~Too Many Brain Mets To Count~Mighty Oak's Saga Continues...
 

I was getting upset that we did not receive a return call from GammaMan's office with the results....now I know why.

He had to collect his bearings before telling me that Ed had "Numerous brain mets, too many to count or to have the Gamma Knife as an option..."

Why did this news take me for a loop? I am blown away into the darkness again and cannot digest this all right now. I am breathing but I am numb. The GammaMan already contacted the OncoMan. I asked about Whole Brain Radiation being done again. He has heard of instances but will be talking with Ed's Radiation team to consult this possibility.

In the meantime I have contacted my Nurse Advocate and asked for a phone call tonight from OncoMan. He will probally call about 8 or 9 p.m. and we will go over this situation as a whole. I want to go over my 'Last Options' folder with him and discuss where do we go from here.

Monday holds a day for calling Dana Farber and exploring in depth the other hospitals. Any suggestions or guidance you can give us right now will help. I feel lost and tired and downright numb. I know what this may all be but I refuse to give up. I do believe in miracles but I feel we have been granted so many thus far and am losing faith that there will be any more.

This news is fresh so I write in the state of mind I am in. I remind you that I am breathing and may have to take something so I can relax. My thoughts are racing through my mind and I cannot stop them. Of course I know you will pray for us and I thank you for loving us. I feel that in the entire journey I need you all the most right now and I am so blessed that you will walk besides us through this.

I am scared to death this time. You know I sit here and I give and get support.....I constantly research....I educate myself in how a gene works......but I do not know how to do the rest. I do not know how to do this, no one can prepare you for that.

Oh yeah, and this is for you cancer one more time; you are not getting it! It is The Mighty Oak and you now, head to head! Do not think he will not grab you by the throat and stare you in the eyes. He will not go down without a hell of a fight and will spend his last breathe telling you goodbye. We thought you would have gotten that by now so I guess you are not as smart as I thought. He is prepared to fight for every moment and no matter what the outcome, he will always come out the Winner!

I am lighting a candle for my boy who in his calm and journeyed voice tells me "one moment at a time, Marie." He has listened to the options I can supply right now and knows of the calls completed. I love this brave man who still continues to smile and not complain. God, how did I get so lucky?>>Marie

PS: The most ironic thing of it all is that.......I did not even think this would happen to him....Duhhh! Where was I living???

Marie, words escape me. Like the mighty Oak says, take one moment at a time. You guys can prevail once again. Our prayers are with you. You hang in there. Love, Bill

marie, i am so sorry to hear this. i will send lots of prayers and hugs your way over the next few days.

Marie, we live from truth to fantasy and back to truth again as the circumstances demand. You must sometimes live in the make believe to be able to handle the horrible ups and downs that make this disease so mean!
You have done this journey just as you should....forward, stop, back, but always forward once more. I believe it's who you are and how you live.
Why not just be right now. You'll make decisions soon. Just be and let all the love and admiration we feel for you wash over you. I can only send much love and many, many prayers for you both.
Luv and faith, sweet friend,
ma

Dear Marie,

Rats! S.P.F.!!!! Ofcourse you are scared and confused and oh, I don't know what you feel! It's a big blow. Somehow the two of you will face this. And you will find a way through this. Give yourself a break. You need to absorb this before moving on and dealing with this. I'm holding both of you in my heart.

Jacqueline

Sending you guys my heartfelt love and care! I wish I could say or do more......but knowing you can make it through the weekend makes me happy for you.

Love you guys.......

Mary Jo

Well hell. You know that I hate this is the latest 'news' for Ed... and for YOU.

I just this morning faxed 7 pages of detailed info my onc asked for at yest. appt. These meds are what we are looking to add in some fasion ASAP to try and control my own brain mets. They continue to grow, but slowly. Yet, he said: "at this point even if your brainstem lesion grew marginally, it could cause real trouble and symptoms right now." It will be seven years of brain mets in Sept.... that is pretty scary if I think too much.

I will be more than happy (not such a great word under circumstances) to send you any kind of info you might want. Names and /or details.

And here I sit, still keeping WBR as a very last option. call me chicken, stupid....... you'd probably be right.

Bless that ED. I've used those same words... as that's all we really can do while the river keeps on flowing.

Still hoping and wishing,

XOXOX patty

OncoMan just called and first asked how we were digesting what is happening. We are okay. He will be contacting Dana Farber himself on Monday to see what they may have to offer. If they can help, he will take care of everything to get there. If they cannot, treating Ed systemically would not be a problem but he wants me to know that if he wants to stop treatment, it is understandable. This drug is not proven to pass the blood/brain barrier. He feels that the brain should be treated right now "if" we have an option to.

OncoMan tells us like it is and has always inspired some 'glimmer of hope' with each visit or call. The only hope we have now is if Dana Farber or another facility has something experimental or new. This is the only hope we have. Whole Brain Radiation for the second time is almost not an option.

We are almost out of options here. There is nothing we can add to this regime that will help. Miracles are something I would give up some of my life for right now. Hospice will be called if or when he decides to give up treatment.

I pushed the OncoMan for a projection of time and you know how I do not believe in that. Somehow, this time I needed to know.....Ed will start showing signs of disease within 3 months and it is projected that this is all the time we will have. Within 3 months. Why will I not believe that? It is only obvious.

I think part of me died today, but not the part that will continue to plead and search for that miracle. I am sorry to have to give you all this news.>>Believe51

Marie I am so saddened by your latest news about Ed. I will be praying hard for one more miracle to come your way. Your strength, courage and grace through everything you are facing is beyond words.

