Ultrasound-based follow-up does not increase survival in Stage IB-IIA melanoma

"You have melanoma."  No matter the stage, no matter the situation, these words create chaos and panic for anyone who has ever had to hear them.  BUT!  As I've been posting...

Data for long term survival in thin cutaneous melanoma

SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines) {This one includes links to all things SLNB and CLND...which always comes up upon initial melanoma diagnosis!}

...thin, cutaneous melanoma lesions, caught in early stages, often never progress!  Still....what is one to do for follow-up?  What tests should be done?  When?  A mish mash of follow up options have been recommended over the years...from various sorts of scans, X-rays, nothing, as well as ultrasound.  Now, there's this:

Ultrasound-based follow-up does not increase survival in early-stage melanoma patients: A comparative cohort study. Ribero, Podlipnik, Osella-Abate, et al.  Eur J Cancer. 2017 Sep 7.

Different protocols have been used to follow up melanoma patients in stage I-II. However, there is no consensus on the complementary tests that should be requested or the appropriate intervals between visits. Our aim is to compare an ultrasound-based follow-up with a clinical follow-up.

Analysis of two prospectively collected cohorts of melanoma patients in stage IB-IIA from two tertiary referral centres in Barcelona (clinical-based follow-up [C-FU]) and Turin (ultrasound-based follow-up [US-FU]). Kaplan-Meier curves were used to evaluate distant metastases-free survival (DMFS), disease-free interval (DFI), nodal metastases-free survival (NMFS) and melanoma-specific survival (MSS).

A total of 1149 patients in the American Joint Committee on Cancer stage IB and IIA were included in this study, of which 554 subjects (48%) were enrolled for a C-FU, and 595 patients (52%) received a protocolised US-FU. The median age was 53.8 years with a median follow-up time of 4.14 years. During follow-up, 69 patients (12.5%) in C-FU and 72 patients (12.1%) in US-FU developed disease progression. Median time to relapse for the first metastatic site was 2.11 years for skin metastases, 1.32 for lymph node metastases and 2.84 for distant metastases. The pattern of progression and the total proportion of metastases were not significantly different in the two centres. No difference in DFI, DMFS, NMFS and MSS was found between the two cohorts.  Ultrasound-based follow-up does not increase the survival of melanoma patients in stage IB-IIA.

So....in this study, researchers looked at the status of 1149 Stage Ib and IIa melanoma patients.  554 were provided with "clinic based follow-up" (though what that was exactly is not entirely clear) and 595 were followed via ultrasound.  They were all observed for an average of 4.14 years.  During that time, 12.5% of the clinic followed folks and 12.1% of the ultrasound followed peeps developed disease progression.  Median time for that progression was:  2.11 years for skin mets, 1.32 years for progression in lymph nodes, and 2.84 years for a distant metastasis.  The pattern, proportion, and disease progression was the same in both groups.  In the end, per these researchers, "Ultrasound-based follow-up does not increase the survival of melanoma patients in Stage IB-IIA."

It seems that the bottom line is this:  When you combine a group of Stage I/II melanoma patients, about 12% progress.  That is pretty consistent with the prior reporting, bearing in mind that some "thicker" melanomas would be included here.  And, perhaps most importantly, ultrasound follow-up didn't change that outcome.

Stage I/II melanoma peeps still need to be watched for progression.  Because if you ARE part of that 12% who do progress, you need to deal with that as soon as possible.  But HOW and WHEN to monitor these patients remains elusive.  In the end, I'm betting on a blood draw for DNA markers!!!  Sadly, we aren't there yet.   Sigh. 

For what it's worth.  Hang tough, peeps! - c

Chemo via isolated limb perfusion followed by ipi = response rate of 85% in 26 melanoma patients

Isolated limb perfusion with chemotherapy is not a new treatment in melanoma.  I reported on its use for in-transit melanoma here in 2014:  In-Transit Melanoma..a little info.  I watched videos about its use while waiting for my treatments when I was at Moffitt between 2010 and 2013.  In this latest report, I am a little unclear about the status of the patients.  Maybe they were just your average melanoma patient with "advanced melanoma" in random organs...or perhaps (and this seems more likely...though not clearly stated) they were patients who had lesions specifically in the limb that was treated with the chemo infusion.  At any rate....here's the report...

Robust antitumor responses result from local chemotherapy and CTLA-4 blockade.  Arivan, Brady, Siegelbaum, Hu, et al. Cancer Immunol Res. 2018 Jan 16.

Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a non-inflamed microenvironment, and response rates to immunotherapy in melanoma have been less than 50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings to a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate), and a 58% progression-free survival at one year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.

