Holiday Wishes to you All !! Melanoma..Jim Breitfeller

I would like to wish each and every one of my carepage friends the warmest and deepest greetings this Holiday Season. We been through a lot and with the comfort of family and friends we can beat the Beast Melanoma.

It has been truely a renewed emergence in Melanoma therapy this past year with TWO therapies being FDA approved that extends survival for us Melanoma patients. At this time of the Season, please relect on the Worriors that are no longer with us, but made this all possible by offering their life to the progress of science.

They truely have shown us the gift of giving.

They truely are my/our HEROS!!!

We will miss them dearly.

Happy Holidays




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,

Jimmy B

Diagnosing Skin Cancer Without Biopsy..Melanoma ..Jim Breitfeller

BACKGROUND: Skin cancer is the most common form of cancer, affecting approximately 1 million people annually. The easiest way to recognize skin cancer and the possible formation is a change in skin appearance such as color or soreness. Doctors say if there is a new growth that has appeared and will not go away, this is also a sign of the possible formation of skin cancer. There are three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and melanoma. Melanoma is the most serious form of the three.

To diagnose skin cancer, doctors must do a biopsy, or take a sample of the skin and send it to a lab to be processed. It can take more than a week for the patient to get results. According to the American Cancer Society, as many as 80 percent of biopsies for some types of cancers come back negative.

TREATMENT: There are four main types of treatment for people who have skin cancer: surgery (which also includes dermabrasion and laser surgery), radiation therapy, chemotherapy, and photodynamic therapy (which uses a drug and a certain type of laser to kill cancer cells). A new type of treatment, called biological therapy, is being tested in clinical trials. With biological therapy, doctors use the patient's immune system to fight the cancer.

DIAGNOSING SKIN CANCER WITHOUT A BIOPSY: Researchers say they are working on an invention that could radically change how doctors find skin cancer. It is a hand-held, non-invasive cancer scanner that diagnoses skin lesions on a patient. The handheld scanner uses a lens to look at a patient's skin, but instead of illuminating the skin with normal white light, the device uses laser light. The laser light is used to form an image of the skin's cellular structure, and it monitors the way a
patient's cells change the reflected laser light. Doctors say those changes can tell them the chemical composition of the skin cells. Doctors would then compare that chemical signature to a database containing the chemical signatures of known cancers to see whether the patient's cells are cancerous. The device would be able to tell if a patient has a form of skin cancer within minutes.



MelaFind uses a digital camera to record suspect skin patches in 10 different bands of light, including a deep probing infrared beam that examines cells below the skin's surface. The collected images are sent to a computer and compared against thousands of malignant and benign skin images, determining in seconds whether skin cancer is likely and eliminating the need for painful, scarring biopsies.

This pattern-recognition technology was originally developed by the Department of Defense for use in spy satellites to distinguish potential military targets from civilian objects.

In a clinical trial at seven locations across the U.S. last February, researchers used MelaFind to study more than 1,800 skin lesions from 1,300 patients, finding that MelaFind's ability to accurately rule out skin cancer was 2.5 times greater than that of dermatologists.


MelaFind demonstrated 98% sensitivity (correctly identifying the disease when it is actually present) in the detection of melanomas (identifying 125 out of 127 overall melanomas) and 9.5% specificity (ability to rule out the disease when it is not present), compared to 3.6% for the 39 dermatologists who participated in the study.


It is up for review with the FDA and hopfully will get approval by the end od this.

MelaFind is a breakthrough product with the potential to save lives!!!!



“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

CureHunter Professional Research Interface, For the Researcher in all of us. Melanoma..Jim Breitfeller

Many thanks to Judge Schonfeld for the tools to continue the research On Melanoma.

Jim,

I am happy to support both your goals to help other patients and continue your own research and fight with Melanoma with a free subscription to the CureHunter Professional Research Interface.

You will be fully enabled with the same access that physicians and scientists around the world have by 12:00 pm PST today.

There is so much poor or biased health information on the web, that raising the profile of real science is always a good deed.

To login...go to the home page, use your registered name and password...then CLICK RESEARCH
on the black header bar to begin. Enter Melanoma in the query field, select specific type, and click: Data and graphs will auto populate your screen.

Attached is a 1-page Basic User Guide and a Physician Overview
Brochure with other views of the system's core utility and functions.

You probably don't know this, but CureHunter was built by a single family of scientists in memory of my brother Dr. Gene Schonfeld, Ph.D., who founded the first on line patient organization for those with terminal disease--including himself--1989, Kidney Cancer Association.

