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| After icy conditions yesterday, this beautiful Lenten Rose promises that Spring is on its way!!! |
Saturday, January 26, 2013
For Jonathan....a taste of Spring!!!!
Sunday, January 13, 2013
Better in 2013...jump up, jump around...and fire up those Natural Killer cells!!!
IMPACT OF BRIEF EXERCISE ON PERIPHERAL BLOOD NK CELL GENE AND Micro RNA EXPRESSION IN YOUNG ADULTS
From: Journal of Applied Physiology, January 3, 2013 By: Radom-Aizik, Aldivar, Haddad, Cooper.
"Natural Killer (NK) cells are unique innate immune cells that increase up to fivefold in the circulating blood with brief exercise and are known to play a key role in first-response defense against pathogens and cancer immunosurveillance." "Thirteen healthy men performed ten 2 minute bouts of cycle ergometer exercise at a constant work equivalent to an average of 77%, interspersed with 1 minute of rest. Blood was drawn before and immediately after the exercise challenge." Lots of fancy tests "were used to determine that exercise significantly altered the expression of 986 genes and 23 miRNAs....We found exercise-related gene pathways were predominantly associated with cancer and cell communication, including p53 signaling pathway, MELANOMA, Glioma, Prostate cancer, Adherens junction and Focal adhesion."
Ok...so that's a little rich for my blood...have to admit...no idea about Adherens junction and Focal adhesion...but....what the heck. B can't yell at me for my INSANITY with Shaun T after my treatments. I got some proof it's doing me good!! So, COME ON Y'ALL!!!!!!
It may be a House of Pain... But... Jump around! So get out your seats and jump around! Jump around! Jump up, jump up and get down!!!!! Make those Natural Killer cells even better in 2013!!!!!
OMG!!!! My scientific editor in chief...the Big B, MD...is very woebegone! Saying, "You didn't say anywhere in there that I SENT you that article!!!" So....Hear Ye, Hear Ye!!!! The Big B sent me this article. And now...he's gonna... Jump around! Jump up, jump up and get down!! Jump! Jump! Jump!
Love you, B!!!! - c
From: Journal of Applied Physiology, January 3, 2013 By: Radom-Aizik, Aldivar, Haddad, Cooper.
"Natural Killer (NK) cells are unique innate immune cells that increase up to fivefold in the circulating blood with brief exercise and are known to play a key role in first-response defense against pathogens and cancer immunosurveillance." "Thirteen healthy men performed ten 2 minute bouts of cycle ergometer exercise at a constant work equivalent to an average of 77%, interspersed with 1 minute of rest. Blood was drawn before and immediately after the exercise challenge." Lots of fancy tests "were used to determine that exercise significantly altered the expression of 986 genes and 23 miRNAs....We found exercise-related gene pathways were predominantly associated with cancer and cell communication, including p53 signaling pathway, MELANOMA, Glioma, Prostate cancer, Adherens junction and Focal adhesion."
Ok...so that's a little rich for my blood...have to admit...no idea about Adherens junction and Focal adhesion...but....what the heck. B can't yell at me for my INSANITY with Shaun T after my treatments. I got some proof it's doing me good!! So, COME ON Y'ALL!!!!!!
It may be a House of Pain... But... Jump around! So get out your seats and jump around! Jump around! Jump up, jump up and get down!!!!! Make those Natural Killer cells even better in 2013!!!!!
OMG!!!! My scientific editor in chief...the Big B, MD...is very woebegone! Saying, "You didn't say anywhere in there that I SENT you that article!!!" So....Hear Ye, Hear Ye!!!! The Big B sent me this article. And now...he's gonna... Jump around! Jump up, jump up and get down!! Jump! Jump! Jump!