If I were dealing with lesions localized in an extremity, be it nodular or in-transit lesions, this is certainly a treatment option I would discuss with my oncologist.  Hang tough, guys.  - c 

Sew Chaotically! - The Berlin Skirt from Orageuse

I LOOOOOVE this skirt!!!!  (I know! I know!  I still have one unblogged 2017 make!  But....this delicious skirt gets to jump ahead!!  Sorry cute Linden sweatshirt!!!)  I discovered Orageuse patterns through this group of exuberant sewists when they stitched up the Bristol dress/top here:  Mix and Sew: WAYS TO BRISTOL  and thereby discovered this pic from the Orageuse site itself!  I was hooked...with MANY of their patterns!  Then, I realized the Mixers had actually made versions of the Berlin skirt here:  Mix and Sew: BERLIN THE ENCHANTER  I was enchanted indeed.  This beautiful version ~ Bee Made's "Skirt with Indian Colors" was icing on the cake!   I bought this lush emerald green wide rib cord with Berlin in mind during my fabric shopping adventure on Goldhawk road!!  I studied all the hints and tidbits from the other sewists.  After measuring and re-measuring I added 2 inches to the length (at the advised line) and cut the 40, giving a little bit of ease at the hips as that had been mentioned as a sticking point!  I was a bit worried about the thickness of my fabric choice, so I used a remnant of some Liberty of London cotton for the inner waist band and pocket linings.

Daniel Day Lewis is not the only one who can sew hidden messages inside his clothes!!!  Does anything say, "You are special!" better than a little Liberty in your pocket???

This pattern went together very well.  No hiccups at all!!  I ended up having to take in the extra bit I had allowed myself at the hips in the outer layer, though I actually needed the room in the lining.  This was something "Bee" had mentioned when describing her make.  As she noted, the front lining doesn't include the extra room the pleats in the outer skirt gives you, so you need to keep that in mind.  I kept my lining the "extra" size and made a couple of tucks as I attached the waist band.  I am glad I lined this version, as this fabric is one I am likely to wear tights under and it would stick.  I might not line a summer weight version, but the lining did provide a really pretty finish.

Making the tie and the belt loops (plus placing them) may have taken longer than the entire rest of the skirt.  Turning my sticky corduroy was a little tricky and I may have been a tad anal!!!

I know it's silly, but I wanted to experiment and figure out just how versatile this skirt is!!!

Pretty versatile, huh???  I'm looking forward to making another and a short version as well! Thanks for the inspo, ladies of Mix and Sew and Bee Made!!  Thanks for a great pattern, Orageuse!   Sew Chaotically!!! - les

In other news....

That means I am positive for flu A, y'all!!  Blech!  This stuff don't play!  Oh, well....it could be worse.

Stay well guys!  I still love my skirt!!! - c

Data for long term survival in thin cutaneous melanoma

FIRST ~ Take a long, slow, cleansing breath.  Now, read slowly...the words below.  DO. NOT. FREAK OUT!!!!!  (I will explain!!!)

Long-Term Survival of Patients with Thin (T1) Cutaneous Melanomas: A Breslow Thickness Cut Point of 0.8 mm Separates Higher-Risk and Lower-Risk Tumors. Lo, Scolyer, Thompson. Ann Surg Oncol. 2018 Jan 12. 

Counterintuitively, more deaths from melanoma occur among patients with thin (T1) primary melanomas (less than and = to 1 mm) than among those with thick primary melanoma because the great majority present with T1 tumors. Therefore, it is important to stratify their risk as accurately as possible to guide their management and follow-up. This study sought to explore the relationship between tumor thickness and prognosis for patients with thin primary melanomas.

A retrospective, single-institution study investigated 6263 patients with cutaneous melanoma (including 2117 T1 cases) who had a minimum follow-up period of 10 years.

For the entire patient cohort, the 10-year melanoma-specific survival (MSS) rate ranged between 92% for the patients with primary melanomas up to 0.3 mm thick and 32% for those with melanomas thicker than 8 mm. When divided into 25-quantile-thickness groups there was a significant difference in 10-year MSS between the two consecutive groups 0.8 and 0.9 mm; the differences in survival were not significantly different for any other consecutive cut points within the less than or equal to 1 mm thickness range, indicating a biologically-relevant difference in outcome above and below 0.8 mm. For the patients treated initially at the authors' institution, the 10- and 20-year MSS rates for those with tumors up to 0.8 mm thick were respectively 93.4 and 85.7%, and for tumors 0.9 to 1.0 mm, the rates were respectively 81.1 and 71.4%. Only 29.3% of the T1 patients who died of melanoma were deceased within 5 years.

A naturally occurring thickness cut point of 0.8 mm predicts higher or lower risk for patients with thin primary cutaneous melanomas. Long-term follow-up assessment of patients with T1 melanoma is important because late mortality due to melanoma is more common than early mortality.