Gene, like yourself, was a great believer in empowering patients with knowledge and by vigorously learning about his own disease and fighting it passionately, he extended his own life by 11 years past the prognosis of death, established the Young Investigators Research Foundation, and went on to help many, many others around the world live longer and better lives: www.kidneycancer.org



I don't know how technical your own research background is, but last year my son Dr. Justin Schonfeld, Ph.D. Computational Biology, was invited to give his 4th university lecture on the CureHunter machine's ability to autonomously discover new cures for human disease in experimental settings.
lecture on the CureHunter



To explain CureHunter to a more general public/non-technical audience, last year we also put up a YouTube video, entitled "CureHunter's Brain on Breast Cancer":



CureHunter's Brain on Breast Cancer



The video explains how Network Graph Theory (a type of math for relating massive numbers of variables-- not unlike modeling social networking on the Internet itself) is used in CureHunter to discover functional clinical networks that illuminate potential new pathways and molecules for cures: TCP in our jargon = Transmissive Curative Packets.

Lastly, I have attached a copy of the Poster from my National Science Foundation conference presentation (2007) on the general systems biology theory of CureHunter, its plan to "instrument" biomedical knowledge, make it usable at the point of clinical care, and document results for all patients.

Please feel free to share any of the content of this note or the attachments with those you believe would be interested.

My best wishes to you and your family and thank you for fighting too. Everyone who does, helps us all by good example.

Judge

Judge Schonfeld
CEO and Chief Scientist
CureHunter Inc.
www.curehunter.com





Take Care,

Jimmy B

Lifesaver... PLX-4032 Therapy for BRAF Mutations..Melanoma ..Jim Breitfeller

"Now, an incredible breakthrough. A tiny capsule that can stop even advanced Melanoma in its tracks.

It's called PLX 4032 — and the results are so swift and dramatic that it's got even the usually conservative medical community excited. Even better, this drug could mark the beginning of a cure for other forms of cancer. Already, it's giving some patients back their lives and, for people like 24-year-old Brendan Robbins, offering hope — just in time."

Reporter: Liz Hayes
Producer: Phil Goyen

Lifesaver... PLX-4032 Therapy for BRAF Mutations



Source:http://sixtyminutes.ninemsn.com.au/stories/927744/lifesaver-cancer

You may want to be checked for the BRAF Mutation.

Take Care,

Jimmy B

Main roads to melanoma..Jim Breitfeller

Main roads to melanoma

This paper is very technical but gives great insight into Melanoma and the pathways that are associated with it. It is quite long and should be read in small bites. Please don't be intimidated by it.

Giuseppe Palmieri1, MariaElena Capone2, MariaLibera Ascierto2, Giusy Gentilcore2, David F. Stroncek3, Milena Casula1, MariaCristina Sini1, Marco Palla2, Nicola Mozzillo2, and Paolo A. Ascierto*2


ABSTRACT

The characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects
regarding the main molecular changes responsible for the onset as well asthe progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying thepathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of downor up-regulation of various effectors acting on different molecular pathways.

Source:
http://www.translational-medicine.com/content/pdf/1479-5876-7-86.pdf

Main Roads to Melanoma



Take Care,

Jimmy B

Mole or Melanoma? Tell-Tale Signs in Benign Nevi and Malignant Melanoma: Slideshow

Mole or Melanoma? Tell-Tale Signs in Benign Nevi and Malignant Melanoma: Slideshow

Take Care,

Jimmy B

“You Can’t Start a Fire Without a Spark!!” Melanoma.. Jim Breitfeller

“You Can’t Start a Fire Without a Spark!!” anti-CTLA-4 blockage

Recent improvements in the Researcher’s understanding of the Immune System such as the role of costimulatory T-Cells and Antigen presenting cells has led to the renewal of the developmental efforts in Immunology of Melanoma. Monoclonal Antibodies (mAbs). The theory has been around about 100 years.

According to Dr. Ehrlich’s theory, the surface of white blood cells is covered with many side chains, or receptors, that form chemical links with the antigens they encounter. After binding of the specific antigen the cell is stimulated to produce more of the suitable type of receptor, which would then be shed into the blood stream as antibodies.
Antibodies, also called immunoglobulins (Ig) are proteins that are found in blood or other bodily fluids of humans, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.Antibodies are produced by a kind of white blood cell called a B cell. 1


The antibody that we are interested in is the Cytotoxic T lymphocyte-associated antigen.(CTLA-4). This antigen can inhibit T-cell responses and is involved in tolerance against self antigens. It was reported back in 1970 Bretscher and Cohn put forth the two-signal model of lymphocyte activation to explain self/nonself discrimination 6This model proposes that T-cell activation requires two independent signals. As the antigen interacts with the antibody receptor on the antigen-sensitive cell also known as the antigen presenting cell (APC) (Signal 1), it performs a conformational change which in turns paralyzes the whole cell. A new signal is now invoked (inductive signal) base on the new carrier of the antigen and antibody combined. (Signal 2) The T-cell activation not only requires the T–cell interacting with the antigen-MHC complex, but also the interaction of the CD28 receptor and the B7 as well. Once activated, the CD28 signaling leads to Interluekin-2 (IL-2) gene expression which helps promotes the immune system to propagate more T-cells.

