Friday, April 20, 2018

Creating vitiligo with monobenzone to help melanoma patients????

We have known for some time that melanoma patients who develop vitiligo do better than those who do not.  Lot's of posts regarding vitiligo and melanoma can be seen here:  All things vitiligo

I've thought for a long time, that if we could figure out the exact cause of the development of vitiligo in some...and trigger it in would certainly be a good thing!  Now, there's this ~

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial. Teulings, Tjin, Willemsen, et al. Oncoimmunology. 2018 Jan 15.
Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

Okay,  So, in this trial 25 Stage III/IV folks (though only 21 were evaluated in the end) had monobenzone and imiquimod applied to their skin on and around existing melanoma skin lesions.  At 12 weeks Partial Regression was noted in 8 patients and 1 had stable disease.  As treatment continued, a Clinical Response was noted in 11 patients and 3 had a Complete Response.  Vitiligo (depigmentation of the skin) was noted in areas NOT treated in 7 patients, implying a systemic response to this therapy.

What is not clear to me is whether or not these patients had been treated with any other prior or concomitant immunotherapy.  I mean, if I were a Stage IV patient (Wait, I am!!!  HA!) I don't know that I would settle for just applying a cream.  On the other hand, if they would treat me systemically AND apply a cream....I would totally go for it!  It may be that these peeps had actual cutaneous lesions, almost like intrasit mets or something, given the way the authors describe the application process.  This condition is not something all Stage III/IV melanoma patients have.  Unfortunately, information about the exact sort of lesion and the prior or simultaneous systemic treatment of the patients included here is not divulged in this abstract.  Even so, monobenzone applied to the skin with imiquimod sounds like a low risk procedure with some positive results.  

Here's to a whiter shade of pale!!! Keep on teaching us, ratties! - c

Thursday, April 19, 2018

Sew Chaotically! - McCall's 7726, wide legged faux paper-bag waist trousers!!

I've worn real live paper-bag waist trousers and loved them...but for all their apparent insouciance they can be tricky to wear and keeping the gathers in place over the course of a day can be difficult.  When I saw this pattern, with what I suppose you call box pleats (???), I knew it would be perfect!!!  I was actually thinking of making them in a light weight denim but when I found this really lovely fabric at JoAnn's...well...there you go!  It washes and dries perfectly and was easy to sew.  Thanks goodness, since I had to make this simple, well drafted pattern difficult with my plaid matching!!!

And, YES!!!!  Pattern matching of which I am inordinately proud!!!  Right down to the belt loops!!!!  I cut a straight 12, adding no length as the pattern allows for a deep hem so I had plenty of material to play with.  I took in the waist and hip at the side seams after fitting.  My only change was to add some interfacing to the inner waistband facing which is simply the top edge of the pant folded down.  The pattern makes no recommendation for this, but if your fabric is as fluid as mine and you don't want your faux paper-bag waist flopping down, it is probably something to consider.

I really love these pants!!!  The perfect combo of "men's wear" made more feminine with the fluidity of the shape.  Still planning on another pair...possibly a bit that soft denim if I can find the right material.  Or maybe a grey flannel for winter????  Sew chaotically! - les

Wednesday, April 18, 2018

Alkaline diets and "complementary" treatments??? Be VERY careful! They may cause an increased risk of progression in melanoma!!!

While it makes complete sense that we are all searching for get rid of our melanoma and/or make our treatments more effective...even "benign" "natural" supplements can cause problems!!!  I published this in 2016:  Combining alternative and conventional treatments for melanoma....a risky business!

Now, there's this:

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study. Knapen, Koornstra, Driessen, et al. Target Oncol. 2018 Apr 11. 

The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.

To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.

A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.

In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone, which became statistically significant in a sensitivity analysis.

There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating  full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

While this is not the most definitive study...these data certainly point to the need for caution when adding "complementary" treatments to your melanoma therapy!!!  Stay well! - c

Friday, April 13, 2018

Sew Chaotically! - Wardrobe review and repair with new skirt and top! (M6842 and M6282)

Wardrobe review with Roo!!!  She took advantage of one day of her spring break to do spring cleaning in her closet!  She had done a rushed college student/cum mathematics teacher wardrobe up-grade several years ago, adding a few things here and there, since. However, she felt it was time to give it all a good hard look.  We went through EVERYTHING!!!  It was FUN!  We allocated items to:  keepers, repairs, trash, donate, and sell if possible.  So far, the yield is much more closet space, a large bag to the homeless center, more than $20 bucks in her pocket, with the possibility of more.  The mending pile came home with me. 
Button with braided loop added to the purple top M6896 on the left for modesty and cuteness.  Black and greenish khaki pants hemmed.  Grey shorts taken in at the waist in the back to remove the extra room in the waistband found in so many ready-to-wear pants.  The facings secured in the New Look 0926 sleeveless dress I made her before I became more savvy about bias tape finishes.  Little summer top hemmed more to her liking.   Waist bands of three skirts taken in - coral rtw, purple fine cord I made her several years ago, and purple plaid M3341 (along with their facings and linings!!! Big self congratulatory pat-on-the-back for myself there!!!).  And...a new little black flippy skirt!  (More on that below!)
A new combo already working!!!
And then there is this new and needed addition!  A really great, easy pattern I've used several times before McCall's 6842 top that off...