I quickly put Lani brain met into the search above and found
 

here is info I just quickly gathered on Boswellia Serrata and intrathecal herceptin
from a 9/06 thread I started--I recently read a post from someone who thanked me for providing the info--she had used Boswellia and had a 40% decrease in the size of her brain mets and a long period of stable disease (couldn't find the post, but found these by putting Boswellia into the search function above). I also post my info on intrathecal (injected into the cerebrospinal fluid so it doesn't have to cross the blood-brain barrier) herceptin:
Here is the first post:

for those with brain mets (and those scared of developing brain metastases)

a most remarkable article--I felt it inappropriate to place it with interesting articles as only one tenth as many her2support readers view those posts and it is my impression that there are some out there who could definitely need this news, published in a very respectable journal

I was happy to see an email address attached to the abstract and have forwarded on more information...


1: J Neurooncol. 2006 Sep 26; [Epub ahead of print] Links
A lipoxygenase inhibitor in breast cancer brain metastases.

Flavin DF.
Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT, 06831, USA, Dana_FK@hotmail.com.
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwile consideration for testing in brain metastases not responding to standard therapy. Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.
PMID: 17001517 [PubMed - as supplied by publisher]






hmerch
Member

Join Date: Apr 2006
Posts: 5





I contacted Dr. Flavin for my mother who has brain mets and she said that Boswellia serrata should be used right away at 800mg 3 times a day.

My understanding from my conversation with her was that those of her patients who are using this had regression of brain mets. She also has a few patients who are met free now for a few years.

This sounds pretty great and I'm going to get this for my mom if her onc allows it, but I am curious if anyone else has used this compound and if so what has been your success?

Thanks,
Hina














10-27-2006, 03:31 PM
#15
heblaj01
Senior Member

Join Date: Apr 2006
Posts: 543



Caution: possible interaction of Boswellia with some chemo drugs

In checking the pharmacokinetics of Boswellia Serrata I found this article which describes it as an iinhibitor of P450 enzymes which are required in the liver to metabolize some chemo drugs such as Navelbine.
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
Analysis of frankincense from various Boswellia species with inhibitory activity on human drug metabolising cytochrome P450 enzymes using liquid chromatography mass spectrometry after automated on-line extraction.
The abstract does not state if the inhibition is occuring only in he gut or in the liver or both.
If the inhibition is restricted to the gut then intravenous chemo drugs would not be affected.
If however the inhibition is in the liver the consequences could be lowered effectiveness of the chemo treatment & possibly higher level of side effects due to longer persitance of the drug in the body & higher accumulation.

I hope this will turn out to be a false alert for most of those planing to use Boswellia but it needs to be clarified by someone with the right background such as Lani.


heblaj01
Senior Member

Join Date: Apr 2006
Posts: 543





This article posted by Lani is most interesting for members of this forum since it deals with metastatic brain cancer from breast.

It appears that Boswella Serrata might also be usefull for primary brain tumors since a phase 2 clinical trial is under preparation:

http://www.clinicaltrials.gov/ct/gui/show/NCT00243022
Boswellia Serrata Combined With a Low-Fat, Vegan Diet or a Standard Diet Alone in Treating Patients Who Have Undergone Surgery and Radiation Therapy for Newly Diagnosed Glioblastoma Multiforme





from my 11/06 post:



Here are two articles on IT herceptin--the latest(hot-off-the-press) I do not yet have access to:
1: Lancet Oncol. 2006 Nov;7(11):888. Links
Care with intrathecal trastuzumab.

Siderov J.
PMID: 17081914 [PubMed - in process]

Related Links
Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.[Oncol Rep. 2006]

Hope this helps!

PS I have very little internet access at the moment(visiting for the holidays), so sorry not to post more info on this
















11-22-2006, 03:50 PM
#9
Lani
Senior Member

Join Date: Mar 2006
Posts: 1,988



got it!

The Lancet Oncology
Volume 7 • Number 11 • November 2006
Copyright © 2006 Elsevier






Reflection and Reaction
Care with intrathecal trastuzumab


Jim Siderova
a Cancer Services, Austin Health, Studley Road, Heidelberg, VIC, Australia 3084

E-mail address: jim.siderov@austin.org.au




PII S1470-2045(06)70917-2

I read with interest the Case Report on the use of intrathecal trastuzumab published in The Lancet Oncology because it is an uncommon method of administration for a monoclonal antibody.[1] I wish to point out a potential issue with the intrathecal administration of trastuzumab.

In Australia and the UK, trastuzumab is supplied in vials of 150 mg powder,2, 3 which contains histidine, trehalose dihydrate, and polysorbate, among other excipients. Once reconstituted with water for injection, the resultant solution is free of preservatives. In the USA, trastuzumab is supplied in vials of 440 mg powder,[4] together with 20-mL bacteriostatic water for reconstitution. This bacteriostatic water contains 1·1% benzyl alcohol—a preservative.

Products that contain preservatives, particularly benzyl alcohol, should not be administered intrathecally because of the risks of anaphylaxis and potential for neurotoxicity from the preservative agent.[5] Reported events include paraparesis, fibrosis of the cauda equina, and segmental demyelination of the dorsal and ventral roots.[5]

Thus, colleagues in the USA who might consider treatment with trastuzumab intrathecally should do so without the use of the diluent provided.

Intrathecal administration is an important component of the management of malignant disease, but products injected in this way should not contain preservatives, especially benzyl alcohol. Physicians, pharmacists, and nurses involved in the preparation or administration of intrathecal treatment should ensure that preservative-free products are used.

I declare no conflicts of interest.
















