Radiation and immunotherapy...not just safe together...but better!!! (AGAIN!!!)

I keep saying it!!!  Here's a link to lots of data (and my rants)!!!!

radiation and immunotherapy

Now this:

Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination.  Aboudaram, Modesto, Chaltiel, et al.  Melanoma Res. 2017 Aug 28.

A combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% and 58.8 versus 76.4%, respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.

Now....we already know that anti-PD-1 gains better responses with fewer side effects both in the brain and body than ipi.  But there is even this...in regard to ipi combined with radiation:

Stereotactic Radiosurgery and Ipilimumab Versus Stereotactic Radiosurgery Alone in Melanoma Brain Metastases. Nruyen, Castreljon, Vaidis, Johnson.  Cureus. 2017 Jul 25.  

Benefits of stereotactic radiosurgery (SRS) have been well established in melanoma brain metastases (MBM). Immunotherapy agents such as ipilimumab (ipi) have recently demonstrated clinical efficacy in advanced disease as well. The theoretical synergistic effects of combining these therapies in MBM have not been explored in detail, however, we conducted a systematic review with meta-analysis of studies that compared combined SRS and ipi versus SRS alone in MBM. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Central databases were used for our literature search, which was conducted by three reviewers. We included studies that examined SRS and ipilimumab compared to SRS alone in MBM. Pertinent results were tabulated in a standardized spreadsheet. Newcastle-Ottawa Scale (NOS) Risk of Bias Assessment and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method for rating evidence quality were used for qualitative analysis. Review Manager was used for statistical analysis. We identified four cohort studies that compared SRS plus ipi versus SRS alone in MBM. As per the GRADE criteria, we found low-quality evidence for survival benefits associated with combined treatment. Meta-analysis confirmed a significant benefit in survival for SRS and ipilimumab. There were no significant differences between comparison groups for local control, distant brain control, radiation necrosis, or intracranial bleeding. We conclude that low-quality evidence exists for superior overall survival in MBM treated with SRS and ipilimumab compared to SRS without ipilimumab. There is also no increased risk of radiation necrosis and/or intracranial bleeding with combining radiation and immunotherapy in this setting.

If your doc tells you that he can't administer immunotherapy WITH radiation...that some delay is needed between the two...or some other tommy rot  ~  Print and read aloud to him or her...this...or any of the other MANY research articles noted in the link above!!!

Whew!!!  Someday I'm gonna get to quit yell'n!!!  - c

Ooops! Opdivo (Nivolumab), did it again...this time it's approved for Liver Cancer

To back up a bit...here's some history, Opdivo style:

2014 - Opdivo (previously known as ONO4538, then MDX1106 [as it was called when I first started taking it], then BMS936558, then Nivolumab, and finally...Opdivo...dun, da, da dun!!!!) was approved for advanced melanoma patients after they had failed ipi and, if BRAF positive, BRAFi as well.
2015 - Opdivo was approved as a first line drug for unresectable or advanced melanoma, BUT....you had to be BRAF positive - though there was an abundance of data demonstrating that BRAF status made no difference!!!
2015 - also saw Opdivo approved for use in advanced renal cell carcinoma as well as non-squamous and non-small cell lung cancer, after platinum based chemo.
2016 - FINALLY,  Opdivo was approved for use alone or with ipi, in advanced melanoma patients, no matter BRAF status.

Now....

Bristol-Myers Squibb’s Opdivo® (nivolumab) Receives FDA Approval for the Treatment of Hepatocellular Carcinoma Patients Previously Treated with Sorafenib

That's all great news.  The more help provided to cancer peeps the better!!  NOW!!! How bout seeking approval for folks with Stage III melanoma, hmmmmmm???  I think we ratties have more than provided the needed data....with this research pretty much saying it all:  Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!! 

Check out the link...or....here it is in a nutshell:

Stage IIIB, C, or Stage IV melanoma patients were allowed...even those with brain mets...as long as all were completely resected.

Patients joined from March 2015 to November 2015

There was a 5% cutoff for PD-L-1 staining (ie positive for PD-L-1 staining on tumors)

Nivo was given at 3mg/kg every 2 weeks or ipi was given at 10/mg/kg every 3 weeks for 4 doses then every 12 weeks.  Either drug was given for one year.

Patients were assessed via CT's of body and MRI of the brain every 12 weeks for 2 years, then every 6 months until year 5.

905 patients were studied, none of whom were still getting the drug by the final report.

Only 397 of these patients completed the full year of drug treatment.