I've liked the look of this top/dress, and had this pattern at hand, for some time.  However, when perusing the pattern instructions I was always put off by the seeming complexity of the lining installation!!!  But last week, with years of sewing experience now attained, I thought, "Pish posh!!!  A lining???  How difficult could that be????"  Well!!!  While this pattern (and pattern designer) seem super proud to offer page after page on how one can adjust it for a high or low back hump, bust name offers very little on how to actually put the garment together!!!  Maybe it's just me...but the methodology was incredibly unclear on how to attach the shoulder seams in a manner that allows one to pull the lining right side around once neck and arm holes have been stitched together!  However, after a good bit of angst and almost driving poor B nutters with my frustration....I made it work.  I made a straight 12.  No adjustments apart from leaving out the back zip which the pattern says usually works if your knit is stretchy enough.  Next time, I will look at the way the lining is installed on a different top that went together easily and do it that way!
Rosie was very happy with it was all worth it!  And, it works well with much of her purple durple wardrobe!!
Including her new skirt!!!
Sew much fun with my girl!!!  And a big thanks to Roo for being a great model after a long day pouring Algebra II, Calculus and Pre-cal into the craniums of our future!!! Sew chaotically!!! - c

Tuesday, April 10, 2018

BRAF/MEK for melanoma brain tumors? Yep! It works!

Brain mets suck great big green hairy wizard balls.  Period.  Now, this....

Clinical and radiological response of BRAF inhibition and MEK inhibition in patients with brain metastases from BRAF-mutated melanoma. Geukes, Boogerd, Blank, et al. Melanoma Res. 2018 Jan 19.

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months (n=30), 8.8 months for dabrafenib alone (n=31), and 5.7 months for vemurafenib (n=85). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group. Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months, 5.7 months for dabrafenib, and 3.6 months for vemurafenib. A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

Okay, so most of this is a no-brainer!!!  The BRAF/MEK combo does better than BRAF inhibitors alone - in brain or body!  We have known this for how long????  BUT, it does confirm (again) that targeted therapy...the BRAF/MEK combo for melanoma peeps whose tumors are BRAF in the brain and the body!

For what it's worth. - c

Sunday, April 8, 2018

T-VEC in melanoma, after progression on immunotherapy and BRAFi with good results! 3 case reports...

I have been a fan of intralesional (also called intratumoral) therapies for some time...esp in combination with systemic therapy, noting in a prior report ~ "These drugs are injected directly into a relatively superficial melanoma tumor.  They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy."

These drugs include:  T-VEC, PV-10, CAVATAK, HF10, SD101 and IMO-2125 (both TLR agonists), ISF35 (a CD40 agonist), and even IL2 has been used in this fashion.  Here's a link to bunches of reports on all of these:  ALL the intralesionals!!!

Here are multiple reports on T-VEC in particular:  All things T-VEC (talimogene laherparepvec) are three case reports on melanoma peeps who had failed multiple therapies but gained a response with T-VEC...

Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors. Chesney, Imbert-Fernandea, Telang, et al. Melanoma Res. March 20, 2018.

Talimogene laherparepvec is a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol. Intralesional talimogene laherparepvec (day 1, greater than/= to 4 ml 10 PFU/ml; after 3 weeks, greater than/= to 4 ml 10 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte-macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (greater than 60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4 and CD8 T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.

...and the final peep....

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition. Blake, Marks, Gartrell, et al. J Immunother Cancer. 2018 Apr 6.
Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy.

We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab.

Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.
Now...these abstracts describe only 3 peeps.  Patient #1 is still with us a year later and, given the T cell response noted, seems to be benefiting.  Patient #2 attained a complete response.  Patient #3 attained a complete response in the brain and partial in the body.  (I still really hate it when melanoma patients - or anybody really - has to resort to WBR, but desperate times call for desperate measures.) 

So...for what it's worth.  Sounds like something I would certainly be interested in should I have the need.  Hang tough ratties!!! - c

Friday, April 6, 2018

Such a bummer!!!! An apparent end to the ECHO 301 trial testing epacadostat (an IDO inhibitor) combined with the anti-PD-1 product Keytruda (pembrolizumab) for melanoma

That is really unwelcome news!!!  I had placed a lot of hope on this combo!  And I was not alone!!!

