Travel Chaotically! - We arrive in Paris - and fabric shopping!!!

I can't believe it's been over a year!!!  But, last September B and I shared a wonderful adventure that started in New York:
Travel Chaotically! - New York - it begins.....
Travel Chaotically! - New York and FABRIC shopping!!!
Travel Chaotically! - New York - Mulberry Street!
Travel Chaotically! - New York - Street Fair and Central Park

We left New York at 5:20 PM and arrived in Paris at 06:45 AM!  Yee hah!!! After a coffee and croissant, we dropped our bags at our hotel, to check in later, and were off to fabric (en tissu!!!) at the base of Montmartre and the Sacre-coeur!

Paris style!!!

Quintessential Parisian view....

Ya gotta have some 'tude when you're near the Moulin Rouge!!!

Voulez-vous des friandises?

En tissu!!!

Are we tired, or psycho?????  Maybe both!!!

If only I knew what I could do with an African wax print!!!

Why waste fabric on full size models when you can have itty bitty tiny ones????  Additionally, Tissu Reine was AMAZING...with Liberty Prints at only 29 euros per meter.  In NY they were $36.00 per yard!  Just say'n!

Frou Fou was the cutest shop.  And then they had this!!!???  You KNOW what that means!!!

I can't explain this...but we saw this phenom....

...throughout...

...Paris!

Coffee before the trek back!!!

If I had to smell this from a balcony all day....

....this is how I'd look!!!  So very sad that I couldn't eat there!!!

Got only slightly lost on our way back to our hotel.  Happens when you've been up for a while!  No dinner needed.  Just SLEEP!!!!!  Still....a great first day in Paris!! - c

Adjuvant treatments in melanoma - They WORK!!! Now, let's make sure people can get them!!!!!

It was certainly good news when the FDA (FINALLY!!!) approved ipi as an adjuvant treatment for melanoma.  And....it works!  ASCO 2017: Ipi 3 mg vs 10 mg in advanced melanoma and as adjuvant

We also KNOW that anti-PD-1 works EVEN BETTER, with fewer side effects, as an adjuvant treatment in melanoma. The trial that I and my fellow ratties started in 2010 proved that...and so have other studies since:  Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!!

We also KNOW that BRAF/MEK inhibitors are extremely effective as an adjuvant therapy in patients with BRAF positive melanoma:  2016: Straight Outta Boston!!! Latest melanoma research ~
One abstract included in that link notes:

Stage IIIB/C treated with adjuvant BRAFi = 100% 6 month survival vs 28.6% with standard care!!!

Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma.  Amaria, et al.

The treatment of stage IV melanoma has been revolutionized by targeted therapy and immune checkpoint blockade, and there is a strong rationale to evaluate these agents in earlier stages of disease. The current SOC in patients (pts) with high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery +/- adjuvant therapy, but relapse rates are high. We hypothesized that treatment with neoadjuvant + adjuvant D+T in this population would result in lower relapse rates compared to SOC. Methods: We conducted a prospective randomized clinical trial (NCT02231775) in pts with resectable Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Pts were randomized in a 1:2 fashion to SOC (Arm A) or neo + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). Planned enrollment was 84 pts. Primary endpoint was RFS. Results: Randomization was halted after 21 pts were enrolled (arm A=7, arm B=14). Arms were well matched for gender and stage of disease, though pts in arm A were younger. Perioperative complication rates were similar and toxicity in arm B was manageable. At week 8 the RECIST response rate with D+T was 77% and the pathologic complete response (pCR) rate was 58%. Early analysis revealed a significantly higher RFS in the D+T arm over SOC, with 6-month survival estimated at 100% in Arm B and 28.6% in Arm A, leading to trial closure. Conclusions: Treatment with neoadjuvant + adjuvant D+T is well tolerated, results in high clinical response and pCR rates, and markedly improves RFS in pts with high-risk resectable metastatic melanoma. Correlative analyses are underway to characterize mechanisms of response and resistance to neo + adjuvant D+T.  

Now...there's this:  

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long, Hauschild, Santinami, et al. N Engl J Med. 2017 Sep 10. 

Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. 

In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. 

At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group. The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group, but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. 

Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects.

Relapse free survival...58% with treatment, 39% with placebo!  Sounds good to me...of course you have to be BRAF positive....but it's something!!!

Now this is something "new"....and VERY old!!!  Remember this post:  Immunotherapy....The Original Super Heroes and Ratties!!!!  When you talk about CpG-B - Coley's toxin comes to mind, who, in the 1890's, injected bacteria into tumors and found that they would GO AWAY!!!  In 1983 an underlying DNA component of the bacteria, responsible for the effect, was discovered.  And in 1995, the specific DNA molecules (CpG) were found to be the component that specifically stimulated the immune response, with the B group in particular, causing B cell and monocyte maturation.  And since some of the patients were also given GM-CSF in the study below, here's a reminder about what that is:  Sargramostim ~ aka GM-CSF or leukine (and other related posts)  Here's the latest:

Local Adjuvant Treatment with Low-Dose CpG-B Offers Durable Protection against Disease Recurrence in Clinical Stage I-II Melanoma: Data from Two Randomized Phase II Trials. Koster, Van den Hout, Sluijter, et al. Clin Cancer Res. 2017 Oct 1.  

Although risk of recurrence after surgical removal of clinical stage I-II melanoma is considerable, there is no adjuvant therapy with proven efficacy. Here, we provide clinical evidence that a local conditioning regimen, aimed at immunologic arming of the tumor-draining lymph nodes, may provide durable protection against disease recurrence (median follow-up, 88.8 months).

In two randomized phase II trials, patients, diagnosed with stage I-II melanoma after excision of the primary tumor, received local injections at the primary tumor excision site within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy of either a saline placebo (n = 22) or low-dose CpG type B (CpG-B) with (n = 9) or without (n = 21) low-dose GM-CSF.

CpG-B treatment was shown to be safe, to boost locoregional and systemic immunity, to be associated with lower rates of tumor-involved SLN (10% vs. 36% in controls), and, at a median follow-up of 88.8 months, to profoundly improve recurrence-free survival, even for patients with histologically confirmed (i.e., pathologic) stage I-II disease.

Potentially offering durable protection, local low-dose CpG-B administration in early-stage melanoma provides an adjuvant treatment option for a large group of patients currently going untreated despite being at considerable risk for disease recurrence. Once validated in a larger randomized phase III trial, this nontoxic immunopotentiating regimen may prove clinically transformative. 

What's not to like????? 

And there's this....  Here, CancerVax (canvaxin) was given along with BCG.  

Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. Faries, Mozzillo, Kashani-Sabet, et al.  Ann Surg Oncol. 2017 Oct 10. 

This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma.  After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test.  Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group. Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group. Positive DTH skin testing correlated with increased survival.  In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

So...that adjuvant therapy is a big NO!!!  As much as I love the idea of a vaccine (peptide vaccines - 6 of them actually - were included in my trial and DID NOT HELP!!!!) as treatment for melanoma, and have hope that someday....  Well, so far - it has been a no go!!!  But...we have all the options noted above that DO WORK!!!

I have been yelling about melanoma adjuvant treatment options since 2003!!!!!!!!!!!!!!!  Could we please take some action?????

The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients. Eggermont, Dummer.  Eur J Cancer. 2017 Sep 28.  

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. [No shit!!!!] In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. [No shit!  And...ABOUT TIME!!!] In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

"Important paradigm shifts in the management of high-risk melanoma patients are upon us." I hope so!!!  It is more than time!  So many ratties have done the work.  Let's make this so!!!! - c

Sew Chaotically!! - Another Alder shirt dress

Yes, I love Grainline Studio Patterns.  Yes, I've made their Alder shirt dress before!

With bum ruffle...

...and without!

Now in a beautiful Art Gallery cotton.

The hem is a little lower in the back.  I made the size 8 with no adjustments.

Proud of my details!!

Thanks for help finding the buttons, B!!!

And to finish with a little sister love!!!  Ruthie used the same print, though in the voile, to stitch up V9970.  (A pattern she does not really recommend due to poor drafting of the pin tucks in the bodice...but she made it work!!!)  Isn't she beautiful????

