SH#& HAPPENS so GET OVER IT!!!!

This is the title of a little book that I was given recently.  Inscribed inside:  "I think I have heard this before...somewhere...!  Love, Rose"  Hmm, I guess she has indeed.  It seems a rather hardened bit of advice to be given from your mother.  But, there it is.  During rough spots, my kids were petted, favorite dishes cooked. They were flattered and cajoled...but in the end....  You picked the wrong career, college, friend, lover? Didn't work out? Flat tire, speeding ticket, broken heating unit, over flowing toilet?  Life decided to put bird poo on your head?  Really, really, sorry...really.  NOW...get over it!!!!

Despite my own very sage advice, it is not always easy to apply.  Since BEFORE May 20th....I have endured non-stop mouth ulcers.  At the worst, the gums, tongue, lips....are all inflamed with bleeding areas and denuded lesions. Lost 8 pounds with that business.  At the best, there are scattered lesions and a tongue that feels like you sipped a huge gulp of scalding tea.  Along, with that...fun, itchy, but painful, pustular rashes have been scattered about.  PLUS, my right great toe "knuckle" has been pretty consistently red, swollen and painful...enough to wake one from sleep, with random arthralgias, especially in my ankles and knees.  I've had bout enough of this business!!!! 

Work has been particularly challenging.  It has rained almost daily for the past 6 weeks!!  We have had over 12 inches in just the past 2.  My beautiful daises, hostas, lilacs, and tomatoes have moldered!  My roof is leaking.  The air conditioner gave up.  Said, "Forget it!  I'm done!" SHIT definitely happens.

On the other hand....  Last weekend was exquisitely lovely.  I got to meet my pen pal, now dear friend, and his wonderful wife.  Friends from melanoma world for almost two years, and now friends from the real world...forever.  We chatted and chi'laxed.  And, as I already told them, though we spoke of melanoma, what we were dealing with, and where we were with things...it was not our focus.  It did not define us!  It was not what we most wanted to learn and share of each other!!!!  Lives well lived and shared.  Friends indeed.

And then...there is work.  Work that is hard and worrisome and irritating.  But...work that brings a smile and makes me proud. With women that look after me, keep up with me, support me...in all that I try to do for our children and with what I am going through.  Even taking it upon themselves to text Brent when they feel he needs to be aware of how loose my pants have become and that I am not eating enough at lunch in their estimation!!!!  I am there for them as well, for better or worse.  B says, "They are your support. That is why you will never leave."  Maybe so.  That...and the best boss in the world...who grants my vacation requests...and when he gets a bonus check from an insurance company for meeting all their evaluation criteria....what does he do????  Put it in his account?  NO!  He divides it equally among the roughly 50 employees...as an unexpected bonus!  I don't think it gets much better than that.


And, there's my Roo flitting about London as we speak.  Bringing joy by sharing hers.  And, Freddo, who knows exactly how to make me laugh, and carefully checks with his daddy to see how I am doing.  And, poor Ruthie, dealing with a leaky floor...OH yeah...SHIT happens!!!!  But, always making time for me, bringing a smile, letting me jabber, KNOWING me.  AND....SOMEBODY...who risked a great deal of wrath....falling directly upon his noggin head....who rang the door bell....INCESSANTLY....until I answered it...so I could see a beautiful rainbow.

Yep.  SHIT happens.  Get over it!  Cause rainbows and lots of other really great stuff does, too. - c

Patent application for a biomarker gene set for prediction of anti-PD1 efficacy. No conflict of interest here!!!

Predictive Biomarkers for Programmed Death Protein-1 Blockade Immunotherapy

This technology is a diagnostic biomarker gene set for the prediction of anti-Programmed Death Protein-1 (PD-1) blockade immunotherapy efficacy. Immunotherapy is regarded as a valid treatment option for melanoma patients with metastatic disease; however, its long-term efficacy in patients is poor as evidenced by 90% relapse rates in ipilumumab immunotherapy-treated patients. A set of biomarkers that predict patient outcome could influence treatment decisions and lead to a more efficacious and cost-effective tailored cancer therapy. In a retrospective study using our biomarker gene set on metastatic melanoma patient samples receiving PD-1 blocking antibody (BMS-936558) therapy, we show a statistically significant association between biomarker expression and patient response to PD-1 therapy.


