Such an honor....

 Brent and I recently had the distinct honor and privilege to travel to Maxwell Air Force Base, Gunter, in Montgomery, Alabama to attend the retirement ceremony of Chief Master Sergeant Scott.....my brother-in-law.  Frank has been a been an amazing husband, father, son, BROTHER, and military leader...for over 30 years!!!!  (You're only getting to retire from ONE of those positions, buddy!!!)  It was a real blessing to get to witness the beauty of the military ceremony itself, the joy of shared family moments, and the enduring gift of friendship.  Thanks for letting me share that special time and allowing me to share it again with others.

Awwww......

"Thanks".....just isn't enough!!!

The reception.....and Cake!!!

The "trees" just kept on coming!  The admirers came from far and near.  You're a good man, Frankie!!!

Celebration time!!!

That's my Sha!!!

And Char!!!!

Beautiful family.

Beautiful love.

Thanks guys. Love you.  - c

New Anti-PD1 trials!!!!....and others....Check this site!

Clinical Trial # = NCT01621490
Phase 1 Biomarker study in advanced melanoma
BMS sponsored trial of Nivolumab at 3mg/kg every 2 weeks for 2 years, depending on response, while measuring biomarkers.
Sites actively recruiting include:  Los Angeles, Boston, New York, Portland, Nashville, Houston. 
Requirements:  No brain mets, measurable disease, etc.

Clinical Trial # = NCT01703507
Phase 1 Ipi and Whole brain or SRS in treating melanoma with brain mets
Sites actively recruiting - Thomas Jefferson University,  Philadelphia
Will soon be opening at Ohio State University

Clinical Trial # = NCT01672450
Phase 1 with Intratumoral injection of IL2 and ipi in patients with unresectable Stage III or IV
Requires accessible tumors.
Site = Salt Lake City Utah

Clinical Trial # = NCT01497808
Stratified Phase 1/2 - Dose escalation trial of SRS (stereotactic body radiotherapy) followed by ipi in metastatic melanoma.
Sites actively recruiting = Philadelphia
Only 4 of 40 slots filled per site.

Clinical Trial # = NCT01590082
Phase 1/2 - Doxycycline, Temozolomide, and Ipi in Unresectable Stage III/IV melanoma
Site = MD Anderson
Total enrollment to be 58...seems that only 20% have been filled.
(Remember that post about everything killing melanoma???  Well, doxy was on that list!)

Outside the states... Clinical Trial # = NCT01844505
Nivolumab plus ipi OR ipi alone
Sites = US sites appear to be full.  Internationally Recruiting= Canada, Italy, Netherlands, Norway, Sweden, Switzerland.  Soon to be recruiting = Brazil, Poland, Romania, Russia, South Africa, Turkey
Stage III unresectable or Stage IV, treatment naive, melanoma.
Prior anti-PD1, PDL1 or yervoy = not allowed.

Obviously each trial and site has their own particulars. Check out the link below for more trials and information!!!! Information like this gets outdated quickly!  But, the trials I cross referenced with other sites (including NIH) seem to still be enrolling.  Please....if you are interested in any of them...CALL the location indicated!

Mdlinx.com for more clinical melanoma trials

Cancer survivor, runner, and bad sports! BUT......

 ...an amazing runner and video tape will prevail.  Bottom line...in a 3,000 meter event this past Saturday, Grunewald ran an amazing race.  Check out her personal history here:

Grunewald....runner....cancer survivor!


Now, nothing against Hassay...the little blond in pig-tails in the coming video...but she didn't like losing.  So when Grunewald sprinted to an amazing finish and a beautiful win, Hassay....possibly under the influence of ego inflated coaches....filed an official complaint, stating that Grunewald purposefully tripped, knocked, blocked....whatever you want to call it....her in the next to last lap....  Well... Look for yourself.  And watch a cancer survivor leave the entire pack of amazing athletes in the dust!!!!

No! REALLY! Watch this girl run!!! 

So...not an expert...but have to say....I've watched A LOT of races!  Seems to me, Hassay stepped out of HER lane and swung her right arm wide HERSELF!!!  And, besides.....Grunewald LEFT you, honey!!!!  But, that complaint had Grunewald stripped of her win within hours after the race.  BUT....just as officials were about to rule, Hassay withdrew her complaint and the win was returned to Grunewald.

Good grief!  What a bunch of silly noise about a race that was never more clearly won!  Glad the winner is back in the winner's seat.  Glad she is a two time cancer survivor.  This little kerfuffle is nothing SHE can't handle.  Keep on runnin'! - c

For melanoma...eat that curry...again!!! We just don't know why!

