Tuesday, January 31, 2012

New Perspectives On Cancer And The Immune System..Melanoma. Jim Breitfeller

BY AMEILIA, ON MARCH 27TH, 2011

In a new review article published in yesterday’s special section of Science focusing on the past forty years since the U.S. declared “War on Cancer,” three Cancer Research Institute scientists describe how advances in the field of tumor immunology have revealed a complex and paradoxical relationship between cancer and the immune system, and discuss how a growing understanding of this relationship is providing a scientific foundation for new therapies capable of unleashing the immune system’s protective powers against cancer.
Several recent breakthroughs in cancer treatment are based in immunological principles described in the review. These include Provenge® (sipuleucel-T), a dendritic cell vaccine that received FDA approval in April 2009 for the treatment of advanced, hormone-refractory prostate cancer, the successful monoclonal antibodies Herceptin® and Rituxan® approved in the 1990s for the treatment of breast cancer and non-Hodgkin’s lymphoma, emerging therapeutic cancer vaccines, and new treatment strategies that combine standard chemotherapy and radiation therapy with investigational cancer immunotherapies. The review places these treatment advances within a scientific context spanning a century of laboratory and clinical effort aimed at learning how to direct the power of the immune system to fight cancer.
Authors Robert D. Schreiber, Ph.D., at the Washington University School of Medicine in St. Louis, MO; Lloyd J. Old, M.D., at the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, NY; and Mark J. Smyth, Ph.D., at the Peter MacCallum Cancer Centre and University of Melbourne in Melbourne, Australia, describe in their review how fundamental discoveries made over the past forty years reveal that the immune system plays a dual role in protecting against cancer and in promoting cancer growth. Taken together, these insights support a unifying conceptual framework they call “cancer immunoediting.”





“The cancer immunoediting paradigm succeeds in answering a number of questions that have eluded tumor immunologists for decades, such as why tumors can sometimes lie dormant in patients for years before re-emerging, and why tumors grow despite evidence that they provoke an immune response,” says Schreiber. “It also provides a platform for improving current cancer treatments and developing new therapeutic strategies that aim to interfere with or reverse phases of the immunoediting process that contribute to tumor growth.”
During cancer immunoediting, the immune system is able to recognize and attack the most immunologically vulnerable cancer cells, i.e. those cancer cells that clearly appear dangerous to the immune system because they display molecular markers, called antigens, that identify them as damaged, secrete chemicals associated with dysfunctional cellular activity, or otherwise behave in ways the immune system recognizes to be dangerous. Schreiber, Old, and colleagues have called this first phase of cancer immunoediting the “elimination” phase.



“It has long been thought that elimination is occurring all the time in healthy hosts,” says Schreiber, “where the immune system is able to destroy nascent cancerous cells before they can develop into tumors.” This process has not yet been observed directly in living animals or humans, but has been inferred by the presence of tumor-specific immune cells and antibodies found in cancer patients.



In the second phase of cancer immunoediting, called “equilibrium,” surviving cancer cells continue to divide rapidly, accumulating mutational changes by chance or in response to immunological pressures that enable tumors to impair the immune system’s ability to eliminate them. Rather, a balance between immune control and tumor growth is maintained, giving the appearance of tumor dormancy.



Over time, however, cancer cells can continue to undergo sculpting by the immune system and eventually enter into the third and final phase, “escape.” During the escape phase, tumor cells that have acquired the ability to circumvent immune recognition and/or destruction emerge as progressively growing, visible tumors. The switch from equilibrium to escape can be caused either by changes in the tumor cells in response to the immune system’s editing functions, or because the immune system changes in response to increased cancer-induced immunosuppression or immune system deterioration.



The ability of cancers to evade immune attack has recently been accepted as one of the key defining characteristics, or hallmarks, of cancer, as described in a recent paper from Hanahan and Weinberg published earlier this month in Cell. How cancer evades the immune system is still a topic of intense research, as Schreiber, Old, and Smyth describe in their review.
“Some cancer cells stop signaling danger to the immune system through loss of the ability to process and present surface markers that help identify them to the immune system,” says Old. Without signals that differentiate them from normal cells, these cancer cells become “invisible” to the immune system.



Another channel for tumor escape is opened when cancer cells establish an immunosuppressive state within the tumor microenvironment. According to Old, tumor cells initiate a process involving a complex network of regulatory cells and molecules that can effectively shut down immune recognition and control of the tumor. This process normally functions to prevent the dangers of autoimmunity, a state where the immune system attacks and destroys normal cells of the body.



A key immune cell involved in inhibiting immune responses in both tumor immunity and autoimmunity is the regulatory T cell. Studies of tumors infiltrated with immune cells have demonstrated a clear relationship between the ratio of regulatory cells to effector, or cell-killing, immune cells and overall patient prognosis, with those having fewer regulatory cells faring better than patients whose tumors are more immunosuppressive.



