Thursday, December 8, 2016

Analysis of IL-2 after ipi in melanoma - and a bit more


IL-2:  An old drug in melanoma, tough to take, recognized to have a response rate around 10%, though about 4-5% of those can be durable.  Now, researchers are looking for ways to use it to improve responses when combined with other drugs.  There was this from 10/2016:  Killing melanoma (in mice) is enhanced in cells treated with reovirus and radiation OR with a combo of tumor-antigen-targeting-antibody, IL-2, anti-PD1 and a T cell vaccine!!!!

Use as an intra-tumoral agent from 7/2016:  Report on intratumoral IL-2 with intratumoral ipi for nonresectable Stage III/IV melanoma 

And this out of ASCO in June:  ASCO 2016 - immunotherapy after HD IL-2 and vice versa - HD IL-2 after anti-PD1 

Now there is this:

A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma.  Buchbinder, Gunturi, Perritt, et al.  J Immunother Cancer. 2016 Sep 20.

High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored.  The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed.  A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death.  In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

And this:  

Clinical Response Rates From Interleukin-2 Therapy for Metastatic Melanoma Over 30 Years' Experience: A Meta-Analysis of 3312 Patients.  Bright, Coventry, Eardley-Harris, Briggs.  J Immunother. 2016 Nov 21.    


Interleukin-2 (IL-2), initially used in 1986, can induce clinical regression-complete responses (CR) and partial responses (PR) of metastatic malignant melanoma. IL-2 has been used alone or in combination, and in different dosage schedules, as an immunotherapeutic agent for melanoma treatment. This meta-analysis aimed to document and evaluate the spectrum of reported clinical response rates from the combined experience of almost 30 years of IL-2 clinical usage. Clinical trials using IL-2 for metastatic melanoma therapy that reported: dosage, combinations, study details, definitions and clinical CR, PR, and overall response (OR) rates were included. A meta-analysis was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. In total, 34 studies met inclusion criteria, with 41 separate treatment arms. For all IL-2 treatment modalities collectively, the CR rate was 4.0%, PR 12.5%, and OR 19.7%. CR pre-1994 was 2.7% versus 6.1% post-1994. High and intermediate-IL-2 dosage showed no CR difference, while low-dose IL-2 showed a nonstatistical trend toward an increased CR rate. The highest CR rate resulted from IL-2 combined with vaccine at 5.0%. The meta-analysis showed that IL-2 immunotherapy for advanced metastatic melanoma delivered a CR rate of 4% (range, 0-23%) across nearly 30 years of clinical studies, with gradual improvement over time. The significance is that, contrary to popular belief, the data demonstrated that CR rates were similar for intermediate versus high-IL-2 dosing.

Keep on keeping on, dear ratties!!! - c

Tuesday, December 6, 2016

Radiological evaluation of response to melanoma treatments


Another reason liquid assays (as discussed here last month:  Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma! ) would be so helpful:

Patterns of response to anti-PD-1 treatment: an exploratory comparison of four radiological response criteria and associations with overall survival in metastatic melanoma patients.  Khoja, Kibiro, Metser, et al. Br J Cancer. 2016 Oct 4.  

Radiological assessment of response to checkpoint inhibitors remains imperfect. We evaluated individual lesion and inter-patient response by response evaluation (RECIST) 1.1, immune-related response criteria (irRC), CHOI and modified CHOI (mCHOI) and correlated response with overall survival (OS). Thirty-seven patients with 567 measurable lesions treated with pembrolizumab in the Keynote 001 trial were studied. Association of response with OS was determined.  Response varied according to site; lung lesions had the highest rate of complete response (69 out of 163 (42%) vs other sites 71 out of 404 (18%). Delayed response post first scan was seen in 2 out of 37 (5%) deemed progressive (PD) by RECIST and 2 out of 14 (14%) deemed PD by irRC. Modified CHOI criteria showed response of 38% (14 out of 37). Change in tumour size and density on first follow-up assessment was associated with OS with each 1000 mm2 increase in tumour size from baseline increasing the hazard of dying by 25.9%.  Response defined by any criteria had superior OS. Response by any criterion was prognostic. Novel patterns of response and changes on treatment in tumour density suggest complex anti-tumour responses to immunotherapy.  