The CD28 signaling activates the PI3 kinase and AKT pathway but they believe that there are no signal proteins involved according to Thompson and colleagues. They suggest that gycoloysis occurs along with energy metabolism causing the growth of the T-Cell.7
That T-cell is the T-Helper cell.
The AKT signaling can either lead to cell survival or programmed cell death called
Apoptosis.


It has been noted that CD4+ T-cells can be cross-prime CD8+ T-cells via IL-2.8
Once the CD8+ T-cell is activated correctly, it can deliver a hit to the tumor cells
if it can make its way passed the microenvironment of the tumor or tumors.

Happy Father's Day to all fathers who love their children and are trying to make a difference in their lives!!!!



Take Care,

Jimmy B

The Federal Coordinating Council for Comparative Effectiveness Research..Melanoma..Jim Breitfeller

FasterCures submitted the below comments on the prioritization criteria and strategic framework developed by the Federal Coordinating Council for Comparative Effectiveness Research.

Source:http://fastercures.blogspot.com/

fastercures


Now is the time to get your voice heard. We as Cancer Patients can Move Mountains. Please send in your comments. Your opionion Counts.

http://www.hhs.gov/recovery/programs/cer/draftdefinition.html

Federal Coordinating Council for Comparative Effectiveness Research



Take Care,

Jimmy B

Experimental Vaccine Improves Melanoma Outcomes..Melanoma ..Jim Breitfeller

Experimental Vaccine Improves Melanoma Outcomes

By CancerConsultants.com

Patients with advanced melanoma experienced higher response rates and longer survival without cancer progression when treated with an experimental anticancer vaccine in addition to standard therapy. These were the preliminary findings from a Phase III clinical trial presented at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO).

Patients with metastatic melanoma are usually treated with a combination of chemotherapy and immunotherapy. Chemotherapeutic agents with activity include dacarbazine, temozolomide, cisplatin, vinblastine, thalidomide, and docetaxel. Immunotherapy agents include interferon-alfa (INF-alfa) and Proleukin® (interleukin-2,IL-2). However, because most therapy is palliative, tolerability of treatment is a significant factor. Recently, researchers have emphasized the development of tolerable regimens.

Proleukin in high doses is an FDA-approved drug for the treatment of metastatic melanoma. However, Proleukin produces responses in only a minority of patients and at high doses is associated with significant toxicities. There have been innumerable studies performed over the past two decades to improve the response rate and decrease the toxicities of Proleukin-based regimens for the treatment of melanoma. Despite all of these efforts, biologic therapy or combined biologic and chemotherapy still benefit only a minority of patients with melanoma. Various vaccines have been tested in patients with melanoma, but none have been approved for this use by the U.S. Food and Drug Administration.

In the current study, researchers evaluated an experimental anticancer vaccine known as gp100:209-217(210M) peptide. The vaccine acts by stimulating T cells to attack melanoma cells. This study enrolled 185 patients with Stage IV or locally advanced Stage III melanoma. Study participants were assigned to receive treatment with Proleukin alone or with Proleukin plus the vaccine.

Follow-up is not yet complete, but the following results were presented at ASCO:

•The overall response rate was 22% for patients treated with Proleukin plus the vaccine compared with 9.7% for patients treated with Proleukin.

•Progression-free survival was 2.9 months among patients treated with IL-2 plus the vaccine compared with 1.6 months among patients treated with Proleukin alone.

•Overall survival was 17.6 months among patients treated with Proleukin plus the vaccine compared with 12.8 months among patients treated with Proleukin alone. The difference between groups in overall survival did not meet the criteria for statistical significance.

•The vaccine was well tolerated. Side effects were swelling and redness at the injection site.


Comments: This study is one of the first to show promising results for vaccine in metastatic melanoma. Researchers will continue to follow the patients enrolled in the study to assess longer-term results.





Reference: Schwartzentruber DJ, Lawson D, Richards J et al. A phase III multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. Journal of Clinical Oncology. 2009;27:15s, abstract CRA9011.




Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

Official Title: A Phase III Multi-Institutional Randomized Study of Immunization With the GP100: 209-217 (210M) Peptide Followed by High Dose IL-2 vs. High Dose IL-2 Alone in Patients With Metastatic Melanoma

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
•Whether the addition of peptide vaccine to high-dose aldesleukin is superior to alaldesleukin alone by response rates after each course of treatment [ Designated as safety issue: No ]


Secondary Outcome Measures:
•Toxicity of treatment by NCI Common Toxicity Criteria after each course of treatment [ Designated as safety issue: Yes ]

•Disease-free and progression-free survival comparison by disease evaluation every 3 months after treatment [ Designated as safety issue: No ]

•Immunologic response to treatment by various laboratory studies before and after each course of treatment [ Designated as safety issue: No ]

•Quality of life by Functional Assessment of Chronic Illness Therapy Fatigue Subscale RSF-36 SDS before and after the first course of treatment [ Designated as safety issue: No ]



Do you reconize the graph, you should . Now Look closely at the timing of the addition of IL-2. Do you see a major problem?????