11-22-2006, 03:51 PM
#10
Lani
Senior Member

Join Date: Mar 2006
Posts: 1,988



references

REFERENCES:

1 Platini C, Long J, Walter S: Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7. 778-780.2006; Full Text
2 Roche products Pty Ltd: Herceptin (trastuzumab) Australian approved product information. Therapeutic Goods Administration approved amendment, Roche products Pty Ltd Sydney 21 April, 2006.
3 Electronic Medicines Compendium: (accessed Sept 20, 2006) http://emc.medicines.org.uk/emc/indu...ocumentid=3567
4 In: McEvoy GK, ed. American Hospital Formulary Service (AHFS) Drug Information, American Society of Health-System Pharmacists Bethesda 2006: 1209-1215.
5 Hetherington NJ, Dooley MJ: Potential for patient harm from intrathecal administration of preserved solutions. Med J Aust 173. 141-143.2000; Abstract

01-07-2008, 06:08 PM #3
Lani
Senior Member

Join Date: Mar 2006
Posts: 2,762
another article I just refound:
Anticancer Drugs. 2007 Jan;18(1):23-8. Links
Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier.

Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V.
Medical Department III, Ludwig-Maximilians University of Munich, Clinic Grosshadern, Munich, Germany. Joachim.Stemmler@med.uni-muenchen.de
Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.
PMID: 17159499 [PubMed - indexed for MEDLINE]

more references
 

new drug improves survival, qual of life when combined with WBR(whole brain radiation
Am J Clin Oncol. 2007 Dec;30(6):580-7.
Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases.

Scott C, Suh J, Stea B, Nabid A, Hackman J.
CBS Squared, Inc., Fort Washington, Pennsylvania 19034, USA. cbssquared@comcast.net
OBJECTIVE: To determine whether efaproxiral, an allosteric modifier of hemoglobin, improves quality of life and quality of survival in patients with primary breast cancer and brain metastases when used as an adjunct to whole-brain radiation therapy (WBRT). METHODS: Patients with brain metastases from breast cancer were randomly assigned to receive WBRT and either efaproxiral or no efaproxiral. The primary endpoint for this analysis was quality of life and quality-adjusted survival. Quality of life was assessed prior to initiation of WBRT and periodically in follow-up using the Spitzer Quality of Life Index (SQLI). RESULTS: A subgroup of 106 eligible breast cancer patients with baseline SQLI were randomized into this study and represent the target population discussed in this report. Treatment, age, and SQLI were significant predictors of survival. The addition of efaproxiral to WBRT reduced the death rate by 46% (P = 0.0086). Quality of life was improved in the WBRT + efaproxiral arm compared with the WBRT alone arm (P = 0.019). Quality-adjusted survival was statistically significantly improved by the addition of efaproxiral to WBRT (P = 0.001). CONCLUSION: Survival, quality of life, and quality-adjusted survival were all improved in breast cancer patients with brain metastases receiving efaproxiral and WBRT compared with those receiving WBRT alone.
PMID: 18091051 [PubMed - in process]

Article shows the other people involved in writing the paper were with University Cancer centers (not the drug company), that her2+ was responsible for an inordinate number of the bc brain met population due to its proclivity for the the brain, other factors.

Marie - I don't have any details, but a friend of mine was offered intrathecal treatment (a port in the head and direct delivery of chemo/targeted agent) for brain mets. She opted not to do it. Me? I probably would consider it... everyone is different. I think this is what Lani's post refers to...

love and prayers.

they do deliver herceptin intrathecally
 

All the articles agree it is very advantageous to keep herceptin going once you have brain mets-they theorize the blood brain barrier is somewhat more permeable or some indirect effect is responsible

I also came by this (not mine) in the search function:
RTA 744 in Breast Cancer Patients With Progression of Previously Irradiated Brain Met
RTA 744 in Breast Cancer Patients With Progression of Previously Irradiated Brain Mets

RTA 744 is a novel, anthracycline that has shown the ability to circumvent ATP-binding cassette transporters (Multidrug Resistance Protein 1, Breast Cancer Resistance Protein, P-glycoprotein) in vitro. This action enables RTA 744 to penetrate across the blood brain barrier. In a Phase I safety study, RTA 744 was shown to be generally well tolerated in patients with recurrent gliolastoma multiforme (GBM). Additionally, anti-tumor activity was observed. Breast cancer is known to be sensitive to anthracycline therapy. Based on the preliminary Phase I clinical results and the sensitivity of breast cancer to anthracycline therapy, this Phase II study will investigate the safety and efficacy of RTA 744 in patients with breast cancer and metastatic disease to the brain which has progressed following whole brain irradiation.

http://www.clinicaltrials.gov/ct/sho...395112?order=2

Marie... can I say more than just 'hell' here??? Pretend I did, ok.

I can't think of what I sent that must be written off if it was not tried?

My onc wants to go right to Irinotecan w/my Temodar. There is an oral Irinotecan, which I like, at a dose of about 50/60mg/m2 Dx5. It is also in trial now for 'us' this way.

Besides w/Temodar, it is also used or in trial with:
*Oral etoposide aka: VePesidR
*Avastin - yes, honest for brain mets.


There is an older chemo 'Lomustine':
Lomustine Offers Effective Low Cost Treatment for Lung and Breast Cancer Brain Metastases (Doctor's Guide)
Reports results from a small study presented at the 14th International Congress on Anti-Cancer Treatment (ICACT) of the efficacy and toxicity of lomustine in patients with lung or breast cancer brain metastases. [2/03]
What this drug is used for:Treatment of brain tumors, both primary (developed in the brain) and metastatic

*And: Temodar w/Doxil -
2004 ASCO Annual Meeting
Category: Central Nervous System Tumors
Abstract No: 1576 Two CR and two PRs was recorded in the four patients with breast tumours,
Conclusions: the schedule was a well tolerated treatment (also in elder pts.) and has suggested an encouraging activity in brain metastases from breast.