COMMERCIAL OPPORTUNITY:
● In 2010, over 68,000 new cases of melanoma were diagnosed in the US. Immunotherapy treatment is recommended for many patients with metastatic disease, although the NCCN recognizes limited knowledge of which patients derive the most benefit from it.
● For example, over 90% of melanoma patients treated with the immunotherapy drug ipilimumab relapse after therapy. If patients were selected for this therapy based on their likelihood of response, insurance payers would save an average of over $115,000/patient on this large group of patients who receive no lasting benefit from the immunotherapy.
● Our biomarker set can be readily measured using standard RT-PCR expression assays on mRNA purified from CD8+ T-cells isolated from patient peripheral blood , making this a minimally invasive diagnostic procedure.
● Anti-PD-1 immunotherapies such as BMS-936558 and BMS 936559 (antibodies in clinical trials for a broad spectrum of cancers) could benefit from patient response prediction to maximize efficacy while reducing cost.

TECHNOLOGY:
This technology is a biomarker gene set where expression levels of a specific gene combination are used to predict clinical response to PD-1 blockade therapy. Primary CD8+ T-cells are isolated from samples of cancer patients’ peripheral blood, and the low expression of CD276 (p=0.0003) and high expression of NKTR (p=0.0263), PTEN (p=0.0232), and GATAD1 (p=0.0258) at baseline are correlated with clinical response to anti-PD-1 therapy. To date, efficacy of clinical response prediction using these biomarkers has been studied retrospectively in 22 melanoma patients (11 clinical responders and 11 clinical non-responders) at Moffitt Cancer Center.

PUBLICATION/PATENT: ● US Provisional Patent Application filed May 9, 2012 for Drs. Jeffrey Weber and Wenshi Wang and Bin Yu

I don't make this stuff up!!!  This is a copy of the patent application.  Just what I always dreamed to be....a "COMMERCIAL OPPORTUNITY" for Moffitt, Weber, Wang and Yu!!!! Not to mention my burning desire to have MY data, create a better methodology for insurance companies to deny care based on a "biomarker"!  Wouldn't want the insurance company to lose any money!!! Awesome! So...Weber, Wang, and Yu?  If you were suddenly forced to walk in any melanoma patient's shoes...you would prefer that, let's say...Blue Cross Blue Shield...would save $115, 000, and thereby deny you treatment, if your "test" showed that you would NOT have a permanent, relapse free response to immunotherapy?  Six months, a year, whatever, is less important than saving those insurance dollars since YOU wouldn't get "lasting benefit"?  AND....you would have this decision based on the gigantic, hugely significant number of 22 patients?  Hmmmmm....  They don't make them like Marie Curie anymore...apparently.  - c

I've looked at life from both sides now....

...and I think Twain had it right:  The two most important days of your life are:  the day you are born, and the day you find out why.

Beautiful rainy day with the binga-heads...who are finding out why.

Much love - c

Ode to Pati....a fallen comrade.

Shit!  What the hell?  She was beautiful and smart and kind and funny and an amazing wife, daughter, mom, and professor.  And I didn't even get to know her.  But, I've learned from her.  So can you.

As best as I can piece together Pati was diagnosed with melanoma, thin, easily removed, in 2008.  (Five years after my diagnosis.) Despite that surgery and sentinel node biopsy, melanoma returned in March of 2009 with a node found under her arm.  She had a complete lymphadenectomy with 24/45 nodes positive for melanoma and started radiotherapy.  In August she entered a trial with dendritic cell vaccines and interferon.  In December on 2009, distant metastases were found.  In January of 2010, she had surgery to remove 5 small tumors.  She was happy that the tumors were positive for the BRAF V600 mutation.  However, fighting her insurance company for coverage proved an impossible feat.  She discovered an organization called "Cross Border Health".  Through the help of that agency, she attained a place in a Phase III randomized trial comparing PLX4032 (which ended up being one of the first BRAF inhibitors approved...later named Vemurafenib) with a 60-70% response rate vs. a conventional chemo agent with a 5-13% response rate.  She railed against such insanity much as I have done here before. Why on earth would you place sick and dying people in a trial with a drug that is ALREADY KNOWN TO WORK FAR BETTER pitted against a drug KNOWN to do little or nothing?  WHY????  What does that prove?  What pretend game of science are we playing?????  But, there it was.  Finding she had been randomized to the chemo arm, she dropped out.  In July of 2010 there was Temazolomide.  In September - Ipi 3mg/kg for four doses.  March of 2011 - more ipi, same song, second verse.  In June she began Vemurafenib and was NED in Feburary 2012.  At some point things changed and she began a course of ipi with DCX (not really sure what that is exactly).  Finally, later that year, she was allowed into a Merck anti-PD1 trial.  Success was not to be found.  In December of 2012 she learned that anti-PD1 was not working and began a reinduction of  Zelboraf.  In February, always the fighter, she began the arduous TIL process.  Raising hope, gaining participation, finding funding.  Then, girding her loins for one hellacious ride.