Love you, B!!!! - c
Better Diet advice for Melanoma
I love food. I like the taste, the history, the culture, the socialization the sharing of food allows with family and friends. When the kids were home, we all had supper together EVERY DAY. It was a cherished time together, to share our day, to learn how to carry on adult conversation, to love each other. In my travels, the food of other cultures is a big part of the allure for me. As a nurse practitioner I have taken at least three different college level nutrition courses. I teach parents and children about food daily. How to introduce and make first fruits and veggies a positive experience for little 4 and 6 monthers. How to reduce portion size, cut out junk and sweets and emphasize fruits and vegetables, while incorporating the family's budget and preferences for children who are obese. I have helped many children and their families attain success. For some, I have not. Diet and nutrition advice and education are a huge part of my life EVERY DAY.
I will eat anything. The only things I can think of that I don't particularly care for are mango, rutabagas, and papaya. I eat more fruits and vegetables than most people can name. Many of my meals are vegetarian. However, I love a good steak. I rarely eat fast food, prepackaged or processed foods, carbonated or other types of sugared drinks, fried foods, or sweets. I do love a delicious piece of chocolate cake, fried chicken (especially the skin!!!!), and fruit desserts. I drink coffee or tea in the morning and often have wine with dinner. I practice what I preach and believe in: I eat predominantly fruits and vegetables with whole grains, some chicken or fish..no junk and few sweets. Nevertheless, my habit of a life-long healthy diet, still allowed me to contract melanoma...and though I continued down my healthy path, I even progressed to Stage IV. Yet, I still advocate for a healthy diet and exercise as a part of life for EVERY person.
With all that said....there is NOTHING that makes me more angry than some charlatan selling "diet" products or even well meaning, but totally uninformed individuals, putting out information about "DIETS" that prevent or cure melanoma and other cancers!!!! The damage here is two fold. The "diets" don't work and desperate individuals waste precious time and treasure on these miraculous "cures and treatments", often delaying or bypassing real therapies that have some chance of actually helping them. So....here's the real scoop on some of the most recently touted "diets" to fix your melanoma right up....
THE SUGAR FREE DIET
The idea here is that if you eat no sugar or carbohydrates your body will have no glucose to feed the tumors and they will miraculously die. Oh, what a joy it would be if things were that simple. However, if you eat nothing but termites, dandelion leaves, and spinach - your body will turn that into glucose just as it will when you ingest nothing but cotton candy, snickers bars, and sugar cubes. That's what our body does. It turns quinoa and white bread, steak and chicken, turnips and chocolate....all of it...into glucose. PERIOD. Going sugar free to stop cancer doesn't work. Doesn't make sense. And remember....this is from the woman who doesn't want you to eat a lot of sugar...especially if you are over weight, or if you have diabetes...for other reasons....but, this WILL NOT CURE CANCER!!!!!! Would that it could. But it can't. Sorry.
THE KETOGENIC DIET
Kind of the same idea. Starve the tumor of glucose by putting the body into ketoacidosis by eating nothing but fat and protein, ie no carbs. This is the same diet Atkins made a "killing" off of for weight loss, and it does work in that regard...to some extent...though increased cholesterol levels are noted on the diet and usually the weight returns rapidly once a normal diet is resumed. I won't go into all the details about what a diet like this does to the arteries in your heart and brain, but just remember....Atkins admitted having experienced cardiac arrest personally!!! Some studies have shown some usefulness for a ketogenic diet in the control of seizures...but it is a very difficult diet to maintain and ironically, ketoacidosis is what one works very hard to avoid in patients with diabetes (individuals who can't metabolize glucose because they lack a fully functioning pancreas which normally produces the insulin required for the job) because it can lead to seizures, coma, and DEATH!!! I have taken care of patients in PICU in this circumstance and they just about scared me to death!!! I digress. Back to melanoma. This got kicked off in the melanoma/cancer world because a radiologist noted that people who were in ketosis had less uptake in their tumors on their scans. Yet, studies done to examine this in cancer patients DO NOT show that tumors went away or that cancer patients fared any better on such a diet. So...again...the proponents of this diet tout its magical powers to starve tumors with no real data to back it up.