Of the 452 in the nivo arm, 275 completed the year.  Of the 453 in the ipi arm, 122 completed.

Nivo outcomes were better than ipi no matter the patient's age, sex, disease stage, or BRAF status.  Nivo had fewer side effects.

In prior studies, ipi has demonstrated a pretty consistent 60% recurrence free survival in Stage III NED patients when used as adjuvant.  That number held in this study even when Stage IV patients were included.

Recurrence free survival at 12 months:

70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:

66.4% for nivo                    52.7% for ipi

Median distant metastasis free survival was not reached in either group.  However, it was longer in the nivo group with mets developing in 93 of the 369 peeps in the nivo group and in 115 of the 366 ipi group.

OVERALL recurrence free survival was 70.5% for the nivo group (vs 60.8% for ipi) at 1 year...but...when you pull out the Stage IV folks the number was 63% for nivo vs only 57% for ipi.

Call it by any name you like, BMS!  Let's get THIS approval DONE!!! - c

Travel Chaotically! - London and the Cotswolds!! (and fabric shopping!!!!)

I am such a lucky girl!!!  We just got back from a lovely visit to London and the Cotswolds.  The A##hole who decided to try to blow up part of the London tube:  London tube bombing: PM says terror threat level raised to critical  be damned!!!  (Along with the jerk who, almost a year ago to the day in September of last year, tried to create havoc in New York and New Jersey during our visit there:  Travel Chaotically! - New York - Street Fair and Central Park!)

Instead of giving any cred to such weirdo's, I'll tell you what is really important!!!  The real live wonderful people we met and shared our visit with ~ Dave, Clive, Ibrahim, Amal, Batsy, the proprietress of the Persian restaurant, the little boy there that we taught to fist bump, the couple with family in Turkey (and the US) in the fabric shop in Walthamstow, the lady who better be making her fleece jacket so she won't be cold when she's out with her walking club, the Welsh couple and the bar keep at The Black Bear Inn....and ever so many others!!  I have SO MANY STORIES!!!!  (Plus, I have yet to share the remainder of last year's New York trip, that took off from there and explored Paris, Sarlat, and Marseilles!!!)  B took a great many more and better pics than I did...but lest it be a whole year before I get around to it....I wanted to share these snippets of memory with you now....

Classic!  X's three!  As in: 1) The quintessential British phrase.  2) Big Ben.  3) B being the worst person in the world to take a photo of, as he is constantly looking at HIS camera!

Boat trip along the Thames!  The London Eye (big ferris wheel in the background) cannot be avoided!!!

Back side of the Tower of London.

A little cuppa and a 'pick-me-up' along the Thames.

A change from our last visit...about 10 years ago...are the bollards that now line many London streets.

Westminster Abbey

Train station, watching the board to learn the platform at which the train will appear, for our trip to the Cotswolds.

We stayed in Moreton-in-Marsh at the Bell Inn (supposedly the Inn and area that inspired Tolkien's tales of Hobbiton and Inn, The Prancing Pony) and visited Stow-on-the-Wold and Bourton-on-the-Water!  Loving these names!!!  If only we had also visited Wotton-under-Edge and Fuddlebrook!

Hiking along the public footpath!

My cutie!!!

Learning to Belly-up-to-the-Bar!!!  The Black Bear Inn!

Back in London.  Lovely visit to the British Museum and the National Gallery.  Emotive Turners.  Exquisite Dutch Masters.  Beautiful Monets.  Great chats with various floor watchers.  Such decadence.  And it's FREE y'all!!!!  I mean they ask for a donation...but seriously!!!!  You do have to pay to pee in the city, though.  It'll cost you a pound in London, but only "20 p" (Yes, it is actually said like that - Twenty P [pence]!!!) in the Cotswolds at the "Public Conveniences".  But, you can pee for free in pubs, restaurants, museums and galleries.  The more you know....
Oh.  And, yes.  That is a thumb in the pic above.  No.  I cannot explain the phallic nature of it!

My silly B before seeing "The Mousetrap" in London!

One of his many "Full English" breakfasts!

Fabric shopping in Walthamstow AFTER checking out all the shops around Oxford Circus along Berwick Street AND Goldhawk Road at Shepherds Bush Market!!!  I loved it all, but REALLY, REALLY enjoyed Walthamstow Market along High Street.  SO. ABSOLUTELY.  FABULOUS!!!!  Great thanks to Tilly of Tilly and the Buttons and Rachel of House of Pinheiro who have great London fabric shopping tips on their blogs!  Even bigger thanks to B, who is the world's sweetest and most patient man!!!

