Thursday, November 22, 2007

On this day we Give Thanks for what we have.

1) A Caring Family
2) Wonderful Friends
3) Memories that will last a life time.
4) A God that has given me more time to say Thanks.

Happy Thanks Giving

You Have given me strength in times of need.

Love, Jimmy B. and Family

Sunday, November 18, 2007

11/18/2007 Going to see Dr. Brown the Dermatologist

I have an appointment with Dr. Brown to check a spot on my right ankle. It has been there for qiute along time. I thought it was a scrape but it is now raised a little. I think it could be Basal carcinoma. So I am having it checked out on Tuesday the 20th of November at Strong "Wilmot Cancer Center". Hey you never know. Better safe than sorry.


Jimmy B.


P.S. Thanks Steve B. for the wonderful pics of the fishing trip this summer.

Thursday, November 15, 2007

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 5 of 5)

Anti-41-BB (CD137) agonistic antibody. Anti-41-BB (CD137) agonistic antibody has just entered clinical testing. Although no clinical data are available yet, there are strong preclinical justifications for its use in patients with melanoma.[34] This antibody is capable of augmenting antigen-specific T-cell responses, and its use with a peptide vaccine resulted in regression of established poorly immunogenic tumors in mice.[35] Of note, the combination of anti-CD137 and CTLA-4 appeared to decrease autoimmune side effects yet increase antitumor effects compared with either antibody alone.The recent explosion of knowledge on immune regulatory pathways and receptor-ligand pairs on T cells has facilitated several innovative phase 1/2 trials and the development of 2 antibodies in no less than 5 registration trials. Patients with metastatic melanoma have never before had access to as wide a variety of promising agents.
As you can see, they are making great in roads in finding a cure or just stabilizing the progression of the disease.

Jimmy B.

Wednesday, November 14, 2007

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 4 of 5)

New Immunomodulatory Agents in Development

Four types of new immunomodulatory agents are in development for use in patients with malignant melanoma, including STA-4783, a heat shock protein inducer; PD-1 antagonistic antibody; anti-41-BB (CD137) antagonistic antibody; and CD40 agonistic antibody.

Heat shock protein inducer.

STA-4783 is a novel agent that promotes natural killer cell activity and augments levels of heat shock protein 70.[28] It is active as a single agent and with a taxane in human xenografts in mice. In phase 1 studies, STA-4783 appeared to have little clinical activity in kidney cancer or melanoma. In a randomized phase 2 study[29] that included 84 patients, STA-4783 plus paclitaxel were administered weekly intravenously for 3 weeks on/1 week off until progression or dose-limiting toxicity. The primary study end point was PFS. An intent-to-treat analysis found that PFS was 112 days for the combination of STA-4783 plus paclitaxel vs 56 days for paclitaxel alone (P = .035). The RR was 15.1% in the combination group vs 3.6% for the paclitaxel group. Patients in the combination group had a 54% grade 3/4 adverse event rate, compared with 57% for the paclitaxel-alone group. STA-4783 is being studied further in a phase 3 randomized registration trial.

PD-1 antagonistic antibody.

PD-1, a member of the TNF super-family, is another inhibitory molecule present on T cells.[30] PD-1 is increased on activated T cells and can bind to the PDL-1 molecule present on macrophages and dendritic cells as well as many tumors. The PD-1/PDL-1 interaction appears to limit the immune response, acts as a down-modulatory influence on antigen-specific immunity, and may represent a means by which tumors actively suppress immunity.A human immunoglobulin G4 antibody has been prepared that binds to and abrogates the activity of PD-1. In vitro, it can significantly augment the proliferation and functional activity of activated T cells; it is active alone, with chemotherapy, or with CTLA-4 abrogating antibodies in different murine tumor models.[31] This antibody has been tested in a phase 1 trial and thus far has not resulted in any dose-limiting toxicities after single dosing.

CD40 agonistic antibody.

CD40 is a receptor expressed on a variety of immune cells, including B cells and antigen-presenting dendritic cells.[32] It is bound by CD40 ligand expressed on T cells and represents an important axis of stimulation for antigen-specific T cells. An agonistic CD40 antibody, CP-870893, has been tested in a phase 1 single-dosing study, predominantly in patients with melanoma, at doses ranging from 0.03 to 0.3 mg/kg.[33] The reported side effects consist of chills and fevers, with deep venous thrombus and headache being the dose-limiting toxicities. Among 29 patients in the trial, 4 of 15 (27%) with melanoma sustained a PR at day 43 after only 1 dose of CP-870893. All responders received the drug at a dose level of 0.2 mg/kg or above, suggesting a dose-response relationship. Multidose phase 2 trials are pending for this promising agent.