Okay. Take one more slow deep breath.  All this is saying is ~ while death due to a thin melanoma is very rare, it is pretty significant in Stage IV melanoma (given that melanoma sucks great big green hairy wizard balls) and we have to face the reality that many Stage IV folks were once folks with a thin melanoma.  The majority of folks with thin melanomas NEVER progress but, in those that do, the price they pay is pretty dang high!!  So....what the folks in this study did is this: 

They looked at 6263 patients with cutaneous melanoma over 10 years.  For the entire group, survival (leaving out car wrecks, heart attacks, etc.) related to melanoma was 92% if the thin melanoma was 0.3 mm thick or less.  The survival rate was 32% over those 10 years for folks with melanoma thicker than 8 mm.  (Now.  I find this data point a little weird to be included in this abstract.  Is it a typo????  Because they are talking about all melanomas less than 1 mm. Did they mean 0.8 mm???  Or were there patients with thicker melanomas in the entire group reviewed....since they mention there were only 2117 T1 cases of the 6263 they reviewed?  Not sure, but I will assume it is correct and they were just pointing out what happens when you include the odds for ALL the cutaneous melanoma patients' cases they reviewed.) When they really broke the survival rates down for each thickness measure, the only one that had a significant difference in comparison to the others was the break point between those with a 0.8 mm and 0.9 mm lesion. NOW...even there...the 10 and 20 year melanoma survival rates were 93 and 85% for those with 0.8 mm lesions and 81 and 71% for those with lesions measuring 0.9 - 1.0 mm!!!  Only 29% of the T1 patients who did succumb to melanoma passed within 5 years of diagnosis.

And...No!  Before you start yelling, I do not know how the folks who did pass or advance were treated.  There are no dates given for the point from which these patients were followed.  Though, given the 5, 10 and even 20 year follow up that is mentioned, it is likely that with current, FDA approved drugs to treat melanoma at Stage IV and as adjuvant at earlier stages, the death and progression numbers will be greatly reduced in the future.

Now....if you recall this whole conversation about SLNB and thin melanomas: SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines) ....  This article provides some confirmation of why the 0.8 mm cutoff was assumed as the point for consideration of SLNB and advanced a patient's stage to T1b.  However, the data in this paper actually presents an 8% chance of death (while in my argument I was talking about a 5% chance of recurrence) for those with a thin....but thicker than 0.8 mm....cutaneous melanoma lesion.  Overall, I think this paper simply confirms that recurrence (and subsequent death) of/from melanoma is very small in folks with thin lesions less than 0.8 mm and pretty small in folks with thicker "thin" lesions.  However, the risk is not NONE and we should all be smart about that.  Still, with the current advances in melanoma treatments for Stage IV folks and as more folks are attaining effective adjuvant treatment in earlier stages, I am hopeful that the future of MELANOMA is bleak indeed....and is FABULOUS (or at least ever so much better!!!) for RATTIES!!!!!!!!!!!!!!!!!!!

For what it's worth - c

Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

This past November I posted this:  Back to the cooties in our guts....again!!!

In June, 2017, there was this:  ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

In February of that year:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

From 2016, there was this:  Intestinal bacteria as a way to determine risk for ipi induced colitis!

And in 2015...with a review of where all this bacterial mess started...there was this:  Cooties in our gut keep us skinny, smart and cure cancer!?????

With all that...now, there's this.....

The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Matsson, Fessler, Bao, et al. Science. 2018 Jan 5.

"Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients."

And, I present excerpts from:
CANCER THERAPY, Precision medicine using microbiota.  Intestinal microbiota influence cancer patient responses to immunotherapy.  Jobin. Science. 2018 Jan 7.

"…Conceptually, these findings suggest that bacteria-mediated interactions with the immune system are essential for optimal drug efficacy. However, there is limited information regarding the functional impact of the composition of the human microbiome and therapeutic outcomes in cancer patients. ...

...patients can be stratified into responders and nonresponders to immunotherapy on the basis of the composition of their intestinal microbiomes, suggesting that microbiota should be considered when assessing therapeutic intervention....

…Because microbiota have a pronounced modulatory effect on the immune system, they may enhance responses to immune checkpoint therapies...

...They observed that the strongest fecal microbial predictors of anti–PD-1 therapy response were bacterial diversity and abundance of Faecalibacterium and Bacteroidales...

... responding patients had an increased abundance of eight microbial species, including Bifidobacterium longum. The presence of this species in the intestines of tumor-bearing mice was previously found to improve anti–PD-L1 therapy. Interestingly, two species were also associated with nonresponsiveness (Ruminococcus obeum and Roseburia intestinalis). …

…introduction of A. muciniphila to mice receiving human nonresponder FMT reversed the low response to PD-1 blockade, improving antitumor immune cell infiltration and activity in tumors. Overall, these studies report a fascinating interaction between intestinal bacteria and antitumor efficacy of PD-1 blockade in patients, suggesting that precision medicine strategies should include the intestinal microbiota as a potential treatment modifier....

