Friday, January 19, 2018

Nivo after nivo? Or nivo after progression? Can melanoma patients still attain a response???

A question frequently asked...with no absolute answer is.... What if I take nivo after I've progressed....having already been on nivo....or if currently on nivo??????  These reports begin an answer:

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Nomura, Otasua, Konda, et al.  Cancer Chemother Pharmacol. 2017 Oct 5. 

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.

A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.

Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.

This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Here, 8 patients were given nivo (3 of them had chemo beforehand).  37.5% had a partial response.  37.5% had stable disease.  Nivo was stopped due to progression in 7 of the patients and colitis in 1.  6 were subsequently treated with ipi.  1 was given vemurafenib.  4 got radiation at that point.  Then...these 8 folks were given a new round of nivo.  2 attained a partial response.  3 attained stable disease. Eventually, 7 of them had to stop nivo again due to progression.  Interestingly, it sounds as though those that had radiation between therapies did least for a while - though that is not entirely spelled out here.  

So, it seems that round two of nivo can give patients a reprieve.  Though for these 8 patients it doesn't sound as though it lasted long enough!

And....there's also this....

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Long, Weber, Larkin, ….Hodi, Wolchok.  JAMA Oncol. 2017 Jun 29.

Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.  Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.  Tumor response and safety in TBP and non-TBP patients.

Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP greater than 30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP greater than 30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP greater than 30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Here they looked at the outcomes of 3 trials in which nivo was 526  patients.  306 had progression.  But 85 of those who progressed were given nivo more than 6 weeks AFTER their known progression, while 221 were not. Of those 85 patients "treated beyond progression", 24 "had a target lesion reduction of greater than 30% after progression compared to baseline."  And at follow-up further down the line, many of those were still alive.

There is much we still don't understand about immunotherapy.  But, I think the statement Agarwala and Weber made to, "Be patient with the patient!" still holds.  Hang tough, ratties! And, thanks!  - c

Tuesday, January 16, 2018

Sew Chaotically! - Coppelia Cardi by Paper Cut Patterns

I had really looked forward to this make.  Pattern procured by B at my request a bit ago.  Fabric chosen during my Goldhawk Road shopping adventure.  I even had great fun making the ingenious little instruction booklet Paper Cut prints in their patterns!!!  However, there were a few issues...not the least of which was poor fabric choice.  Which makes me rather sad, as I picked this fabric out especially with this top in mind!!!  Many sewists have noted a bit of an issue with the fit of the pattern itself, despite making some very lovely tops. This is one of my favorites: Gray All Day and her Coppelia cardi.  Anyhow, after reading many posts about the fit being large and various other tips, I felt prepared to knock it out of the park!  I cut the size small.

It went together easily.  Though I would not attach the wrist bands the way the pattern advises (and I almost didn't this time).  Done per their direction, the band is attached as a circle to the already put in sleeve.  Doing it that way is:  1.  Just more work.  2.  A right palaver, as the opening was too small to fit around the free arm of my machine.  Next time, I would attach the sleeve binding to the sleeve end flat.  Sew up the sides.  Turn up the cuff.  Anyhow...not too bad right?  Not entirely pressed.  Already with some large adjustments made to remove extra fabric from the shoulder seams, fore and aft, and a good bit on either side. you see the trick required to make it look even this good?
Yep.  Quite a lot of the "front" is tucked into the side/bottom as I wrapped the top around.  Not that cute in the first place, and impossible unless you are going to stand stock still like a sewing dummy!!!  Then again, when you make a top with material that is clearly too stiff, lacking in sufficient stretch (there's some in the this French terry, but not enough, given its heft), and without the necessary boobage....maybe you ARE a sewing dummy!!!  Hee, hee!!!
I let it sit for a bit...then I came up with this!!  I cut the bottom band off.  Took some MORE off the sides.  Folded the front pieces over each other where I wanted them to be.  Stitched them in place at the bottom.  Cut the bottom even all around as it was pretty jacked after those adjustments.  And finally, added a self drafted bottom band that was wider at the bottom edge than the top to accommodate my bootie!
Sew much better!!!
At least it is a wearable garment at this point!!!  I've worn it a few times in variations like this.  However, the material is so stiff (especially with those overlapping front layers), that I've found it more useful as a cover-up/warm layer over my workout wear on the way to my Barre workouts with Rosie.  Seems a waste in my mind, somehow.  But, as B says...."You gotta wear something there, too!!!"  Maybe he's worried I won't????
When sewing adventures go this crazy, you gotta laugh, right????
I think I'll try this pattern again, albeit with a fabric that is a great deal thinner with more stretch.  But....still loving my 2016 make:  Vogue's 9136 Cozy Coat 
One more knit top and final sewing adventure of 2017 to go!  Sew chaotically! - les

Sunday, January 14, 2018

HDAC again - decreases resistance when encorafenib was combined with panobinostat - in the petri dish at least!