Sew Chaotically!!! Love, les

Melanoma research results to which my only response is: Are you guys for real right now?????

B keeps perusing the literature, hoping for something better for melanoma peeps to pop up.  There are some new things and combo's in the works... but some of the stuff researchers are publishing right now is just tired!  But...here you go:

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. Kaufman, Andtbaka, Collichio, et al.  J Immunother Cancer. 2017 Sep 19.

Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting greater or equal to 6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival.  

We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation).

Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months, 12 months, and 18 months that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI and a higher TOI improvement rate (58.1% versus 30.0%).  

Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint.

The grand summary finding here is that when a durable response is achieved - it is associated with improved overall survival, and a longer treatment free interval.  Well, duh!!!  Did we really need a study to tell us that???????

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Chapman, Robert, Larkin, et al.Ann Oncol. 2017 Oct 1.

The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3.

Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.
Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months versus 9.7 months}, as was median OS without censoring at crossover [13.6 months versus 10.3 months]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.

Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.

Here...the shocking take-away is:  DACARBAZINE sucks in the treatment of melanoma when compared to immunotherapy or BRAF inhibitors.  THIS IS NOT NEWS!  Could we stop with the dacarbazine already?????  This post is from 2013!!!!!!!  Ipi, BRAF/MEK, Anti-PD1 [and NO MORE DACARBAZIN???!] - per chat with Antoni Ribas A conversation in the wake of data presented at the European Cancer Congress 2013....  Come on, Man!!!!!

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Schachter, Ribas, Long, et al.  Lancet. 2017 Aug 16.

Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis.

In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319.

Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab. 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.

Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. 

Finally, while this study provided essential information when we wanted to make sure that the data we were seeing in studies of nivo and pembro alone...like mine back in 2010...were valid when compared head-to-head with ipi...this study is also testament to how long it takes to get data reported out from a trial that started 4 years ago!  Additionally, though we already knew that ipi has a response rate of about 15% in melanoma patients vs. a response rate of about 40% when anti-PD-1 products are used, it does take the data one step further.  Despite an average time of follow-up of almost 23 months, median overall survival was not yet reached with pembro...while median overall survival for ipi maxed out at 16 months.  Another point was that overall 24 month survival was the same, at 55%, for pembro no matter if patients took it every 2 weeks or every 3 weeks....vs only 43% for the ipi group.  So....at least there is SOMETHING new here!!!

Thanks, ratties!!!  And researchers, "Are you guys for real right now????" - c

Sew Chaotically! - ANOTHER Linden! Thanks, Grainline Studio!

I adore every pattern I've made up from Grainline Studio!!  From their Morris Blazer to the Alder Shirtdress!!!  I've made a straight 8 in all of them and they've been perfect.

And then there are all the Lindens!

Now there is this one!!!

Given my love of words, grey, and blue ~ when I found this lovely, lusciously soft Art Gallery Jersey I was sold!!!  It was a bit of a pain to get lined up for cutting...but after that, stitching it up was a breeze. (It comes out of the washer and dryer looking great, too!!)  I made the slightly cropped Linden version, that's a little shorter in the front than the back, with no waist or arm bands.

I'm telling you...this pattern is drafted so well, putting in the neck band is a breeze!

Was the fact that "DREAM BIG" and "SUNSHINE" ended up front and center - fate or planned???  You decide!!!

It's perfect on its own...

...but also great for layering - over and under - other garments!

Linden love!!!  You gotta try it!  Sew Chaotically!!! - les

Pembro no better than chemo in ipi refractory melanoma??? Disconcerting.... but I think I know why!

So this sounds weird....

Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Hamid, Puzanov, Dummer,...Ribas, et al.  Eur J Cancer. 2017 Sep 26. 

PURPOSE:  To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.

In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAF^V600 mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. 

A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1-35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg and 10 mg/kg  resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 and 14.7, respectively, versus 11.0 months, with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III-V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively.

Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.