... Therefore, the presence of specific strains of bacteria may be able to modulate cancer progression and therapeutics, raising the possibility that precision medicine directed at the microbiota could inform physicians about prognosis and therapy. ..."

WOW!!!  If that's not a lot of shoo shoo, I don't know what is!!!!  So...let's break it down.  Through all the reports, the good cootie is overwhelmingly Bifidobacterium. That's the doo dad found in yogurt, chocolate, kefir, sauerkraut, spirulina, pickles, kimchi, kombucha!  Now, in addition to the bifidobacterium....the other factor that does a body good is a lot of other shit.  OR, actually...a lot of other STUFF in our boo boo.  A diverse population of cooties...living happily together...improving the lives of one another BECAUSE of their differences and what each "culture" brings to the table!!  (Damn!  Sounds like what the welcoming torch of the Statue of Liberty represented all along!!!!)  At least in little mice, the presence of Ruminococcus obeum and Roseburia intestinalis led to a decreased response to anti-PD-1.  However, by giving those nonresponders a different bacteria (A. muciniphila) the NON responsiveness, was removed.

Okay!  What does all that mean??  Not, sure.  I think a lot of this data meanders back and forth between melanoma peeps and melanoma mice (not to mention koalas in one of the prior reports!!!), so it is hard to know how much we can take as the gospel.  In the end, (HA! HA!  I CRACK myself up!  Poops!  I did it again!!!) I think we've always known that live cultures in foods like kimchi, yogurt, and kefir are good for us.  We also know that, though antibiotics save lives and misery when they are needed, they can also cause harm by killing off microbes that we would actually be better off keeping around.  So....eat the best you can.  Include fiber and culture rich foods in your diet.  Take antibiotics only when you need them.  Keep a sense of humor.  Wipe front to back.  And know that despite all the Latin names...poop...really is...poop!   - c

Aspirin, NSAID's, and melanoma

I first posted on this bunch of mess in 2012!!!!  (I'm getting old and in melanoma land ~ or any other land, really ~ that is AWESOME!!!!)   Here's a link to a complete re-cap:  Sooo....advil works for SOME melanoma patients?????  As you can see from these posts:  Aspirin and other NSAID's decrease rates of melanoma!!  Well, maybe!!!  Advil and such make immunotherapy work better in treating melanoma.  Oh, perhaps not....or just for certain peeps! 
Hmmmm......  Now, there's this....

Post-diagnosis aspirin use and overall survival in patients with melanoma.  Wallace, Li, et al.  J Am Acad Dermatol. 2018 Jan 6.   

Mouse studies show that tumor-derived prostaglandins and platelets promote melanoma progression and immune-evasion. [To] Determine if aspirin confers longer survival in patients with melanoma - A retrospective cohort study of 1,522 patients at Indiana University Health (IUH) diagnosed with melanoma between 2000 and 2014 and followed up through September, 2016.

Aspirin use was associated with longer overall survival in univariate analysis and after controlling for age, sex, stage, and treatment modalities. Aspirin use was not associated with survival in patients with in situ and stage I melanoma, but was associated with better survival in stages II and III. No statistical significance was observed in stage IV patients. In turn, patients using aspirin before diagnosis were less likely to be diagnosed in stages III or IV disease. Observational study. Aspirin could provide a survival advantage in melanoma. Clinical trials investigating the therapeutic potential of aspirin are warranted.

In this study, researchers in Indiana reviewed the files of 1,522 melanoma patients diagnosed at their university between 2000 and 2014 and followed them through September of 2016.  Aspirin use was NOT associated with survival in patients with Stage I and in situ melanoma.  However, aspirin WAS associated with better survival for Stage II and III patients, while no statistical difference was found in Stage IV patients.  However, patients who used aspirin BEFORE they were diagnosed were found less like to "be diagnosed in Stages III or IV disease". 

Hmmm.....You gotta love it when a new study only adds more confusion (or is that confirmation?????) to a yes/no situation!!!  Oh, well.  Melanoma provides no easy answers.  Low dose aspirin daily rarely hurts and helps some in a variety of ways.  Not something I've every partaken in....though advil has been an almost daily drug since taking anti-PD-1 for 2 1/2 years.  I think you'd be hard pressed to find immunotherapy patients who haven't been simultaneously "contaminated with" NSAID use, given the aches and pains the treatment produces.  Anyhow....still not sure what all this really means...if anything.  Be sure to talk to your doc about all your over the counter medicines and before starting a legit ASA regimen!  For what it's worth..... - c

Nivo after nivo? Or nivo after progression? Can melanoma patients still attain a response???