GERSON THERAPY
Now this is a real doozy!!! Fresh organic juices, "from 15 pounds of organically grown fruits and vegetables each day" are to be made and consumed hourly in the individual's home in order to "break down diseased tissue" while "coffee enemas aid in eliminating toxins from the liver". (Seriously, did these people not learn the children's song...the ankle bone is connected to the leg bone? Coffee up my patoot is NOT going to connect with my liver!!! Simultaneously, I know their response to that. Many things, like bilirubin in jaundiced babies is excreted from the liver to the gut...and we get it out of the baby's body by getting them to poop!!! However, this is NOT what they said on their site....I don't think they have that much sense...AND...cancer DOESN'T work like that!!!!) For cancer patients, the web site recommends 13 glasses of raw fresh juice daily, prepared and consumed each waking hour. (How on earth would you have time to live your life if you are doing this???!!!!!) The juicer they recommend costs $2,400.00. Additionally, they have the patients take supplements of potassium, Lugol's solution, Vit B12, Thyroid hormone, and pancreatic enzymes. Thyroid hormone???? Really??? This is NOT something you want to mess with!!! And THEN...ironically....Lugol's solution, an elemental iodine and potassium iodide mixture in water, was once used as a treatment for HYPERTHYROIDISM!!!! Meaning, administering iodine causes temporary cessation of function of the thyroid gland and can lead to HYPOthyroidism!!! No wonder they prescribe additional thyroid hormone. On top of that, the price of Lugol's solution runs $20-25.00 per 1-2 ounces. Furthermore, while it is used legitimately for the emergency purification of drinking water, the lethal dose of free iodine for an adult human, 2-3 grams, is about 40-60ml of 5% Lugol's solution. Not exactly a risk free proposition is it????? But, even more...GERSON THERAPY DOESN'T CURE CANCER!!!!!!!!!!!! It just doesn't. And worse, I know of at least one individual, who abandoned his cancer therapy to try it. His melanoma grew and grew. He kept trying to hold onto the idea that Gerson would give him the cure he sought. It didn't. And, when he finally realized that, and started taking a BRAF inhibitor....it was too late. Things were too far along. He is no longer with us. I have to believe he is helping me write this blog. Gerson therapy is NOT a cancer cure!!!
CELLECT
WOW!!! That's the only legitimate response to this one. The lurid "details" of supposed cancer patients "coughing up" lung tumors that some folks have repeatedly been posting on some of the melanoma forums is just....WOW!!! Per their site, Cellect is a dietary supplement that comes in capsules or a chocolate, strawberry or vanilla flavored powder. You are to take at least one "serving" per day which is the equivalent of 24 capsules or 1 scoop of powder along with three cod liver gel caps daily. The cost for a one month supply of one "serving" daily dosing (caps or powder) is a mere $100.00. For an individual weighing 100-175 pounds the site recommends the one scoop daily regimen for "maintenance". To "Slow Symptoms" you need 48 caps or 2 scoops plus cod liver oil daily...or....$200.00 per month. For "chemistry support with a maximum weight of 175 pounds" you need triple the dose...and the price...$300.00 per month. And if you weigh more than 175, you will require 96 caps or 4 scoops daily at a cost of $400.00 a month!!!! So...what is in this magical elixir??? Vitamins A, C, D3, E, Calcium (68% of recommended daily value), Iron (at 10% of RDV), iodine, magnesium, zinc, selenium, and chromium. Here's the best hot news I can give you folks!!!! Ready????? For $4-13.00 depending on brand...you can get 100 tablets of a Women's daily multivitamin. In each daily vitamin, you will get the exact same thing as one "SCOOP" of Cellect minus the iodine...but if you eat one teaspoon of salt per day...you are more than covered. Plus, the one a day vitamin will give you 100% of the recommended daily value of iron. Two final points: 1. The Cellect web site repeatedly warns about the risk of "loose bowels", "diarrhea", and "upset stomachs". With all those vitamins washed down with a healthy dose of cod liver oil....I guess so!!! If you are taking ipi or anti-PD1..PLEASE reconsider before starting this business!!!! You could get disqualified from your trial, or from ever getting to participate in another one for these drugs, because of "collitis" which is an inherent risk with these immunotherapies, that was perhaps brought on by Cellect. 2. And I think this says it all... In 4 different places on the Cellect web site THEY say: "Please know that CELLECT, or any person relative to this product do not make any implications, promises, nor guarantees that CELLECT will reverse any disease." "CELLECT is a dietary supplement manufactured and formulated by CELLECT. It is manufactured to meet the highest quality and standards set by Cellect." Please tell me that the rest of you are laughing out loud...or at least staring incredulously at the screen. CELLECT can't even make any claims to help you because they would have their pants (probably very expensive pants) sued off them if they did, cause it's just not true!!! AND....they make CELLECT in order to meet "the highest quality and standards" (What on earth does that even mean???) "set by Cellect." Set by: themselves. I like how they capitalized CELLECT in all their crap except when they note that the "standards" were set by "Cellect". Nice touch, huh? I warned you!!! WOW!!!!!!!!!!