So, these are beat up melanoma patients who have already failed ipi or BRAF/MEK or both. (Meaning they had already been treated with those drugs and progressed!)  THEN, patients were randomly place in these groups:  180 to Pembro 2mg/kg, 181 to pembro 10mg/kg, and 179 to chemo (exact treatment not noted, old school chemo suggested).   All patients who progressed on chemo were allowed to "cross over" to the pembro arms.  At median follow-up 28 months later - 368 of 540 patients had died and 55% of the chemo patients had crossed over to pembro.  (Meaning less than half of the 179 chemo patients, stayed on chemo...they do not break down deaths in that particular group...while the rest switched over to pembro.)  In the end of this business, researchers found no significant difference in OS  (with 2 year survival rates at 36 and 38% for the pembro groups vs 30% for the chemo group) between the 3 groups...though PFS, RR, and duration of response was better for the pembro groups than for chemo.

Here's what I think is important:

1.  The data here is really muddy due the cross over component in the chemo group combined with the lack of information related to their specific outcomes.  More than half of the chemo ratties ended up on pembro...a drug known to take time to work...time that was wasted on chemo!  Ultimately, 459 of the 540 patients in this study ended up on pembro.
2.  Folks already treated with ipi do less well on anti-PD-1 than those who take anti-PD-1 at the start.  This is not news:  Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????
3.  The dose of Pembro 2mg/kg vs Pembro 10mg/kg made no difference in results.  So, as we are gradually learning in immunotherapy generally, the larger dose for an infinite amount of time, does not necessarily gain better responses.

Hang tough, ratties.  You are some amazing peeps!!! - c

Late Note:  10/28/2017 - This article I just reviewed from the Society for Melanoma Research 2016 Congress, published 29 January 2017 - confirms my suspicion that "crossover" accounted for their "results"!!!

Adjusting overall survival when accounting for treatment switch in the KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory advanced melanoma.  Drummer, Robert...Pavlick, et al.  

In the randomized phase 2 KEYNOTE-002 (NCT01704287) study, pembrolizumab 2 mg/kg and 10 mg/kg Q3W significantly improved PFS versus investigator-choice chemotherapy at the second interim analysis in ipilimumab-refractory advanced melanoma, with no difference between pembrolizumab doses. Intent-to-treat (ITT) analyses showed a numeric, but not statistically significant, trend toward improved OS with pembrolizumab 2 mg/kg Q3W versus chemotherapy. Final analysis of the KEYNOTE-002 study will be presented at this year's European Society for Medical Oncology congress. Here, we aim to adjust for the bias introduced by crossover from the chemotherapy to pembrolizumab arms. We applied both the 2-stage method for crossover adjustment to OS, and the rank-preserving structural failure time (RPSFT) correction as prespecified in the statistical analysis plan. The resulting adjusted survival curves for chemotherapy were evaluated against external literature-based evidence. With crossover correction for the pembrolizumab 2 mg/kg arm, the HR was 0.79 for the RPSFT and 0.58 for the 2-stage method. When comparing against external literature-based evidence, the adjusted OS for chemotherapy from the 2-stage method was found to fit best with external historical data. Results of the pembrolizumab 10 mg/kg arm will be included in the presentation. In conclusion, the OS benefit of pembrolizumab versus chemotherapy using the best-fitting crossover adjustment was statistically significant.

Just say'n!!! Come on researchers!!!  Don't write crap just so you have something to publish! - c

Everything Cures Melanoma....#8

Here's links to previous reports:  Everything Cures Melanoma...#7
And I recently reported this:  I like me some shrimp!!! Now their micro-RNA can suppress the stem like qualities of some melanoma cells???!!!

But there's still more...

The Inhibitory Activity of Luzonicosides from the Starfish Echinaster luzonicus against Human Melanoma Cells. Malyarenko, Dyshlovoy, Kicha, et al.  Mar Drugs. 2017 Jul 18.    