I've posted articles here before, regaling the benefit of curcumin (Turmeric- the yellow part of mustard and curry).  Curcumin has long been proven to eradicate melanoma...at least in a petri dish. And while that's nice and all...how am I supposed to get my melanoma cells in that dish???!!!  Well, this study took that up a notch!

Curcumin Intake Affects md RNA Dignature in Murein Melanoma with mmu-miR-205-5p Most Significantly Altered.  Dahmke, et al.  PLoS One. Dec 2013.

"Melanoma is the most aggressive form of skin cancer with an estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties.  Accordingly, dietary intake of the compound may be suitable for melanoma prevention.  However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma."  So...ratties (real rats...this time) were given melanoma tumors on their sides.  But, they were fed their regular chow OR a curcumin diet two weeks prior to the tumor cell injection and until the experiment was stopped. "Curcumin significantly reduced the growth of the flank tumors.  Furthermore, the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls."

Well!  You go my little real live curcumin eating ratties with your altered mmu-miR-205-5p!!!!  I'm gonna see if I can alter mine, too!!! Curry with a side of mustard, anyone? - c

Lymph node removal after superficial melanoma lesions...to do or not to do????

My TWO primary melanoma lesions (first to my right back - 0.61mm) and later to my left forearm (0.5mm) were technically thinner than the depth indicating the need for a sentinel node biopsy.  However, since I was more of the bent to...get that shit out of there....I pushed for it anyway.  I feel it was a good thing I did.  After my first primary, a node in my right axillae was indeed positive for micrometastasis.  I had a complete right axillary lymphadenectomy done with the removal of 16 additional nodes, none of which were positive.  However, I feel certain I would have dealt with spread very soon after that initial lesion had I not taken the steps I did.  As it was, I was disease free until almost 5 years later, when I had the second primary and pre-emptively had all the nodes (13) in the left axillary basin removed.  None were positive.  Luckily, I have never developed lymphedema in either arm.  Unluckily, I obviously progressed to Stage IV with lung and brain mets three years after the last superficial lesion.  Perhaps this is easier for me to say since I did NOT develop lymphedema, but I am glad I had the complete lymphadenectomies done and really do not think I would be here today had I not.  For what it's worth....

Lymph Node Test a Good Strategy for Melanoma: Study.    Maureen Salamon.
HealthDay Reporter.  2/12/2014.  Source:  New England Journal of Medicine, Faries and Balch.


"The study, initiated in 1994, randomly assigned about 2,000 patients to two groups.  The observation group had their [initial] lesion removed and their lymph nodes OBSERVED for recurrence, at which time they were removed.  The biopsy goup underwent lesion removal and a sentinel node biopsy, with immediate lymphadenectomy if melanoma was in the sentinel node."

Patients with intermediate-thickness melanoma lesions, who had their lymph nodes removed after the sentinel node tested positive, were 44% more likely to survive their melanoma, said Dr. Mark Faries (Director of melanoma research at John Wayne Cancer Institute, CA)."

"It makes sense:  Those who were not treated up front had their melanoma spread from the sentinel lymph node to the other lymph nodes in the area, [which can facilitate] a spread throughout the body," Faries said.  "This study provides concrete evidence that everything we had assumed about the sentinel node procedure...and lymph node treatment is true."

In the study's biopsy group, sentinel node results were the most important predictor for 10-year survival...in patients whose melanoma lesion was considered thick or intermediate. Disease free survival rates over 10 years were significantly better in the biopsy group in patients with intermediate lesion depth (71% vs 65% in the observation group) and at rates of (51% vs 41%) in patients with thick melanoma lesions.  Removing all the lymph nodes from an area of the body can result in lymphedema in some patients. But, with the survival rate improvements found in this study, the risk can be supported.

"If we know there's an increase for leg or arm swelling, we can justify [node removal]more to the patient if it increases survival, " Balch (Professor of surgical oncology, University of Texas, Dallas) said.  "This is the largest study ever done on this subject, and it's multinational with the longest follow-up.  It's really a seminal work."

It's a tough decision, but I hope this helps if you are being faced with it.   - c

BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

"You have metastatic melanoma." Those words prompt immediate panic, fear, confusion, an onslaught of new tests, new terms, generalized and specific CRAZINESS!!!  The fact that every drug name seems to be some unreal combination of letters derived from a bizarre Czech language crossed with the imaginary "Unobtainium" from Pandora in Avatar only increases confusion.  Granted, even strangely named drugs and their greatly increased effectiveness compared to interferon and even IL-2 is a boon.  Yet, when vermurafenib (Zelboraf) was granted FDA approval in August of 2011, dabrafenib (Tafinlar) in May 2013, and the BRAF/MEK combo (dabrafenib and trametinib [Mekinist]) was approved just this past January, patients were left with even more questions.