SO.....lets make melanoma better in 2013.
I do not want another person to give up what might be a viable treatment...and believe me...in melanoma world....they all suck great big hairy green giant wizard balls...just to fall for snake oil and its salesmen. No matter how convincingly packaged. No matter how adamant the testimonials. Do your research. Talk to a real live melanoma oncologist. Think about whether the things you are advised to do really make sense. Eat right. Get some exercise. Hang tough. You've got me and a lot of other ratties on your side. Yours - c
I will eat anything. The only things I can think of that I don't particularly care for are mango, rutabagas, and papaya. I eat more fruits and vegetables than most people can name. Many of my meals are vegetarian. However, I love a good steak. I rarely eat fast food, prepackaged or processed foods, carbonated or other types of sugared drinks, fried foods, or sweets. I do love a delicious piece of chocolate cake, fried chicken (especially the skin!!!!), and fruit desserts. I drink coffee or tea in the morning and often have wine with dinner. I practice what I preach and believe in: I eat predominantly fruits and vegetables with whole grains, some chicken or fish..no junk and few sweets. Nevertheless, my habit of a life-long healthy diet, still allowed me to contract melanoma...and though I continued down my healthy path, I even progressed to Stage IV. Yet, I still advocate for a healthy diet and exercise as a part of life for EVERY person.
With all that said....there is NOTHING that makes me more angry than some charlatan selling "diet" products or even well meaning, but totally uninformed individuals, putting out information about "DIETS" that prevent or cure melanoma and other cancers!!!! The damage here is two fold. The "diets" don't work and desperate individuals waste precious time and treasure on these miraculous "cures and treatments", often delaying or bypassing real therapies that have some chance of actually helping them. So....here's the real scoop on some of the most recently touted "diets" to fix your melanoma right up....
THE SUGAR FREE DIET
The idea here is that if you eat no sugar or carbohydrates your body will have no glucose to feed the tumors and they will miraculously die. Oh, what a joy it would be if things were that simple. However, if you eat nothing but termites, dandelion leaves, and spinach - your body will turn that into glucose just as it will when you ingest nothing but cotton candy, snickers bars, and sugar cubes. That's what our body does. It turns quinoa and white bread, steak and chicken, turnips and chocolate....all of it...into glucose. PERIOD. Going sugar free to stop cancer doesn't work. Doesn't make sense. And remember....this is from the woman who doesn't want you to eat a lot of sugar...especially if you are over weight, or if you have diabetes...for other reasons....but, this WILL NOT CURE CANCER!!!!!! Would that it could. But it can't. Sorry.