Initially, HDAC inhibitors were hoped to be useful in overcoming resistance to BRAF inhibitors.  Then, some data has demonstrated that they may improve responses to immunotherapy.  Here's a post, with links within, that cover those reports:  HDAC inhibitors for melanoma....what are they again????
(Sometimes it helps to review the alphabet soup!)
Now, there's this....
HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Gallagher, Gunatilake, Beaumont, et al.  Int J Cancer. 2017 Dec 6.

Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo- derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase-dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro-apoptotic BIM or NOXA together with reduced expression of anti-apoptotic proteins. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK-independent pathways.

For what it's worth!  Here's hoping! - c

Saturday, January 13, 2018

Sew Chaotically! - Toaster Sweater from Sew House Seven, Version 1

This sweater pattern, from Sew House Seven, has gotten great reviews from a variety of sewists and I know why!!  It's awesome.  I snatched up the pattern when I happened upon a Makers Fair just after a visit to Hampton Court!!!  I stitched it up in a rich, soft, not-too-thick, navy blue French terry, that my camera refused to photograph well, acquired in my fabric shopping adventures on Goldhawk Road.  It is comfy and cozy without being too boxy or shapeless.  It stitches together very quickly and easily.  I made 'version 1' size medium.  My only changes were to add 2 inches to the length of the body, then added the waist band as prescribed.  But, had to cut 1 inch OFF the main sleeve before adding the cuff as directed.

When you have to give your sissie a shout out mid sew and show her how proud you are of your finished seams!!!!

I've worn it a good deal this winter, having finished it at the end of last year.  In fact, I have two more knit tops to share before moving on to 2018!!!!  As my first sews of this year, in a bit of a closet clean out, I hemmed a pair of pants, fixed two with waist band gappage at the back, slimmed down some slacks with too large a "bell" at the bottom, re-hemmed those, and turned a dress into a skirt!
Since it came with a matching fabric belt, my questionably matching fabric as waistband will be covered.  I think it will be fab!!!  However, I am Scott boy stoked about the project I'm working on now!!!  Here's a sneak peak:

I'm sew excited!!!  Have a great weekend and Sew Chaotically!!! -  les

Wednesday, January 10, 2018

Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)

Yes, I look forward to the day when I can make that announcement with no sarcasm and cease to make these crazy lists!  Here's the link to the last installment:  Everything Cures Melanoma....#8  Sigh.  Until then....

We have known for sometime that psychotropic agents like Thorazine kills melanoma.  Now:

Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects. Jiang, Chen, Shen, et al. Biomed Pharmacother. 2017 Nov.

Psychotropic agents have been shown anti-tumor potential in recent years. In the present study, our in vitro pharmacological data indicated that thioridazine inhibited melanoma cells proliferation. The growth-arresting effect of thioridazine was accompanied by autophagy induction, as shown by immunoblotting of increased LC3II. Besides, certain apoptotic events had also occurred after thioridazine exposure. The in vivo anti-melanoma effect of thioridazine was confirmed by showing that intraperitoneally injection of thioriazine remarkably retarded tumor growth and reduced tumor vasculature. Our results imply that thioridazine might be an available therapeutic agent for melanoma patients with no better options.
Of course, that does leave the tiny little hiccup of having to take psychotropic agents...among other things!!!
Antimelanomic Effects of High- and Low-Molecular Weight Bioactive Subfractions Isolated from the Mossy Maze Mushroom, Cerrena unicolor (Agaricomycetes). Statkiewicz, Matuszawska, Jaszek.  Int J Med Mushrooms. 2017

Three bioactive fractions isolated from Cerrena unicolor cultures-crude endopolysaccharide (c-EPS), laccase, and a subfraction of low-molecular weight secondary metabolites-were used to determine potential cytotoxic effects on the mouse melanoma B16-F10 cell line (American Type Culture Collection CRL-6475). The results obtained prove that all examined fractions exhibited activity against the investigated tumor cells. In addition, an evident immunomodulatory effect of the c-EPS fraction was observed. Our results show that the levels of 2 cytokines (tumor necrosis factor-a and chemokine ligand 2) in mouse inner medullary collecting duct mIMCD-3 cells (American Type Culture Collection CRL-2123) stimulated by c-EPS were significantly higher. A lipopolysaccharide model was used at the same concentration (10 μg/mL) as a positive control.