It (IL-2) is being added before and close to the maximum propgation of the CD4+ T cells. This means they are growing the Tregs cells which we want to deplete or surpress.

VERY INTERESTING to say the Least...

Take care

Jimmy B


Melanoma_Missionary


Take Care,

Jimmy B

Analysis Sheds Light on Protein's Role in Cancer .."I Think we Can See Land!!! Melanoma..Jim Breitfeller

Posted:Date:6/5/2009 Bio-Medicine

Scientists make strides in finding ways to slow tumor growth !!!

FRIDAY, June 5 (HealthDay News) -- A protein called PHD2 that regulates blood vessel growth is often found at lower-than-normal levels in tumors, say researchers who analyzed levels of the protein in tumor samples and healthy tissue.

When they blocked the expression of PHD2, researchers at Stanford University School of Medicine in California found that human cancer cells grew more quickly when implanted into mice and there was an increase in the number of blood vessels feeding the tumors. To grow and spread, tumors require a good supply of blood, the study authors noted in a Stanford news release.

Further investigation revealed that blocking PHD2 expression increased levels of two other proteins -- IL-8 and angiogenin -- that play an important role in blood vessel formation. Blocking the activity of these proteins may slow tumor growth, the researchers said.

"Prior to this study, it was unclear which of the many proteins involved in vessel growth, or angiogenesis, should be targeted. But now we know they play a predominant role in tumor growth," Amato Giaccia, a professor of radiation oncology, said in the release.

The findings are published in the June 2 issue of Cancer Cell.

In the next phase of their research, Giaccia and colleagues will study whether mice that lack PHD2 expression develop more aggressive tumors, and whether blocking IL-8 or angiogenin slows tumor growth.




Sourc:http://www.bio-medicine.org/medicine-news-1/Analysis-Sheds-Light-on-Proteins-Role-in-Cancer-48086-1/

As Columbus would have said ,"I Think we can see Land!!!!


Take care

Jimmy B

You have questions for Me? Why DTIC & PaTrin-2?..Melanoma..Jim Breitfeller

Remember I went to United Kingdom virtually to scour the research papers Last year?

Introduction:

"Temozolomide is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG) DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs
can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which after a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and
bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2).

The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4).

MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as ‘‘pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma
xenografts (7)."


Source:http://mct.aacrjournals.org/content/3/10/1215.full.pdf

Sensitization of a human ovarian cancer cell line totemozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase


That is why, and I forgot to tell you that I did a trial with Patrin and DTIC Prior to CTLA-4 Blockage Therapy.

Take Care

Have a Great Weekend!!!!!

Jimmy B

What We Can Learn From Individual Patients is Often Overlooked.Melanoma..Jim Breitfeller

"What we can learn from individual patients is often overlooked in oncology," he said, adding that many of these remarkable cases have led to the development of new treatment strategies for melanoma such as vaccinations against specific antigens and bone marrow transplantation. "From clinical observation, we can learn a lot from these remarkable cases."

Alan Houghton, M.D., chief of immunology at Memorial Sloan-Kettering Cancer Center, New York



This my Theory to Date as of 6/5/2009.

I will be sending out a Very, Very long list of ACKNOLOGEMENTS.

"In melanoma patients treated with CTLA-4 blockade, not only were more T cells specific for melanoma antigens present, but those CTL were more likely to be polyfunctional — thus more likely to be effective at destroying the tumor — and those patients were much more likely to have regression of their tumors than in people without CTLA-4 blockade.

So the concept that TRegs — or some other inhibitory effect associated with CTLA-4 — suppress anti-tumor immune responses is likely to be correct, and it seems that at least in some cases it’s possible to override that inhibition and drive T cells to once again attack the tumor effectively. When that happens, cancer can be cured. It’s just a question of being able to do this on a consistent basis. Unfortunately, that’s still the hard part."

Unknown

“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”

Greg Simons

“Don’t ever give up. Don’t ever give up.” “Cancer can take away all my physical abilities. It can not take away my mind, it can not take away my heart, and it can not take away my soul”.

Jimmy Valvano from his speech during the 1993 ESPN ESPY Awards


I have so many papers that I don't recall where I got the above quote.

My Hope is that this doesn't fall on deaf ears.

Take care
Jimmy B

I guess having diabetes is Good for Somethining!!!!! Melanoma...Jim Breitfeller

I guess having diabetes is good for something!!!!!

Talk about LUCK!!!!

Thank you Dr. Marino!!!!!


I have been taking metformin for years. I guess it is worth the COPAY.


Study Shows Metformin Maximizes Immune Memory.

By Daniel J. DeNoon
WebMD Health News

Reviewed by Louise Chang, MD

June 3, 2009 -- The diabetes drug metformin may make vaccines work better, exciting new studies suggest.