A question frequently asked...with no absolute answer is.... What if I take nivo after I've progressed....having already been on nivo....or if currently on nivo??????  These reports begin an answer:

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Nomura, Otasua, Konda, et al.  Cancer Chemother Pharmacol. 2017 Oct 5. 

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.

A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.

Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.

This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Here, 8 patients were given nivo (3 of them had chemo beforehand).  37.5% had a partial response.  37.5% had stable disease.  Nivo was stopped due to progression in 7 of the patients and colitis in 1.  6 were subsequently treated with ipi.  1 was given vemurafenib.  4 got radiation at that point.  Then...these 8 folks were given a new round of nivo.  2 attained a partial response.  3 attained stable disease. Eventually, 7 of them had to stop nivo again due to progression.  Interestingly, it sounds as though those that had radiation between therapies did better....at least for a while - though that is not entirely spelled out here.  

So, it seems that round two of nivo can give patients a reprieve.  Though for these 8 patients it doesn't sound as though it lasted long enough!

And....there's also this....

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Long, Weber, Larkin, ….Hodi, Wolchok.  JAMA Oncol. 2017 Jun 29.

Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.  Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.  Tumor response and safety in TBP and non-TBP patients.

Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP greater than 30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP greater than 30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP greater than 30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Here they looked at the outcomes of 3 trials in which nivo was used....in 526  patients.  306 had progression.  But 85 of those who progressed were given nivo more than 6 weeks AFTER their known progression, while 221 were not. Of those 85 patients "treated beyond progression", 24 "had a target lesion reduction of greater than 30% after progression compared to baseline."  And at follow-up further down the line, many of those were still alive.

There is much we still don't understand about immunotherapy.  But, I think the statement Agarwala and Weber made to, "Be patient with the patient!" still holds.  Hang tough, ratties! And, thanks!  - c

Sew Chaotically! - Coppelia Cardi by Paper Cut Patterns

I had really looked forward to this make.  Pattern procured by B at my request a bit ago.  Fabric chosen during my Goldhawk Road shopping adventure.  I even had great fun making the ingenious little instruction booklet Paper Cut prints in their patterns!!!  However, there were a few issues...not the least of which was poor fabric choice.  Which makes me rather sad, as I picked this fabric out especially with this top in mind!!!  Many sewists have noted a bit of an issue with the fit of the pattern itself, despite making some very lovely tops. This is one of my favorites: Gray All Day and her Coppelia cardi.  Anyhow, after reading many posts about the fit being large and various other tips, I felt prepared to knock it out of the park!  I cut the size small.

It went together easily.  Though I would not attach the wrist bands the way the pattern advises (and I almost didn't this time).  Done per their direction, the band is attached as a circle to the already put in sleeve.  Doing it that way is:  1.  Just more work.  2.  A right palaver, as the opening was too small to fit around the free arm of my machine.  Next time, I would attach the sleeve binding to the sleeve end flat.  Sew up the sides.  Turn up the cuff.  Anyhow...not too bad right?  Not entirely pressed.  Already with some large adjustments made to remove extra fabric from the shoulder seams, fore and aft, and a good bit on either side.

But...do you see the trick required to make it look even this good?

Yep.  Quite a lot of the "front" is tucked into the side/bottom as I wrapped the top around.  Not that cute in the first place, and impossible unless you are going to stand stock still like a sewing dummy!!!  Then again, when you make a top with material that is clearly too stiff, lacking in sufficient stretch (there's some in the this French terry, but not enough, given its heft), and without the necessary boobage....maybe you ARE a sewing dummy!!!  Hee, hee!!!

I let it sit for a bit...then I came up with this!!  I cut the bottom band off.  Took some MORE off the sides.  Folded the front pieces over each other where I wanted them to be.  Stitched them in place at the bottom.  Cut the bottom even all around as it was pretty jacked after those adjustments.  And finally, added a self drafted bottom band that was wider at the bottom edge than the top to accommodate my bootie!

Sew much better!!!

At least it is a wearable garment at this point!!!  I've worn it a few times in variations like this.  However, the material is so stiff (especially with those overlapping front layers), that I've found it more useful as a cover-up/warm layer over my workout wear on the way to my Barre workouts with Rosie.  Seems a waste in my mind, somehow.  But, as B says...."You gotta wear something there, too!!!"  Maybe he's worried I won't????

When sewing adventures go this crazy, you gotta laugh, right????

I think I'll try this pattern again, albeit with a fabric that is a great deal thinner with more stretch.  But....still loving my 2016 make:  Vogue's 9136 Cozy Coat 

One more knit top and final sewing adventure of 2017 to go!  Sew chaotically! - les

HDAC again - decreases resistance when encorafenib was combined with panobinostat - in the petri dish at least!

Initially, HDAC inhibitors were hoped to be useful in overcoming resistance to BRAF inhibitors.  Then, some data has demonstrated that they may improve responses to immunotherapy.  Here's a post, with links within, that cover those reports:  HDAC inhibitors for melanoma....what are they again????

