanoma cells migration, invasion, and adhesion and TGF-β1-induced EMT through the PI3K/Akt/GSK-3β signaling pathway. These findings suggest that ORI is a promising anti-metastasis agent for melanoma.

In this study, oridonin (ORI) extracted from a herb (the isodon plant) kept melanoma cells in a petri dish from getting their groove on!!!  Apparently it has had various uses in Japan, China, and Korea as a herbal remedy and was examined here as well:  Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on leukemia in vitro and in vivo. Blood Journal, 2007.

Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice. Kokolus, Zhang, Sivik, et al. Oncoimmunology. 2017 Dec 21.

Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of β-adrenergic receptor (βAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (β-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan β-blockers. This retrospective analysis is reinforced by results showing that βAR blockade enhances the control of murine melanoma growth by anti-(α)PD-1 checkpoint blockade. However, this effect was most significant when β-blocker was combined with dual αPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of β2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies.

I first reported on Propranolol use in melanoma back in 2014 here: Kill melanoma....with snake venom or Vietnamese sophora root...beta-blockers...not so much!  Where it was noted that: "Beta-blockers were prescribed after malignant melanoma diagnosis to 20.2% of 242 patients who died from malignant melanoma and 20.3% of 886 matched controls.  Contrary to some previous studies, beta-blocker usage after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in the UK population based study."  In the report above, researchers state that they saw improved OS in melanoma peeps who were simultaneously given immunotherapy, as was the case for more poor little melanoma affected mice.  They do point out that the effect was greater when melanoma peeps (or maybe they mean the's not clear) were also given high dose IL-2 with their anti-PD-1/beta blocker cocktail! 

Antioxidative and Anti-Melanogenic Activities of Bamboo Stems (Phyllostachys nigra variety henosis) via PKA/CREB-Mediated MITF Downregulation in B16F10 Melanoma Cells. Choi, Jo, Yang, et al. Int J Mol Sci. 2018 Jan 30.

Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. The anti-melanogenic and antioxidative activities of the EtOAc fraction (PN3) of a P. nigra stem extract were investigated in a cell-free system and in B16F10 melanoma cells. PN3 consisted of a mixture of flavonoids, such as catechin, chlorogenic acid, caffeic acid, and p-coumaric acid. The antioxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)), and hydroxyl radical scavenging) was evaluated, as well as the inhibition of reactive oxygen species (ROS) produced by the Fenton reaction. PN3 showed in vitro tyrosinase inhibition activity with the half maximal inbihitory concentration (IC50) values of 240 μg/mL, and in vivo cytotoxic concentration ranges > 100 μg/mL. The protein expression levels and mRNA transcription levels of TYRTRP-1, and MITF were decreased in a dose-dependent manner by the treatment with PN3. PN3 interfered with the phosphorylation of intracellular protein kinase A (PKA)/cAMP response element-binding protein (CREB), demonstrating potent anti-melanogenic effects. PN3 could inhibit PKA/CREB and the subsequent degradation of microphthalmia-associated transcription factor (MITF), resulting in the suppression of melanogenic enzymes and melanin production, probably because of the presence of flavonoid compounds. These properties make it a candidate as an additive to whitening cosmetics.

Hmmm....  The "whitening/anti-melanomagenetic" properties of compounds found in bamboo stems make this interesting given what we know about vitiligo improving the prognosis for those with melanoma.  Wonder if pandas ever get melanoma!!!???

RK1, the first very short peptide from Buthus occitanus tunetanus inhibits tumor cell migration, proliferation and angiogenesis.   Kjammessi, Ben Mabrouk, El Fessi-Magouri, Krarrat.  Biochem Biophys Res Commun. 2018 Jan 20.