What is BRAF??? The BRAF gene tells the cell how to make a protein (B-Raf).  This protein is part of a signaling pathway that regulates cell growth, movement, and death.  When the BRAF gene changes (mutates) and fails to give the correct instructions, cells can become cancerous.

Should I want to have this mutation? Hmmm, well if you didn't have the mutation, about 50% of melanoma patients wouldn't have melanoma.  A lot of folks with cardiofaciocutaneous syndrome, Noonan's syndrome, Langerhans cell histiocytosis, and Leopard syndrome, wouldn't be dealing with their disease either.  But, in order for BRAF inhibitors to work on melanoma, you do need to have that particular mutation in your tumor cells.

Do I have it?  Docs are now routinely sending tumors of melanoma patients (or should be) for mutation testing to include: BRAF, NRAS, and cKIT.  Older BRAF tests were less accurate so folks with tumors tested some time ago may need to have the newer tests done on their tumor to determine their status.

What's with all this V600 business? Most BRAF mutations occur at the same place on the gene... codon 600. At that spot on the gene, the proper amino acid, valine (V), has been changed to either glutamic acid (E) or lysine (K).  {I know...they should be V600G and V600L...right???} Anyhow, if you have BRAF V600E or K your tumor meets the criteria to be treated with BRAF inhibitors (dabrafenib, vemurafenib) or the MEK inhibitor (trametinib).

If one BRAF inhibitor doesn't work for me, will the other one?  Do they work on brain tumors? Short answers....yes.  More info below.

GENERAL INFO:

Dabrafenib and its potential for the treatment of metastatic melanoma.  Menzies, Lon, Murali.
Drug Design, Development and Therapy. December 2012. 

Summary points:

• BRAF mutations occur in 50% of melanomas; 70%–90% are V600E and 10%–30% are V600K.
• Selective (type 1) BRAF inhibitors (dabrafenib, vemurafenib) target mutant BRAF kinase and inhibit the MAPK pathway.
• Both drugs provide high response rates and rapid modes of action, but both are limited by the rapid development of acquired resistance. (About 70-80% of BRAF positive patients respond, but most tumors figure out a work around in about 7-8 months, though there are exceptions.)
  
• Both dabrafenib and vemurafenib are effective in treating BRAF^V600E melanoma patients, with prospective evidence of dabrafenib activity in BRAF^V600K melanoma and in those with brain metastases.
• Both drugs have similar toxicity profiles (Side effects include - arthralgias, rashes, extreme sun sensitivity, development of benign skin cancers and other fun stuff.); dabrafenib appears to have less cutaneous and hepatic toxicity than vemurafenib, but is associated with pyrexia [fever].
• Emerging combination strategies, such as the CombiDT, [the dabrafenib and trametinib combo] are designed to improve response and delay resistance. [It takes tumors much longer to find  a work-around and patients experience fewer side effects when they take the combo, than when they take a single BRAFi!]
  

BRAF therapy and BRAIN METS:

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.  Azer, et al.   Cancer. 2/2014.

23 patients studied. Response rates in intracranial (78%) and extracranial (90%) sites.  Of 20 patients with progressive disease, 6 had IC progressive disease and 6 had progressive disease in EC only and 8 experienced progressive disease in both sites. 5 of 6 with isolated progressive disease to the brain underwent local therapy to the brain and continued on dabrafenib longer than 30 days.  Bottom line:  IC and EC tumors respond similarly to dabrafenib.

Vemurafenib in metastatic melanoma patients with brain metastasis: as open label, single-arm, phase 2 multicenter study.  Kefford, et al.

As of April 2013, 146 patients with melanoma brain mets (Patients had an average number of 3 mets...though the range was from 1-30.) were treated with vemurafenib.  In patients with previously untreated MBMs, vemurafenib produced a response in 61% of those patients. The median progression free survival was 3.7 months and the overall survival median was 7 months.  So...Vemurafenib works on brain tumors, too.


HOW TO DEAL WITH TUMOR WORK-AROUND:

Switching therapy pre-emptively from vermurafenib (Zelboraf) to ipilimumab (ipi/Yervoy) in patients with BRAF-mutated melanoma.  Angelo et al.  Memorial Sloan Kettering.