(Sometimes it helps to review the alphabet soup!)

Now, there's this....

HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Gallagher, Gunatilake, Beaumont, et al.  Int J Cancer. 2017 Dec 6.

Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment. Using patient- and in vivo- derived melanoma cell lines with acquired BRAFi resistance, we show that combined treatment with the BRAFi encorafenib and HDACi panobinostat in 2D and 3D culture systems synergistically induced caspase-dependent apoptotic cell death. Key changes induced by HDAC inhibition included decreased PI3K pathway activity associated with a reduction in the protein level of a number of receptor tyrosine kinases, and cell line dependent upregulation of pro-apoptotic BIM or NOXA together with reduced expression of anti-apoptotic proteins. Independent of these changes, panobinostat reduced c-Myc and pre-treatment of cells with siRNA against c-Myc reduced BRAFi/HDACi drug-induced cell death. These results suggest that a combination of HDAC and MAPK inhibitors may play a role in treatment of melanoma where the resistance mechanisms are due to activation of MAPK-independent pathways.

For what it's worth!  Here's hoping! - c

Sew Chaotically! - Toaster Sweater from Sew House Seven, Version 1

This sweater pattern, from Sew House Seven, has gotten great reviews from a variety of sewists and I know why!!  It's awesome.  I snatched up the pattern when I happened upon a Makers Fair just after a visit to Hampton Court!!!  I stitched it up in a rich, soft, not-too-thick, navy blue French terry, that my camera refused to photograph well, acquired in my fabric shopping adventures on Goldhawk Road.  It is comfy and cozy without being too boxy or shapeless.  It stitches together very quickly and easily.  I made 'version 1' size medium.  My only changes were to add 2 inches to the length of the body, then added the waist band as prescribed.  But, had to cut 1 inch OFF the main sleeve before adding the cuff as directed.

When you have to give your sissie a shout out mid sew and show her how proud you are of your finished seams!!!!

I've worn it a good deal this winter, having finished it at the end of last year.  In fact, I have two more knit tops to share before moving on to 2018!!!!  As my first sews of this year, in a bit of a closet clean out, I hemmed a pair of pants, fixed two with waist band gappage at the back, slimmed down some slacks with too large a "bell" at the bottom, re-hemmed those, and turned a dress into a skirt!

Since it came with a matching fabric belt, my questionably matching fabric as waistband will be covered.  I think it will be fab!!!  However, I am Scott boy stoked about the project I'm working on now!!!  Here's a sneak peak:

I'm sew excited!!!  Have a great weekend and Sew Chaotically!!! -  les

Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)

Yes, I look forward to the day when I can make that announcement with no sarcasm and cease to make these crazy lists!  Here's the link to the last installment:  Everything Cures Melanoma....#8  Sigh.  Until then....

We have known for sometime that psychotropic agents like Thorazine kills melanoma.  Now:

Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects. Jiang, Chen, Shen, et al. Biomed Pharmacother. 2017 Nov.

Psychotropic agents have been shown anti-tumor potential in recent years. In the present study, our in vitro pharmacological data indicated that thioridazine inhibited melanoma cells proliferation. The growth-arresting effect of thioridazine was accompanied by autophagy induction, as shown by immunoblotting of increased LC3II. Besides, certain apoptotic events had also occurred after thioridazine exposure. The in vivo anti-melanoma effect of thioridazine was confirmed by showing that intraperitoneally injection of thioriazine remarkably retarded tumor growth and reduced tumor vasculature. Our results imply that thioridazine might be an available therapeutic agent for melanoma patients with no better options.

Of course, that does leave the tiny little hiccup of having to take psychotropic agents...among other things!!!

Antimelanomic Effects of High- and Low-Molecular Weight Bioactive Subfractions Isolated from the Mossy Maze Mushroom, Cerrena unicolor (Agaricomycetes). Statkiewicz, Matuszawska, Jaszek.  Int J Med Mushrooms. 2017

Three bioactive fractions isolated from Cerrena unicolor cultures-crude endopolysaccharide (c-EPS), laccase, and a subfraction of low-molecular weight secondary metabolites-were used to determine potential cytotoxic effects on the mouse melanoma B16-F10 cell line (American Type Culture Collection CRL-6475). The results obtained prove that all examined fractions exhibited activity against the investigated tumor cells. In addition, an evident immunomodulatory effect of the c-EPS fraction was observed. Our results show that the levels of 2 cytokines (tumor necrosis factor-a and chemokine ligand 2) in mouse inner medullary collecting duct mIMCD-3 cells (American Type Culture Collection CRL-2123) stimulated by c-EPS were significantly higher. A lipopolysaccharide model was used at the same concentration (10 μg/mL) as a positive control.