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 3 of 5)

Abrogation of CTLA-4 in patients produces side effects known as "immune-related adverse events" (IRAEs). IRAEs are auto-inflammatory and may represent a breaking of tolerance to self-antigens.[16,17] The most common IRAEs are rash, colitis, and hepatitis. Other types of inflammation -- hypophysitis, pancreatitis, and sarcoid -- are more rare. IRAEs appear to be associated with tumor regression in patients with renal cell cancer and metastatic melanoma,[12,17-19] and a similar phenomenon may be observed in patients with prostate cancer.[14] There also appears to be a correlation between IRAEs and prolonged time to relapse in patients with resected high-risk melanoma.[12,17-19] The kinetic onset of IRAEs is highly variable and is likely dependent both on peak dosing and area under the curve of the drug. Similarly, the timing of the onset of antitumor responses can be variable and may be prolonged for weeks after cessation of ipilimumab[20]
(J Weber, unpublished data, 2007).

If these immunomodulators and others like them -- CD40 agonistic antibody, anti-41-BB antibody, and programmed death (PD)-1 antibody, which are entering early-phase clinical testing -- are approved for cancer treatment, then understanding the kinetics of antitumor responses, their relationship to IRAEs, and how to manage and minimize IRAEs will take on great importance.

Ongoing and Completed Trials With Ipilimumab and Tremelimumab

Ipilimumab has been used as a monotherapy or in combination with other therapies including chemotherapy, vaccines, and cytokines. In an initial phase 1 trial,[21] 17 patients with malignant melanoma received a single intravenous dose of ipilimumab 3 mg/kg. The drug was well tolerated, and there was evidence of immunologic and antitumor activity. In another phase 1 trial, Hodi and colleagues[13] reported that a single dose of ipilimumab 3 mg/kg may have increased antitumor immunity and induced necrosis in biopsied tumors in patients with metastatic melanoma who were previously vaccinated. No serious adverse events were noted in the 7 patients who received ipilimumab in that trial.
Because of the known mechanism of action of ipilimumab and experience in murine models, an important goal has been its evaluation in combination with antitumor vaccination. Attia and colleagues[12] reported that ipilimumab (3 mg/kg every 3 weeks or a 3-mg/kg initial dose followed by 1 mg/kg every 3 weeks) plus a peptide vaccine resulted in 2 complete responses (CRs) and 5 partial responses (PRs) among 56 patients with previously treated and progressive stage IV melanoma. The CRs were ongoing at 30 and 31 months, and 3 of the PRs continued at 25, 26, and 34 months. The remaining 2 PRs lasted for 4 and 6 months.

A trial is ongoing with ipilimumab plus a multipeptide vaccine in the adjuvant setting,[20] which includes patients with resected stage IIIC/IV melanoma and no evidence of disease. After a median follow-up of 12 months, 6 of 25 (24%) treated patients had relapsed. Patients who relapsed were managed either surgically or with biochemotherapy, and all were alive at the time of the report. Subsequently, 4 patients have died at a median follow-up of more than 2 years, but 19 are still free of disease. Time to progression is associated with development of IRAEs (J Weber et al, unpublished data, 2007).

Ipilimumab has also been administered in combination with cytokines. Maker and colleagues[22] reported data from a trial of ipilimumab 0.1-3 mg/kg every 3 weeks with IL-2 in 36 patients with advanced melanoma. Three patients (8%) sustained a CR and 5 (14%) had PRs, yielding an overall objective RR of 22%. Responses occurred in 1 of each of 3 patients treated with ipilimumab at 0.3, 1, and 2 mg/kg, and in 5 of 24 patients treated at 3 mg/kg. Six of the 8 responders had ongoing responses at follow-up periods of between 11 and 19 months.

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 2 of 5)

A method to my Madness

As you can see from above I tried Interferon, dacarbazine (DTIC), Then a novel new agent called CTLA-4, and then onto IL-2 (Interlukin-2).