Scorpion toxins have been the subject of many studies which explore their pharmacological potential toward diverse molecular targets, known to monitor key mechanisms in cancer such as proliferation, migration and angiogenesis. The few peptides from scorpion venom that have an anti-tumor effect are generally cytotoxic. Herein, we present the first description of a short 14 amino acid peptide (called RK1), purified from the venom of Buthus occitanus tunetanus, with the particular capabilities, among different other scorpion peptides, to inhibit cell proliferation, migration and angiogenesis of U87 (Glioblastoma) and IGR39 (Melanoma). Moreover, RK1 is a first peptide derived from scorpion venom exhibiting a potential anti-tumoral activity with no manifest toxicity. Our results suggest that, in terms of its primary structure, RK1 is unique compared to a variety of known peptides purified from scorpion venoms. In addition, RK1 is the first natural peptide able to abolish completely the proliferation of cancer cells. The Chicken chorioallantoic membrane model revealed that RK1 strongly inhibits ex-vivo vascular growth. RK1 could open new perspective for the pharmaceutical application of short scorpion venom peptides in anticancer activity and may represent the first member of a new group of scorpion peptides

So a little scorpion venom can do in melanoma and glioblastoma cells in a petri dish!  And the RK1 peptide noted here, can do that without any collateral toxicity.  That's cool!!  But what the heck is a "Chicken chorioallantoic membrane"????  Reckon it would be tasty fried up with hot sauce????  Coming soon to the KFC near you!!  Just watch!

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells. Shang, Feng, Cuj, et al. Oncol Lett. 2018 Jan;15.

Propofol is an intravenous anesthetic, which is widely used in clinical anesthesia induction and maintenance and is critical in the sedation of patients. However, the functions and mechanisms of propofol on apoptosis of melanoma cells remain unclear. The present study investigated whether propofol promotes cell apoptosis and suppresses the HOX transcript antisense RNA (HOTAIR)-mediated mechanistic target of rapamycin (mTOR) pathway in melanoma cells. B16F10 cells were cultured with different concentrations (0-10 µM) of propofol for 24 or 48 h. Proliferation and apoptosis of B16F10 cells were detected using MTT assay and flow cytometry. The pcDNA 3.1(-)-HOTAIR and pcDNA 3.1(-)-control plasmids were transfected into B16F10 cells using Lipofectamine 2000. In the present study, treatment with propofol significantly reduced viability, and induced apoptosis and caspase-3 activity in melanoma cells. Propofol treatment significantly inhibited HOTAIR expression and the expression of phosphorylated (p)-mTOR and p- p70S6K protein in melanoma cells. Overexpression of HOTAIR significantly increased viability of melanoma cells, and increased HOTAIR, p-mTOR and p-p70S6K protein expression in melanoma cells. These results indicated that propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR signaling pathway in melanoma cells.

In this study, once again, in the petri dish, melanoma cells couldn't get their groove on when treated with proprofol.  That's good!  Of course, the rest of the body can't get its groove on either if one is given too much propofol!!!!

Thai Water Lily Extract Induces B16 Melanoma Cell Apoptosis and Inhibits Cellular Invasion Through the Role of Cellular Oxidants. Aimvijarn, Palipoch, Okada, Suwannalert. Asian Pac J Cancer Prev. 2018 Jan 27.

Melanoma is a cancer that is associated with a high capacity of invasion. Oxidative stress is recognized as cancer growth and progression. The phytochemical pigments of natural products show either anti-oxidant or pro-oxidant activity from the redox system. In addition, the phytophenolics also prevent cancer cell proliferation and progression. This study aims to investigate the effects of Thai water lily on cell apoptosis and cellular invasion through the role of cellular oxidants in B16 melanoma cells.  The cytotoxicity and cell apoptosis of Thai water lily extract treating B16 cells were performed by using the MTT and Annexin V/PI-flow cytometry methods, respectively. In addition, cellular oxidants and cancer cell invasion were also obtained by using DCFH-DA and Boyden chamber assays, respectively.  Thai water lily, Nymphaea stellate extract was shown to be markedly toxic to B16 melanoma cells with IC50 = 814 μg/ml. The extract at 800 and 1,000 μg/ml demonstrated pro-oxidant activity relating to the cell apoptosis. The low concentrations of the extract at 200 and 400 μg/ml showed the anti-oxidant function associated with the inhibitory effect of melanoma cell invasion.  Thai water lily extract may play an important role in bioactive work as a chemo preventive agent on the modulation of cellular oxidative stress-induced apoptosis and suppressed cancer cell invasion.
Again, in the petri dish, Thai water lily extracts seemed to inhibit melanoma cell invasion.  That's sounds very fierce and calming all at the same time!!!

Lectin Isolated from Japanese Red Sword Beans (Canavalia gladiata) as a Potential Cancer Chemopreventive Agent. Une, Nonaka, and Akiyama.  J Food Sci. 2018 Feb.