Yes, mossy maze mushrooms look like lichen I see on trees everywhere....but there you go!  Wanted you to see it just in case you thought anti-melanoma effects were limited to Shiitakes! (If you're interested in that one, check out this post from 2012: Shiitakes - Much ado about mushrooms!)  And speaking of lichen....

The Polysaccharide Extracted from Umbilicaria esculenta Inhibits Proliferation of Melanoma Cells through ROS-Activated Mitochondrial Apoptosis Pathway. Sun, Li, Zhang, et al. Biol Pharm Bull. 2018;41.

Cooked!

Raw as found in nature...

Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROS-mediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta.

The more you know!!!  Apparently pretty delicious and part of Korean cuisine!

Dietary Crocin Reverses Melanoma Metastasis. Bakashi, Lukmanul, Sam, and Javid. J Biomed Res. 2017 Nov 1.

Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase (g-GGT), sialic acid, tumor necrosis factor alpha (TNF-a), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 h of crocin (5 and 10 µg/mL) treatment. Administration of crocin to tumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid andg-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion, migration and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.

And what, you might ask, is Crocus Sativus.....that so helpfully cured these poor little mice???

Yep, my favorite Harbinger of Spring....the pretty, tiny, unassuming crocus that grows from bulbs.

It is not clear from the report if they are referring to using the bulbs, leaves, petals, or the super pricey saffron threads harvested from the crocus.  If it's the saffron threads themselves...that may set your bank account back just as much as immunotherapy!!!

Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells. Beberok, Wrzesniok, Minecka, et al. Pharmacol Rep. 2017 Jul 16.

Low effectiveness of anti-melanoma therapies makes it necessary to search for new drugs that could improve or replace the standard chemotherapy. Fluoroquinolones are a group of synthetic antibiotics, used in the treatment of wide range of bacterial infections. Moreover, this class of antibiotics has shown promising anti-tumor activity in several cancer cell lines. The aim of this study was to examine the effect of ciprofloxacin on cell viability, apoptosis and cell cycle distribution in COLO829 melanoma cells.  Cell viability was evaluated by the WST-1 assay. Cell cycle distribution and apoptosis in cells exposed to ciprofloxacin was analyzed by the use of fluorescence image cytometer NucleoCounter NC-3000.  Ciprofloxacin decreased the cell viability in a dose- and time-dependent manner. For COLO829 cells treated with ciprofloxacin for 24 h, 48 h and 72 h the values of IC₅₀ were found to be 0.74 mM, 0.17 mM and 0.10 mM, respectively. The oligonucleosomal DNA fragmentation was observed when the cells were exposed to ciprofloxacin in concentration of 1.0 mM for 48 h and 72 h. At lower ciprofloxacin concentrations (0.01 mM and 0.1 mM) cells were arrested in S-phase suggesting a mechanism related to topoisomerase II inhibition. Moreover, it was demonstrated that ciprofloxacin induced apoptosis as a result of mitochondrial membrane breakdown.  The obtained results for COLO829 melanoma cells were compared with data for normal dark pigmented melanocytes and the use of ciprofloxacin as a potential anticancer drug for the treatment of melanoma in vivo was considered.

So this is all rather old, in terms of how melanoma treatment is addressed, but in the petri dish it seems cipro  decreased the viability of melanoma cells.  Okay.  Plus...there's this....

The effect of ciprofloxacin on the growth of B16F10 melanoma cells. Jaber, Jallad, Abdelnoor. J Cancer Res Ther. 2017 Oct-Dec;13.

The antitumor effect of ciprofloxacin has been widely assessed in-vitro, and positive results have been reported. The aim of this study was to investigate the influence of ciprofloxacin treatment on the growth of B16F10 melanoma cells both in-vitro and in-vivo.

Groups of C57BL/6 female mice challenged with B16F10 melanoma cells were kept untreated or were treated with sterile water, intraperitoneal ciprofloxacin, or ciprofloxacin through drinking water for 10 days. The serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA 1 and 3 h after the last dose of ciprofloxacin. Mice were monitored for an additional 10 days for survival assessment. Moreover, B16F10 melanoma cells were cultured in 24-well plates and exposed to different concentrations of ciprofloxacin (10-1000 μg/ml). Viability was determined, after 24 and 48 h, using trypan blue.

The serum levels of VEGF significantly decreased in ciprofloxacin-treated mice when compared to the controls. None of the control mice survived beyond day 8, whereas 16.67% of those treated with ciprofloxacin survived up to 18 days. In addition, the viability of B16F10 melanoma cells, in-vitro, significantly decreased with increasing concentrations of ciprofloxacin after 24 and 48 h.

Ciprofloxacin seems to exhibit antitumor activity both in-vivo and in-vitro. This effect might be explained by several mechanisms such as directly inducing cancer cell death or altering the immune response through the modification of the normal microbiota.

