SRS combined with anti-PD1 makes things better in ratties....this one's for you Artie!!!!

Stereotactic Radiation Therapy Augments Antigen-Specific PD-1 Mediated anti-Tumor 
Immune Responses via Cross-Presentation of Tumor Antigen.  Cancer Immunol Res.  Sharabi, Mirschl, Kochel, et al.  2014 Dec19.

"The immune modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. ....we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.  [In] small animal radiation research...image guided sterotactic radiotherapy to...melanoma or...breast [cancer] tumors resulted in development of antigen-specific T-cell and B-cell mediated immune responses.  These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control.  ...radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells.  ...radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors.  These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic."

Prior post with two articles noting synergistic benefit when radiation was combined with ipi: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/01/ipi-and-radiationa-good-combo-for.html

Individual patients, like dear Artie, seem to be experiencing this sort of effect when given radiation for pain control and other reasons, when already on or in rapid succession with immune therapy.  Way to go, ratties....the big and little ones!  Best wishes, Artie!  You rock!   - c

With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade.  Lipson, Velculescu, Pritchard, et al.  J Immunotherapy Cancer. 2014 December 16.

Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation.  We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.

Tumors from 12 patients with metastatic melanoma undergoing treatments with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT.  Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.  In 5 of 10 patients studied, mutations were detected in BRAF (1), NRAS (2), TERT (1) and ALK (1).  Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens.  Plasma ctDNA levels ranged from undetectable to 5.5% of total circulating cell-free DNA.  In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography.  In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit.  In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement.

Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression.  Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs.

How cool would this be if it works?!!!  Patients and their docs would be able to accurately assess tumor response earlier, allowing patients to proceed to a different therapy sooner rather than later when needed, thus saving time and money....and ultimately, lives!!!

Fingers crossed! - c

Songs that make movies worth watching...and romantic!!!

I've always loved and easily remembered tunes and lyrics. Once when I was a little girl I cried because I couldn't remember the multiplication tables.  However, I insisted that if only they were a song I would have no problem!!! Yes, I hear the Muzak...in the elevator, the grocery store.  But when I comment on the song, folks I'm with often say, "What song?"  Yep, that's me...the sound man's girl.  Whenever and wherever I hear these songs, I can see the scene in the movie...NOT necessarily the scenes shown in the videos below.  Check out all the songs...and maybe some of the movies.  You'll hear how perfectly placed within the story they are. Some of my fav's....

The reason to watch GI Jane

The reason to watch Playing by Heart

Step Mom

Good Morning Vietnam

A Man and A Woman

Love Story

Last of the Mohicans

Pretty Woman

Mrs. Doubtfire

Phenomenon

One more....from Phenomenon

Mr. and Mrs. Smith

Knotting Hill

Bridget Jones's Diary

And if the sound man's smart, here's what she'll be using next......

Joan Osborne....what if God was one of us?

Joan Osborn...Work on Me

Norah Jones...Turn Me On

Norah Jones...I've got to see you again


Sing out loud, sing out long!!!! - c

Vitamin D and Melanoma

Vitamin D level at diagnosis and its variation during follow up as prognostic factor of cutaneous melanoma.  Saiag, Aegerter, Vitous, et al.  June 2014 ASCO.

Low 25-hydroxyvitamin D3 serum concentration at diagnosis of melanoma might be associated with worse survival.   Patients were collected from Paris hospitals from 2003 -2008 as they were diagnosed with Stage I-IV melanoma and were followed until June 2011.  1,171 patients were included, with 411 relapses during f/u, and 303 deaths.  Median serum Vit D levels at inclusion were inversely correlated with prognostic factors such as AJCC stage, Breslow's thickness and ulceration, but were not associated with disease free survival.  Changes in Vit D levels during follow-up were significantly associated with worse disease free survival.  We show that Vit D variation during follow-up is an independent melanoma prognostic marker, but not its level at diagnosis.  Previously reported association between low Vit D level at diagnosis and poor prognosis were probably due to insufficient adjustment for prognostic factors.

I'm not sure what these peeps are saying in their last sentence.  That seems an odd conclusion for them to draw.  By their own admission, folks with lower levels of Vit D had increased Breslow thickness and ulceration.  So...we can't KNOW that the decreased Vit D levels CAUSED that...but....  And, we can't KNOW whether low Vit D or those known risk factors for worse prognosis (increased thickness and ulceration) did in fact, create the poor prognosis that did materialize....but....???

Low Serum 25-Hydroxyvitamin D Concentrations are Associated with Increased Risk for Melanoma and unfavorable Prognosis.  Bade, Zdebik, Wagenpfeil, et al.  PLoS One.  Dec 2014.