An appropriate cuppa to start our last day.

Smithfield Market.  And an amazing lunch at St. John.  So yummy!!!  A place we found quite by accident on our last visit...but is now a family tradition...with Rosie making her way there during her study abroad...and an absolute must for us on this trip.  We're going to have to manage to fit this in more often, B!!!!

Buckingham Palace

Heading to the tube for our return to Heathrow and home.

But, I didn't leave empty handed!!!  Here's my fabric haul from Goldhawk Road (Shepherd's Bush).... 

  ...and this lovely selection from Walthamstow! No more fabric buying for me for some time!!!

And as if fabric alone was not enough!!!  I got patterns!!!  Most of them at an amazing Makers Fair that materialized out of thin air while we were inside Hampton Court!  As we came out to catch the train back to London...there it was!!  Fate, I tell you!  Fate!  There were food stalls with paella, curries, jams, sausages, cheese, baked goods.  We settled on The Hippy Chippy and had the best "chips" (French Fries!) ever!!!  Big tents with training sessions were available.  Other tents housed makers with soaps, jewelry, fabric, assorted crafts, and so much more.  Tilly and the Buttons and Sew Over It even had stalls!  My newest, yet to be blogged, Alder shirt dress, I happened to be wearing, was recognized as such and admired!!!!  AND...there were patterns for sale in lots of the booths!  So, I really couldn't help it!  Right, B?????

Home again...but with lots of new friends and wonderful memories.  Plus, getting back to work with my kiddos can't be too bad if this is your view along the way.

Finally, B makes my average Wednesday anything but, with a Full English Breakfast...replete with HP Brown Sauce, roasted tomatoes, beans, sausage AND bacon, toast, and perfect eggs.  B knows how to do it right!  Rosie may have to roll me around on my mat at our exercise class later today!!

Thanks, London and all the wonderful peeps who made our visit so very special.  Thanks, B.  You really don't have to spoil me so! But, it's pretty awesome that you do!  Hee hee!!! More stories to come, I promise!  Travel Chaotically!!!  I gotta go sew!!!! - love, les

Childhood experiences and PCBs relative to melanoma

This is a little weird and there is much to be considered when looking at an epidemiological study....was it strictly the point in question (here elevated PCBs), or the genetic make-up of the population, or something else they all happened to eat, drink, participate in, be exposed to????? - that makes the outcome what it is????  Nevertheless, this study caught B's eye because he knows that my grandparents and several aunts/uncles lived in this area while I was a child and young adult.  As such, I spent a fair amount of time visiting Anniston, Munford, Talledega, and Jacksonville, Alabama from early childhood until my granny passed in 1992.  I was born in 1964...so not sure what all this means or if it played any role in my condition.  For the record, no one else in my extended family who lived in that area, nor any of my siblings have melanoma, though my grandfather died of what was said to be "leukemia" though some of the information that has been passed on doesn't really line up with that, sounding more like lymphoma instead, but I was too young to understand much at the time and by the time I had a medical education there was really no way to extract more information.  However, an aunt in the area has dealt with non-Hodgkin lymphoma for about as long as I have been dealing with melanoma.  So...here you go:

Serum polychlorinated biphenyls and leukocyte telomere length in a highly-exposed population: The Anniston Community Health Survey. Callahan, Pavuk, Birnbaum et al.Environ Int. 2017 Sep 5.

Serum polychlorinated biphenyls (PCBs) have previously been associated with longer leukocyte telomere length (LTL) in most, but not all, of the few previous studies. PCBs were produced in Anniston, Alabama from 1929 to 1971 and participants of the Anniston Community Health Survey (ACHS) were highly exposed.

We evaluated serum levels of 35 PCBs and relative telomere length in 559 ACHS participants.

Relative LTL was measured in DNA extracted from blood clots. We assessed PCBs individually, grouped by chlorination, and summed PCBs. We used linear regression to assess the association between each PCB metric while adjusting for pertinent covariates.  

Serum PCBs were associated with longer LTL among white participants and the oldest age group of black participants. Among white participants, compared with those in the first quartile of sum PCBs those in the third quartile of sum PCBs had 8.09% longer relative LTL and those in the fourth had 7.58% longer relative LTL. Among African American participants, serum PCBs were associated with longer relative LTL among those over age 64 only. Tests for interaction were not statistically significant.  