"These findings were unanticipated, but are potentially extremely important and could revolutionize current strategies for both therapeutic and [preventive] vaccines," University of Pennsylvania researcher Yongwon Choi, PhD, says in a news release.

Choi's team wasn't initially interested in diabetes drugs -- and wasn't trying to improve immunizations.

The scientists were trying to figure out how the immune system remembers disease-causing agents so that it can mount a rapid immune response the next time it sees that agent.

This so-called immune memory depends on cells called memory T cells that lurk in the body, becoming active only in the presence of the pathogen they're programmed to recognize.

During an infection -- or after an immunization -- the body mounts a massive T-cell response to fight off the invasion. These T cells go away after the threat is neutralized, but a few of them survive to become memory T cells. How this happens has been a mystery.

Choi's team found that memory T cells survive by switching their fuel supply. Instead of burning glucose, as most cells do, they start burning fat. The researchers bred a strain of mice that lacked the ability to switch fuel sources, and these mice could no longer make memory T cells.

One of metformin's effects is to help cells burn fat. When Choi and colleagues gave metformin to the specially bred mice, the drug restored the animals' ability to make memory T cells.

This led the researchers to wonder what would happen if they gave metformin to normal mice. So they injected the mice with doses of an experimental cancer vaccine that, under normal circumstances, does not protect the animals. But in mice given metformin, the vaccine was vastly more effective at preventing cancer.

"The finding was very unexpected. We were lucky," Choi tells WebMD.

The serendipity may pay off in big ways.

"The findings do not mean that if you take metformin you automatically have better memory responses," Choi says. "But this widely used drug might enhance vaccination programs. If we combine our finding with those strategies, we may be able to improve vaccine efficacy."

Choi and colleagues report their findings in today's advance online issue of Nature.


Someone is looking out for me . I better say my prayers

Best Regards to all,



Jimmy Breitfeller

Ah haaaaa!!!!!!!!! Road map to Recovery Melanoma..Jim Breitfeller

Follow the Yellow Brick Road!!!



"What we can learn from individual patients is often overlooked in oncology," he said, adding that many of these remarkable cases have led to the development of new treatment strategies for melanoma such as vaccinations against specific antigens and bone marrow transplantation. "From clinical observation, we can learn a lot from these remarkable cases."



Alan Houghton M.D., Chief of Immunology at Memorial Sloan-Kettering Cancer Center, New York





Well here are all the outside pieces to the Melanoma Puzzle. Now this may not work for every one but it did work so far for me. My last hurtle was how did my Immune system have the right antigen to present.



Without that piece of the puzzle, there would be no effective response.



Bobby Luker, this is for you and everyone who is still on the Yellow brick Road.







Take care



Jimmy B

I got that “a-hah!” Feeling!!! Melanoma.. Jim Breitfeller

Establishment of an immune response against Melanoma cancer may depend on the capacity of dendritic cells to transfer tumor Antigens (Ags) into T cell-rich areas.

Most Melanoma tumors are accepted by the host’s immune system and progress even when they contain potentially antigenic proteins. Analysis of this response may help to understand how most tumors escape immune rejection. Overexpression of the anti-apoptotic protein Bcl-2 in Melanoma cells prevented the development of an antitumor immune response. This suggested that induction of a specific immune response involved the release of antigenic proteins from tumor cells undergoing apoptosis.

O6-methylguanine DNA-methyltransferase (MGMT enzyme) overexpression in melanoma cells also induces resistance to Chemotherapy. This increased DNA-repair activity in tumor cells has been associated with resistance to treatment to DNA-directed drugs, while defects in DNA repair pathways result in hypersensitivity to these agents. In the past years the unraveling of the molecular basis of these DNA pathways, with a better understanding of the DNA damage caused by different anticancer agents, has provided the rationale for the use of some DNA repair inhibitors to optimize the therapeutic use of DNA-damaging agents currently used in the treatment of tumors. In addition, the possibility to specifically target the differences in DNA repair capacity between normal and tumor cells has recently emerged as an exciting possibility.

In a model using melanoma cells in mice, phagocyting cells were observed to be attracted at the injection site and ingest tumor cell fragments. It has been recently demonstrated that dendritic cells selectively recognized and captured apoptotic cells and cell fragments liberated following apoptosis. Moreover, antigenic proteins that were contained in apoptotic bodies and engulfed by dendritic cells were shown to be 1–10,000 times more efficient in generating MHC-peptide complexes than preprocessed peptides.

So with all this in mind, we need the tumor to shed some antigenic proteins/fragments to be used by the Antigen Presenting Cells. (APCs) undergoing apoptosis.

There are three types of APCs:
1) Macrophages
2) Dendritic cells
3) B cells

This was one of last pieces of my puzzle that I will share wth you soon.

I am so excited, I hope I can get some sleep.