*Topotecan:
Single-agent topotecan, especially in patients with SCLC or breast cancer, has demonstrated excellent response rates against brain metastases and may be safely and effectively combined with other chemotherapeutic drugs that have the ability to pass the intact blood-brain barrier....

*And these trials:
* ZK219477 in Patients With Breast Cancer and Brain Metastases
The purpose of this Phase II clinical trial is to determine the effects, both good and bad, of a new chemotherapeutic drug called ZK219477 that appears to cross the blood-brain barrier and penetrate into the brain.
* Epothilone B in Treating Patients With CNS Metastases From Breast Cancer
This phase II trial is studying how well a new experimental treatment known as epothilone B (patupilone) works in treating patients with CNS metastases from breast cancer that have recurred after whole brain radiation. Patupilone does cross the blood-brain barrier.

However, the trial Lani posted was terminated = Business decision. ?? the RTA 744

Gd, I pray you can find something for Ed to try. I'm focused on oral at the moment. IV's next... or whatever happens.

xoxopatty

more references
 

Please see my post in the last couple of days of a new and more effective way of taking lapatinib00ie higher dose but intermittently

J Natl Cancer Inst. 2008 Aug 6;100(15):1092-103. Epub 2008 Jul 29. Links

Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain.

Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD, Steeg PS.
Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 1122, MSC 4254, Bethesda, MD 20892, USA.
BACKGROUND: The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. METHODS: EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 microm(2)) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22-26 mice per treatment group). All statistical tests were two-sided. RESULTS: In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with either dose of lapatinib had 50%-53% fewer large metastases than those treated with vehicle (mean number of large metastases per brain section, 30 mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P < .001; 100 mg/kg vs vehicle: 3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P < .001). Immunohistochemical analysis revealed reduced phosphorylation of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with the higher dose of lapatinib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-treated mice (P < .001). CONCLUSIONS: Lapatinib is the first HER2-directed drug to be validated in a preclinical model for activity against brain metastases of breast cancer.
PMID: 18664652

Patricia Steeg is at the NIH and has made bc brain mets here baileywick
 

here is one of her paper's abstracts:
Breast Dis. 2006-2007;26:139-47. Links

Brain metastases of breast cancer.

Palmieri D, Smith QR, Lockman PR, Bronder J, Gril B, Chambers AF, Weil RJ, Steeg PS.
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Central nervous system or brain metastases traditionally occur in 10-16% of metastatic breast cancer patients and are associated with a dismal prognosis. The development of brain metastases has been associated with young age, and tumors that are estrogen receptor negative, Her-2+ or of the basal phenotype. Treatment typically includes whole brain irradiation, or either stereotactic radiosurgery or surgery with whole brain radiation, resulting in an approximately 20% one year survival. The blood-brain barrier is a formidable obstacle to the delivery of chemotherapeutics to the brain. Mouse experimental metastasis model systems have been developed for brain metastasis using selected sublines of human MDA-MB-231 breast carcinoma cells. Using micron sized iron particles and MRI imaging, the fate of MDA-MB-231BR cells has been mapped: Approximately 2% of injected cells form larger macroscopic metastases, while 5% of cells remain as dormant cells in the brain. New therapies with permeability for the blood-brain barrier are needed to counteract both types of tumor cells.
PMID: 17473372

Thinking out louad. To get rid of the dormant cells, the bc stem cells, Dr. Max Wicha has started a trial of gamma secretase inhibitor (a drug normally tried vs. Alzheimer's so it must get into the brain)

How about seeing if those trials allow brain mets (U of Michigan, Baylor and one or two other sites if I recall correctly)

It is 224 am in Denmark, so got to get some ZZZZ

Try the website brainmets.org that Dr. Steeg advocates at all the meetings

Marie, you already know how I feel. Holding you and Ed in prayer and a great big hug to you both.

Sagopilone ( a relative of Ixempra)
 

9/11/08 2:10 PM
Sagopilone crosses the blood-brain barrier in vivo...[Neuro Oncol. 2008] - PubMed Result
Page 1 of 1
http://www.ncbi.nlm.nih.gov.laneprox...ubmed_RVDocSum
1: Neuro Oncol. 2008 Sep 9. [Epub ahead of print]
PMID: 18780814 [PubMed - as supplied by publisher]
Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor
growth and metastases.
Hoffmann J, Fichtner I, Lemm M, Lienau P, Hess-Stumpp H,
Rotgeri A, Hofmann B, Klar U.
Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse 172178, 13342 Berlin,
Germany.
The aim of this study was to determine the efficacy of sagopilone
(ZK-EPO), a novel epothilone, compared with other anticancer agents
in human orthotopic models of primary and secondary brain tumors.
Autoradiography and pharmacokinetic analyses were performed on
rats and mice to determine passage across the blood-brain barrier
and organ distribution of sagopilone. Mice bearing intracerebral
human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma,
or patient-derived non-small-cell lung cancer [NSCLC]) were treated
with sagopilone 510 mg/kg, paclitaxel 812.5 mg/kg (or temozolomide
100 mg/kg), or control (vehicle only). Tumor volume was measured
to assess antitumor activity. Sagopilone crossed the blood-brain
barrier in both rat and mouse models, leading to therapeutically
relevant concentrations in the brain with a long half-life. Sagopilone
exhibited significant antitumor activity in both the U373 and U87
human glioblastoma models, while paclitaxel showed a limited effect
in the U373 model. Sagopilone significantly inhibited the growth of
tumors from CNS metastases models (MDA-MB-435 melanoma and
patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of
nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has
free access to the brain. Sagopilone demonstrated significant
antitumor activity in orthotopic models of both glioblastoma and CNS
metastases compared with paclitaxel or temozolomide, underlining the
value of further research evaluating sagopilone in the treatment of
brain tumors. Sagopilone is currently being investigated in a broad
phase II clinical trial program, including patients with glioblastoma,
NSCLC, breast cancer, and melanoma.