In this study, we investigated the chemical and biological profile of lectin isolated from Japanese red sword beans (Canavalia gladiata; RSBs). RSB lectin was purified using maltamyl-Sepharose 4B and subjected to amino acid composition and partial amino acid sequencing analyses, and evaluated for blood and carbohydrate specificity, mitogenic activity, splenic natural killer (NK) cell activity, and its effect on B16 melanoma cell proliferation, compared with Concanavalin A (Con A). The amino acid composition and sequences of RSB lectin were similar to those of Con A. RSB lectin showed specificity to mannose, glucose, maltose, methyl-D-mannoside, and thyroglobulin, but not rhamnose, using mouse, sheep, and rabbit erythrocytes. Compared with Con A, RSB lectin showed low resistance to proteases and to temperatures greater than 70 °C, but high mitogenic activity for mouse splenic cells. Notably, while treatment with RSB lectin and Con A (0.01 and 0.1 μg/mL) promoted similar levels of splenic NK cell activity, which were higher than that observed in the control (0 μg/mL) and interleukin 2 (IL-2) (25 U)-treated populations, RBS lectin exerted a significantly stronger antiproliferative effect than Con A at a concentration of 125.0 μg per well. Overall, our results show that RSB lectin might exert immunological effects on mouse splenic cells and could thus be used as a potential cancer chemopreventive agent.  Japanese red sword bean (RSB) is a tropical perennial legume consumed in many Asian countries. RSB lectin shows specificity to mannose, glucose, maltose, methyl-d-mannoside, and thyroglobulin, but not to rhamnose, using mouse, sheep, and rabbit erythrocytes. RSB lectin exhibits similarities to Concanavalin A in amino acid composition and sequence, shows mitogenic activity for mouse splenic cells and strong antiproliferative activity for B16 melanoma cells, and also enhances the activity of splenic natural killer (NK) cells against YAC-1 cells. Thus, RSB lectin has the potential to be used as a bioactive protein in medical research.

I like beans!!!  Sounds like something I could get behind!

Bioaccessible selenium sourced from Se-rich mustard cake facilitates protection from TBHP induced cytotoxicity in melanoma cells. Jaiswal, Prakash, Prahu, Tejo Prakash. Food Funct. 2018 Apr 12.

Selenium (Se) is an essential dietary supplement that resolves inflammatory responses and offers antioxidant cytoprotection. In this study, we present the data on the cytoprotective effect of Se-rich mustard protein isolated from mustard cultivated in seleniferous soils in Punjab, India. The concentrations of total Se in mustard seed, oil-free mustard cake, and mustard protein were 110.0 ± 3.04, 143.0 ± 5.18, and 582.3 ± 6.23 μg g-1, respectively. The cytoprotective effect of Se-rich mustard protein was studied on tert-butyl hydroperoxide (TBHP)-induced cytotoxicity in a mouse melanoma cell line (B16-F10). When compared with TBHP treated cells (where no viable cells were found), Se-rich protein made bioaccessible through simulated gastrointestinal digestion protected melanoma cells from cytotoxicity with decreased levels of oxidative stress resulting in 73% cell viability. Such an effect was associated with a significant increase in glutathione peroxidase activity as a function of bioaccessible Se and its response towards cytoprotection.

So, this is a bummer.  For all the good things that curcumin (derived from mustard seeds) is supposed to do for melanoma peeps...we now have to worry if the mustard seeds used were grown in selenium rich soil!!  GAH!!!!!

Helix aspersa maxima mucus exhibits antimelanogenic and antitumoral effects against melanoma cells. Ellijimi, Ben Hammouda, Othman, et al. Biomed Pharmacother. 2018 May.