"Median time to progression on Zel is 6.9 months; 75% of patients progress by 1 year.  Once patients progress on Zel, melanoma sometimes grows too quickly for patients to benefit from subsequent ipi treatments.  In July 2011, researchers adopted a strategy of treating previously untreated patients with BRAF-mutated melanoma with Zel for a limited time, then, after maximal response but before developing resistance, switching to ipi. Review of 19 patients:  Initial plan = 4 months of Zel, was changed to 2 months after some patients progressed at 4.  All patients were switched to ipi and received a median of 4 doses starting at a median of 1 week after last dose of Zel. At the time of the first ipi dose, 8 patients had progressed on Zel, 11 had not, but 5/11 ultimately progressed on ipi and were retreated with Zel.  Among the 11 patients switched to ipi before progression, there have been no melanoma specific deaths to date (median follow-up = 1 year) compared to 7/8 deaths among patients who had progressed at the time of the switch.  There is potential selection bias in this small, on-going experience.  However, the results are consistent with a benefit of switching patients pre-emptively from a BRAF inhibitor to ipi prior to onset of resistance."

Response to BRAF inhibition in melanoma is enhanced by the addition of immune checkpoint blockade.  Cooper, Hodi, Flaherty, et al.  Mass General, Harvard, Dana Farber.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (about 6 months).  In contrast, treatment with immune checkpoint inhibitors results in lower response rates, though responses tend to be more durable.  We...have preliminary evidence that these two strategies may be combined to provide more durable responses. ...BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltration and a decrease in immunosuppressive cytokines.  However, there may also be an increased expression of the immunoinhibitory molecule PD-L1, which may contribute to resistance.  ...[So] we sought to test the hypothesis that responses to BRAF-targeted therapy would be enhanced by the addition of immune checkpoint blockade (like anti-PD1, anti-PDL1 and ipi).  [So....when poor ratties (really....rats) were given a BRAF(V600E) melanoma tumors, then BRAF targeted therapy combined with anti-PD1 and anti-PDL1], they demonstrated enhanced response, significantly prolonging survival and slowing tumor growth....suggesting that the addition of PD1 pathway blockade may augment responses to BRAF-targeted therapy. Clinical trials combining these two strategies are ongoing..."

COMBO of Dabrafenib and Trametinib (BRAF/MEK):

Note:  From Jan 22, 2014 post - I've mentioned before various trials have demonstrated that the combination of these meds created better responses and fewer side effects than when they were used alone.  Approval of the combination was based on the demonstration of durable objective responses in trials where objective response rates and response durations were 76% and 10.5 months with the combo and only 54% and 5.6 months in the single agent arm.  Squamous cell carcinoma was 7% in the combo arm, but was 19% in the single agent arm. The most common (at least 20% incidence) side effects experienced with the combination were:  fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.  The most frequent complicated adverse events (with at least a 5% incidence) were:  acute renal failure, fever, hemorrhage, and back pain.

Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor.  Flaherty, Infante, Falchook, et al. Pigment Cell Melanoma Res. 2011;24 (1022):  Abstract.

"Additionally, in the Part B expansion cohort of patients with prior disease progression during [single] BRAF inhibitor treatment, an impressive 19% response rate was seen with CombiDT therapy."

I realize that for the uninitiated, non-medical person this is just a bunch of mess.  But, I tried to simplify things as much as possible and hope it helps answer some of the basic questions about BRAF, BRAF-inhibitors, and how researchers are trying to make them work better for melanoma patients.  Best - c

Overview of treatments for Melanoma Brain Metastases

Novel Treatments for Melanoma Brain Metastases
Kenchappa, Tran, Rao, Smalley, Gibney, Sondak, and Forsyth. October 2013.  Cancer Control.

Twenty years ago, treatment options for patients with melanoma brain metastases (MBMs) were limited, and patients would generally die of the disease within 2 months.  Because of today's rapid progress of effective surgical, radiation, and systemic therapies for metastatic melanoma, hope exists for these patients....trials are being specifically designed for patients with MBMs rather than "lumping" them together with all types of brain metastases.  We believe this approach will accelerate the discovery of effective...therapy.

...Incidence of metastatic brain tumors is 200,000 cases per year in the US, which is ten times higher than the incidence of primary brain tumors.  Melanoma is the third most common cancer that metastasizes to the brain (5-10%, compared with 20-30% of breast, and 40-50% of lung), with a reported survival of less than 9 months.  A total of 50-75% of patients diagnoses with melanoma revealed brain mets at autopsy....

The metastatic process, particularly as it applies to the brain, is complex and poorly understood. [But basically, it takes cancer cells escaping from the primary tumor site, then invading the blood stream, traveling into the brain, surviving, stimulating the growth of circulation develop to supply them, and then prospering - using the brain's microenvironment!] Each step is controlled by genes and signaling pathways. [Therefore, researchers have looked at every step in the process to see if they can find ways to stop continued brain met development at any point.]