oh, sweet marie, I have no wordsI am surrendering you into God's loving hands and seeing you enfolded in His grace... and the doctors finding wisdom

Fulvestrant AKA ICI 182,780 best given monthly as double dose in buttocks crosses BBB
 

ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology

Articles by Alfinito, P. D.
Articles by Deecher, D. C.


Endocrinology, doi:10.1210/en.2008-0532
Endocrinology Vol. 149, No. 10 5219-5226

ICI 182,780 Penetrates Brain and
Hypothalamic Tissue and Has
Functional Effects in the Brain
after Systemic Dosing
Peter D. Alfinito, Xiaohong Chen, James Atherton,
Scott Cosmi and Darlene C. Deecher
Women’s Health and Musculoskeletal Biology (P.D.A., X.C., S.C.,
D.C.D.), Drug Safety and Metabolism (J.A.), Wyeth Research,
Collegeville, Pennsylvania 19426
Address all correspondence and requests for reprints to: Darlene C.
Deecher, Ph.D., Wyeth Research, RN 3164, 500 Arcola Road,
Collegeville, Pennsylvania 19426. E-mail: deeched@wyeth.com.

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not
cross the blood-brain barrier (BBB). However, this hypothesis has
never been directly tested. In the present study, we tested whether
ICI crosses the BBB, penetrates into brain and hypothalamic tissues,
and affects known neuroendocrine functions in ovariectomized rats.

ICI crosses the BBB and penetrates into brain and hypothalamic
tissues
An earlier report suggested that ICI did not cross the BBB of OVX
rats because it failed to block nuclear uptake of [3H]estradiol in
hypothalamic tissue after once daily dosing at 1.0 mg/kg sc for 3 d
(2). However, the ability of ICI to cross the BBB and penetrate brain
tissues was not directly tested in these experiments. In the present study, the same dosing
paradigm was followed as reported by Wade et al. (2) (Fig. 1A), and ICI levels were
measured in plasma and brain (total brain minus hypothalamus and pituitary) and hypothalamic
tissues over time. The ICI compound was detected in all samples and at all time points tested
(Fig. 1B). The concentrations and pharmacokinetic profiles of ICI in plasma, brain, and
hypothalamus were found to be similar (Fig. 1B and Table 1 ). ICI levels were stable in
plasma and brain and hypothalamic tissues over the entire 24-h testing period, and the
concentrations of ICI in plasma and hypothalamic tissue were similar at the 24-h time point.

TABLE 1. Pharmacokinetic profile of ICI (1.0 mg/kg, sc, 3 d) in
plasma and brain and hypothalamic tissues of OVX Sprague Dawley
rats over time