According to the paper’s authors, to be effective, cancer immunotherapies will have to increase the quality or quantity of immune cells capable of eliminating cancer cells, reveal additional protective tumor antigens, and/or eliminate cancer-induced immunosuppression. Multiple forms of immunotherapy are being explored to achieve these objectives, including therapeutic cancer vaccines, adoptive transfer of tumor-specific immune cells, monoclonal antibodies that target cancer cells for elimination, and approaches that inhibit or destroy molecular or cellular mediators of cancer-induced immunosuppression.



“Indeed, the interface between conventional approaches such as surgery, radiotherapy, standard, and new small molecule targeted chemotherapies (e.g. Gleevec®, kinase and B-raf inhibitors) and all of these new immunotherapeutic approaches is extremely exciting,” Smyth says. “It will prove a special challenge for institutions, pharmaceutical companies, and regulatory authorities alike to rationally deliver these combinations to cancer patients in a timely way.”
“After a long and controversial history, immunological approaches to the control and treatment of cancer are now established on a firm experimental foundation,” says Old. “Advances in the field of cancer immunology, from the definition of cancer antigens to the understanding and control of cancer related immunosuppression, are pointing the way to a new era in cancer therapy based on the specificity and power of the immune system.”



The authors point to future work in cancer immunoediting that will address questions like: which components of the immune system play a role in each of the three phases of cancer immunoediting and how, what are the specific differences between tumor antigens on immunoedited cells compared to unedited tumors, is it possible to predict how a tumor will be immunoedited based on the types of antigens that are expressed, is a durable state of immune equilibrium a desirable and attainable endpoint for cancer immunotherapy, and how can we most effectively inhibit cancer-induced immunosuppression at the tumor site without inducing autoimmunity?



Finding answers to each of these important questions will provide tumor immunologists with further insights needed to optimize immunotherapies for use in treating cancer patients.
In 2007, the Schreiber, Old, and Smyth jointly received the Charles Rodolphe Brupbacher Prize for Cancer Research for their joint and complementary contributions to the field of cancer immunology and, particularly, to a better understanding of the concepts of cancer immunosurveillance and immunoediting. The three scientists also received the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic and Tumor Immunology: Old (1975), Schreiber (2001), and Smyth Smyth (2002).

Source: Cancer Research Institute


“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

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Monday, January 30, 2012

Using Immunohistologic Characteristics of Tumor Infiltrating Immune Cells to the advantage of Melanoma Patients.Jim Breitfeller

In the research paper “Immunotype and Immunohistologic Characteristics of Tumor Infiltrating Immune Cells are Associated with Clinical Outcome in Metastatic Melanoma”1 et al Slingluff 2012, it breaks down the Immunohistologic Characteristics into three distinct immunotypes:

A) No infiltration of immune cells in the tumor’s microenvironment.
B) Infiltrating Immune cells only in close proximity to the tumor’s vascular system
C) Diffuse immune cell infiltrates throughout a metastatic tumor and its microenvironment.





Overall, the most predominant immune cells were T cells (53%), followed by the B cell lineage cells (33%), and then by macrophages (13%), with NK and mature dendritic cells only hardly present.

With the setting of the tumor’s microenvironment evaluated, we will focus the low survival immunotype A patients. How can we improve the overall survival and the immune response to Melanoma?

Here are just some of the therapies we have to date:

Dacarbazine (FDA approved)
High Dose Interluekin-2 (FDA approved)
Yervoy (Anti-CTLA-4) (FDA approved)
Zelboraf (Braf inhibitor) (FDA approved)

These therapies work well in a subset of melanoma patients but the overall survival rates are still quite low. We need to somehow combine these immunotherapies with a cancer vaccine to invoke an immune response with memories T-cells so we can eliminate any reoccurrence.
Oncologists have been working on this for decades.

I believe they may have discovered the right combination to just that. Dr. Kingston Mills and colleagues from the Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Immunotherapy with PI3K Inhibitor and Toll-Like Receptor
Agonist Induces IFN-g þIL-17þ Polyfunctional T Cells That
Mediate Rejection of Murine Tumors

Neil A. Marshall1, Karen C. Galvin1, Anna-Maria B. Corcoran1, Louis Boon3,
Rowan Higgs2, and Kingston H.G. Mills1,2

Authors' Affiliations: 1Immune Regulation Research Group, School of
Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity
College Dublin, Dublin, Ireland; 2Immunology Research Centre, Trinity
Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and
3Bioceros, Utrecht, The Netherlands


Dr. Mills and colleagues discovered that if you combine a PI3k inhibitor with TRL agonists (TRL-9 and or 5) with DC vaccine/tumor antigen, you invoke a tremendous immune response along with memory cells.





This combination actually tilts the T-cell differentiation towards the Th1 phenotype that is needed to activate the CD8+ T-cells. I believe this is a major breakthrough toward curing/stabilizing the Melanoma Cancer.