Surgical Treatment:
....Per guidelines from the National Comprehensive Cancer Network, when possible, surgery is the first step for the management of MBM.... This rule should be heavily qualified.  For example, in patients with extensive extracranial mets, initial treatment with BRAF or other targeted treatments may take priority, with surgery for MBM reserved for salvage.  Resection eliminates tumor-associated edema and obviates the need for sustained corticosteroid therapy and associated adverse events, which represents an important consideration in melanoma mets because corticosteroids may impair the effectiveness of immunotherapeutic treatment regimens.  For small asymptomatic MBM lesions (<2cm i="" stereotactic="">radiation (SRS) may be considered as first-line treatment over surgery...

Radiotherapy:
Surgical treatment alone is not sufficient for prolonging survival.  Historically, whole brain  radiotherapy (WBRT) has been used to augment surgical resection....  However, SRS is the treatment of choice for patients who are not surgical candidates in an effort to "save the brain."  Melanomas are less sensitive to RT than, for example, lymphomas are, so the efficacy of WBRT is lower. Moreover, the long term cognitive "costs" are high.  Focused RT minimizes the neurocognitive deficits.  Hence, whenever possible, WBRT should be delayed or avoided if other treatment options are available.  The advent of effective systemic treatments (ipi, vermurafenib) to treat MBMs may further change the cost-benefit ratio in favor of SRS.  A new paradigm might include SRS to provide local control followed by systemic therapy to treat and prevent "micro"-brain mets.

Chemotherapy:
...standard chemotherapy for the treatment of MBMs [has been] disappointing.  This may be due to poorly understood factors such as inadequate BBB penetration, [etc].... Temozolomide and fotemustine, both of which do penetrate the BBB, have the best response rates among conventional chemotherapies; however, even they are associated with low response rates and short durations of response...

Novel Treatments:
The use of selective BRAF inhibitors or immunotherapies has indicated that these agents are safe, have significant activity in systemic melanoma, and are active in some patients with MBMs, raising the possibility of changing future treatment approaches for patients with MBMs.


Antiangiogenics:
Although antiangiogenics are commonly studied in systemic cancer, few clinical trials study them in MBMs because of their tendency to produce hemorrhage (up to 20% in some series). Although melanoma is a highly vascular tumor that secretes VEGF [a growth factor that helps vessels grow] and preclinical models show that angiogenesis is required for "dormant" MBMs to grow, a small phase II trial using bevacizumab did not show benefit in systemic melanoma (MBMs were excluded). No trial of antiangiogenics has been conducted for isolated MBMs...

BRAF Pathway inhibitors:
....Dabrafenib was studied in a small cohort of patients with untreated MBMs. Nine of the 10 patients with MBM responded...  ...a phase II study of dabrafenib was conducted...a total of 172 patients with between 1 - 4 active MBMs were stratified...:  no prior brain therapy (cohort A) or prior brain therapy (cohort B).  The overall intracranial response rates in patients with BRAF V600E-mutant melanoma were 39% and 31% in ... A and B respectively.  Median progression free survival rates were 33.1 and 31.4 months, respectively. A lower response rate was seen in BRAF V600K-mutant melanoma....  Patients with BRAF V60E-mutant melanoma may develop brain mets while taking BRAF inhibitor therapy, with the central nervous system as the only site of disease progression in 19% of patients. It will be important to investigate the underlying mechanisms involved in this paradoxical phenomenon and the potential strategies to prevent it....  Currently, patients who develop MBMs while experiencing control of their extracranial disease on BRAF inhibitor therapy can be managed with RT or surgery while temporarily withholding the drug.  An intact BBB may also protect small micrometastases from the effects of systemic BRAF inhibitors until these micromets grow large enough to damage or destroy the barrier, in which case some MBMs that develop while patients are on BRAF inhibitor therapy may retain a degree of sensitivity of the drug.

Immunotherapies
High-Dose Interleukin:
Reports exist of complete response in patients with MBMs who were treated the HD IL-2. A retrospective analysis of 1,069 patients either with metastatic melanoma or renal cell carcinoma found that 7 patients had untreated brain mets and 2 had a brain response. Another...review of  15 patients with MBMs treated with HD IL-2 reported that 2 had a complete response.  Given the nature of this treatment, it is unlikely to be used routinely for this indication...