What is TIL?  TIL (Tumor infiltrating lymphocytes) are used in an ACT (adoptive cell transfer) therapy like this:  A tumor is removed from the patient's body.  Lymphocytes are collected from it.  Those lymphocytes are tested in order to identify the cells that show the greatest anti-tumor activity.  Then....those particular cells are grown in a lab for several weeks.  If the TIL cells grow sufficiently, the patient is given a body pounding dosing of chemotherapy to rid the body of other lymphocytes so that the new TIL batch will be accepted more readily when they are infused with no other immune cells there to attack them.  The newly grown lymphocytes are then returned to the patient in an infusion along with a cytokine (immune stimulating agent) like IL2 (interleukin 2).  In numerous studies TIL demonstrates a 50% response rate in patients with metastatic melanoma.

For the past 5 months (not to mention the past 5 years) Pati dealt with painful procedures, horrible side effects, demeaning debilitation, and fought on.  She had her 43rd birthday in April, while still in the hospital receiving TIL.  She was not to fall in the successful 50%.  I learned today that she has passed.

Life is a great deal dimmer.  A world class warrior, a beautiful human, will no longer share her amazing self with the rest of us.  Pati brought the world together - literally.  Born in El Salvador, moving to Australia, time in Geneva and California, her life in Brussels.  Not only that, while working and dealing with melanoma full time, not to mention creating a family with her husband and two beautiful little boys, she founded M-ICAB, The Melanoma Independent Community Advising Board.  To say that she will be missed is an understatement like no other.

Feel her spirit here:

Pati's video...What is one life worth?

and here:

Pati's blog about her life with TIL

and here:

m-icab

Thank you, Pati.  You showed us how to live. I wish you and your loved ones peace. - c

Continued love and support...Thanks, Peds Care!!!!

On May 6, 2010, not long after experiencing sterotactic radiation for a brain met, followed by a right lung upper lobectomy, a beautiful basket with two lovely lavender hydrangeas arrived from my dear ones at Peds Care.  After enjoying their beauty indoors as long as possible, I planted them outside in a spot I thought they would like.  But, as we all learn, life happens...and in August, a storm brought a tree down on one of the plants.  Yet, as in life, the other continued to thrive and here is its beauty and success...today.  It made me smile and I thought I would share it with you all. Enjoy - c

3 miles....for my girls

I ran today, for my girls; for Kidlet and Rosie, Dania and Kathryn.  There was no PR. It was not particularly beautiful, being overcast and muggy.  It was not pain-free.  But, I did hear a tree fall in the woods. I saw a gold finch feeding on wild thistle on the side of the road.  I scoped out wild crab apples that I may forage later. And....it is done. But...I am not.

I wish I could tell you each day will bring sunshine and roses, with clear skin, good hair, and a number on the scale that will make you smile.  I wish those who, by all that is right, SHOULD love and support you, would never fail to do so.  I wish that your professors and friends, bosses and lovers would always play fair.  I wish all that for you and so much more....but it is unlikely to be so....ALL of the time.  So, you must enjoy those who ARE there and the small but tangible gift that EVERY day brings.  Even if the best you can say of some days is:  It is done.  But, I am not.