The use of a combination of IL-2, other immunotherapy agents, and chemotherapy, known as biochemotherapy, has been shown to result in high response rates (RRs) in patients with stage IV melanoma, but long-term survival without recurrence occurs in less than 10% of patients.[7] Biochemotherapy has not been shown to prolong survival beyond that seen with chemotherapy alone, which has averaged only 7 to 8 months. Therefore, a reasonable consensus is that patients with unresectable stages III and IV melanoma should be referred to a clinical trial as the first treatment for metastatic disease. More than ever before, those patients have access to a broad variety of agents --both targeted biologic drugs and immunotherapy compounds -- that have shown promise in treating unresectable disease.
The landscape for the development of new drugs for the treatment of patients with metastatic and resected high-risk melanoma is more promising than at any time in recent memory. The understanding of signaling pathways at the biochemical and molecular level and the identification of new immunoregulatory receptor-ligand pairs associated with outcome in patients with metastatic melanoma are paving the way for new drug development. A number of novel targeted and biologic agents (see below) are showing promise. A new biologic agent, as well as 2 new immunotherapeutic drugs now in registration trials, have the potential to be the first agents approved by the FDA for use in patients with stage IV melanoma in over a decade.
Potential New Agents for the Treatment of Melanoma
Human Antibodies Directed Against Immune Regulatory Molecules
Human antibodies directed against immune regulatory molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) induce tumor regression and improve long-term survival in tumor-bearing mice. Early clinical studies in patients with melanoma have shown that disease stabilization and prolonged survival can be achieved by manipulation of the immune system.[8,9] CTLA-4 antibodies are currently being tested in phase 2/3 trials in melanoma and phase 1/2 trials in other tumor types. Currently, 2 human antibodies are in clinical testing: ipilimumab (MDX-010) and tremelimumab (CP-675206). Although the 2 agents have similar pharmacokinetic properties, tremelimumab has a 3-week half-life, which is slightly longer than that of ipilimumab.
As you can see, Dr. Kirkwood and I wanted to induce tumor regression by using my own immune system. If we could get my immune system to recognize the tumors as foreign, then we might have a fighting chance. So we decide to try the CTLA-4 Therapy,
Antitumor response with prolonged time to progression has been seen in patients with melanoma who have received either of the CTLA-4 antibodies,[10,11] and durable antitumor responses have been observed with ipilimumab in patients with melanoma,[12] ovarian cancer,[13] prostate cancer,[14] and renal cell carcinoma.[15] Of note, antitumor responses may be characterized by short-term progression followed by delayed regression.
An important, possibly unique, clinical characteristic of anti-CTLA-4 antibodies is that the duration of clinical response -- and even stable disease -- is often quite prolonged.

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 1 of 5)

A method to my Madness


* When I first started out trying to figure out what therapies I should try, Dee and I worked with Dr Kirkwood and developed a plan of attack (a flow diagram). We put together if and than statements to create a path forward. Coming from a research environment, this made the most practical sense.
So here is my path.

* Most of information was taken from an article written by Adil I. Daud, MDJeffrey S. Weber, MD, PhD entitled:

* “Novel Treatment Approaches For Patients With Metastatic Melanoma”

* Release Date: August 30, 2007


Introduction


According to the American Academy of Dermatology, an estimated 108,230 new cases of melanoma will be diagnosed in the United States in 2007, including 48,290 in situ and 59,940 invasive cases.[1] Invasive melanoma is the fifth most common cancer in men and women. About 8000 deaths from melanoma are expected in 2007 in the United States.[1]


Melanoma is a cancer of the melanocyte, a long-lived pigment-producing cell normally found at the dermo-epidermal junction within the skin. During the process of transformation of melanocytes to melanoma, histologic and clinical changes occur.[2] The initial stage of transformation can result in an atypical or dysplastic nevus. The next stage is the so-called epidermal radial growth phase (RGP) melanoma, which involves proliferation of the transformed melanocytes in the epidermis. This is followed by an invasive RGP melanoma wherein the tumor cells invade the dermis. In the next phase, the vertical growth phase, melanocytes proliferate in the dermis and are competent for metastatic invasion. Finally, the metastatic phase is characterized by invasion of lymph nodes and distant organs.