Adoptive Cell Therapy:
...retrospective analysis...[of] 26 patients with untreated MBM's discovered incidentally in a cohort undergoing immunodepletion (with chemo or total body irradiation) followed by autologous tumor-infiltrating lymphocytes (TILs) or autologous peripheral lymphocytes transduced with a T-cell receptor (TCR)....[showed]....of the 17 patients...[given] TILs, 7 had a complete response in the brain and 6 achieved an overall partial response.  Two of the 9 patients [given] TCR had a complete response in the brain.  Therefore, aggressive immunotherapy used in patients with small asymptomatic MBMs may produce CRs.  These results also suggest that activated T cells traffic into MBMs in the CNS.


Ipilimumab:
Another strategy that has changed the treatment of melanoma is the use of drugs to upregulate T-cell function using antibodies to block the cytotoxic T-lymphocyte antigen (CTLA)4, which potentiates antitumor immune responses.  Ipi, the anti-CTLA-4 monoclonal antibody, prolonged overall survival rates in patients with metastatic mel in two phase III studies. Although traditional radiographic responses were seen in a small percentage of patients (10-15%), many of these responses lasted months to years.  These first pivotal studies excluded patients with MBMs. [Later studies using ipi in brain mets showed that patients with asymptomatic brain mets and NOT on corticosteroids had a 25% rate of disease control, while symptomatic patients with MBMs currently taking corticosteroids had a 10% rate of control.]  ...this study revealed that ipi has activity in MBMs...it is unknown whether the treatment was more effective in larger MBMs in which the highly permeable BBB may allow a greater ingress of activated cytotoxic T cells.

     ...Patience...[in monitoring clinical benefit] is required when using immunotherapies.  Early in the course of treatment, lesions may grow and become symptomatic, which is a pattern seen in systemic melanoma lesions treated with ipi, even though significant clinical response will ultimately occur.  In general, we attempt to wait until the end of the induction phase of ipi before concluding the presence of progressive disease.
      One retrospective review sought to answer whether combination therapy with CTLA-4 antibodies was effective. Control rates using SRS combined ipi were reported and favorable survival and response rates were seen.  In this context, SRS may synergistically work with ipi by lysing tumor cells and presenting a broader antigen repertoire to primed T cells.....

Programmed Death 1 Inhibitors:
Programmed death (PD) 1 is an inhibitory co-receptor on antigen-activated T-cells.  Activated T cells may be suppressed by ligands PD-L1 and PD-L2...Inhibiting the PD-1 receptor with a blocking antibody enhances T-cell responses and antitumor activity. Response rates have been reported in melanoma and in non-small-cell lung cancer.  Patients with radiographically stable (>/= 8 weeks) brain mets were enrolled in these trials, but results in MBMs were not separately reported...

Special challenges:
The use of immune modulators (CTLA-4, PD-1 antibodies) poses...challenges...in treating brain mets...  Although T cells pass through an intact BBB, which is disrupted in MBMs, the brain remains "immunoprivileged"....  This suggests that strategies to increase BBB penetration may increase the efficacy of immune-based approaches...  The concept of delayed response - for example, with ipi - is important to avoid discontinuing the drug too early because of changes in volume enhancement unrelated to tumor growth....

So...not such terribly new information.  But, I thought this presented a nice overview of treatments so far.  I think it is good that they are looking at the fact that when radiation (in the form of SRS) is combined with immunotherapies patients show better responses.  Also glad they are looking at ways to make the T-cell action even better in the brain and in MBMs in particular.

To all my MBM buddies, I wish you my very best. - c

Side effects of Nivolumab....9 months after last dose!!!

In the words of Weber...."This stuff is weird!"

So, for the past 9 months I've been going about my business.  Had my last anti-PD1 (Nivolumab) infusion in June.  Had a recheck at Moffitt in September at which time my mouth ulcers were finally resolving after their 4 month residence!  I did have a little flare of oral lesions in October, but it only lasted 3-4 weeks and never got nearly as bad as they had been. Since then, I've been working as usual, increasing my running and elliptical workouts and feeling well.  Many of my co-workers have been stricken with flu and strep this season despite our early flu immunizations...but not me!  My asthma hasn't even been too much of a bother.  However, during and after my runs at the end of January, I began to notice that my ankles and knees were aching.  I've run much of my life and have been lucky never to experience joint issues with it, but thought, "Guess, I've been overdoing things a bit!"  I took several days off from exercise, took Advil, but the joint pain just kept getting worse!  Nurses at work noticed I was unconsciously supporting my right side and arm, and had a bit of a limp.  "I'm fine, just ran a little too hard too soon, I guess." But, last week, despite having had no fever, the body/joint aches were so persistent and I felt so very tired generally, that I had one of the nurses run a flu test on me.  Negative!  "Well, that's good," I thought.  Figured it must be some other nasty virus, even though I still had no fever.  But, just a couple days later, as my wrists, hips, elbows, and toes...joined my knees and ankles with their aches and pains...two ulcers appeared on my lip.  The area to the side and beneath my tongue, though not ulcerated, was suddenly red and tender.  The light of recognition dawned!  The bug juice was at it again!!! 