Low vitamin D status (Serum 25(OH)D concentration is associated with increased incidence and unfavorable outcome of various types of cancer.  Serum Vit D concentrations were retrospectively analyzed in 324 melanoma patients and 141 healthy controls.  Vit D levels were significantly lower in melanoma patients (med = 13.6 ng/ml) vs controls (med = 15.6 ng/ml).  When looking at Vit D levels in the melanoma patients:  those with lower levels of Vit D had greater Breslow thickness and inferior survival (med = 80 months) vs the melanoma patients with higher levels (med = 195 months).  Our data support that concept that serum Vit D concentrations are associated with risk and prognosis of melanoma.  Whether normalizing serum Vit D in these patients improves outcomes will require testing in future clinical trials.

This report is at least consistent within its own data.  Clearly, there is much related to Vit D and its effects on cancer that we don't understand.

For what it's worth! - c

In-Transit Melanoma..a little info

In-transit mets for melanoma are a type of Stage III regional metastatic disease, occurring in about 10% of melanoma patients, that are within or just below the skin as nodules within the lymph system and not in nodal basins. Unfortunately these lesions are an independent adverse prognostic factor and are frequently associated with distant metastasis....which makes sense when you think about where they reside.  Isolated limb perfusion therapy has been utilized with some success.  Here are a few of the latest articles:

In-transit Melanoma Metastasis:  Incidence, Prognosis and the Role of Lymphadenectomy.
Read, Haydu, Saw, et al.  Ann Surg Oncol. 2014 Sep 26.

11,614 patients with single primary cutaneous tumors were treated at Melanoma Institute in Australia between Jan 1994 and Dec 2009.  Of these, 505 developed ITM.  Their clinical characteristics, sentinel node status, disease pattern and progression as well as outcomes were analyzed.

Of this 505:  Primary tumor thickness was 2.95mm.  39.4% were ulcerated.
ITM rates for patients with primary melanomas less than 1 mm = 0.4%, for those with primaries equal to or greater than 1 mm = 7.8%, and for those with  sentinel node biopsy = 7.2%.
ITM rates for SN positive = 21.6%.  For SN negative = 4.7%.  
Median time from primary diagnosis to development of ITM = 17.9 months.
After dx, median survival time = 19.9 months.  5 year survival = 32.8%.  10 year survival = 27.5%.
Primary tumor site (head/neck and trunk) and ulceration were predictors for poorer survival.
Five year survival from the time of ITM ranged from 47.9% for non-ulcerated limb primary lesions to only 13.6% for ulcerated trunk lesions.
Elective lymph node dissection in clinically node negative patients with ITM did not significantly alter overall survival.

CONCLUSION:  "This large study demonstrated that the diagnosis of melanoma ITM carries serious adverse prognostic implications and will assist in improving the accuracy of staging and prognostic estimates as well as treatment in these patients."

Burden of Disease Predicts Response to Isolated Limb Infusion with Melphalan and Actinomycin D in Melanoma.  Muilenburg, Beasley, Thompson, et al.  Ann Surg Oncol. 2014 Sep.

Isolated limb perfusion with melphalan is minimally invasive, effective treatment for in-transit melanoma.  Databases from two academic centers were analyzed. Burden of disease was characterized as high or low (with low being ten or fewer lesions with none greater than 2 cm). Responses were measures at 3 months post isolated limb perfusion.  60 patients had low and 100 patients had a high burden of disease (BOD).  Low BOD patients had an overall response rate of 73%  and complete response of 50%.  Patients with high BOD had only a 47% ORR and CR of 24%.  Patients with a CR at 3 months demonstrated improved progression free survival, but overall survival was similar.  Low BOD patients had an increased median PFS of 6.9 months vs 3.8 months and an increased median overall survival of 38.4 vs 30.9 months.

Pathologic Complete Response to Intralesional Interleukin-2 Therapy Associated with Improved Survival in Melanoma Patients with In-transit Disease.  Hassan, Petrella, Zhang, et al.  Ann Surg Oncol.  2014 November.

Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies.  Retrospective collection of data on 31 patients treated with intralesional IL-2 for in-transit melanoma:  Ten patients (32%) achieved complete response.  17 (55%) had a partial response.  4 (19%) had progressive disease.  Higher CD8+ T cell infiltrates were noted in patients having a complete response vs that which was present in other lesions and improved progression free survival.

So, much like treatment data for melanoma generally, patients with the lowest disease burden and the greatest infiltration of T cells did best.  No real surprises there.  When thinking about this aspect of melanoma, I realized...this is a hard row to hoe, in the already difficult melanoma field.  Wishing you all my best. - c

Patient rights in a clinical trial. An oxymoron???? Redux...