Snail secretion is currently revolutionizing the world of cosmetics and human skin care. The efficacy of snail secretion in wounds healing has been proven both in vitro and by clinical studies. However, the potential anti-tumor effect of snail secretion was poorly investigated. In this report, our in vitro study showed that Helix aspersa maxima species snail slime (SS) could not only treat melanogenesis but also endowed with anti-tumoral activity against human melanoma cells. Indeed, SS reduced melanin content and tyrosinase activity on B16F10 cells with IC50 values of 288 μg/mL and 286 μg/mL, respectively, without altering cell viability. This effect was also observed, at a lesser extent, on human melanoma IGR-39 and SK-MEL-28 cell lines. On another hand, SS specifically inhibited the viability of IGR-39 and SK-MEL-28 cells associated to an apoptotic effect highlighted by PARP cleavage. It is worth to note that SS did not affect the viability of B16F10 cells and non tumorigenic HaCaT cells. Interestingly, this extract was found to inhibit migration and invasion of both human melanoma cells through reducing the expression of Matrix metalloproteinase MMP2. Snail slime also exerted a high inhibitory effect on IGR-39 cell adhesion through blocking the function of α2β1 (45%), αvβ3 (38%) integrins and by reducing the expression levels of αv and β1 integrins. The presented results shed light on the potential anti-melanoma effect of SS and support its use against skin diseases.

Wow!!!  Snail slime???  Really???  Well, if it works, okay!!!  Hope we won't have to eat it!!!

Hang in there, my melanoma peeps!!  Thanks to all the researchers (esp the ones who had to deal with snail slime!!!), petri dishes and melanoma mice!  Maybe something wonderful is in the offing!!! - c

Friday, April 20, 2018

Creating vitiligo with monobenzone to help melanoma patients????

We have known for some time that melanoma patients who develop vitiligo do better than those who do not.  Lot's of posts regarding vitiligo and melanoma can be seen here:  All things vitiligo

I've thought for a long time, that if we could figure out the exact cause of the development of vitiligo in some...and trigger it in would certainly be a good thing!  Now, there's this ~

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial. Teulings, Tjin, Willemsen, et al. Oncoimmunology. 2018 Jan 15.
Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

Okay,  So, in this trial 25 Stage III/IV folks (though only 21 were evaluated in the end) had monobenzone and imiquimod applied to their skin on and around existing melanoma skin lesions.  At 12 weeks Partial Regression was noted in 8 patients and 1 had stable disease.  As treatment continued, a Clinical Response was noted in 11 patients and 3 had a Complete Response.  Vitiligo (depigmentation of the skin) was noted in areas NOT treated in 7 patients, implying a systemic response to this therapy.

What is not clear to me is whether or not these patients had been treated with any other prior or concomitant immunotherapy.  I mean, if I were a Stage IV patient (Wait, I am!!!  HA!) I don't know that I would settle for just applying a cream.  On the other hand, if they would treat me systemically AND apply a cream....I would totally go for it!  It may be that these peeps had actual cutaneous lesions, almost like intrasit mets or something, given the way the authors describe the application process.  This condition is not something all Stage III/IV melanoma patients have.  Unfortunately, information about the exact sort of lesion and the prior or simultaneous systemic treatment of the patients included here is not divulged in this abstract.  Even so, monobenzone applied to the skin with imiquimod sounds like a low risk procedure with some positive results.  

Here's to a whiter shade of pale!!! Keep on teaching us, ratties! - c

Thursday, April 19, 2018

Sew Chaotically! - McCall's 7726, wide legged faux paper-bag waist trousers!!

I've worn real live paper-bag waist trousers and loved them...but for all their apparent insouciance they can be tricky to wear and keeping the gathers in place over the course of a day can be difficult.  When I saw this pattern, with what I suppose you call box pleats (???), I knew it would be perfect!!!  I was actually thinking of making them in a light weight denim but when I found this really lovely fabric at JoAnn's...well...there you go!  It washes and dries perfectly and was easy to sew.  Thanks goodness, since I had to make this simple, well drafted pattern difficult with my plaid matching!!!

And, YES!!!!  Pattern matching of which I am inordinately proud!!!  Right down to the belt loops!!!!  I cut a straight 12, adding no length as the pattern allows for a deep hem so I had plenty of material to play with.  I took in the waist and hip at the side seams after fitting.  My only change was to add some interfacing to the inner waistband facing which is simply the top edge of the pant folded down.  The pattern makes no recommendation for this, but if your fabric is as fluid as mine and you don't want your faux paper-bag waist flopping down, it is probably something to consider.

I really love these pants!!!  The perfect combo of "men's wear" made more feminine with the fluidity of the shape.  Still planning on another pair...possibly a bit that soft denim if I can find the right material.  Or maybe a grey flannel for winter????  Sew chaotically! - les

Wednesday, April 18, 2018

Alkaline diets and "complementary" treatments??? Be VERY careful! They may cause an increased risk of progression in melanoma!!!