Can't really tell any of you what all this means.  Some of my folks are happy to think that "it" is "still working"....but, Good Grief!!!!  Anyhow, the lesions on my lip have already mostly healed and the joint aches are improving, with my tongue only vaguely tender.  Just did a work-out on the elliptical and am no worse for wear!  There are far more difficult things I could be dealing with for certain!!  But, thought some of you out there might like to know.

Hang in there, ratties!  Love - c

Tears and melanoma...they're not always sad...

Rosie was assigned...."Write a poem in a voice other than your own."  I think she chose mine...

Melanoma Muse

They wheedle

and complain-

How tired they

are today!

Eyes lowered,

shoulders clutched,

a slight cough,

a muscle cramp.

I do not doubt the

discomfort-

they have a cold,

they are in pain.

They have no experience

of the realm hurt,

where standing alone is

unexpected.

Yet still

I hope a stubbed toe,

a bout of flu,

is the worst they

have been dealt.

When I see a doctor,

(And I am not the doctor for

            someone else)

I wait in a room

where

by comparison,

I am in the best of health.

 crm

She knows me well.  We have often spoken of the weird world I feel I inhabit.  Rather....I spoke...she listened.  It is strange to seem to be the sickest, and alternately the most healthy person, in the room at odd times.  Like the time I had to step out of a room in the middle of a patient's exam, to take a call from my doctor who told me that, "Yes, the tumor in your lung came back positive for melanoma."  I was expecting the call that day, that is why my phone was on. And...I pretty much knew that was what he was going to say.  But....that didn't change the dry mouth, the lump in my throat.  I returned to the room and finished the exam.  I do not feel that the cute little 8 year old with strep throat was in any less need of care than myself.  But...it was still weird.  Weird to be trying to get a perfectly healthy, albeit overweight, 16 year old to exercise...just a little...fully aware that when YOU run...which you do...your right side and arm burn like fire from all the surgeries, subsequent nerve damage, and scars.  I just want them to be the most happy, healthy kid they can be.  I don't matter.  Then....I go to the doctor.  It was even more dramatic when I saw a general oncologist or surgeon.  I felt that the waiting bald, wheelchair bound, frail, cachexic folks were always thinking, "Poor thing.  She still looks good, has all her hair and everything.  She has no idea what she's in for!"  OR..."'Wow!  That's cool!  Somebody made it!!  If that girl can do it...I can, too!  She made it through.  She looks strong...hair grew back... I can do this!"

Melanoma doesn't fit the "cancer" mold.  I don't look like a "lung cancer" or "brain tumor" patient...though I have been both.  There is no traditional chemo.  There is [mostly] no baldness.  Skin cancer can't be THAT bad, can it?  I have a charm on my bag that carries my gear from room to room...otoscope, ear currettes, ophthalmoscope head....that says, "STUPID CANCER!"  People understand that one.  Very few ever suspect it applies to me.  And...that's ok.

 We all have our baggage.  We all have our scars.  Some are visible.  Some are not. I have been lifted up at times I didn't believe it was possible.  I hope I have paid it forward. Yet, I am changed.  For better?  For worse?  I guess time and those who know me will be the judge.  But, I have changed a poet.  And that.....gives me pause.

I love my girl.  Mommy     

Purple up! Bucks from Chevy to the American Cancer Society!!!

Bucks for the American Cancer Society

If you have a Face Book page, click on the link above.  In a few easy clicks, turn your FB pic purple and Chevy will donate one dollar to the American Cancer Society!  Go ahead!  Take their money.  Purple up!!!! - c

Intralesional therapy for melanoma, PV-10, and Provectus. Now there's a mashup!

Intralesional melanoma therapy (A procedure in which the "treatment" is directly injected into superficial tumors and in theory, not only does that tumor die, but "by stander" tumors at more distant sites die too!!!) was first recorded back in 1975.  A 75 year old male with 64 melanoma mets just below the skin, as well as junk in his lungs, had 17 superficial lesions injected with Bacille Calmette-Guerin over a period of 8 months. (BCG is a vaccine against some strains of tuberculosis, but does contain a weakened version of the bacteria itself within it.) In the end, all 17 tumors injected resolved and his pulmonary mets diminished by more than 50%!  However, enthusiasm for BCG as a melanoma treatment waned as patients in subsequent trials experienced anaphylactic reactions and death due to disseminated BCG, and randomized trials failed to replicate significant clinical benefit.