Jimmy B

ASCO summary By Dr. Eric Whitman.. Melanoma ..Jim breitfeller

ASCO Summary
Posted on June 1, 2009 by dr Eric Whitman

"I have been going to ASCO for years and I’m still waiting for that “a-hah!” moment when somebody presents something for melanoma that is so revolutionary and effective that we all have something tangible and exciting to come home with and build on in the future. I feel like we are getting closer as a “melanoma community.” I know that in my own clinical experience and current practice, I am able much more frequently to walk into someone’s exam room and tell them, congratulations, the tumors are shrinking. Honestly, there were many years where that **never** happened.

However, for all the hopes extended each year towards ASCO as the ultimate cancer meeting, I honestly can say that there was nothing presented over the last few days that will immediately change therapy or even holds out hope for some drug or combination of drugs posterizing DTIC or Temodar. (Posterizing somebody is a reference to pro basketball, when you savagely dunk the basketball over an opponent with such force and superiority that it becomes an instant classic athletic poster. Like the Michael Jordan slam dunk contest when he still had hair, took off from the foul-line, and the open mouth, wide-eyed stares of the sideline onlookers were forever captured.)

The closest we came in my career was the early data from about 2004 on Sorafenib/Nexavar, but that has melted away with larger scale, multicenter studies and is just a footnote at this point.

I will provide more detailed updates in other posts, but unfortunately there are no new treatments that show undeniable improvement over existing treatments. There are a few things that suggest the potential for improved therapy, but these are best described as “hypothesis-generating” or in other words, deserving of further, large scale, testing.

I know that this is frustrating to the melanoma patient community also; we’re just not there yet. We have new drugs coming down the road and they do have promising early results but the emphasis has to be on the word, promising.

The two take home words this year from the ASCO melanoma presentations were “Biomarkers” and “Targeted therapy”. In that regard, I don’t think the melanoma talks were that different from other disease areas. Biomarkers are things that can be measured, either in the blood or tumor tissue (or even in normal tissue) that classify an individual’s cancer by its behavior or potential to resp0nd to specific therapies. A biomarker could also monitor a patient’s response to therapy. A good example of this is the PSA level for prostate cancer. Finally, biomarkers could also identify patients either at risk for bad outcomes or those likely to respond to specifc treatments.

Targeted therapy refers to drugs that alter cellular biochemical pathways that are believed to influence a cancer cell’s ability to survive, grow, and/or resist therapy. Presumably, targeted therapy would have fewer side effects that standard chemotherapy but this exaggerates our true knowledge about these various pathways and their role in normal, non-cancerous, tissue. The other caveat about targeted therapy is that many of the ones that look most promising (to me) act by increasing cancer cells’ responsiveness to standard chemotherapy. As a result, these targeted agents often have no effect by themselves (ie monotherapy) and require simultaneous (concurrent is the medical word) chemotherapy drugs which obviously cause a range of side effects.

As you read my other summaries of ASCO papers and posters, keep biomarker and targeted therapy in the back of your mind; they came up over and over again"


WE NEED TO FIND THE “a-hah!” MOMENT!!!

I personally think we are getting closer.

The first step is to initiate the immune response

As our fellow carepage friend Jen has said, " DON'T STOP BELIEVING!!!!"

Take care

Jimmy B

Plexxikon Announces PLX4032 Phase 1 Data Showing Objective Responses in Metastatic Melanoma Patients.Melanoma .Jim Breitfeller

Personalized Medicine for Deadliest Form of Skin Cancer --


Business Wire
posted: 1 HOUR 58 MINUTES AGO

Plexxikon Inc. today announced preliminary data from a Phase 1 clinical study investigating PLX4032 (R7204). PLX4032 is a novel, oral and highly selective drug that targets the BRAF V600E cancer-causing mutation that occurs in most melanomas and about eight percent of all solid tumors. In patients whose cancer harbors this mutation and who were treated with therapeutic doses of PLX4032, tumor shrinkage and extended progression-free survival have been observed. Currently, two extension studies are being conducted in mutation-positive melanoma and colorectal cancer patients. Following the initial positive findings announced today, larger clinical trials to support a registration program for product approval are targeted to start later in 2009. Plexxikon and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.
“PLX4032 has shown both tumor shrinkage and delay in tumor progression in patients whose tumors harbor a BRAF mutation as well as reports of clinical symptom improvement in some patients,” stated Keith T. Flaherty, M.D., assistant professor at the Abramson Cancer Center of the University of Pennsylvania and principal investigator for the PLX4032 Phase 1 clinical trial. “Seven years after BRAF mutations were first identified, we have validation that this mutation is a cancer driver and therapeutic target. This is a new and important chapter in the story of targeted therapy development in cancer, and we are especially excited for our melanoma patients, for whom there are currently few treatment options.” Link to video clip of Dr. Flaherty
In the dose escalation phase of the study, 55 cancer patients have been treated, including 24 mutation-positive melanoma patients and 3 mutation-positive thyroid patients, as well as 28 melanoma, rectal and ovarian cancer patients who did not have the mutation or whose mutation status was not known.
In 16 BRAF mutation-positive melanoma patients treated with PLX4032 doses at or above 240 mg twice daily (BID), representing targeted drug exposure levels, data show:
PLX4032 is well tolerated at very high doses, with 960 mg BID under evaluation as the maximum tolerated dose
Partial responses in 9 patients showing greater than 30% tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with 7 confirmed
Regression of metastatic lesions in every site to which melanoma commonly spreads, including liver, lung and bone
Minor responses in 4 patients showing tumor regression greater than 10% but less than 30%
Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment
Interim median progression-free survival of at least six months, with many responding patients still receiving treatment
By contrast, no treatment response was observed in a small group of patients without the mutation, and progression-free survival was less than 2 months, consistent with historical data.
Dose-limiting toxicities, primarily rash, fatigue and joint pains, were seen at 1120 mg BID. Drug-related adverse events have been predominantly mild in severity and transient, including rash and photosensitivity. Serious adverse events were observed in some patients after chronic treatment, including possibly drug-related cutaneous squamous cell carcinoma. A risk management plan has been implemented for baseline evaluation of the skin and monitoring of all patients while on study. Cutaneous squamous cell carcinoma is typically excised by a patient’s dermatologist.