Then there is this report on using ultrasound to determine progression vs pseudo progression ~
 
Ultrasonographic findings can identify 'pseudoprogression' under nivolumab therapy.   Imafuku, Hata, Kitamura, et al.  Br J Dermatol. 2016 Nov 22. 

'Pseudoprogression' is often seen in patients with melanomas who are treated with immune-checkpoint inhibitors such as nivolumab or ipilimumab. We sometimes evaluate metastatic lesions by imaging tests such as CT or PET-CT. 'Pseudoprogression' usually occurs upon the initial administration, which may make it difficult for the physician to determine the disease condition. In our two cases of metastatic melanoma treated with nivolumab (anti-PD-1 antibody), we examined the ultrasonography (US) of target lesions that could be accessed from the body surface, such as those of the regional lymph node or subcutaneous metastasis. In both cases, the US revealed a lesion approximately 10% greater in size after 40-50 days of nivolumab administration, even though the blood flow inside the tumour was reduced by about 20% within 50 days. From about 100 days after blood flow reduction was detected by US, the tumours began to decrease in size. However, contrast CT was unable to detect the association between tumour size and tumour blood flow. The present cases suggest that US could be a powerful tool for differentiating between 'pseudoprogression' and real progressive disease in patients treated with cancer immunotherapies such as those involving immune-checkpoint inhibitors. The misdiagnosis of progressive disease can lead to unnecessary alternations in the current treatment. Therefore, the US findings in our study could be clinically useful and educational for physicians.  

Good data to know when depending on radiology studies as evaluation of status and progression.  But wouldn't it be nice to just do a blood draw????  At least some of the time???? - c

Sunday, December 4, 2016

Sew Chaotically! - The Tale of the (SCARY) Twelve Dollar pants - B5895 - or....Part 2!


This story began a bit ago, as posted here.... Sew Chaotically! - The Tale of the $10.00 pants - B5895

My results with my first two pants were okay....but I had high hopes for this pair!!!! I mean they are made of stretch corduroy at $6.00 a yard! However, that's not exactly how things turned out!!!  I went to the trouble to work on raising the crotch.  This tutorial was really great:  How to alter crotch length in a pants pattern by: Professor Pincushion
I probably should have taken a picture before I moved in them, because at that time, the fit (crotch and all) was perfect!  However, after sitting for just 30 minutes or so...this happened.....

THEN.... by the end of the day.....
 
...there was this!!!!  B said I could use them as maternity pants.  Not sure about that, but they certainly do grow - whether you need it or not!!!!
Sooooo.....I guess you get what you pay for????  Again, not entirely sure if the problem is me, the pattern, or the fabric.  I'll probably use all three of these (if I can keep the last pair on my body!!!) as play pants with a looooooong top!!!  But, I think I'm done with pants for a bit!!!  

It seems that Dr. Seuss was on to something here!!!!  Enjoy....

Well…
I was walking in the night
And I saw nothing scary.
For I have never been afraid
Of anything. Not very.
Then I was deep within the woods
When, suddenly, I spied them.
I saw a pair of pale green pants
With nobody inside them!
I wasn’t scared. But, yet, I stopped
What could those pants be there for?
What could a pair of pants at night
Be standing in the air for?
And then they moved? Those empty pants!
They kind of started jumping.
And then my heart, I must admit,
It kind of started thumping.
So I got out. I got out fast
As fast as I could go, sir.
I wasn’t scared. But pants like that
I did not care for. No, sir.
After that a week went by.
Then one dark night in Grin-itch
(I had to do an errand there
And fetch some Grin-itch spinach)……
Well, I had fetched the spinach.
I was starting back through town
When those pants raced around a corner
And they almost knocked me down!
I lost my Grin-itch spinach
But I didn’t even care.
I ran for home! Believe me,
I had really had a scare!
Now, bicycles were never made
For pale green pants to ride ‘em,
Especially spooky pale green pants
With nobody inside ‘em!
And the NEXT night, I was fishing
For Doubt-trout on Roover River
When those pants came rowing toward me!
Well, I started in to shiver.
And by now I was SO frightened
That, I’ll tell you, but I hate to….
I screamed and rowed away and lost
my hook and line and bait, too!
I ran and found a Brickle bush
I hid myself away.
I got brickles in my britches
But I stayed there anyway.
I stayed all night. The next night, too
I’d be there still, no doubt,
But I had to do an errand
So, the next night, I went out.
I had to do an errand,
Had to pick a peck of Snide
In a dark and gloomy Snide-field
That was almost nine miles wide.
I said, “I do not fear those pants
With nobody inside them.”
I said, and said, and said those words.
I said them. But I lied them.
Then I reached inside a Snide bush
And the next thing that I knew,
I felt my hand touch someone!
And I’ll bet that you know who.
And there I was! Caught in the Snide!
And in that dreadful place
Those spooky, empty pants and I
were standing face to face!
I yelled for help. I screamed. I shrieked.
I howled. I yowled. I cried,
“OH, SAVE ME FROM THESE PALE
GREEN PANTS WITH NOBODY INSIDE!”
But then a strange thing happened.
Why, those pants began to cry!
Those pants began to tremble.
They were just as scared as I!
I never heard such whimpering
And I began to see
That I was just as strange to them
As they were strange to me!
So…
I put my arm around their waist
And sat right down beside them.
I calmed them down.
Poor empty pants
With nobody inside them.
And now, we meet quite often,
Those empty pants and I,
And we never shake or tremble,
We both smile and we say…”Hi!”                 Dr. Seuss