So in little mice and petri dishes, ciprofloxin, a fairly common antibiotic "exhibits antitumor activity".  Though their commentary about "altering the immune response through the modification of the normal microbiota" is NOT a good thing if you believe this report:  Antibiotic use MAY decrease effectiveness of immunotherapy?????  Not to mention the more recent: Science magazine: Precision medicine using microbiota Researchers really need to learn to communicate and discuss their results!!!

Non Polar compounds of Persian Gulf Sea Cucumber Holothuria parva Selectively Induce Toxicity on Skin Mitochondria isolated from animal Model of Melanoma. Arast, Seyed, Nazemi, et al. Cutan Ocul Toxicol. 2017 Dec 12.  

Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melonama. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling.

In the present study, selective toxicity and apoptotic effect of three extracts of Holothuria parva (H. parva) were assessed on skin mitochondria isolated from mouse animal models of melanoma. The mitochondria was isolated from melanoma cells via differential centrifuges and treated with various concentrations (250, 500 and 1000 µg/ml) of metanolic, diethyl ether and n-hexane extracts of H. parva.

All the applied concentrations (250, 500 and 1000 µg/ml) of three extracts of H. parva increased the reactive oxygen species (ROS) generation only in the skin mitochondria isolated from melanoma cells group (In comparison to the control group). Additionally, all three extracts (250, 500 and 1000 µg/ml) induced swelling within the mitochondria, the collapse of the mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria. Flow-cytometry analysis demonstrated that n-hexane and diethyl ether extracts of H.parva selectively and progressively induced apoptosis only on melanoma but not healthy control skin cells group

Given these results, the potentially bioactive compounds found in H. parva render it a strong candidate for further research in molecular identification and confirmatory in-vivo studies. Clinical trials are also warranted in the general process of novel drug discovery for the treatment of melanoma cancer.

I feel it is important to note that this little feller' is not just any ol' sea cucumber.  No!  He is a Persian Sea Cucumber Holothuria Parva!!!  Just in case you were going to make a sea cucumber slurry to sprinkle on the random melanoma mitochondria you have sitting around in your petri dishes!!!

MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum. Bae, Karadeniz, Oh, et al. Evid Based Complement Alternat Med. 2017 Sep 20.

Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent-partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties.

Hey!  I swear this is the same as the pretty, paper-like, stiff, long-lasting, long stemmed flower that is in mixed bouquets you can get from Wally World!!!  Hmmm.....  

Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile. Campeiro, Marinovic, Carapeto, et al. Amino Acids. 2017 Dec 12.

The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions [No, I can see that injecting stuff into your abdomen wouldn't be the preferred route for drug consumption by many!!!] herein, we evaluated the antitumor effect of this native polypeptide employing the oral route. The efficacy of crotamine in inhibiting the melanoma growth in vivo, even after passing through the gastrointestinal tract of the animal, was confirmed here. In addition, biochemical biomarkers and also histopathological analysis showed both the absence of any potential toxic effects in tissues or organs of the animal in which the highest accumulation of crotamine is expected. Interestingly, a reduction of weight gain was observed mainly in animals with tumor treated with crotamine by IP route, but not by oral administration. Albeit, oral administered crotamine was able to significantly decrease the body weight gain of healthy animals without tumor. Taking advantage of this same experimental animal models receiving crotamine by oral route, it was possible to show metabolic changes as the increased capacity of glucose clearance, which was accompanied by a reduction of the total cholesterol, and by increased high-density lipoprotein levels, both observed mainly in the absence of tumor. Triglycerides and low-density lipoprotein were also significantly decreased, but only in the absence of tumor. Taken together, these data suggest a clear trend for metabolic positive effects and mischaracterize unhealthy condition of animals, with or without tumors, treated with crotamine for 21 days. In addition, this study confirmed the efficacy of crotamine administered by oral route as antitumor agent, which besides the additional advantage of administration convenience and decreased risk of toxic effects, allowed the serendipitous observation of several positive metabolic effects on treated animals.

Damn, while croatamine helped mice with melanoma a little, this shiz is the new lipitor...producing weight loss and decreased cholesterol in mice who did NOT have tumors!!!!  Just when you think injecting snake venom into the abdomen of little mice or putting it in their kibble couldn't get any weirder!  Mother Nature...what do you think of that kink in your food chain????

Well!!!  All of that is a lot of business, isn't it????  (Not to mention all the ground that is covered in the prior posts!!!!)  I never say NEVER!!!  Ha!  Here's hoping.....as I nibble my lichen, pop my cipro and thorazine, with a glass of red wine and dine on curry over saffron flavored rice with a bit of kimchi and mustard on the side!!!  After dinner coffee, anyone???  - c