THE KETOGENIC DIET
Kind of the same idea. Starve the tumor of glucose by putting the body into ketoacidosis by eating nothing but fat and protein, ie no carbs. This is the same diet Atkins made a "killing" off of for weight loss, and it does work in that regard...to some extent...though increased cholesterol levels are noted on the diet and usually the weight returns rapidly once a normal diet is resumed. I won't go into all the details about what a diet like this does to the arteries in your heart and brain, but just remember....Atkins admitted having experienced cardiac arrest personally!!! Some studies have shown some usefulness for a ketogenic diet in the control of seizures...but it is a very difficult diet to maintain and ironically, ketoacidosis is what one works very hard to avoid in patients with diabetes (individuals who can't metabolize glucose because they lack a fully functioning pancreas which normally produces the insulin required for the job) because it can lead to seizures, coma, and DEATH!!! I have taken care of patients in PICU in this circumstance and they just about scared me to death!!! I digress. Back to melanoma. This got kicked off in the melanoma/cancer world because a radiologist noted that people who were in ketosis had less uptake in their tumors on their scans. Yet, studies done to examine this in cancer patients DO NOT show that tumors went away or that cancer patients fared any better on such a diet. So...again...the proponents of this diet tout its magical powers to starve tumors with no real data to back it up.
GERSON THERAPY
Now this is a real doozy!!! Fresh organic juices, "from 15 pounds of organically grown fruits and vegetables each day" are to be made and consumed hourly in the individual's home in order to "break down diseased tissue" while "coffee enemas aid in eliminating toxins from the liver". (Seriously, did these people not learn the children's song...the ankle bone is connected to the leg bone? Coffee up my patoot is NOT going to connect with my liver!!! Simultaneously, I know their response to that. Many things, like bilirubin in jaundiced babies is excreted from the liver to the gut...and we get it out of the baby's body by getting them to poop!!! However, this is NOT what they said on their site....I don't think they have that much sense...AND...cancer DOESN'T work like that!!!!) For cancer patients, the web site recommends 13 glasses of raw fresh juice daily, prepared and consumed each waking hour. (How on earth would you have time to live your life if you are doing this???!!!!!) The juicer they recommend costs $2,400.00. Additionally, they have the patients take supplements of potassium, Lugol's solution, Vit B12, Thyroid hormone, and pancreatic enzymes. Thyroid hormone???? Really??? This is NOT something you want to mess with!!! And THEN...ironically....Lugol's solution, an elemental iodine and potassium iodide mixture in water, was once used as a treatment for HYPERTHYROIDISM!!!! Meaning, administering iodine causes temporary cessation of function of the thyroid gland and can lead to HYPOthyroidism!!! No wonder they prescribe additional thyroid hormone. On top of that, the price of Lugol's solution runs $20-25.00 per 1-2 ounces. Furthermore, while it is used legitimately for the emergency purification of drinking water, the lethal dose of free iodine for an adult human, 2-3 grams, is about 40-60ml of 5% Lugol's solution. Not exactly a risk free proposition is it????? But, even more...GERSON THERAPY DOESN'T CURE CANCER!!!!!!!!!!!! It just doesn't. And worse, I know of at least one individual, who abandoned his cancer therapy to try it. His melanoma grew and grew. He kept trying to hold onto the idea that Gerson would give him the cure he sought. It didn't. And, when he finally realized that, and started taking a BRAF inhibitor....it was too late. Things were too far along. He is no longer with us. I have to believe he is helping me write this blog. Gerson therapy is NOT a cancer cure!!!