And should you ever fail to remember how beautiful and smart, creative and strong you really are?  Carry me in your heart and I will always be there to remind you.  Much love with hugs and kisses - c

Melanoma: Long Overall Survival in Patients Receiving Nivolumab

From presentation and interview given by Sznol at ASCO: Published:  Wednesday, June 05, 2013 Melanoma: Long Overall Survival in Patients Receiving Nivolumab BY RABIYA S. TUMA, PHD Favorable One- and Two-Year Survival Rates A total of 107 patients with metastatic melanoma enrolled in the trial, which was led by Mario Sznol, MD, Professor of Medical Oncology at Yale Cancer Center. To be eligible, patients had to have had at least one prior therapy but no more than four for advanced disease and no prior treatment with ipilimumab. Patients received intravenous nivolumab every two weeks at a dose of 0.1 to 10 mg/kg. The patients had a median age of 61.... the group was heavily pretreated, with 66 percent of patients having had at least two prior therapies and 25 percent,  three or more. Additionally, 78 percent of patients had visceral metastases and 36 percent had elevated lactate dehydrogenase, which is associated with a poorer outcome. The investigators saw no dose limiting toxicities. (With all the usual side effects I've already mentioned.) "There was no additional safety signal seen with the additional year of follow-up," Sznol said. The overall response rate was 31 percent across all doses, with no apparent dose response. The median duration of response was two years and 45 percent of the responders showed a response at the first tumor assessment at eight weeks, indicating that the responses can be both rapid and durable. Moreover, 12 of 17 patients who went off drug for reasons other than disease progression continued to respond for at least 16 weeks, and eight of those were continuing response at the time of the data analysis (range of 16 to 56 weeks). "You don't need continued treatment in a subset of patients in order to maintain response," Sznol said. Pointing to the Kaplan-Meier curve for progression-free survival, he noted that the curve dropped rapidly at first but then flattened out. "Although the median progression-free survival of 3.7 months is not overly impressive, the one- and two-year progression-free survival rates of 36 and 27 percent are," Sznol said. The median overall survival for the study group is 16.8 months. The one-year estimated overall survival rate is 62 percent and the two-year rate is 43 percent. With a median follow-up of 22 months (range 14 to 51 months), 47 patients remain alive. [When] asked about the optimal duration of treatment with nivolumab. Sznol said the optimal duration remains unclear, but that his group at Yale have discontinued therapy on two patients with near complete responses, one after three cycles and the other after five cycles. Neither patient has relapsed. "So at least at complete responders, you probably don't need to continue the drug," he said. "The question is, what do you do in patients with stable disease or partial response. Do you continue to give them drug every two weeks or do you decrease the interval of dosing? I don't think we have an answer to that question." [When] asked if it was possible to biopsy lesions in responders to see if the lesions really contain residual disease. "I think the rate of complete response here is a little bit underestimated," Sznol responded. "Of the five patients we treated at Yale who are responders, four are complete responders or near-complete responders and the fifth patient, who has a liver nodule, is PET negative. “So there wasn't much for us to biopsy in our long-term responders. We have biopsied a few patients with progressive disease, but we haven't analyzed that tissue yet." Brain Metastases? ...Asked about the likelihood that the drug works on brain metastases. Sznol noted that this trial excluded patients with active brain lesions, but accepted patients with previously-treated central nervous system tumors. Therefore the answer to the question remains unknown. "But we have long-term responders who didn't develop any brain metastases, so that suggests that maybe we are controlling disease in the brain," he said. There are now three ongoing Phase III trials testing nivolumab in patients with metastatic melanoma. A trial testing the drug in patients with brain metastases has been proposed, but Sznol said he did not know if it was approved or would go forward.

For what it's worth....Overall, the response is still very good over 2 years...and if you're a complete responder you may not "ever" need to have any more drug.  While the "brain effect" remains unknown...in a backwards way...Nivolumab looks like it may have a good effect there as well.  Now...my group is in a different group all together, because of the volume of disease THIS group was dealing with vs the NED level my group had. Still a lot of unanswered questions:  How long does response REALLY last?  What is the best treatment dose?  What is the best treatment frequency?  What about folks with no prior treatment?  What about folks with brain tumors?  Come on BMS and Merck....risk a little of your bottom line for the ratties.  Let brain tumor patients in a trial.  YOU don't have anything to REALLY lose....now do you????  Just say'n - C