This post is a bit of a re-hash from a recent conversation on one of the melanoma forums.  Forgive me if you've already seen it, but I keep thinking about it all....so I thought it was worth a post for those of you who did not.

It began with 'M' speaking out about her frustrations when dealing with Big Pharma and the way clinical trials operate.  Her husband has been through a lot.  Most recently he joined an ipi/nivo trial which miraculously rendered 8 lung nodules and 5 lymph nodes shrinking or inactive on subsequent scans. However, he developed hemolytic anemia and did continue to have 1 or 2 pesky lesions in his lungs that did not respond.  So, M was very frustrated that though the hemolytic anemia was resolved in February, BMS removed her husband from the trial, and even more disturbing, was the fact that they had no interest in an examination of the tissue that will be available after his upcoming lung surgery to remove the remaining active nodule.

An 'anonymous' Pharma/Clinical Trial defender replied {CAPS = theirs}:   
    "If he is still on a trial, BMS has their hands tied.  There are criteria for staying on a trial DEFINED BY THE FDA and if those criteria aren't met, the patient is dropped.  These criteria are setup PRIOR to the clinical trial starting and only people who fit this criteria can be used in the final drug approval.  The only thing you can do is ask if he could be treated "off protocol" - basically someone who doesn't fit the criteria needed for approval.  The reason you signed so many papers is to protect you and the company, and those papers clearly define the protocol for staying on the trial.  FDA requires this and it is the nature of clinical trials."

I really don't get these folks.  Are they simply completely taken in by the Big Pharma propaganda of 'poor pitiful us, just struggling to make a living and help the world' that their PR departments spew?  Do they just speak out of turn because they have no idea what it is REALLY like to be on a clinical trial?  Or, are they afraid that somehow Big Brother (I mean Big Pharma) is watching....and they don't want to be caught criticizing lest they somehow lose out on treatment when THEY decide they need it???  I really don't know.  But...here's what I said:

Oh, M!  Sorry you are having to deal with all this.  When I was a little girl Marie Curie was my hero.  She still is.  Her work in radioactivity paved the way for the radiographic treatments and diagnostics that exist today.  But perhaps something she contributed apart from her work made an even greater difference.  She refused to patent her processes!!!!  Thus, allowing many other researchers to work on radiation and her ideas simultaneously...moving science forward exponentially....rather than waiting for only those researchers and institutions who could afford it to participate; to build on something that, in her view, belonged to humanity.  Marie Curie's today are few and far between.  Certainly BMS, Merck, et al. operate in a manner that seems to be lacking such a creed.

To the Pharma Defender's point. Yes, that assessment is pretty accurate regarding clinical trial protocols.  However, it is not so clear cut and easy as all that.  Additionally, the protocol is not as much in favor of the patient as is implied.  I have signed many such documents.  They all basically say:  "You will be getting this, for this long.  Here's how you qualify.  Here's how you get kicked out. If you live, die, grow three purple heads...so be it.  The company, researcher and the research institution will bear no responsibility....ethically or financially.  Costs will be paid by you for this, this and this....and for all expenses related to any side effects that may develop."

Now, as a patient...of course...I agreed.  I signed...my life and my rights away.  Patients are desperate.  No one signs up for a clinical trial when there are better options available.  And while various protocols are more fair to the patient than others, they are a legal document designed much more to protect the providers than the rights of those on the receiving end.  The best we can hope for as patients is that we will be giving "informed" consent.  Additionally, researchers, institutions and Pharma change the protocol ALL THE TIME!!!!  I have signed innumerable iterations of my ONE trial!!!  Never once has a patient been able to exact a change in such a document!

Additionally, for those who like to tout the lack of control Pharma, the FDA, and researchers have - I beg to differ.  Exceptions can be made any time they choose to make them.  They just don't often choose to do so.  For instance:  Take the case of Ralph M. Steinman.  Don't know Ralph?  Well, he was an amazing researcher in the area of the immune system and cancer....very smart....was awarded the Nobel Prize just three days after his death in 2011...and apparently, a really great guy.  Well.  Ralph got pancreatic cancer.  Perhaps the only cancer along with renal cell carcinoma that gives melanoma a good name.  So what happened?  His research buddies, folks at the FDA and various review boards pulled every string in the book.  "In addition to standard treatment, Steinman ended up enrolled - under a special patent provision - in four ongoing clinical trials of various dendritic cell-based cancer treatments, most of which were not even being tested for pancreatic cancer, along with several other experimental immunotherapy and chemo treatments.  Schlesinger, a member of the Rockefeller Institutional Review Board, steered his treatment through all the necessary IRB and FDA channels..."  [The Patient Scientist, Scientific American,  Harmon, Jan 2012]  Hmmm....  So, did Ralph deserve that special treatment?  Treatment that kept him alive years longer than most folks with his disease...and without said special treatment?  Sure!!!  I think so!  But!  Don't we all????  Must we all be brilliant, well connected scientists in order to be granted such care?