Yes, mossy maze mushrooms look like lichen I see on trees everywhere....but there you go!  Wanted you to see it just in case you thought anti-melanoma effects were limited to Shiitakes! (If you're interested in that one, check out this post from 2012: Shiitakes - Much ado about mushrooms! And speaking of lichen....

The Polysaccharide Extracted from Umbilicaria esculenta Inhibits Proliferation of Melanoma Cells through ROS-Activated Mitochondrial Apoptosis Pathway. Sun, Li, Zhang, et al. Biol Pharm Bull. 2018;41.

Raw as found in nature...
Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROS-mediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta.

The more you know!!!  Apparently pretty delicious and part of Korean cuisine!
Dietary Crocin Reverses Melanoma Metastasis. Bakashi, Lukmanul, Sam, and Javid. J Biomed Res. 2017 Nov 1.

Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase (g-GGT), sialic acid, tumor necrosis factor alpha (TNF-a), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 h of crocin (5 and 10 µg/mL) treatment. Administration of crocin to tumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid andg-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion, migration and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.

And what, you might ask, is Crocus Sativus.....that so helpfully cured these poor little mice???

Yep, my favorite Harbinger of Spring....the pretty, tiny, unassuming crocus that grows from bulbs.

It is not clear from the report if they are referring to using the bulbs, leaves, petals, or the super pricey saffron threads harvested from the crocus.  If it's the saffron threads themselves...that may set your bank account back just as much as immunotherapy!!!
Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells. Beberok, Wrzesniok, Minecka, et al. Pharmacol Rep. 2017 Jul 16.

Low effectiveness of anti-melanoma therapies makes it necessary to search for new drugs that could improve or replace the standard chemotherapy. Fluoroquinolones are a group of synthetic antibiotics, used in the treatment of wide range of bacterial infections. Moreover, this class of antibiotics has shown promising anti-tumor activity in several cancer cell lines. The aim of this study was to examine the effect of ciprofloxacin on cell viability, apoptosis and cell cycle distribution in COLO829 melanoma cells.  Cell viability was evaluated by the WST-1 assay. Cell cycle distribution and apoptosis in cells exposed to ciprofloxacin was analyzed by the use of fluorescence image cytometer NucleoCounter NC-3000.  Ciprofloxacin decreased the cell viability in a dose- and time-dependent manner. For COLO829 cells treated with ciprofloxacin for 24 h, 48 h and 72 h the values of IC50 were found to be 0.74 mM, 0.17 mM and 0.10 mM, respectively. The oligonucleosomal DNA fragmentation was observed when the cells were exposed to ciprofloxacin in concentration of 1.0 mM for 48 h and 72 h. At lower ciprofloxacin concentrations (0.01 mM and 0.1 mM) cells were arrested in S-phase suggesting a mechanism related to topoisomerase II inhibition. Moreover, it was demonstrated that ciprofloxacin induced apoptosis as a result of mitochondrial membrane breakdown.  The obtained results for COLO829 melanoma cells were compared with data for normal dark pigmented melanocytes and the use of ciprofloxacin as a potential anticancer drug for the treatment of melanoma in vivo was considered.

So this is all rather old, in terms of how melanoma treatment is addressed, but in the petri dish it seems cipro  decreased the viability of melanoma cells.  Okay.  Plus...there's this....

The effect of ciprofloxacin on the growth of B16F10 melanoma cells. Jaber, Jallad, Abdelnoor. J Cancer Res Ther. 2017 Oct-Dec;13.

The antitumor effect of ciprofloxacin has been widely assessed in-vitro, and positive results have been reported. The aim of this study was to investigate the influence of ciprofloxacin treatment on the growth of B16F10 melanoma cells both in-vitro and in-vivo.

Groups of C57BL/6 female mice challenged with B16F10 melanoma cells were kept untreated or were treated with sterile water, intraperitoneal ciprofloxacin, or ciprofloxacin through drinking water for 10 days. The serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA 1 and 3 h after the last dose of ciprofloxacin. Mice were monitored for an additional 10 days for survival assessment. Moreover, B16F10 melanoma cells were cultured in 24-well plates and exposed to different concentrations of ciprofloxacin (10-1000 μg/ml). Viability was determined, after 24 and 48 h, using trypan blue.

