No. Concealed. Ugliness. Redux!

no concealed ugliness per Oona!

The link above certainly explains my attachment to the phrase and the mission.  It is not always easy to be open and honest and proud of what's on the inside.  It takes a lot of work to keep things pretty, neat, and clean in places that are fairly easily hidden - under appliances, inside closets, clothing innards, and our hearts.  However, when we go to the trouble - there are fewer bad smells, less time wasted searching for what we need, and clothing as well as life...just hangs better.  You can walk around with much fewer worries about all your underpinnings. 

 

For years I have challenged myself to purge the anger, share the love, and go to the trouble to clean up messy layers - inside and out.  Every new experience and garment certainly comes with a learning curve.  I have never attained 100% success.  The inside of these dresses took more work than the outside!!! Yet, I am happy with my attempts, what I've learned, and what I am able to share with those who want to share with me.  Sadly, there is always ugliness - disease, war, disasters (natural and man-made), and plain old, mean, ornery folks to deal with.  I will still work to keep my side of any relationship open and honest.  What others choose to do will either foster their own lives and feelings of self worth as well as their relationships....or not!  And while the beautiful forsythia was indeed planted to block the view of a power pole and its supporting wires, I know what's real, what's underneath, and what I can do (if I choose) to make the world a better place....with no. concealed. ugliness.

Working to make the world beauty full! - c
PS  Happy day, Roo!!!

Across Five Aprils

I made it.  Across Five Aprils.  Having had SRS to a brain tumor April 27 and right upper lobectomy to my lung days later on April 30, 2010.  As promised, ready for our book club discussion. The back story:

Across Four Aprils: A melanoma perspective

Across Two Aprils

Worst part is over

SRS done - home again

Across Five Aprils, a historical novel by Irene Hunt, tells of joy and tears, love and hate, broken hearts and survival, as a family in the border state of Illinois is torn apart during the Civil War:  April 1861 through April of 1865.  Initially, I mentally attached my journey with melanoma and this blog effort to the title due to its matching chronology, the struggle both families endured, the beauty of the writing that captured my heart so many years ago, and the incredible, almost enchanted loveliness, April brings to Appalachia.  However, over the years, I've come to realize the tales are even more connected.  It seems that all the suffering during the Civil War, in which an unimaginable number, 620,000 American soldiers (2% of the population) died, was the only way to abolish the horror that was slavery in our country.  In 2015, it is predicted that 73,870 new melanoma patients will be diagnosed and about 10,000 of them will die. As such, MY personal, internal civil war and my family's struggle, has been necessary in order to banish melanoma from my life, at least for the past 5 years.  I hope that as more and more melanoma soldiers like myself march on and better treatments and treatment combinations are developed, the tide will turn.  It is also my hope that we recognize the value of those 620,000 dead Americans and their families who suffered through the loss, so that brutality and loss of life due to prejudice and fear, with riots and destruction as a response, in cities like Oakland, Los Angeles, New York, and Baltimore - will be no more.

May the beauty of April be with you in the coming year.  Love - c

On loss, domestic violence, Melissa and Grayden...

A community, an office, multiple families....experienced loss today.  Sadly, I don't mean Nepal and its earthquake.  Though if human losses there number only 4,000 souls, I suspect it will be a miracle.  But, no.  I refer to a loss much smaller.  Much greater.  More frequent.  More horrific.  The loss of women and their children from domestic violence.  A nightmare in life. A tragedy in death.  In retrospect, an event as clear and as relentless as an oncoming hurricane.  Mac Truck.  Earthquake.  A famine.  A plague. Why do we, as a society, allow these men guns?  Why do we fail to take the actions we need to take?  Why do restraining orders require a meeting?  Later?  A separate appointment?  After local authorities have already documented the terrible, most recent event?  When we, and law enforcement, and life, and the administrator of every women's shelter KNOW the tragic, repetitive, relentless result?  Why?

"The real hell of this is that you're going to get through it.  Like a starfish, the heart endures its amputation."  Gail Caldwell, From - Let's Take the Long Way Home

Life is fleeting.  That is all I know.   Make sure those you love know you do.  Melissa and Grayden would agree.   - c

BRAFi better when combined with or after immunotherapy and surgery!!!

Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.  Cooper, Juneja, Sage, et al.  Cancer Immunology Research.  April 2015.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (approx - 6 months).  In contrast, immunotherapy results in lower response rates, but responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltrates and a decrease in immunosuppressive cytokines.  However, there is also increased expression of the immunomodulatory molecule PD-L1, which may contribute to resistance."  So, with that info these peeps figured that BRAF therapy may play well with the PD-1 pathway to get rid of tumors.  They produced mice with BRAF positive melanoma and found that sure enough BRAF inhibition increased intratumoral CD8+ T cell density and cytokine production like it does in people.  When they gave the mice anti-PD1 or anti-PD-L1 WITH the BRAF inhibitors the got an "enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor infiltrating lymphocytes....demonstrating synergy between combined BRAF-targeted therapy and immune checkpoint blockade."

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.  Wyluda, Cheng, Schell, et al.  Cancer Biol Ther.  March 2015.

"We report 3 cases of complete response in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (HD IL2 followed by ipi with or without concurrent radiation).  After progression during or post immunotherapy, these patients were given BRAFi and developed complete responses.  Based on the concomitant presence of autoimmune manifestations (vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAFi.  Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months.  The 3 patients remain well and in CR off all therapy at up to 15 months with radiographic follow-up....with high levels of non-T-regulatory CD4 positive effector phenotype T cells, which persisted after completion of therapy."


Successful (neo)adjuvant BRAF-targeted theapy in patient with locally advanced BRAF V600E mutant melanoma.  Seremet, Suppa, Trepant, et al.  Melanoma Research. January 2015.

62 year old patient, dx'd with Stage IIIB melanoma with large, inoperable, primary lesion surrounded by ~25 secondary satellite and intransit lesions.  She started on 960 mg daily vemurafenib.  Stopped and resumed at 720 mg twice daily.  Was then placed on combined dabrafenib and trametinib to decrease side effects.  Successive exams showed gradual reduction in the thickness of the lesion.  After about 5 months of therapy, surgery was performed and the path analysis showed almost complete regression of tumor cells.  Dabrafenib/trametinib therapy was continued only 3 months after surgery and stopped at the patient's request.  She remains in complete remission 8 months after surgery.

My thoughts:
1.  Really heartening to hear that BRAF inhibitors can improve outcomes in these patients.
2.  Especially so, when these responses are already more durable than is typically seen when BRAF inhibitors are given alone AND responses have continued with patients OFF the meds!!!
3.  Combining BRAFi and immunotherapy can cause real problems with side effects.
4.  Like the rest of us, it remains to be seen how durable these "durable" responses will be.

Go, ratties!  GO! - c

Sping in Charleston is...

Bigger.  Brighter.  Bolder.  Even, a little badder!!!  Than just about anywhere else!

 

Thanks for an early Spring and a wonderful trip, Bentie!!! - c

Anti-PD1 (Opdivo/Nivo and Keytruda/Pembro) effective in treating lung cancer! ($$$$$$$$$$$$$...)

Reuters report on Merck's Keytruda

In her report, author Deena Beasley states that Keytruda shrank tumors "in nearly half" of patients with squamous and non-squamous non-small cell lung cancers (NSCLC), IF they had high levels of PD-L1.  Merck is seeking FDA approval of the drug for patients who have progressed despite previous treatment.  In the study noted, 495 NSCLC patients were tested.  Response rates (defined as tumor shrinkage of at least 30%) were influenced by the presence of PD-L1 expression on the tumor.  45% of patients with high PD-L1 levels responded vs only 16.5% of patients with lower (1-49%) expression of PD-L1, while patients with minimal PD-L1 expression (less than 1%) had a response rate of only 10.7%.  Overall, 19% of patients in this trial responded.  Side effects included thyroid problems as well as pneumonitis (seen in 3.6% of patients, from which one died).  Ms. Beasley also notes that as lung cancer kills approximately 160,000 Americans annually this population is the "biggest opportunity" for anti-PD1 drugs with sales expected to reach in the billions.

Reuters report on Bristol-Myers Squibb's Opdivo

In this article, author Ransdell Pierson reports that BMS halted the study "Checkmate-057" after an independent monitoring committee concluded Opdivo was better than standard chemo used in patients with previously treated nonsquamous NSCLS.  Opdivo is already FDA approved for squamous NSCLC.  Wall Street is expecting Opdivo to be the market leader of the anti-PD1 drugs with peak annual sales of $7 BILLION by 2020.