Later, intralesional therapy was tried using all sorts of things.  More recently Allovectin-7, OncoVEX, and PV-10 have demonstrated positive results, killing melanoma at the injected site and systemically.

Allovectin-7, is a soup of DNA, that attempts to change the gene make-up of tumor cells. In a study reported in 2012, it provided a 12% overall response rate with no grade 3 or higher toxicities in patients with stage III/IV melanoma with injectable cutaneous lesions.

OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.) But, in OncoVEX, it is thought to only replicate in the tumor cells.  The white cells produced in the process kill off the tumor cells.  In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients.

Rose Bengal was first utilized in the 1800's to dye fabrics and color the feet of Bengali women red for weddings and celebrations. Later it was used as a staining agent to find corneal lesions and then as an IV preparation to check for impaired liver function.  The "Aha!" moment came in the 1980's when Japanese tests of a "food dye" to determine tumor origin, found dose-dependent survival increases. After a few other sundry studies....PV-10 was born.  It is a 10% Rose Bengal solution, with a 30-minute half-life, excreted via bile. PV-10 is excluded from normal cells, but slips through the cell membrane of cancer cells (liver, breast, melanoma, and others) because their cell walls have a higher lipid content. Once inside, PV-10 triggers lysosomal release (the part of the cell that digests waste), killing the cell in 30-60 minutes. Antigenic tumor fragments are believed to produce the 'bystander effect' leading to immediate reduction in tumor burden and concomitant immunologic activation.

(See blog posts on 10/12/2012 and 12/14/2013 for particulars on Rose Bengal studies.)

Results from a study with Rose Bengal, published in 2012 by Agarwala:  Objective response was achieved in 51% of target lesions (25% complete response and 26% partial response).  Furthermore, disease control (combined Complete, Partial, and Stable responses) was achieved in 69% of lesions.  In bystander lesions: 33% = objective response and 50% achieved disease control in these lesions.

Now....I don't know if any of these treatments will live up to their initial studies or hype!!!  I'd like to think they would because of the people they could help.  I have high hopes for PV-10 in particular because it is so cheap, has so few side effects, and is doing rather well...so far.  The big dogs at Moffitt seem to find it promising, too, and have started a study (enrolling now) to examine what injections of PV-10 does for melanoma patients and their tumors as well as the immunologic agents that start floating around in their blood after its use.  However....

Provectus (the company making PV-10) would like to have you think that, as well.  They have been very big on touting their new Moffitt connection! (Blogger dude [see reference below] even quotes Dr. Weber.  Wonder if The Wizard Weber knows that??!!!) But, for very different reasons...their stock price being foremost.  Per their premier blogger..."It costs very little to manufacture PV-10." (No Shit Sherlock...poor women used to dye their feet in it!!!) Yet, Provectus gurus predict a $20,000 - $30,000 treatment price...assuming several cycles using 1-2 vials per cycle at a cost of $5,000 per single use vial!  "At these prices, however, PV-10's gross margin would be more than 80%.  If (THEIR TYPO NOT MINE!) would be in excess of 99% should a sales return-type allowance not be included."

Seriously????  No final data in.  Touting their stock price rise after the trial began at Moffitt. And then, as an aside to their investors..."Hey, boys and girls!!!  We can make you a 99% return on your investment on these sad schmucks, with all their cancer, and this cheap ass shit!!!!"

And you thought.... "Man, I've got cancer.  What the hell?  I'll just take the best medicine I can find, damn the side effects."  Sadly...Big Pharma Provectus thought..."Desperate Bastards!  Look at 'em.  This shit is super cheap!  They are used to paying out the ass for ipi.  Lord only knows what they'll end up paying for anti-PD1!  We can make a fortune!"

Check it Mr. Provectus Blog Man.  We don't all roll over for you. - c

By the way....had I purchased stock in Provectus in November 2013, by the end of December, I would have quadrupled my investment!  You heard it here first.  I feel sorry for all those patients on the boards looking to these factors as indicators as to when drugs like Nivolumab and others will be hitting the market.  Sadly, these folks are not about "us".  They are about their companies, pleasing their investors, and making big bucks.  They don't care if they make it off of hype or real success in cancer treatment.  It is all the same to them.- c

References:
1.  Intralesional Therapy for Metastatic Melanoma. Sanjiv Agarwala, MD, The Melanoma Letter, 2012.
2.  Connecting the dots...Provectus Pharmaceuticals. Sept 30, 2013...A blog by "the author" with a complicated investment disclaimer but with admittedly HUGE investments in Provectus!!!