Sew Chaotically! - Vogue 1440 - such a cute top!!

Another sewing post...just for fun!!!  Here's the pattern.  I have to say...from looking at the directions and pieces...the jacket could easily turn into a hot mess...but the top...

...how cute it that back??????

Material...from who knows where and sadly when!  When she was little, I used to pick up anything "rosebud" for the Rose Bud...though clearly, this never made it into her wardrobe!!!  I was going to pair it with a pink I had, but the Brentster, with his incredible color skills picked this combo!  Awesome, right?

Hey, if you have a cute design....make it show up, right????

Made a size 12, just had to carve a bit off both side seams.  Didn't want to mess with the substantial darts running down the front!

Proud of my top stitching!!!!

Lurve it!!!  Happy day to you...even if it sneaks up on you from behind! - c

Anti PD-1 and Anti-PD-L1 treatments rarely confer durable remissions for metastatic uveal melanoma (and poor responses in acral and mucosal mel as well!)

As many of you know, I am frequently contacted by folks with melanoma (or those with peeps who are suffering) looking for answers, treatments, explanations.  I help as best I can.  In that capacity, I have discovered many who are facing more than just cutaneous melanoma and are gradually coming to realize that they or their loved one, is probably dealing with uveal, acral, or mucosal melanoma given the history, location, or results of testing.  Unfortunately, while we have made a great deal of progress since 2011 in the treatment of melanoma generally, these sub-types are notoriously unresponsive to the now conventional melanoma treatments.  For instance, this is a report out of ASCO this year: ASCO 2016: Anti-PD1 for acral and mucosal melanoma , where unfortunately it was demonstrated that rather than the more typical 40% response rate to anti-PD1 in treatment naive cutaneous melanoma, folks with acral melanoma had only a 32% ORR, while folks with mucosal attained only a 23% ORR....albeit these peeps were heavily pre-treated and perhaps that contributed to the lower response rates as well.
  
Additionally, these types of melanoma are less likely to be BRAF positive, removing yet another treatment option from their arsenal.  Here's data from a discussion between two melanoma specialists:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma
Here they note the following expected mutation rates -
Mucosal = 9% BRAF, 12% NRAS, 25% KIT
Acral = 22% BRAF, 16% NRAS, 24% KIT

The disconcerting aspect for me has been this response, "Oh, no.  We aren't [or - the doc isn't] calling it that! If that happened, she wouldn't be eligible for the trial!!"  I can hear the fear and desperation in their voice.  I really do understand!  I spent many years, even as a Stage IV patient, in melanoma land BEFORE the FDA approval of the BRAF inhibitors, anti-PD1, or ipi. I fully recognize the desperation and search for an effective treatment.   However, when you are allowed placement into a trial or treatment that we now KNOW provides little to no benefit for your particular mutation....what has been accomplished?  To my mind, time has been wasted, suffering continues, while other possibly more effective options go untapped.  Some Melanoma Big Dogs recently came together in this report regarding uveal melanoma response rates to anti-PD1 and anti-PDL1:

Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-1L antibodies.  Algazi, Tsai, Shoushtari, ... Daud, Sosman, Carvajal, Chmielowski, Postow, Weber, et al.  Cancer. 2016 Aug 17.

Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized.  Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined.  Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6%. Stable disease (greater or = to 6 months) was observed in 5 patients (9%). The median PFS was 2.6 months, and the median OS was 7.6 months. There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity.  PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population.

A sad acknowledgement to be sure.  These response and OS rates are really no different than those I was facing prior to the existence anti-PD1!  Frustrating and powerless do not begin to cover the feelings that this data engenders!!!  However, it is something I would want to know, if I were dealing with uveal melanoma.  For what it's worth.... - c

Titanium....

Rough day....rough week.  More for others than myself. Just when I think it is too much....I know....I am titanium...

Sia/David Guetta - Titanium

You shout it out,
But I can't hear a word you say
I'm talking loud, not saying much
I'm criticized but all your bullets ricochet
Shoot me down, but I get up
I'm bulletproof, nothing to lose
Fire away, fire away
Ricochet, you take your aim
Fire away, fire away
You shoot me down but I won't fall
I am titanium
You shoot me down but I won't fall
I am titanium
Cut me down
But it's you who'll have further to fall
Ghost town and haunted love
Raise your voice, sticks and stones may break my bones
I'm talking loud not saying much
I'm bulletproof, nothing to lose
Fire away, fire away
Ricochet, you take your aim
Fire away, fire away
You shoot me down but I won't fall
I am titanium
You shoot me down but I won't fall
I am titanium
I am titanium
I am titanium
Stone-heart, machine gun
Firing at the ones who run
Stone heart loves bulletproof glass
You shoot me down but I won't fall
I am titanium
You shoot me down but I won't fall
I am titanium
You shoot me down but I won't fall
I am titanium
You shoot me down but I won't fall
I am titanium
I am titanium                        ~ David Guetta