The ratio of brain to plasma exposure is an indication of a compound’s ability to cross the
BBB. Based on 24-h exposure values, brain and hypothalamus to plasma ratios for ICI were
0.33 and 0.66, respectively (Table 1 ). These results demonstrate that ICI crosses the BBB, is
present in brain and hypothalamic tissues, and persists at a constant level in plasma and brain
and hypothalamic tissues for up to 24 h after systemic dosing.
ICI blocks estrogenic actions in the MD model of hot flush but showed estrogenic-like
effects when administered alone
The MD model of hot flush is based on measuring naloxone-induced increases in TST in MD
OVX rats (17, 23). Previous work indicates that estrogen’s ability to abate TST elevations in
the MD model of hot flush occurs through its actions in the brain (18). To determine whether
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P
3), these results demonstrate that ICI rapidly crosses the BBB and persists for an extended
period of time in plasma and brain and hypothalamic tissues. Consistent with its ability to
penetrate brain tissues, repeated systemic administration of ICI blocked the effects of EE on
naloxone-induced TST elevations in the MD model of hot flush and on body weight change.
Interestingly, ICI administration alone (1.0 or 3.0 mg/kg·d) demonstrated weak estrogenic-like
activity in these models. We conclude that ICI is a brain-penetrable compound that can exert
functional (antiestrogenic and estrogenic) effects in the CNS, and specifically the
hypothalamus, after systemic dosing.
Previous studies have concluded that ICI does not cross the BBB because at up to 1.0 mg/kg·d,
it failed to block uptake of [3H]estradiol into nuclei of hypothalamic cells in OVX rats (2) and
failed to mimic the effects of OVX on body weight gain and plasma gonadotropin levels in
intact female rats (1). However, it is possible that these previous studies did not use a high
enough dose to observe inhibitory effects on these endpoints. For example, despite the presence
of ICI in brain and hypothalamic tissue after systemic administration of 1.0 mg/kg·d, we found
that this dose of ICI did not inhibit the effect of EE on all functional endpoints. The 1.0
mg/kg·d dose of ICI did partially inhibit the effect of EE on TST increases in the MD model
but did not block EE’s effect on body weight change. This functional selectivity may be
explained by the fact that ICI’s inhibitory effect on different estrogen-mediated brain functions
can vary depending on the endpoint being studied. For example, Steyn et al. (28) have shown
that intracerebroventricular administration of ICI inhibited estrogen-induced GnRH pulse
frequency but did not block estrogenic effects on progesterone receptor expression in the
hypothalamus or on antepartum prolactin surges. The authors concluded that there might be a
wide range of sensitivities to ICI in the brain that could cause variable results across different
functional endpoints. Thus, it is possible that inhibition of [3H]estradiol uptake into nuclei of
hypothalamic cells or blockade of estrogen’s effect on body weight change may require higher
levels of ICI than other functional endpoints. This idea is supported by our results showing that
ICI treatment at 3.0 mg/kg·d for 8 d did partially block the effect of EE on body weight change.
Because some previous studies (1, 2) only tested ICI at up to 1.0 mg/kg·d, it is unknown if
higher doses would have inhibited [3H]estradiol uptake into nuclei of hypothalamic cells in
OVX rats, or induced body weight gain or increased plasma gonadotropin levels in intact
female rats.
Several lines of evidence suggest that estrogens regulate body weight primarily through central
mechanisms that reduce meal size (15, 16, 29, 30, 31, 32). Lesions of the ventromedial nucleus
of the hypothalamus blocked the effect of systemically administered EB on body weight change
and food intake in OVX rats (29), infusion of estradiol directly into the paraventricular nucleus
or medial preoptic nucleus of the hypothalamus reduced body weight and/or food intake in
OVX rats (30, 31), and direct administration of EB to the hindbrain just above the nucleus
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tractus solitarius reduced food intake in OVX rats (32). However, these results have not been
reproduced in all laboratories (33), and several peripheral feedback mechanisms have been
hypothesized. Therefore, it remains possible that the ability of ICI to block the effect of EE on
body weight change in the present study could occur through peripheral not central
mechanisms. However, direct involvement of peripheral mechanisms in mediating estrogens
effect on body weight is lacking. It has been shown previously that estradiol treatment does not
inhibit feeding by modulating orosensory stimuli (15, 16). Estradiol treatment can inhibit
ghrelin-induced feeding, but this effect does not occur through reduction in meal size as is well
established for estrogens (15). Estradiol does increase the satiating potency of cholecystokinin,
but this effect likely occurs through an estradiol-induced increase in neuronal activity within
the brainstem, not through regulation of signaling in the periphery (15, 16). Finally, leptin
signaling does not appear to directly mediate estrogen’s effect on body weight because estradiol
has reduced body weight and food intake in both leptin-deficient and leptin receptor-deficient
mice (34). Thus, based on current evidence, estrogenic regulation of body weight appears to be
mediated through central mechanisms, and is an appropriate endpoint for predicting whether
ICI crosses the BBB and exerts functional effects in the CNS.
The effect of ICI on body weight has been reported previously in intact cycling female rats and
OVX estrogen-treated rats (2, 24). In these studies body weight changes were unaffected by
daily ICI treatment at either 1 or 1.5 mg/kg·d (higher doses were not tested), and it was
concluded that ICI did not cross the BBB. Our results are consistent with these studies because
the ability of ICI to block EE’s effect on body weight change was not observed at the 1.0
mg/kg·d dose. However, at the higher dose (3.0 mg/kg·d), ICI treatment did block the effect of
EE on body weight change. These data suggest that in previous studies in OVX rats, ICI may
not have been administered at a high enough dose to block estrogenic effects on body weight
regulation.
The effect of ICI alone on body weight change in OVX rats has also been tested previously (2,
24). Results from these studies also suggest that body weight change is unaffected by ICI
treatment at 1.0 or 1.5 mg/kg·d. These data are in contrast to our finding that ICI had weak
estrogenic-like actions on body weight change at both 1.0 and 3.0 mg/kg·d. The discrepancy
between the current work and previous studies is difficult to reconcile. There are several
technical differences such as rat strain and vendor and total treatment length that might account
for the discrepancy. One additional possibility is that the effect of ICI on body weight may vary
depending on initial body weights. In the present work, initial body weights averaged 215 g,
whereas in both other studies, initial body weights were approximately 270–276 g. It is possible
that in heavier rats, ICI may have a greater volume of distribution, increased sequestration into
adipose tissue, and/or increased plasma clearance. These possibilities are supported by studies
showing that increased body mass can alter the pharmacokinetic properties of some drugs (35).
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Therefore, the net result of these effects could be to reduce ICI exposure in brain tissue and
limit its ability to stimulate ER signaling. Importantly, it is unlikely that rats in our study
inadvertently received EE administration because uterine weights were similar to those from
vehicle-treated rats (Fig. 4 ).
Our results suggest that ICI has relatively low clearance in plasma and brain and hypothalamic
tissues of OVX rats when administered at 1 mg/kg·d for 3 d, and can persist in all three
compartments for at least 24 h after the last dose. In fact, the concentrations of ICI for each
tissue were found to be similar at the 0.5 and 24-h time points (Fig. 1B). This relatively low
clearance suggests that ICI could accumulate, particularly in lipid compartments such as brain
and adipose tissues, after daily systemic administration. Although somewhat speculative, this
type of accumulation could alter the pharmacokinetic and pharmacodynamic properties of ICI
over time. Consistent with this idea, ICI treatment at 1 mg/kg·d for 2 d did not block the effect
of EB on lordosis, ear wiggling, or hops and darts but reduced the effect of EB on all three
parameters when administered at 1 mg/kg·d for 24 d (2). Thus, the potential functional effects
of ICI on CNS-mediated endpoints may depend on both the doses tested and the time period
over which dosing is conducted.
A question that occurs is what are the relative roles of ER and β in mediating the effects of
ICI on the endpoints measured in the current study (i.e. TST regulation in the MD model and
body weight change). Because ICI binds to both receptors with similar affinities (36) and both
receptors appear to have broad distribution in the brain, including the hypothalamus (37), the
relative roles of the and β-subtypes are not easily discerned. Regarding body weight, several
studies suggest that estrogen’s effect is ER mediated. In support of this idea, in two separate
studies, the ER agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol decreased food
intake and body weight in OVX rats, whereas the ERβ agonist 2,3-bis(4-hyroxyphenyl)-
propionitrile had no effect (38, 39). In addition, EB had no effect on body weight and food
intake in OVX ER knockout mice, suggesting that the β-subtype is insufficient to mediate the
effect of estrogen on these endpoints (40). Finally, other studies have shown that estrogenic
inhibition of feeding occurs through ER-expressing neurons located in the nucleus tractus
solitarius (32). In contrast to these results, in a single study using oligonucleotide knockdown
of ERs in the brain, only ERβ antisense probes blocked the effect of estradiol on body weight
and food intake (41). However, the ability of their probes to reduce ER expression in the brain
was not reported. Thus, based on current data, it appears that the effect of ICI on body weight
change observed in the current study is mediated through the ER receptor subtype. However,
this hypothesis will need to be confirmed in future studies.
Less is known about the respective roles of the ER and β-receptor subtypes in temperature
regulation. Both receptors have been implicated in the regulation of TST elevations in mice

ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology

regulation.
The antiestrogenic properties of ICI in the brain as well as uterine tissues have been well
established (1, 28, 43, 44). However, results from our work and others suggest that ICI may not
be a pure antiestrogen. Intrahippocampal infusion of ICI has mimicked the effect of EB on
place learning in OVX rats (43). In addition, Sibonga et al. (24) have shown that, like 17 β-
estradiol (45), ICI treatment (1.5 mg/kg·d) decreases the cancellous bone formation rate in
OVX rats. Finally, in primary hippocampal neurons, both ICI and 17 β-estradiol promoted
neuronal survival against excitotoxic- and β amyloid-induced cell death, induced rapid calcium
influxes, increased spinophilin and Bcl-2 expression, and increased phosphorylation of ERK2
and Akt (25). Thus, ICI appears to have mixed antagonist and agonist properties, and its
pharmacology now seems to be more similar to other selective ER modulators (SERMs), such
as raloxifene and tamoxifen, then initially reported. The precise mechanisms supporting the
mixed pharmacology of ICI are unknown, however, it may be related to the differential
regulation of ER dimers in the absence or presence of an estrogen. It is well known that ER
dimerization is a key step in the activation of estrogen signaling pathways. Using a yeast two-
hybrid system, Wang et al. (46) found that ICI induced ER dimerization when given alone but
destabilized ER dimers in the presence of an estrogen. Therefore, it is possible that ICI-induced
receptor dimerization could lead to activation of estrogen responsive pathways, whereas
destabilization of ER dimers in the presence of an estrogen would block signaling. In support
of this idea, ICI was found to activate a subset of estrogen-responsive genes in MCF-7 cells, a
breast cancer cell line, grown in hormone-depleted medium (47). Although this explanation
might account for the antagonist and agonist-like effects of ICI observed in the MD model and
on body weight change in the current study, it cannot be broadly applicable to all endpoints
because ICI had no detectable estrogenic-like effect on uterine tissue. Currently, it is not well
understood how the tissue-selective agonist/antagonist properties of SERMs, like ICI,
tamoxifen, and raloxifene, manifest. It has been hypothesized that agonist/antagonist activities
of SERMs result from specific ligand-induced conformational changes in ERs that alter
coactivator/corepressor protein binding, and selectively influence different genomic and/or
nongenomic signaling pathways (48). In addition, cell-specific promoter context could play a
role in determining whether a SERM will elicit estrogenic or antiestrogenic actions.
The clinical use of ICI is not likely to be altered significantly by the results from the present
work. However, our results do offer a mechanistic explanation for the occurrence of hot flushes
in premenopausal women treated with fulvestrant (8). In addition, the use of fulvestrant in
premenopausal women would be expected to induce other CNS-related menopause-like
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Psymptoms such as sleep disturbances, mood changes, loss of energy, weight gain, and
decreased libido (49). Because most of these symptoms are not life threatening, it is unlikely
that they would limit the use of fulvestrant for treating advanced breast cancer patients.
Although we found that ICI has weak estrogenic-like activity on certain CNS-mediated
functions, it is also unlikely that these results will affect the use of fulvestrant for treating breast
cancer patients. Previous work has shown that ICI inhibits human breast cancer cell
proliferation (1), and agonist-like activity would be inconsistent with the studies showing the
utility of fulvestrant in treating ER-positive breast cancer (6, 7).
In summary, we have shown that, in contrast to previous conclusions, ICI is capable of crossing
the BBB, penetrating brain and hypothalamic tissues, and exerting functional effects on
neuroendocrine endpoints after systemic administration. We have also found that ICI is not a
pure antiestrogen, and may have a mix of both agonist and antagonist activities on certain
CNS-mediated functions. Therefore, future studies should consider the potential for ICI to
influence estrogen-related functions in the CNS after systemic dosing.

this was the reference I was looking for
 

At the conference, Dr. Slamon said this man's results were the most amazing he had ever seen.

the most remarkable lecture I have heard in the last 5 years
was the following

Adoptive T-Cell Transfer for Metastatic Melanoma
James Yang, MD
National Institutes of Health

at a conference in October hosted by Dr. Slamon

He was, I believe, starting to try to do something simiilar with other cancers...or at least thinking of starting to as he stated he believed his method would be applicable to many other sorts of cancer.