Pembro (Keytruda) and epacadostat - a promising combo for melanoma 

In that post I note:

Epacadostat, an IDO inhibitor, studied in combination with Pembrolizumab (anti-PD-1, also known as Keytruda) since the ECHO-204 trial started in 2015, has now morphed into the ECHO 301 study for melanoma patients.   I've been impressed by the data coming out on the combo for awhile, posting this in March of 2016: Immunology webinar update by Dr. Weber

While the webinar covered many topics, there was this on the combo: 
Epacadostat (an IDO inhibitor) + Pembrolizumab:Preliminary Results

                61 patients were enrolled by September 2, 2015  Safety data on 46 patients (19 melanoma, 7 RCC, 7 NSCLC, 5 transitional cell carcinoma, 4 endometrial adenocarcinoma). Most common all-grade treatment-related AEs were rash (22%), fatigue (17%), nausea (11%), and pruritus (11%).   Grade 3/4 treatment-related AEs occurred in 13% of patients (rash, 7%).   One patient discontinued for a treatment-related AE.  IDO inhibitor did not seem to increase side effects.  Melanoma patients only (n - 18) - 56% ORR.  Melanoma treatment naive patients (n - 16) - 63% ORR.  Weber found these results very promising and comparable to the ipi/nivo combo in regard to response rates but with much milder side effects!!!
Within the same link....I also posted:

Now...we have this:  Weber's report: Pembro plus Epacadostat as frontline melanoma treatment

In the link above, Shannon Connelly's June 29, 2017 OncLive report, notes the following:

   'If mature data from the ongoing phase III trial of pembrolizumab (Keytruda) combined with epacadostat are positive, the combination could become the preferred frontline treatment regimen for patients with melanoma, says Jeffrey Weber, MD, PhD.

The ongoing KEYNOTE-252/ECHO-301 study is exploring the efficacy, safety, and tolerability of the PD-1 inhibitor pembrolizumab with the first-in-class IDO1 inhibitor epacadostat in patients with stage III/IV unresectable or metastatic melanoma (NCT02752074).

Findings of the multi-arm, open-label phase I/II ECHO-204 trial of pembrolizumab/epacadostat in patients with advanced solid tumors presented at the 2017 ASCO Annual Meeting showed the combination demonstrated an objective response rate (ORR) of 63% and a complete response (CR) rate of 5% for patients with treatment-na├»ve melanoma. Based on the projected 2-year survival data, the combination could represent a new, less toxic frontline standard of care for patients with melanoma, said Weber, a medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center.

The 1- and 2-year survivals are projected to be as good as ipilimumab (Yervoy)/nivolumab (Opdivo), which means a 64% 2-year survival rate,” Weber said. “Let's say it's around a 62% 2-year survival rate. Given the very favorable toxicity profile, a lot of doctors will want to use pembrolizumab/epacadostat in the frontline setting.”' has been proven out in other may be that naive patients do the best...and they are the only folks in this trial.  But, even so - an ORR of 63% and CR of 5% is just as good as the ipi/nivo combo while epacadostat has far fewer side effects than those produced by ipi.  If these numbers hold...The Wizard Weber may be on to something here!! Thanks, ratties!!  

Sadly, today there is this:  Incyte’s cancer drug fails trial, marking major blow for immunotherapy combination treatment. By Adam Fuerstein 

"Incyte said Friday that its experimental drug epacadostat failed to improve the efficacy of Merck’s checkpoint inhibitor Keytruda when the two drugs were used together to treat patients with newly diagnosed melanoma.
The negative outcome of the Incyte Phase 3 clinical trial, known as ECHO-301, has far-ranging ramifications. It’s a big setback for Incyte and for melanoma patients. But the trial results could also ripple across the fledgling cancer immunotherapy field and the biotech stock sector."
My heart hurts for the ratties who were counting on this!!  While the advent of BRAF/MEK and immunotherapy (ipi, nivo, and pembro) changed the world of melanoma in almost miraculous ways for those of us lucky enough to gain a response to them ~ they leave far too many melanoma patients behind.  Only about half of us are BRAF positive.  The anti-PD-1 products when given alone help only about 40% of us.  The ipi/nivo combo gains a response for about 50% of us, but comes with some difficult side effects for a goodly number.  This experience shows the danger of putting too much credence on studies with such small numbers, like the 19 melanoma patients in the initial trial.  Still, we have to start somewhere.

As my favorite professor (He taught geology...yes, I took geology!  It's a long story!!!) of all time used to say, "We begin again!"

And so we shall.  Thanks ratties.  You continue to lead the way!  - c