The immune activation by CpG ODN +(PI3k inhibitor) initiates with specific binding to the TLR-9 receptor in B cells and plasmacytoid DCs. TLR-9 ligation in DCs results in secondary activation of lymphocytes, macrophage, monocyte, NK-cell, and T-cell populations through the elaboration of cytokines generating a Th1 cytokine milieu. This results in increased NK activity as well as improved antigen presentation and T cell help that can augment
humoral and cell-mediated immune responses. In addition, TLR ligation results in the production of IL-6 by DCs, which helps overcome the suppressive effect of CD4 CD25 Treg cells.

We must break the tolerance to generate immune responses against the tumor antigens.

This combination developes a population of polyfunctional T-cells that produce interferon-gamma and IL-17, both potent mediators of the immune response. Moreover, the combination has a lasting effect. This combination also produces the “Danger Signal” that is needed to recruit the immune cells to the tumor’s microenvironment.






A fledgling startup company (Trimod Therapeutics) holds the patent to this technology.

Dr. Jeremy Skillington
http://www.trimodtherapeutics.com/

As stated in my previous post, we need a cancer vaccine with Anti-CTLA-4 and IL-2 to produce a lasting immune response. I believe this company holds the future of immunotherapy cure/stabilization for Melanoma and maybe more cancers. Only time will tell with the right Clinical protcol in place. This is years away, but holds a temendous promise due to the science behind it. We need to expidite this rationale for the good of the Cancer patients.





“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

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Sunday, January 29, 2012

CTLA-4 Blockade with Ipilimumab: Long-Term Follow-up of 177 Patients with Metastatic Melanoma ..Jim Breitfeller

Peter A Prieto, James C. Yang, Richard M. Sherry, Marybeth S. Hughes, Udai S. Kammula, Donald E White, Catherine L Levy, Steven A. Rosenberg, and Giao Q Phan
Clin Cancer Res clincanres.1823.2011;

Published Online First January 23, 2012

Abstract

Purpose: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. Patients and Methods: Patients with metastatic melanoma were treated in three trials from 2002 to 2005: In Protocol 1, fifty-six patients received ipilimumab with gp100 peptides. In Protocol 2, thirty-six patients received ipilimumab with interleukin-2. In Protocol 3, eighty-five patients received ipilimumab with intra-patient dose escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. Results: With median follow-up for Protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with five-year survival being 13%, 25%, and 23%, respectively. Patients in Protocol 2 had a 17% complete response (CR) rate, compared to 7% in Protocol 1 and 6% in Protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became CRs had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. Conclusions: This report provides the longest follow-up of melanoma patients treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma.

The combination of ipilimumab and IL-2 appears to have an increased (CR)Complete Response rate, but this needs to be tested in a randomized trial.

If you have been following me on Carepage and or Melanoma Missionary, we knew about this combination back in 2009. I have been pushing for this trial. I even wrote and posted an email to Dr. Steven A. Rosenberg on 3/29/2009 at NCI.

"To summarize, Timing and Doses of both Anti-CTLA-4 and IL-2 can have a major effect on the immune response outcome. If you follow the dosing and timing regime, I postulate that you will see a synergist outcome with this combination therapy."

Jimmy B ..3/29/2009


I have learned a lot through my researched and still believe that my systematic combination theory of Anti-CTLA-4 and IL-2 still holds water. In fact as we speak, I am reseaching the tumor's microenviroment to see how we can improve on this response rate. How the tumor operates in the neighborhood of cells. How it changes the neighborhood with Cytokines, Tregs and cell to cell contact. It is simular to having one bad apple in the basket and how it causes other bad apples.

And By adding Cancer Vaccines to this combination, I believe we can CURE Melanoma.

Best Regards,

Jimmy B


“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

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Wednesday, January 11, 2012

Cancer immunotherapy comes of Age,,Melanoma..Jim Breitfeller

Author:Ira Mellman1, George Coukos2 & Glenn Dranoff3

Nature:4 8 0 | NATURE | VOL 480 | 22/29 DECEMBER 2011

"Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest durable and long-lasting response in cancer patients."

We as patients of the Clinical trials are right in the middle of this awakening!!!!

Here is the article:

Cancer immunotherapy comes of age



“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

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.



Kenny B




Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller


My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08

Disclaimer

The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment
(not a PASSIVE RECIPIENT)"

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.


It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.

Preview:

So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.


The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,



On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

https://app.box.com/shared/kjgr6dkztj

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information


Dr. Rosenberg's Clinical Trials


For the Warriors




The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.


http://www.melanomaresearchalliance.org/news/PSA/

Source Fastcures blog



Join the Relay for Life!!!

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Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!

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Sincerely,

Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by "About.com : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma



Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma


Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.


Current Trial Centers


Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies



James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)
PingpankJF@UPMC.edu


Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials



(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.