...and so are you.  Love, c

Immunotherapy and pneumonitis

I am certain I dealt with pneumonitis while taking nivolumab/Opdivo for 2 1/2 years in my trial.  I noted this back in the day:

Dose 7 = 3/25/2011
   My scans at the 3 Month evaluation showed "ground glass appearance" in the right lower lobe of my lung.  I was also having wheezing at the time.  Scans were reviewed by the tumor board at Moffitt and determined to be related to my asthma or an inflammatory process that Weber had seen before in patients on ipi.  Wheezing gradually improved on albuterol and inhaled corticosteroid; symbicort. Perhaps most importantly, the 3mm something???? in my brain on my MRI when I started is GONE!

Additionally, when reviewing my records (created in this blog!!!) it was very clear that my infusions were directly followed by bouts of wheezing. It never got so bad that I had to stop my infusions or required systemic steroids, though my nurses often threatened me with them!  I dealt with my wheeze using albuterol as well as inhaled steroids (symbicort or pulmicort).  My history is a little hazy given my asthma and my work with little germy critters, but as B recently told my local onc, "Celeste, definitely experienced pneumonitis.  But, she and Weber are tough as nails, so they just powered through!"  And, as noted above, my scans were at one point read as having a "ground glass appearance"...the classic radiologic description for pneumonitis....but that's not always how pneumonitis rolls, as this latest article indicates: 

PD-1 inhibitor-related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course.  Nishino, Ramaiya, Awad, ... Hodi, et al.  Clin Cancer Res. 2016 Aug 17.  

The purpose of this study was to...investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer patients.  Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis.  Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy and 15 received combination therapy. Median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. AIP/ARDS pattern had the highest grade, followed by COP, while NSIP and HP had lower grade. COP pattern was most common in all tumors and treatment regimens. Most patients (17/20;85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; two of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.  PD-1 inhibitor-related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients.

(Found this article as well....so it is being added as a late addition to this post...)

Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.  Nishino, Giobbie-Hurder, Hatabu, Ramaiya, Hodi.  JAMA Oncol. 2016 Aug 18.

Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens.  To compare the incidence of PD-1 inhibitor-related pneumonitis among different tumor types and therapeutic regimens.  A PubMed search through November 10, 2015, and a review of references from relevant articles. For the PubMed search, the following keywords or corresponding Medical Subject Heading terms were used: nivolumab, pembrolizumab, and PD-1 inhibitor.  Twenty-six original articles of PD-1 inhibitor trial results were identified. Among them, 20 studies of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) were eligible for a meta-analysis.  The data were extracted by 1 primary reviewer and then independently reviewed by 2 secondary reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparisons of the incidence were based on marginal, exact generalized linear models with generalized estimating equations.  Incidence of all-grade and grade 3 or higher pneumonitis and pneumonitis-related deaths.  Twenty studies of single-tumor-type trials of PD-1 inhibitor (12 melanoma studies, 5 NSCLC studies, and 3 RCC studies) (a total of 4496 unique patients) were included in the meta-analysis. The overall incidence of pneumonitis during PD-1 inhibitor monotherapy was 2.7% for all-grade and 0.8% for grade 3 or higher pneumonitis. The incidence was higher in NSCLC for all-grade (4.1% vs 1.6%) and grade 3 or higher pneumonitis (1.8% vs 0.2%) compared with melanoma. The incidence in RCC was higher than in melanoma for all-grade pneumonitis (4.1% vs 1.6%) but not for grade 3 or higher pneumonitis. Four pneumonitis-related deaths were observed in patients with NSCLC in the monotherapy group. Pneumonitis was more frequent during combination therapy than monotherapy for all-grade (6.6% vs 1.6%) and grade 3 or higher pneumonitis (1.5% vs 0.2%) in melanoma, with 1 pneumonitis-related death during combination therapy. Multivariable analyses demonstrated higher odds of pneumonitis in NSCLC for all-grade and grade 3 or higher pneumonitis and in RCC for all-grade pneumonitis compared with melanoma. The combination therapy had significantly higher odds than monotherapy for all-grade and grade 3 or higher pneumonitis. The incidence of PD-1 inhibitor-related pneumonitis was higher in NSCLC and RCC and during combination therapy. These findings contribute to enhance awareness among clinicians and support further investigations to meet the clinical need.

Nothing is ever simple when dealing with melanoma, its treatments, or their side effects!!!!  If you have a wheeze or cough...talk to your doc!!!  Hang in there melanoma peeps!! - c

Medical studies in children go unpublished!!! Here we go AGAIN!!!

Back in 2013 I wrote this post from a study that noted:  Almost 50% of results of cancer drug trials NOT unpublished!