CELLECT
WOW!!! That's the only legitimate response to this one. The lurid "details" of supposed cancer patients "coughing up" lung tumors that some folks have repeatedly been posting on some of the melanoma forums is just....WOW!!! Per their site, Cellect is a dietary supplement that comes in capsules or a chocolate, strawberry or vanilla flavored powder. You are to take at least one "serving" per day which is the equivalent of 24 capsules or 1 scoop of powder along with three cod liver gel caps daily. The cost for a one month supply of one "serving" daily dosing (caps or powder) is a mere $100.00. For an individual weighing 100-175 pounds the site recommends the one scoop daily regimen for "maintenance". To "Slow Symptoms" you need 48 caps or 2 scoops plus cod liver oil daily...or....$200.00 per month. For "chemistry support with a maximum weight of 175 pounds" you need triple the dose...and the price...$300.00 per month. And if you weigh more than 175, you will require 96 caps or 4 scoops daily at a cost of $400.00 a month!!!! So...what is in this magical elixir??? Vitamins A, C, D3, E, Calcium (68% of recommended daily value), Iron (at 10% of RDV), iodine, magnesium, zinc, selenium, and chromium. Here's the best hot news I can give you folks!!!! Ready????? For $4-13.00 depending on brand...you can get 100 tablets of a Women's daily multivitamin. In each daily vitamin, you will get the exact same thing as one "SCOOP" of Cellect minus the iodine...but if you eat one teaspoon of salt per day...you are more than covered. Plus, the one a day vitamin will give you 100% of the recommended daily value of iron. Two final points: 1. The Cellect web site repeatedly warns about the risk of "loose bowels", "diarrhea", and "upset stomachs". With all those vitamins washed down with a healthy dose of cod liver oil....I guess so!!! If you are taking ipi or anti-PD1..PLEASE reconsider before starting this business!!!! You could get disqualified from your trial, or from ever getting to participate in another one for these drugs, because of "collitis" which is an inherent risk with these immunotherapies, that was perhaps brought on by Cellect. 2. And I think this says it all... In 4 different places on the Cellect web site THEY say: "Please know that CELLECT, or any person relative to this product do not make any implications, promises, nor guarantees that CELLECT will reverse any disease." "CELLECT is a dietary supplement manufactured and formulated by CELLECT. It is manufactured to meet the highest quality and standards set by Cellect." Please tell me that the rest of you are laughing out loud...or at least staring incredulously at the screen. CELLECT can't even make any claims to help you because they would have their pants (probably very expensive pants) sued off them if they did, cause it's just not true!!! AND....they make CELLECT in order to meet "the highest quality and standards" (What on earth does that even mean???) "set by Cellect." Set by: themselves. I like how they capitalized CELLECT in all their crap except when they note that the "standards" were set by "Cellect". Nice touch, huh? I warned you!!! WOW!!!!!!!!!!
SO.....lets make melanoma better in 2013.
I do not want another person to give up what might be a viable treatment...and believe me...in melanoma world....they all suck great big hairy green giant wizard balls...just to fall for snake oil and its salesmen. No matter how convincingly packaged. No matter how adamant the testimonials. Do your research. Talk to a real live melanoma oncologist. Think about whether the things you are advised to do really make sense. Eat right. Get some exercise. Hang tough. You've got me and a lot of other ratties on your side. Yours - c
Better news for MEK and BRAF/MEK combos!
MEK (still available only in trials for melanoma) is a downstream inhibitor in the same pathway as the BRAF inhibitors. Meaning - it turns off the signal the melanoma cells are getting to grow. MEK162 seems to work in patients with NRAS mutations as well as those having V600 BRAF. Patients with NRAS showed a 68% rate of clinical benefit per Sosman, quoted in Uptodate.com. This is important since, while most MEK products have only been tested in V600 BRAF positive patients, at least one MEK product (MEK 162) has activity in, and is therefore an option for, patients who are not positive for the BRAF mutation, though it does require the NRAS mutation. (Clear as mud, yes????)
In September of 2012 the New England Journal of Medicine published the article, "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations." By: Flaherty, Infante, Sosman, Falchook, Weber, et al.
Basically, they noted that "resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted [trials] of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor."
So...in 247 patients with metastatic melanoma and BRAF V600 mutations, they gave various doses of dabrafenib or trametinib to 85 patients and randomly assigned 162 patients to a combo of dabrafenib plus trametinib or dabrafenib only. (Seriously!!! Who names this shit?????)
Anyhow...Squamous cell carcinoma was seen in 7% of patients getting the combo, but in 19% of patients getting monotherapy. Fever was more common in the combo group. "Median progression-free survival in the [combo] group was 9.4 months, as compared with 5.8 months in the monotherapy group. The rate of complete or partial response with combo therapy was 76% vs 54% with monotherapy."
Bottom line....despite increased fevers....the combination group did better in regard to fewer skin lesions and better in progression-free survival.