My thoughts:
1.  I hope they haven't once again made something that is truly more effective than the standard treatment available only after the failure of less effective treatments! I don't know the data for NSCLC well enough to say that this is actually the case.  But, I hope not.
2.  Poor little rich pharmaceutical companies.  Putting all that money into the care of us clinical trial ratties with never a hope of beginning to recoup their losses.  Oh my, oh my, oh my!  
3.  My condolences to the family who lost their loved one to pneumonitis.
4.  My best wishes to NSCLC patients who may have a chance now. 

To you all - I wish you well. - c

What to expect in Ipi vs Nivo Trial as adjuvant for resected melanoma???

The ipi vs nivo trial for resected Stage III and Stage IV melanoma is now recruiting!!!  Check out some info about adjuvant melanoma treatments and the trial reported here:  

New ipi vs nivo trial for resected melanoma

So what can patients expect?  These ratties will most certainly teach us a great deal.  However, the results of my NED arm from the nivo trial I have participated in can give some idea about how the Nivo/Opdivo arm in this trial might go for prospective patients.  Remember we were testing results of Nivolumab in NED vs NON-resected melanoma as well as doses that ranged from 1-3-10mg/kg and for some of us, combined with peptide vaccines as well.  (The vaccines provided no benefits, so no worries about missing out on that!!!) That report and review are here:

Results from 33 ratties in my Nivo/Opdivo trial - published!

Thoughts on my nivo/opdivo trial results, 4 years later

With this sum up from the published results:
"Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up."  AND:  "Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable."  Dosage (1, 3, 0r 10mg/kg) did not seem to have significant effect on relapse rate or adverse events.  AND:  "Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant."  BUT, lower MDSC levels at the start did demonstrate a positive effect:  "There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients."

But, what about the folks who are in the adjuvant ipi arm?  Here is an article reporting on a study that examined just that.

Adjuvant ipilimumab vs placebo after complete resection of high-risk stage III melanoma:  a randomized, double-blind, phase 3 trial.  Eggermont, Chiarion-Sileni, Grob, Drummer, Wolchok, Schmidt, Hamid, Robert, Lebbe, Weber, et al.  Lancet Oncol. 2015 March 31. [epub ahead of print]

"We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.  We did a double blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis greater or equal to 1mm or intransit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not had previous systemic therapy for melanoma from 91 hospitals located in 19 countries.  Patients were randomly assigned (1:1)....to receive IV 10mg/kg ipi or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years. ...Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints."

Between July 10, 2008 and Aug 1, 2011 951 patients were enrolled.  475 = ipi.  476 = placebo.  At a median f/u of 2.74 years there were 528 recurrence-free survival events: 234 = ipi vs 294 = placebo.  Median recurrence-free survival was 26.1 months for ipi vs 17.1 months for placebo.  3 year recurrence-free survival was 46.5% for ipi vs 34.8% for placebo.  

Most common grade 3-4 immune related adverse events in the ipi group:  GI (75 vs 4 in placebo), hepatic (50 vs 1), endocrine (40 vs none).  Adverse events led to treatment discontinuation in 245 patients in ipi group and 182 of these were in the initial treatment period of 4 doses.  5 patients died due to drug related adverse effects in the ipi group.  3 due to colitis (2 of which had GI perforation), 1 with myocarditis, and 1 with multi-system failure with Guillain-Barre syndrome.

"Adjuvant ipi significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma.  The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences...for endocrinopathies.  The risk-benefit ratio of adjuvant ipi at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value."

My thoughts: 
1.  Folks in my trial were much higher risk generally as we were all Stage IV patients (status post brain and lung mets, etc.) at the start, though Stage III peeps were added later.  
2.  I don't know the drug dosages to be used in the coming trial for either ipi nor nivo.  Nivo doses haven't seemed to have that much effect on adverse events, but ipi has proven that the higher the dose the more frequent those events. 
3.  The numbers of patients in the NED arm of my study were obviously very small.  The greater numbers expected for the coming study will certainly provide a great deal more information.
4.  Unlike many phase 3 trials (the ipi one noted above for example), both arms of the currently enrolling trial are likely to derive some benefit!!
I wish you all my best!   - c