Sewing chaotically does not always equal success, and I'm not sure I'm ready to put my arm around these pants, but it makes for fun (and frowns)!!! Hey!  Maybe I'm just ready for a Rocket in my Pocket!!! - c

Saturday, December 3, 2016

Sew Chaotically! - The Tale of the $10.00 pants - B5895


Sooooo (or perhaps...sewwwwww!)....this has been a chaotic experiment!!!  This pattern got good reviews and I was in need of some slim pants that would not be mistaken for leggings and thought perhaps these would fit the bill.

Never having made pants before, I didn't want to ruin expensive material, but didn't have anything that I could really practice with in my possession.  I found some "bottom weight" stretch cottons at  LowPriceFabric.com priced at $5.00 a yard.  Okay!  2 yards please!  Here's the first attempt:




I think the bootie fit turned out pretty well.  I usually make a 10 or 12 in the Big 4 patterns, but after reading up and measuring carefully, went with the 10, adding about 8 inches to the leg length, obviously.  I had to take a good bit off the side seams at lower hip...but that was not big deal. The waist band was a bit of a disaster.  First, the material spazzed completely out when I tried to use iron on interfacing.  (Should have cut another right there...but I moved on.) Second, the pockets are super cute on the pattern and part of why I liked it.  They were easy to make and seemed to fit together very well.  But, once the front pant was sewn to the back...they wadded up very strangely...pulling the entire front of the pant into weird folds.  Not sure if I did something wrong or if this fabric...which was a bit more flimsy and thinner than expected....stretched out too much in the sewing process.  Anyhow, solved this by cutting the pockets out...so the appearance remains...but there is no actual pocket.  Third, the straight, long, rectangle of a waistband, that you simply fold over in the middle, stood straight up around my waist!!!  So...I wrangled it into submission by making very awkward darts at each side seam.  It works.  I will wear them, despite the fact that they require ironing after washing!!  Weird for a stretch cotton in my opinion.  I've even gotten complements on them...but...hmmmm.....

We begin again....  Still with $5.00 a yard fabric from the same source....but this was a thicker...verging toward a soft, stretch denim, with a pin stripe.  Given the prior pocket adventure, especially in the presence of the stripe, I omitted them entirely here.  So, no problems there....although I think the "with the pocket" look is much cuter.  I took up the sides along the hips when cutting...so that worked out.  I fixed the waist band by making my own "contoured waistband" per this amazingly easy (once I wrapped my spatial relation lacking brain around it!!) and awesome tutorial:  A Fashionable Stitch - How to create a contoured waistband  I'll be using that pattern piece on other things!! Bootie still good.  Think there may be a bit too much fabric in the crotch.  But...a girl does have to be able to sit!  Still thinking about it.  I'll probably take it up a bit on the next pair!




So...one more time we sew!!! While wearing my Alder shirtdress with ruffle! styled to accommodate the cooler weather!! Perhaps it will bring me luck!!!