Malignant melanoma is the most dangerous form of skin cancer, with a rapidly increasing incidence rate. Despite recent advances in melanoma research following the approval of several novel targeted and immuno-therapies, the majority of oncological patients will ultimately perish from the disease. Thus, new effective drugs are still required. Starfish steroid glycosides possess different biological activities, including antitumor activity. The current study focused on the determination of the in vitro inhibitory activity and the mechanism of action of cyclic steroid glycosides isolated from the starfish Echinaster luzonicus-luzonicoside A (LuzA) and luzonicoside D (LuzD)-in human melanoma RPMI-7951 and SK-Mel-28 cell lines. LuzA inhibited proliferation, the formation of colonies, and the migration of SK-Mel-28 cells significantly more than LuzD. Anti-cancer activity has been ascribed to cell cycle regulation and apoptosis induction. The molecular mechanism of action appears to be related to the regulation of the activity of cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), along with Survivin, Bcl-2, p21 and cyclin D1 level. Overall, our findings support a potential anti-cancer efficacy of luzonicosides A and D on human melanoma cells.

Antitumor activity and expression profiles of genes induced by sulforaphane in human melanoma cells. Arcidiacono, Ragonese, Stabile, et al. Eur J Nutr. 2017 Sep 1.  

Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown.

Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment.

We demonstrated that SFN strongly decreased cell viability and proliferation, induced G₂/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1).

Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent.

Anti-Melanogenic Activity and Cytotoxicity of Pistacia vera Hull on Human Melanoma SKMEL-3 Cells. Sarkhail, Salimi, Sarkheil, et al. Acta Med Iran. 2017 Jul. 

Pistacia vera seed is a common food and medicinal seed in Iran. It's hull (outer skin) as a significant byproduct of pistachio, is traditionally used as tonic, sedative and antidiarrheal and has been shown to be a rich source of antioxidants. The aim of the present study is to evaluate the anti-melanogenic activity of the pistachio hulls in order to discover a new alternative herbal agent to treat skin hyperpigmentation disorders. In this work, antioxidant and anti-tyrosinase activity of MeOH extract from Pistacia vera hull (MPH) were evaluated in vitro, respectively, by DPPH radical scavenging and mushroom tyrosinase activity assays. Then the effect of MPH on the melanin content, cellular tyrosinase activity and cytotoxicity (MTT assay) on human melanoma SKMEL-3 cell were determined followed by 72 h incubation. The results indicated that MPH had valuable DPPH radical scavenging effect and weak anti-tyrosinase activity when compared to the well-known antioxidant (BHT) and tyrosinase inhibitor (kojic acid), respectively. MPH, at a high dose (0.5 mg/mL), showed significant cytotoxic activity (~63%) and strong anti-melanogenic effect (~57%) on SKMEL-3 cells. The effect of MPH in the reduction of melanin content may be related to its cytotoxicity. The results obtained suggest that MPH can be used as an effective agent in the treatment of some skin hyperpigmentation disorders such as melanoma.

Molecular characterisation, ontogeny and expression analysis of melanoma differentiation-associated factor 5 (MDA5) from Asian seabass, Lates calcarifer. Paria, Makesh, Chaudhari, et al. Dev Comp Immunol. 2017 Sep 15.    

MDA5 is the pivotal member of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and is reported to play a crucial role in type I IFN-mediated responses against pathogen-associated molecular patterns (PAMPs), especially nucleic acids. In this study, we have identified and cloned the full-length cDNA sequence of MDA5, which comprises 3398 nucleotides and encodes for a putative protein of 978 AA length, in Asian seabass, Lates calcarifer. From the putative amino acid sequence of AsMDA5, four different conserved domains could be predicted: two N-terminal CARD domains, a DExDc domain, a HELICc domain and a C-terminal RIG-1_C-RD domain. The mRNA transcript of AsMDA5 could be detected in all the 11 tissues tested in healthy animals with the highest expression in heart followed by gill and skin. The ontogenetic expression profile showed constitutive expression in developmental stages starting from unfertilized eggs, which implies the possibility of maternally acquired immunity of RLRs in offspring. The viral analogue poly I:C could modulate the AsMDA5 expression both in vivo and in vitro. In all the tissues, AsMDA5 expression was found to be highly regulated following injection with poly I:C with the highest expression observed in kidney. The expression level of AsMDA5 was found to be modulated at different time-points following challenge with Gram-negative bacterium, Vibrio alginolyticus, and Gram-positive bacterium, Staphylococcus aureus. Similarly, noticeable change in AsMDA5 expression was detected in SISK cell line induced with either LPS or PGN. The observations made in this study suggest that in euryhaline marine teleosts like Asian seabass, MDA5 gene serves as one of the pivotal receptor for the detection of viral and bacterial PAMP, and might play an important antimicrobial role during early embryonic development.