Meanwhile...the MEK inhibitor trametinib (GSK 1120212), according to a report in Nature Biotechnology, published online on Jan 9, "might be close to reaching the market". The writer reports that, on December 4, an FDA advisory committee "discussed the drug's effectiveness for treating unresectable or metastatic BRAF V600 mutation positive melanoma, including safety monitoring in light of ophthalmologic and cardiac toxicities observed in adults taking the drug." Several MEK products (MEK 162 from Novartis, AZD 6244 [called selumetinib] from AstraZenceca, GADC-0973 from Genentech, as well as trametinib from GlaxoSmithKline, noted above) are to be in Phase 3 trials in 2013. "Roche is also starting a phase 3 trial in melanoma combining its BRAF inhibitor (Zelboraf/vemurafenib) with Genentech's MEK inhibitor." "For now, trametinib is the only MEK inhibitor with major clinical data behind it..." As demonstrated in the article I reported on above. An assistant professor at Moffitt is quoted saying...."results may start to iron out as more companies go into bigger trials."
Bottom, bottom line(s)....
I am glad more MEK products are coming to trial.
I hope all of them work as they should....as melanoma patients will be desperately trying to get into these trials...and ratties will pay the price if they don't.
MEK products may turn out to be effective in a broader group of patients than originally thought.
It seems that combinations of MEK and BRAF inhibitors may be yet another way to make the amazing results of BRAF inhibitors more durable and their side effects more tolerable.
Keep making things better, ratties. - c
In September of 2012 the New England Journal of Medicine published the article, "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations." By: Flaherty, Infante, Sosman, Falchook, Weber, et al.
Basically, they noted that "resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted [trials] of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor."
So...in 247 patients with metastatic melanoma and BRAF V600 mutations, they gave various doses of dabrafenib or trametinib to 85 patients and randomly assigned 162 patients to a combo of dabrafenib plus trametinib or dabrafenib only. (Seriously!!! Who names this shit?????)
Anyhow...Squamous cell carcinoma was seen in 7% of patients getting the combo, but in 19% of patients getting monotherapy. Fever was more common in the combo group. "Median progression-free survival in the [combo] group was 9.4 months, as compared with 5.8 months in the monotherapy group. The rate of complete or partial response with combo therapy was 76% vs 54% with monotherapy."
Bottom line....despite increased fevers....the combination group did better in regard to fewer skin lesions and better in progression-free survival.
Meanwhile...the MEK inhibitor trametinib (GSK 1120212), according to a report in Nature Biotechnology, published online on Jan 9, "might be close to reaching the market". The writer reports that, on December 4, an FDA advisory committee "discussed the drug's effectiveness for treating unresectable or metastatic BRAF V600 mutation positive melanoma, including safety monitoring in light of ophthalmologic and cardiac toxicities observed in adults taking the drug." Several MEK products (MEK 162 from Novartis, AZD 6244 [called selumetinib] from AstraZenceca, GADC-0973 from Genentech, as well as trametinib from GlaxoSmithKline, noted above) are to be in Phase 3 trials in 2013. "Roche is also starting a phase 3 trial in melanoma combining its BRAF inhibitor (Zelboraf/vemurafenib) with Genentech's MEK inhibitor." "For now, trametinib is the only MEK inhibitor with major clinical data behind it..." As demonstrated in the article I reported on above. An assistant professor at Moffitt is quoted saying...."results may start to iron out as more companies go into bigger trials."
Bottom, bottom line(s)....
I am glad more MEK products are coming to trial.
I hope all of them work as they should....as melanoma patients will be desperately trying to get into these trials...and ratties will pay the price if they don't.
MEK products may turn out to be effective in a broader group of patients than originally thought.
It seems that combinations of MEK and BRAF inhibitors may be yet another way to make the amazing results of BRAF inhibitors more durable and their side effects more tolerable.
Keep making things better, ratties. - c
Better ways to use BRAF inhibitors for melanoma!!!