While it makes complete sense that we are all searching for get rid of our melanoma and/or make our treatments more effective...even "benign" "natural" supplements can cause problems!!!  I published this in 2016:  Combining alternative and conventional treatments for melanoma....a risky business!

Now, there's this:

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study. Knapen, Koornstra, Driessen, et al. Target Oncol. 2018 Apr 11. 

The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.

To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.

A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.

In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone, which became statistically significant in a sensitivity analysis.

There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating  full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

While this is not the most definitive study...these data certainly point to the need for caution when adding "complementary" treatments to your melanoma therapy!!!  Stay well! - c

Friday, April 13, 2018

Sew Chaotically! - Wardrobe review and repair with new skirt and top! (M6842 and M6282)

Wardrobe review with Roo!!!  She took advantage of one day of her spring break to do spring cleaning in her closet!  She had done a rushed college student/cum mathematics teacher wardrobe up-grade several years ago, adding a few things here and there, since. However, she felt it was time to give it all a good hard look.  We went through EVERYTHING!!!  It was FUN!  We allocated items to:  keepers, repairs, trash, donate, and sell if possible.  So far, the yield is much more closet space, a large bag to the homeless center, more than $20 bucks in her pocket, with the possibility of more.  The mending pile came home with me. 
Button with braided loop added to the purple top M6896 on the left for modesty and cuteness.  Black and greenish khaki pants hemmed.  Grey shorts taken in at the waist in the back to remove the extra room in the waistband found in so many ready-to-wear pants.  The facings secured in the New Look 0926 sleeveless dress I made her before I became more savvy about bias tape finishes.  Little summer top hemmed more to her liking.   Waist bands of three skirts taken in - coral rtw, purple fine cord I made her several years ago, and purple plaid M3341 (along with their facings and linings!!! Big self congratulatory pat-on-the-back for myself there!!!).  And...a new little black flippy skirt!  (More on that below!)
A new combo already working!!!
And then there is this new and needed addition!  A really great, easy pattern I've used several times before McCall's 6842 top that off...

I've liked the look of this top/dress, and had this pattern at hand, for some time.  However, when perusing the pattern instructions I was always put off by the seeming complexity of the lining installation!!!  But last week, with years of sewing experience now attained, I thought, "Pish posh!!!  A lining???  How difficult could that be????"  Well!!!  While this pattern (and pattern designer) seem super proud to offer page after page on how one can adjust it for a high or low back hump, bust name offers very little on how to actually put the garment together!!!  Maybe it's just me...but the methodology was incredibly unclear on how to attach the shoulder seams in a manner that allows one to pull the lining right side around once neck and arm holes have been stitched together!  However, after a good bit of angst and almost driving poor B nutters with my frustration....I made it work.  I made a straight 12.  No adjustments apart from leaving out the back zip which the pattern says usually works if your knit is stretchy enough.  Next time, I will look at the way the lining is installed on a different top that went together easily and do it that way!
Rosie was very happy with it was all worth it!  And, it works well with much of her purple durple wardrobe!!
Including her new skirt!!!
Sew much fun with my girl!!!  And a big thanks to Roo for being a great model after a long day pouring Algebra II, Calculus and Pre-cal into the craniums of our future!!! Sew chaotically!!! - c

Tuesday, April 10, 2018

BRAF/MEK for melanoma brain tumors? Yep! It works!

Brain mets suck great big green hairy wizard balls.  Period.  Now, this....

Clinical and radiological response of BRAF inhibition and MEK inhibition in patients with brain metastases from BRAF-mutated melanoma. Geukes, Boogerd, Blank, et al. Melanoma Res. 2018 Jan 19.

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months (n=30), 8.8 months for dabrafenib alone (n=31), and 5.7 months for vemurafenib (n=85). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group. Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months, 5.7 months for dabrafenib, and 3.6 months for vemurafenib. A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

Okay, so most of this is a no-brainer!!!  The BRAF/MEK combo does better than BRAF inhibitors alone - in brain or body!  We have known this for how long????  BUT, it does confirm (again) that targeted therapy...the BRAF/MEK combo for melanoma peeps whose tumors are BRAF in the brain and the body!

For what it's worth. - c