Antiproliferative Activity of Walnut (Juglans regia L.) Proteins and Walnut Protein Hydrolysates. Carrillo, Gomez-Ruiz, Ruiz, Carvalho.  J Med Food. 2017 Sep 25.   

Proteins from Juglans regia L. were isolated. Then, proteins were hydrolyzed with different enzymes. Antiproliferative activity of proteins and of the protein hydrolysates of J. regia L. were evaluated using the sulforhodamine B method. Glutelin and prolamin proteins presented a high antiproliferative activity against cancer cells PC-3 (prostate) and K-562 (leukemia) with values of 43.9 and 84.4 μg/mL, respectively. The highest inhibitory effect observed was 50% at 0.25 μg/mL concentration in gastrointestinal digestion with pepsin and corolase pp in a dose-dependent manner against cancer cell UACC62 (melanoma). Pepsin hydrolysate showed inhibitory effects against cancer cell UACC62 (melanoma) with a concentration of 71.0 μg/mL. The effects were studied in a dose-dependent manner. The hydrolysate obtained with neutrase enzyme presented inhibitory effects against cancer cell UACC62 (melanoma) at a concentration of 25 μg/mL. Neither proteins nor protein hydrolysates presented cytotoxicity against normal cell assay VERO (epithelial).

In vitro and in vivo anti-cancer activity of dichloromethane fraction of Triticum aestivum sprouts. Ki, Poudel, Lee, et al.  Biomed Pharmacother. 2017 Sep 29.

Triticum aestivum sprouts (TA) contain significant amounts of chlorophyll, minerals, enzymes, and other functional entities. Furthermore, TA extracts have been shown to possess anti-obesity, anti-diabetic and hepatoprotective effects and are believed to help blood flow, digestion, and general detoxification of the body. In this study, the mechanism underlying the anti-cancer effects of a dichloromethane fraction of TA (TDF) was investigated in vitro and in vivo. In vitro study was done by examining cancer cells growth, morphological changes, cell cycles, expressions of death receptors and apoptosis-linked proteins in wide range of human cancer cell lines. To investigate the effect of TDF in vivo, C57BL/6 mice were injected with B16 melanoma cells and orally administered TDF. TDF markedly inhibited cancer cell growth and induced cellular morphological alterations, cell cycle arrest and apoptosis, and enhanced the expressions of death receptors (DR)-4, 5, and 6 in cell lines. In addition, TDF regulated the expressions mitochondrial apoptosis-linked proteins and induced caspase-dependent cell death. It also significantly enhanced phosphorylation of ERK1/2 and JNK, but not p38, whereas inhibited the activation of NF-κB in cancer cells. In our mouse model, TDF significantly suppressed B16 melanoma growth, to an extent similar to cisplatin (reference control) and augmented immunomodulatory cytokines. In brief, this study presents the mechanism responsible for the anti-cancer effects of TDF in vitro and in vivo.

WOW!! So....to cure our melanoma, we need a little smidge of starfish goo/hormones, cruciferous veggies (Think cabbage, collards, broccoli, brussel sprouts.....stuff I've eaten all my life!!!), the HULL from pistachios  (Just the hull, mind you!!  What do these folks think I am, a termite????), walnut protein (Uh, NO!!  Not for me...as a person with anaphylaxis to tree nuts, I don't think that will turn out very well!!), TA sprouts (That's wheat sprouts, folks!) and my favorite from this list, Asian Sea Bass.    How do you get Asian Sea Bass, you might ask?  Just call them...real loud!!!

Ernie and Bert go Fishing - Sesame Street Rocks!!!  

If any of these work out that will be great!  Til then....I'm just gonna enjoy Bert and Ernie!! - c