Finally, while it is obvious that patients cannot continue to take meds/treatments that result in life threatening side effects like hemolytic anemia....I think perhaps M's ultimate point was this....  If Big Pharma is really, truly interested in saving lives...not just making money....wouldn't they want to know not just what makes their med work, but what makes it fail?  What in those two last sucky little tumors in M's husband protected them while his other tumors responded to his treatment?  Wouldn't you want to know that?  Now, Pharma defenders will say, "Well, the FDA and pharmaceutical industry is not set up to do things like that when they run a trial."  And, those folks are right.  BUT....WHY NOT???????   Why aren't those in the drug industry REALLY set up to do REAL research?  Not just keep a tally of those who rise and fall? Achieve something more than a count of side effects?  Why ISN'T a research team set up to evaluate tissue samples and patients, de rigueur? 

'M', I wish you and your husband my best...with his upcoming surgery and whatever treatment path you seek next.  While there is much that is good in our system of clinical trials, there is much that is broken.  For what it's worth, this is one rattie who does not plan to stop squeaking anytime soon.
Yours, Celeste

M's response says it all:   
"Patients deserve to have some rights in clinical trials!!!  Unless you are a stage 4 patient that has been on a clinical trial, you have not a clue how powerless you are compared to the companies that make the drug."

Sending my very best to every rattie (plus a mouse or two) and their families - c

Colonoscopy done, feeling a bit better, and...Inhaled IL-2 for lung mets??!!!

Arthralgias and mouth ulcers continue to wax and wane in their random fashion, but decreasing overall.  REALLY wishing my lungs would improve more rapidly!!!  Tired of coughing and lack of sleep, but I think that is slowly getting better as well.  But....as I sit here with my albuterol/pulmicort hooka (as the kids call it)....I found this:

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastasis in melanoma patients.  Posch, Weihsengruber, Bartsch, et al.  British Journal of Cancer. March 2014.

Interleukin-2 (IL-2) treatment for...metastatic melanoma has shown remarkable durable responses.  Systemic administration of IL-2 may cause severe side-effects, whereas local administration is considered to be a safe alternative.

20 patients with Stage IV melanoma were treated with 3X3 million IU inhalative IL-2 once daily with monthly dacarbazine bolus injections.  5 (prophy group) were treated after surgical resection of lung mets, 15 (treatment group) had active disease.  Radiographic follow-up was done every 3 months.

9 in the treatment group had clinical benefit with partial regression (27%) or stable disease (33%).  4 had progression of lung mets and 2 were not evaluable.  In the prophy group, none of the patients developed new lung mets during the inhalation therapy.  Median f/u was 7.8 months in the treatment group and 25.7 months in the prophy group.  Treatment was well tolerated in most.  Therefore, IL-2 inhalation might offer an effective and safe treatment option for lung mets and may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy.  Can easily be performed in the outpatient setting.

Sounds like a plan to me!  Albeit with small numbers and limited responses.... Perhaps inhaled IL-2 will be investigated further and be at least part of a successful comprehensive treatment plan.  Not sure about pairing it with dacarbazine, but with other systemic treatments like immunotherapies it may hold real promise.

In news from the other end...colonoscopy was completed.  The day of starvation and "other" sundry activities was not too bad.  All was well within.  No sign of colitis at the moment...perhaps never was.  One 3mm polyp was removed and sent to pathology for review, but it was not ominous looking and is gone now.   In the midst of all that, B did let it be known that 50-60% of all melanoma patients are found to have melanoma in their gut on autopsy. [Clinical Study - Emergency Surgery for Metastatic Melanoma.  Mantas, Tsaparas, Charalampoudis, et al.  International Journal of Surgical Oncology  June 2014  "At autopsy, metastatic deposits are reportedly present in 50 to 60 percent of patients with melanoma; however less than 4 percent of patients are found to have gastrointestinal metastasis during the course of their disease..."]  Hmmmm...  The factoids that man keeps close to his chest.  I'm thinking the next time I do any gut checking, beyond the occasional emotional one, should perhaps wait til MY autopsy!!!  What 'cha think?

From Dinotopia (and folks doing inhaled drugs everywhere) - Breathe deep. Seek peace!  -  c