What the tub?????????  And now this report notes that 19% of studies involving our most fragile population, CHILDREN, are not completed and 30% of those that are, go unpublished!!!

In this report recently on NPR Medical studies involving children often go unpublished reporter Richard Harris notes:

Many medical studies involving children never end up being put to use because scientists frequently don't publish the results of their work, according to an analysis published online Thursday.
The findings raise both scientific and ethical issues regarding research on this vulnerable population.
Previous studies have documented that about a third of all clinical trials conducted in the United States end up as largely wasted effort, because the scientists doing that work don't take the effort to publish and share their results with the scientific community.

[In the study by Bougeois and Pica, Pediatricians at Harvard and Boston Children's Hospital published in the journal] Pediatrics, the experience with childhood research is just about as bad.
The report, reviewing clinical trials started in 2008-10, finds that 19 percent of the studies that recruited children didn't run to completion. That was often because researchers weren't able to recruit as many volunteers as they needed to run the experiments. And of the 455 trials that were completed, the results from 30 percent weren't published.

"That means all the participants who are enrolled in these studies aren't able to contribute in a meaningful way to our clinical information and knowledge," Bourgeois said. One reason may be that scientists didn't get the results they were hoping for. It's less rewarding to publish results that report a failed trial, but Bourgeois says it's just as important for science to do so.

"The harm is we end up with scientific literature that only shows all the things that do work," she said. "It may falsely appear that certain interventions do work. So our literature may become biased and may not be representative of the true efficacy or safety of an intervention."  One result of that is that other scientists may try to run the same failed experiment, and end up down the same blind alley as scientists who had tried it before. "That leads to a lot of inefficiency and waste," she said.  Parents volunteer their children for these studies with an understanding that their efforts are contributing to the advancement of medical science.

The shortcomings of pediatric research come as no surprise to Dr. Joseph Ross [Yale School of Public Health]. He arrived at similar results when he analyzed clinical trials that include adults. Scientists have many explanations for why they don't publish their results. "Maybe the results don't show what the investigator wants and they move on," Ross said. "But more often people are busy and people don't focus enough time and attention on getting those results out."  Ross considers this an ethical lapse. "When you do a clinical study and you're asking patients to participate and subject themselves to a risk, in order to inform science and generate knowledge, you have an ethical obligation to disseminate those results to the wider scientific community," he said.

While clinical trials are necessary and can save lives, there are many, many problems that need to be fixed and publication of data is certainly one!!!  Here's my oped (as it were) from earlier this year:  The Problem with Clinical Trials

However, I am holding out hope.  I recently noted:  Most excellent news! Biden threatens to cut funding if cancer trials conceal results!!!  Let's go, Joe!!!!!!!!!!!!! - c

coBRIM trial (cobimetinib wih vemurafenib) - updated results

I reported on this combo first back in 2014:  BRAF/MEK combo: vemurafenib with cobimetinib

Then this also in 2014:  Combination therapies for melanoma (with some cool graphs)

Here in 2015 with the FDA approval:  Two new FDA approvals for the treatment of melanoma

 

And this was out of ASCO this year: ASCO 2016: cobimetinib and vermurafenib

Here is the latest update:

Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.  Ascierto, McArthur, Dréno, Chang, Ribas, et al. Lancet Oncol. 2016 Jul 29.  

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF^V600-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.  In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.  Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months, the updated investigator-assessed median progression-free survival was 12·3 months for cobimetinib and vemurafenib versus 7·2 months for placebo and vemurafenib. The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months for cobimetinib and vemurafenib versus 17·4 months for placebo and vemurafenib. The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [less than 1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.  These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF^V600-mutant melanoma.

And as one would assume....progression free survival as well as median overall survival was greater when vemurafenib was combined with cobimetinib than when it was given with a placebo.  Perhaps a little surprising was the fact that side effects were higher in those receiving the cobimetinib and vemurafenib combo, as the BRAFi/MEKi combo's are generally shown to have greater efficacy than BRAFi given alone, but also produce FEWER side effects in previous studies.

Thanks, ratties. - c

Something good....

You know the old saying?

Every day may not be a good day, but there is something good in every day!!!

It's true!!!  This was Tuesday...after a hard day at work!!

1.2 miles UP!!!!  The Disney Trail..."ascends  Rocky Face, a mountain west of Dalton, GA, named after confederate civil war soldier George Disney.  This is a very steep hike. It is considered the most challenging trail in northwest Georgia, and the most challenging short trail in the state. It is almost entirely an uphill climb, and then a very direct descent to return to the parking lot."  And it's....AWESOME!!!!!

My dear Danita...who has been with me through thick and VERY thin!!!

Sweet tried and true friends along with fresh faces to make me think, share, smile....a blue sky....new adventures, old scars....it is a circle. Glad to be a part.  May something be good in your day.  Love, les