The serum levels of VEGF significantly decreased in ciprofloxacin-treated mice when compared to the controls. None of the control mice survived beyond day 8, whereas 16.67% of those treated with ciprofloxacin survived up to 18 days. In addition, the viability of B16F10 melanoma cells, in-vitro, significantly decreased with increasing concentrations of ciprofloxacin after 24 and 48 h.

Ciprofloxacin seems to exhibit antitumor activity both in-vivo and in-vitro. This effect might be explained by several mechanisms such as directly inducing cancer cell death or altering the immune response through the modification of the normal microbiota.

So in little mice and petri dishes, ciprofloxin, a fairly common antibiotic "exhibits antitumor activity".  Though their commentary about "altering the immune response through the modification of the normal microbiota" is NOT a good thing if you believe this report:  Antibiotic use MAY decrease effectiveness of immunotherapy?????  Not to mention the more recent: Science magazine: Precision medicine using microbiota Researchers really need to learn to communicate and discuss their results!!!

Non Polar compounds of Persian Gulf Sea Cucumber Holothuria parva Selectively Induce Toxicity on Skin Mitochondria isolated from animal Model of Melanoma. Arast, Seyed, Nazemi, et al. Cutan Ocul Toxicol. 2017 Dec 12.  

Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melonama. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling.

In the present study, selective toxicity and apoptotic effect of three extracts of Holothuria parva (H. parva) were assessed on skin mitochondria isolated from mouse animal models of melanoma. The mitochondria was isolated from melanoma cells via differential centrifuges and treated with various concentrations (250, 500 and 1000 µg/ml) of metanolic, diethyl ether and n-hexane extracts of H. parva.

All the applied concentrations (250, 500 and 1000 µg/ml) of three extracts of H. parva increased the reactive oxygen species (ROS) generation only in the skin mitochondria isolated from melanoma cells group (In comparison to the control group). Additionally, all three extracts (250, 500 and 1000 µg/ml) induced swelling within the mitochondria, the collapse of the mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria. Flow-cytometry analysis demonstrated that n-hexane and diethyl ether extracts of H.parva selectively and progressively induced apoptosis only on melanoma but not healthy control skin cells group

Given these results, the potentially bioactive compounds found in H. parva render it a strong candidate for further research in molecular identification and confirmatory in-vivo studies. Clinical trials are also warranted in the general process of novel drug discovery for the treatment of melanoma cancer.

I feel it is important to note that this little feller' is not just any ol' sea cucumber.  No!  He is a Persian Sea Cucumber Holothuria Parva!!!  Just in case you were going to make a sea cucumber slurry to sprinkle on the random melanoma mitochondria you have sitting around in your petri dishes!!!

MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum. Bae, Karadeniz, Oh, et al. Evid Based Complement Alternat Med. 2017 Sep 20.

Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent-partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties.

Hey!  I swear this is the same as the pretty, paper-like, stiff, long-lasting, long stemmed flower that is in mixed bouquets you can get from Wally World!!!  Hmmm.....  

Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile. Campeiro, Marinovic, Carapeto, et al. Amino Acids. 2017 Dec 12.

The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions [No, I can see that injecting stuff into your abdomen wouldn't be the preferred route for drug consumption by many!!!] herein, we evaluated the antitumor effect of this native polypeptide employing the oral route. The efficacy of crotamine in inhibiting the melanoma growth in vivo, even after passing through the gastrointestinal tract of the animal, was confirmed here. In addition, biochemical biomarkers and also histopathological analysis showed both the absence of any potential toxic effects in tissues or organs of the animal in which the highest accumulation of crotamine is expected. Interestingly, a reduction of weight gain was observed mainly in animals with tumor treated with crotamine by IP route, but not by oral administration. Albeit, oral administered crotamine was able to significantly decrease the body weight gain of healthy animals without tumor. Taking advantage of this same experimental animal models receiving crotamine by oral route, it was possible to show metabolic changes as the increased capacity of glucose clearance, which was accompanied by a reduction of the total cholesterol, and by increased high-density lipoprotein levels, both observed mainly in the absence of tumor. Triglycerides and low-density lipoprotein were also significantly decreased, but only in the absence of tumor. Taken together, these data suggest a clear trend for metabolic positive effects and mischaracterize unhealthy condition of animals, with or without tumors, treated with crotamine for 21 days. In addition, this study confirmed the efficacy of crotamine administered by oral route as antitumor agent, which besides the additional advantage of administration convenience and decreased risk of toxic effects, allowed the serendipitous observation of several positive metabolic effects on treated animals.