“This is a significant day for us at Plexxikon. The clinical data for PLX4032 so far support our hypothesis that a truly selective drug can target tumors harboring this cancer-causing mutation, while at the same time, deliver a treatment that is well tolerated by patients,” stated K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “In conjunction with bio-response markers and a companion diagnostic test, PLX4032 has all the hallmarks of an ideal personalized medicine. Plexxikon’s pipeline includes several highly selective kinase inhibitors, including novel therapies for other cancers as well as other chronic diseases such as rheumatoid arthritis where such precision is anticipated to provide a safety advantage.”

Companion Diagnostic in Parallel Development
Along with the development of PLX4032 therapy, a diagnostic test to identify patients with the BRAF mutation is being co-developed by Plexxikon and Roche, under a separate 2005 agreement. This test is already being used to identify mutation-positive patients for ongoing clinical trials. Most importantly, this companion diagnostic enables the identification of mutation-positive cancer patients considered most likely to respond to PLX4032 treatment.

Source:http://money.aol.com/article/plexxikon-announces-plx4032-phase-1-data/484608?icid=sphere_searchsphere_news


Take care

Jimmy B

Data Mining... Melanoma...Jim Breitfeller

Source:http://www.curehunter.com/public/keywordSummaryD008545.do

Cure Hunter Melanoma




Take care

Jimmy B

Proof-of-concept for V600E BRAF mutation as a therapeutic target in human cancer..Melanoma..Jim Breitfeller

Proof-of-concept for V600E BRAF mutation as a therapeutic target in human cancer

Phase 1 study of PLX4032: Proof-of-concept for V600E BRAF mutation as a therapeutic target in human cancer”
Oral presentation to be made on June 1, 2009, 4:30 p.m. to 6:00 p.m. EDT by Keith T. Flaherty, assistant professor, University of Pennsylvania Abramson Cancer Center, in the “Molecular Phenotype of Melanoma Subtypes and Patient-Specific Therapy” session

Link to video clip of Dr. Flaherty


We just may be getting a handle on this deadly disease!!!!!!!!!


Take care

Jimmy B

Kurt's Story "The Battle with the Beast"

"I will try my best to impart Kurt's story to you.

Kurt was a healthy, 28 year old man living in Bloomington, MN. He was a night manager for the IHOP Restaurant located near the Mall Of America. He was one of nine children and grew up on a farm in southeastern MN. Even as a child he would much rather be in the house cleaning or cooking than doing the outside work. He was very modest and you didn't very often catch him without a shirt or only on a real hot day would he be found in a pair of shorts. He enjoyed playing softball and was on a couple of teams through the summer.

March 2008, Kurt's 92 year old grandmother was extremely ill in the hospital and in his haste to come to see her he slipped and fell in the shower which was in a tub. He hit on the edge of the tub with the left side armpit area. A month later he said it was still sore and he had a slight lump there. Kurt was a 6' 3", 210 lb. man. It was a hard fall and we assumed it was deeply bruised. The first week of May he went to a general doctor and she felt everything was fine on her examination. She thought that a lymph node may have been filled with fluid and to prevent an infection she wanted him to see a surgeon because they could possibly drain it. He saw the surgeon about 10 days later. They agreed with the first doctor. As they were checking things he noticed a mole on the right side of Kurt's back which had been there for at least 10 years or better and Kurt had not noticed any change in it. They did a punch biopsy. The Friday of Memorial Day weekend they called on the phone and told him it was Melanoma but not to worry because they got the whole spot out and they were sure it wasn't going to be a problem. They made an appointment for two weeks so they could check the lymph nodes and see what was happening. When that appointment came the swelling was worse. They decided to do a biopsy and it came back Melanoma. They then did a CT Neck, Chest, & Abd. Then they also did a PET Scan. The scans showed significant left supraclavicular and left axillary lymphadenopathy. A needle biopsy of a node showed metastatic melanoma. The Oncologist that he saw a Park Nicollett in Minneapolis said it was Stage 3 and the best treatment would be Interferon but it would be extremely harsh on the body.