Based on a rigorous statistical analysis of a large sample of patients with melanoma, the American Joint Committee on Cancer proposed revised staging guidelines in 2002. These guidelines are useful for clinical management of patients and for analyzing clinical trial data discussed in this review.[3,4]

Stages I and II are melanomas that are localized to the skin, at varying depths of invasion:

stage III includes patients with regional recurrence and nodal spread of disease, and stage IV patients have distant metastatic spread of melanoma.


Currently, 3 drugs are approved for the treatment of metastatic melanoma:

dacarbazine (DTIC), hydroxyurea, and interleukin-2 (IL-2).

None has ever been tested in a randomized phase 3 trial against a control and been shown to prolong survival. DTIC and hydroxyurea were approved by the US Food and Drug Administration (FDA) more than 20 years ago and would be unlikely to meet current standards for FDA approval. The only approved immunotherapy for melanoma, IL-2,[5] is a toxic agent employed in a complex regimen used by a restricted number of centers in the United States today. Practice guidelines promulgated by organizations such as the National Comprehensive Cancer Network (NCCN) indicate that entry into a clinical trial is an acceptable standard of care for patients with newly diagnosed stage IV melanoma.[6] In fact, the NCCN decision tree for patients with stage IV melanoma with multiple metastases indicates that a clinical trial is the first choice, followed by DTIC or IL-2; lower priority choices include DTIC with other agents in combination. For patients with a small volume of disease, a watch-and-wait plan is considered acceptable, an admission that the armamentarium of drugs for metastatic melanoma is deficient.

Tuesday, November 13, 2007

11/13/2007 Meeting with Dr. Kirkwood

Sorry it has taken so long for me to write. I've been catching up on bills and Health Insurance elections, and Voice your choice on Electricity elections.



If you Rochesterians need to compare suppliers for the cheapest KWHour for your electric needs, you can logon at



www.energyguide.com/finder/ShowOffersUni.asp?NexusRCTarget=res&txtCustomerType=1&CalcType=NoBill&txtenergytype=1&txtWinterBill=&txtSummerBill=&util=116183NY&sort=rate#CompareYourBills.


I am currently in a holding pattern to see if my immune system will continue to fight off the cancer by itself.



The tumors in my lungs have shrunk to the point that they are undetectable by CT scan. (Praise the Lord).



I still have some at my original site but I am hoping that they too will disappear.
I do have new spot on my ankle that looks like basal carcinoma. I am planning to have it looked at by Dr. Brown dermatologist/oncologist at Strong Hospital. I need to make sure I have a referral first so I don’t get stuck with the bill.


I would like to take this time again to thank everyone for their continuing support. Without you, I could not have survived. You have been the rocks of my seawall. Without you, I would have been swept away into the storm. Thanks for being there for me.
Jimmy B.

Monday, November 12, 2007

11/13/2007 Meeting with Dr. Kirkwood

Sorry it has taken so long for me to write. I've been catching up on bills and Health Insurance elections, and Voice your choice on Electricity elections.

If you Rochesterians need to compare suppliers for the cheapest KWHour for your electric needs, you can logon at

www.energyguide.com/finder/ShowOffersUni.asp?NexusRCTarget=res&txtCustomerType=1&CalcType=NoBill&txtenergytype=1&txtWinterBill=&txtSummerBill=&util=116183NY&sort=rate#CompareYourBills.

I am currently in a holding pattern to see if my immune system will continue to fight off the cancer by itself.

The tumors in my lungs have shrunk to the point that they are undetectable by CT scan. (Praise the Lord).

I still have some at my original site but I am hoping that they too will disappear.
I do have new spot on my ankle that looks like basal carcinoma. I am planning to have it looked at by Dr. Brown dermatologist/oncologist at Strong Hospital. I need to make sure I have a referral first so I don’t get stuck with the bill.

I would like to take this time again to thank everyone for their continuing support. Without you, I could not have survived. You have been the rocks of my seawall. Without you, I would have been swept away into the storm.

Thanks for being there for me.

Jimmy B.

Sunday, November 4, 2007

11/04/2007 We are off to Pittsburgh to see Dr. Kirkwood

Dee and I are on our way to the Hillman Cancer Center to see Dr. Kirkwood. We need to find out what the next step in the treatment. We will fill you in when we get the details.

Take care

Jimmy B.