Damn, while croatamine helped mice with melanoma a little, this shiz is the new lipitor...producing weight loss and decreased cholesterol in mice who did NOT have tumors!!!!  Just when you think injecting snake venom into the abdomen of little mice or putting it in their kibble couldn't get any weirder!  Mother Nature...what do you think of that kink in your food chain????

Well!!!  All of that is a lot of business, isn't it????  (Not to mention all the ground that is covered in the prior posts!!!!)  I never say NEVER!!!  Ha!  Here's I nibble my lichen, pop my cipro and thorazine, with a glass of red wine and dine on curry over saffron flavored rice with a bit of kimchi and mustard on the side!!!  After dinner coffee, anyone???  - c

Monday, January 8, 2018

Sew Chaotically! - A Plethora of Christmas pillows!!!

I made a pile of pillows!!  Well, pillow Christmas gifts for all my peeps!

For The Hills

For Fred and Irina

For Rose and Jamie

For Ruth and Frankie
Each peep set got two sets of pillow cases and two pillows, all designed with their tastes and decor in mind!  I looked at lots of pillow case "patterns" on various blogs and videos.  I wanted to make it such that the opening made an envelope over the pillow...keeping it cute and contained.

Yes, it was hard to wrap my non spatial relation oriented brain around this, as I wanted the entire thing to have completely finished seams.  I should have taken pics of the many miniature FAILS I made before I got it straight!!  But, here's my recipe for one American Standard pillow case (20 X 26 inches):

  • Cut a long piece measuring 57 1/2 inches in length and 21 inches wide of your main fabric.
  • Cut a short piece, measuring 7 1/2 inches in length and 21 inches wide, of your border fabric.

(You can split these lengths up any way you want should you wish to add contrasting strips of fabric or ribbon to the border as I did for Fred and Irina's above.)

  • Hem one end of both your pieces by folding over 1/4 inch and 1/4 inch again and top stitch.
  • Sew the unfinished end of your border piece to the unfinished end of your main piece, using a 1/2 inch seam allowance.
  • Flat fell that seam, with top stitching on the main fabric's side or use a French seam.
  • Lay the now pieced fabric on flat surface right side up, with border to your right.
  • Fold fabric, bringing border side to your left, right sides together, until the edge of your border is 6 inches from the edge of the end of the piece.  The fold will be the bottom of your case.

  • Fold the left hand edge OVER the wrong side of the border, by those 6 inches.

  • Stitch both sides using a 1/2 inch seam and serge to finish.
  • Turn the whole ta-dah right side out and press!

Now you have neatly finished seams all around and an envelope for your pillow!!!

So much better than those flappy, open ended ones, isn't it????

I'll confess:  I had to make this one to get my head back around how I did this....even though I'd already made 8!  Still....
Certainly better than the robes, huh????  Sew Chaotically!!! - les

Sunday, January 7, 2018

Long term outcomes with Dabrafenib/Trametinib (BRAF/MEK combo)

While dabrafenib as a single agent for 4 months did not prove to be effective as an adjuvant, targeted therapy has saved lives of melanoma patients.  Now, there's this:

Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. Long, Eroglu, Infante...Daud...Hamid...Sznol...Weber, et al.  J Clin Oncol. 2017 Oct 9.

Purpose: To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. 

Patients and Methods:   BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with greater than/= to 5 years of follow-up. 

Results:   As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed.

Conclusion: This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last greater than/= to 5 years in some patients with MM.

SO....we already knew that BRAF/MEK combined was much better than BRAFi alone...again evidenced here.  With the combo there was 30% survival at 4 years, 28% at 5 years.  Also with the combo, progression free survival was 13% at both the 4 and 5 year mark.  Greater overall survival ocurred when patients started with a low baseline LDH level and fewer organ sites with mets (points that are true in immunotherapy as well).  

While only about 1/2 of melanoma patients are BRAF positive, and thereby have BRAF/MEK as a viable treatment option, this is still good news.  Melanoma's ability to mutate and work around the positive effects of BRAF treatment remains a fight.  As noted in this report:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS  where:

Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS.  This combo showed a PFS of 14.9 months.  Objective response rate was 63% with the comb0.  There was an ORR of 51% to encorafenib alone.  Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending.  OS data for encorafenib/binimetinib has not yet been reported.  OS in most other BRAF/MEK combo's is around 2 years.  

It is heartening to see in this latest report that there are those among the BRAF positive melanoma patients who can maintain responses at 5 years.  Great thanks and admiration to Dick K and Stevie (among others) who pushed this envelope!!! - love, c