In 2011, the FDA approved vermurafenib (Zelboraf) for the treatment of late stage melanoma patients with BRAF positive mutations. (About 50% of all melanoma patients will test positive for the required mutation...though with new, more refined testing perhaps that number will rise...as patients already tested and found negative with older tests have been found to be positive using the newer techniques.) BRAF positive melanoma patients who respond to Zelboraf (about 70-80%) experience a rapid and miraculous decrease in their tumors that lasts for about 7-8 months. At that point, most patients' tumors cease to respond to the drug and develop a lethal form of drug resistant tumors. There are amazing exceptions to this however, from patients themselves reporting a durable and constant response to Zelboraf of more than 13-35 months. (You rock Dick_K and jmmm!!!!!) Sadly, they are the exceptions.
Sooooo, how are we going to make 2013 better??
On January 9, Sciencedaily.com reported (with info largely from a report in Nature, 2013) that researchers in California and Switzerland have discovered that when melanoma cells develop resistance to vermurafenib (Zel) they have simultaneously developed an addiction to it. Once "addicted", the melanoma cells actually use vermurafenib to foster rapidly progressing, drug resistant tumors. The teams began a study of dosing mice with melanoma in an "on-again/off-again treatment schedule" and found that this method of dosing prolonged the lives of mice with BRAFi resistant melanoma tumors.
Specific studies in humans with this sort of on-again/off-again dosing pattern are being formally planned. Additionally, doctors have gradually been noting that in their patients who developed resistance to BRAF inhibitors and went on to other therapies, but were then reintroduced to Zel later, did, in fact, RE-respond. Now, medical opinion is heading toward the idea of reducing tumor burden in patients with Zel then, before tumors develop resistance, switch to a different therapy like ipi or anti-PD1. Or, as noted in the article, use an interrupted pattern of dosing with Zel in the first place. Another way of trying to maintain the response of Zel is to combine it with MEK (more on that later) or with other drugs. Furthermore, there is recent evidence that the use of BRAF inhibitors increases the amount of melanoma specific antigen present and may be a rationale for making the tumor cells more susceptible to immune therapy. Thereby, providing a rationale for planned sequencing of BRAF inhibitors followed by immunotherapy. However, the proof is in the pudding and that remains to be proven.
Bottom line....better. Keep up the research...AND...hang in there ratties!!!! - c
Sooooo, how are we going to make 2013 better??
On January 9, Sciencedaily.com reported (with info largely from a report in Nature, 2013) that researchers in California and Switzerland have discovered that when melanoma cells develop resistance to vermurafenib (Zel) they have simultaneously developed an addiction to it. Once "addicted", the melanoma cells actually use vermurafenib to foster rapidly progressing, drug resistant tumors. The teams began a study of dosing mice with melanoma in an "on-again/off-again treatment schedule" and found that this method of dosing prolonged the lives of mice with BRAFi resistant melanoma tumors.
Specific studies in humans with this sort of on-again/off-again dosing pattern are being formally planned. Additionally, doctors have gradually been noting that in their patients who developed resistance to BRAF inhibitors and went on to other therapies, but were then reintroduced to Zel later, did, in fact, RE-respond. Now, medical opinion is heading toward the idea of reducing tumor burden in patients with Zel then, before tumors develop resistance, switch to a different therapy like ipi or anti-PD1. Or, as noted in the article, use an interrupted pattern of dosing with Zel in the first place. Another way of trying to maintain the response of Zel is to combine it with MEK (more on that later) or with other drugs. Furthermore, there is recent evidence that the use of BRAF inhibitors increases the amount of melanoma specific antigen present and may be a rationale for making the tumor cells more susceptible to immune therapy. Thereby, providing a rationale for planned sequencing of BRAF inhibitors followed by immunotherapy. However, the proof is in the pudding and that remains to be proven.
Bottom line....better. Keep up the research...AND...hang in there ratties!!!! - c
Sad Melanoma stats for 2012
The National Cancer Institute estimates that 76,250 people were diagnosed with melanoma in 2012 and that 9,180 deaths occurred from the same disease.
Let's make the numbers much better in 2013! Here we go!!!!!! - c
Let's make the numbers much better in 2013! Here we go!!!!!! - c
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