We observed a non-linear positive association between serum PCBs and LTL among white participants. Serum PCBs were associated with longer LTL in the oldest age group of African Americans. This association may provide insight into the cancers previously associated with exposure to PCBs, melanoma and non-Hodgkin lymphoma, which have been associated with long LTL in previous studies.

So...if this is true, and the correlation is direct...there seems to be another need for limiting exposure to PCBs (not that we didn't already know that for numerous other reasons)!  For what it's worth. - c

LIVING with cancer. The need for psycho-social services. Pati continues to lead the way

B came upon this abstract today.  It touches on something elemental...the psychosocial aspects of a cancer diagnosis.  Having 'cancer' affects the patient, the family, everything.  We are not who we once were.  But, in the midst of trying to survive our cancer (with the simultaneous need to learn a completely new, and often foreign, cancer language - fit in doctor appointments, surgeries, radiation, oncologic therapies, manage pain and fatigue, not to mention bills and family obligations) - LIVING with cancer is a topic that is almost never addressed, while patients and their families try to soldier on with little to no psychological support or effort by institutions or medical providers to teach needed skills and coping mechanisms for the new cancer reality in which we now live.

A very dear one of mine has written:

Psycho-Oncology: A Patient's View. Garcia-Prieto P. Recent Results Cancer Res. 2018;210:57-66. doi: 10.1007/978-3-319-64310-6_4.  

Culturally the most important, valued, and less stigmatized part of cancer care is the medical part: The surgeon cutting the tumors out and the oncologist leading the strategic decision-making of the medical treatments available. The least valued and stigmatized part of cancer remains the psychosocial care. This chapter describes-through the eyes of an academic, psychologist, stage IV melanoma patient, and patient advocate-how one patient navigated changing psycho-oncological needs from early stage-to-stage IV through a whole range of psychological interventions available. Her voice joins that of all cancer patients around the world whom are urgently calling for psycho-oncological care to be fully recognized as a central part of cancer treatment.

I have tried to address this need, this world ~ many times:
2011:  Chemo Limo
2012:  My Life with Cancer
2014:  Tears and melanoma...they're not always sad...
2015:  Long term melanoma survivors....MARCH FORTH!!!!!
2015:  What to say and do....and NOT!!...for a cancer FRIEND (not patient)!
2015:  Health Monitor Magazine interview
2016:  Don't give up. Don't ever give up.
April 2017:  The Mental Price of Melanoma
June 2017:  ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!

Yes, LIVING with cancer is not for sissies.  Luckily, we have had many advocates and dear cancer friends who, as beacons of light, have helped guide our way...even if current medical systems across the globe fail to address psychosocial needs as best they might.  Not the least of these amazing peeps is the author of the article highlighted above ~  Patricia Garcia-Prieto.

If you do not have time or interest in perusing my links above...I understand completely!!!  But, please!  Do have a peek at this one.... My Ode to Pati....a fallen comrade  especially her video, What's one life worth? [linked within].

You remain in my heart, Pati.  You continue to lead the way.  I hope your husband and sons are doing well.  love, les

I like me some shrimp!!! Now their micro-RNA can suppress the stem like qualities of some melanoma cells???!!!

Me and Bubba, man! "... like I was sayin', shrimp is the fruit of the sea. You can barbecue it, boil it, broil it, bake it, saute it. There's uh, shrimp-kabobs, shrimp creole, shrimp gumbo. Pan fried, deep fried, stir-fried. There's pineapple shrimp, lemon shrimp, coconut shrimp, pepper shrimp, shrimp soup, shrimp stew, shrimp salad, shrimp and potatoes, shrimp burger, shrimp sandwich. That- that's about it."          ~ Forest Gump

Who knew those little shrimpies could demonstrate another route through which to target and defeat melanoma?????

Shrimp miR-S8 suppresses the stemness of human melanoma stem-like cells by targeting the transcription factor YB-1.  Yang, Wei, Shang, et al.  Cancer Res. 2017 Aug 30. 

Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3'UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells.

Oh, yeah!!  If this works out....I'll really be like'n some shrimp!!! - c

Vitamin D and melanoma

We've long known that higher vitamin D levels provide a better prognosis in melanoma.  Here is a link (with others within) discussing Vitamin D:  Vitamin D and melanoma - folks with higher levesl do better - again!!!

Now there is this ~

On the role of classical and novel forms of vitamin D in melanoma progression and management. Slominski, Brozyna, Skobowiat, et al. J Steroid Biochem Mol Biol. 2017 Jul 1.

Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH)₂D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors α and γ, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy.

For what it's worth! - c