While both these pants are ok and will be worn - please...please...please...a little better outcome this go round????  I mean, this is a stretch corduroy that went for $6.00 a yard!!!  Going for the pockets and the whole she bang this time!!  Hee hee!  Lord knows, I Sew Chaotically!!! -  c

Thursday, December 1, 2016

Sew Chaotically!! - Another skirt from Simplicity 2451


I've made a couple of skirts from Simplicity's 2451 pattern -


-and had this denim-like cream and blue piece, dubbed upholstery fabric from now defunct Hancock's for awhile, with the idea of playing with the stripes, when making a version of the first skirt pictured. 























I don't love it as much as I imagined....probably because the material is a bit stiff.  It has gotten better with a couple of washings.  Here it is..."on" a person!!!




 
I think I would like it better styled more like this!!  I'm sure it will get good wear, one way or another!

Happy chaotic skirt making! - c

Tuesday, November 29, 2016

Radiation and ipi = better responses than either alone!!! (AGAIN!!!)




Hopefully, this will soon become routine info and thereby treatment for melanoma patients!!!   Prior posts on the topic:  Better responses when immunotherapy is combined with radiation    

Now this:

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Hiniker, Reddy, Maecker, et al.  Int J Radiat Oncol Biol Phys. 2016 Nov .

Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.

In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.

Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.

This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T-cells.  Tang, Welsh, de Groot, et al.  Clin Cancer Res. 2016 Sep 20.

Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab.

SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. Maximum tolerated dose was determined with a 3+3 dose de-escalation design. Immune marker expression was assessed by flow cytometry.

Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting {greater than or equal to}6 months). Clinical benefit was associated with increases in peripheral CD8+ T-cells; CD8+/CD4+ T-cell ratio; and proportion of CD8+ T-cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T-cells expressing ICOS, GITR, and 4-1BB.  Combining SABR and ipilimumab was safe with signs of efficacy; peripheral T-cell markers may predict clinical benefit; and systemic immune activation was greater after liver irradiation.  

If these latest posts seem like we melanoma patients have been singing the same tune...for YEARS....regarding liquid assays for tumor eval and progression, PD-L1 staining, and radiation COMBINED with immunotherapy....WE HAVE BEEN!!  Come on melanoma researchers, general oncologists and the FDA!!!  This should not be hard to figure out!!! - c

Sunday, November 27, 2016

Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma!


Also from the Boston Conference, Society for Melanoma Research -

And as I said earlier this year:   A valid and specific blood draw that could help diagnose, determine the presence of a response to therapy, and be used as follow-up (instead of scans!) would be sooooooooooo  awesome!!!!  Now there's this: 

Non-invasive monitoring of treatment response to immunotherapy in patients with metastatic melanoma.  Gray, Pereira, Calapre, et al.

Current methods for monitoring melanoma dynamics during treatment are limited to LDH levels and imaging to estimate tumour burden. In particular, responses to immune checkpoint inhibitors vary greatly in timing and extent, and may not be accurately reflected through radiological examination. The analysis of circulating tumour DNA (ctDNA) through sensitive methods can provide a rapid, accurate and quantitative method to determine therapeutic effect as early as possible. In this study mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF, NRAS and TERT variants in 47 patients with advanced metastatic melanoma before commencing treatment with the immune checkpoint inhibitors pembrolizumab (N=30) or ipilimumab (N=17). Tumour-associated ctDNA was detected in 32/47 (68%) plasma prior to treatment, in 76% (N=17) of BRAF mutant and 100% (N=2) of NRAS mutant melanomas. In addition, TERT promoter mutations were detected in the plasma of 61% (N=28) of BRAF/NRAS wild-type cases. Monitoring of ctDNA levels in patients positive at baseline, showed a decrease in ctDNA in response to therapies prior to or concurrently with radiographic response. However, a delayed pattern of response was observed in comparison with our previous data in patients treated with MAPK inhibitors, and consistent with clinical measures of response in ipilimumab and pembrolizumab clinical trials. In conclusion, this study demonstrates the utility of ddPCR assays to monitor ctDNA in the plasma of melanoma patients undergoing immunotherapy.  
Yep!  Been yelling about this for some time:

Here's a post about BRAF testing via a blood draw with lots of previous links to liquid biopsy info:  BRAF testing via blood draw....and more

Here's another demonstrating the value of such non-invasive monitoring:  Melanoma antigens in blood are prognostic of OS and correlate with response to ipi

C'mom man!!!  Let's get this going....for everybody!!! -  c