Our daughter works at Mayo Clinic in Rochester. Kurt had also worked there one summer and one of the doctors that they both were associated with was very concerned and he talked with Dr. Markovic who was a personal friend of his. It was arranged for Kurt to see Dr. Markovic. Kurt also met with an ENT specialist. ENT said that the mass was too large and going under the clavicle so surgery was out of the question at that time because it was such a vascular area that was involved. At the appointment with Dr. Markovic he suggested the best thing was a trial using Avastin. Kurt opted for the trial. We had received material prior to Kurt's appointment from Dr. Markovic on melanoma and treatments and outcomes. I asked Dr. Markovic what stage he thought it was and what type. He said it didn't really matter because it was serious. Come to find out later, they immediately classified as stage 4. At this time, I still never found out what type. My concern was for the 8 other children in the family in case it was familial or genetic in nature.

Kurt immediately started chemotherapy the next day. They called it the BEAM Study. It was one day a week, every three weeks by IV. He would receive Taxol, Carboplatin, and either Avastin or a placebo. They did three treatments and then did another CT Chest, Abdomen, & Pelvis. The results showed that the disease was continuing to progress. They then suggested protocol N0675 which was a combination of Temozolomide and RAD001, and the Taxol and the Carboplatin in pill form. (He was not getting the Avastin on the BEAM Study.) This would continue for 7 weeks. At the end of the 7 weeks they did a CT again and found the disease still progressing and now it appeared the lung was involved. They then decided to go back to the first treatment but not in the study so they could be sure he was getting the Avastin. They also decided to do it once every week.

Kurt tolerated all of the treatments fairly well with minimal side effects. His arm was starting to really swell from the edema due to the lymphadenopathy though and that caused considerable pain. They could not get the pain down below a 7 on a 0-10 scale.

Right before Christmas they repeated the CT. Some of the lymphadenopathy had gone down but it appeared to have spread to the spine and the liver. They could not do a treatment that week because his platelets were too low. They would proceed with treatments the following week.

Kurt had shown them a spot down in the rectal area in November and they said it was a boil and would get better on its own. He showed them again in December and they weren't really concerned. In January it was draining and smelling. Around January 15 while he was having his chemo, Dr. Markovic came in and looked at it and decided to hospitalize him and have it lanced. Instead the surgeons took him to surgery and excised and biopsied it and it was melanoma. The surgeons got Kurt's hopes up because they thought they could go in and do surgery and reduce the mass in his chest and arm area. Upon examination they said there was no way. It was way to extensive. He could not continue with chemo until the surgery had totally healed. His hemoglobin was also very low so they had to transfuse 2 units of blood. When he went in to see the Doctor in February they still could not do chemo. By this time he was having tremendous problems with his arm and he was getting very unsteady. He was hospitalized again the middle of February due to the pain. They decided to try radiation and Kurt thought it was to reduce the mass so they then could do surgery. It was just to control the pain. They never did.

Kurt was hospitalized again in March due to a severe rash. They figure it was just the cancer manifesting itself. They then at that point informed him and our family that to continue with any treatment would be more harmful than it would help. They wanted him to agree to no resuscitation but he wouldn't. He still felt he was going to beat the beast. I was finally able to convince him that it was for the best. He was transferred to a nearby healt care facility on March 18. He was getting 60 mg of Methadone and 45 mg of gabapentin three times a day. He was getting 100 mg of morphine every hour and sometimes if they were doing some type of care it was given every 20 minutes. All of this never really did cut the pain below a 7. He was also given drugs to try and calm him down so that maybe he would accept that he was dying. He lasted abou 2 1/2 weeks in the health care center.

I feel that the doctors could have been a little more informative to him and our family. I am not saying they lied but if we didn't ask the question they weren't about to offer the idea or answer. Going through something like this you don't know what all you are suppose to be thinking about or asking. At the time they said they had done everything they could they said it was a very aggressive and fast moving melanoma but never have told us what type. Never have said that maybe the family should all be checked or be watchful or anything.

I believe that no matter what the outcome was going to be the same. I have no bitterness and I am thankful Kurt was able to have the expertise and care available to him that he did. He fought very hard. It was just not meant to be. He is now out of that pain and despair and for that I thank God daily.

Thanks for listening to Kurt's story. He had a tremendous birthday the other day, I am sure of it. I passed along your wishes."


Rhonda Graner

My heart goes out to the Graner Family.

Being on the frontline of this war, I sometimes become numb on what is going on around me and what we are fighting for. This story helps me focus on the task at hand. We need to find a therapy that at the very least, stops the progression of this terible disease. We all need to work together to find a cure.

Take care

Jimmy B