He only treats patients at the NIH and the patient's whose scans he showed and whose stories he told were widely metastatic.

Perhaps trying to contact his office at the NIH???

Dear Marie,

I cannot stop my tears reading your post. I am praying for you and Mighty Oak. God has to guide you to the right doctors and give you both the strength to deal with this news and stay positive.

Lots of love and peace,
shobha

Marie,

I'm just heartbroken to hear the news for Ed. I don't have any medical suggestions but I will certainly keep you two in my prayers.

praying hard
 

Oh Marie, I have such a lump in my throat and an ache in my heart. You are the epitome of loving support and words will fall short of conveying my heartache at your saddness and today's new.

Sending you back all the loving support you have given out.....which is A LOT!!!

Holding you in prayer tonight and always,

Maureen

p.s. I am such a rookie so I hope this is not a stupid question, but what about Tykerb (crosses the blood brain barrier)...? Is that an option?

Marie,

I know where you have been living....in hope. Stay there. Stay there.

Marie,
Please know that I am praying for you both.
Keep believing in Ed's miracle. Begin to thank God already for delivering him.

Kim

Dear Marie - My body thinks I should be asleep now (9 time zones a lot to adjust in 2 days!), but I just had to check in. Your news jerked me right awake!

I am too dazed now to have any more ideas than Lani has put forward. The Boswellia was coming to mind as I read the start of this thread, but some of the other ideas may have an even better chance.

Pattyz as usual has come through with her latest research. You have so much to come to grips with right now, so keep remembering we are sending you all the love and energy we can.

We will all keep "watering" the Mighty Oak tree and try to see you both through this rough patch. Lots of love to you both.

Marie,
My heart is breaking for you and Ed. Know that PRAYERS ARE COMING YOU'RE WAY.
Eric

Marie ~

I am so saddened to read this about Mighty Oak Ed...you both are in my thoughts and prayers. I wish I had some insight of what to do but just know how deeply you and Ed are loved.

Ruth

Marie, I so did not want to read this.

I am keeping you and Ed in my thoughts and prayers. I am praying for the doctors who will find the next right thing for Ed.

Marie,

This is one of those times when words are not enough. Please tell Ed that we are all pulling for him.

Stay strong.

To Marie and Ed,

You are an inspiration in how to live. Your love for each other, and the caring you share here and, I'm sure, in the rest of your lives is amazing. Please know that I am praying for the greatest good for you both.

Rebecca

Marie, it just sickened me to read your post. We have all come to love and care about you and Ed so much. You know that you have my prayers always. Don't lose hope and never stop believing.
love and hugs to you both

Marie
Holding you and Ed deep in my heart and in my prayers
Keep on Believing!

Hi Marie,

I am so sorry for the terrible news. I send my warm thoughts to you and the Mighty Oak. I took the liberty of doing some quick research on clinical trials for treating brain metastases from breast cancer. Links to a few that looked promising are set forth below. Most are in Massachussetts, with one at Dana Farber and another at Tufts. My guess is that you live in Mass. since you mentioned seeing a Dana Farber oncologist. The other one is at UCSF in San Francisco, where I am being treated.

Other obvious treatment ideas are Tykerb and Xeloda, if the Mighty Oak hasn't tried them.

Take care of yourself.

Best,


Jill



http://www.clinicaltrials.gov/ct2/sh...astases&rank=4

http://www.clinicaltrials.gov/ct2/sh...stases&rank=15

http://www.clinicaltrials.gov/ct2/sh...stases&rank=20

http://www.clinicaltrials.gov/ct2/sh...stases&rank=42

You guys are simply the light in my life and add to the quality of my world, I am too without words. I was touched when I logged on and felt hope even though this looks terrible for him.

We went for a long ride to his Mom's old home to check the mail. Passing over the reservior tonight the sun went down behind giant patches of fog. I envisioned this as my mind and the voices that were screaming in it....cloudy but still able to see some sunshine through the haze.......the water was freakishly calm. Looking out at this calm water which I have passed hundreds of times made me think that this is how I need my mind to be. I am breathing and still numb but need you to know how I appreciate the way you can make me see.

When finished we went to grab dinner, well he had Apple Pie w/extra vanilla ice cream, I had dinner (lol). He had to get some air so I stayed and followed his instructions to buy desserts for my Mom and Dad. Of course they got a visit and a dessert delivery, delivered by Sir Mighty Oak himself. Yes my Lovey's, this man is unreal. On the way home he asked me to call MD Anderson Monday (I will try online to contact tonight). He told me as he smiled and looked deep into my eyes, "I will have no one 'write me off'". Ed knows that OncoMan has not given up and there is much work to do, but he is gearing up with only prayers and hope in his pockets. Now that's my boy.

He did let me know that now is the time I cannot push him. I will provide him with all his options, long shots and travel plans and await their approval. It is fruitless to ask you not to be so sad because I cry with your sagas also. I am asking for you all to just be the pure and loving friends you are and know I can only do this with your help. Prayers and positive thoughts, wish us one last miracle. Thank you so much for allowing me to be sad here and for the sadness I have passed to you.>>Marie

PS: I Love You Santa Claus aka Lani, you are a gift in your own right. The hope and ammo you always supply in our war time allows us to be better Warriors. You have inspired me once more.

what i meant
 

marie,I want you to know that when I said I was surrendering you, that did not mean I am giving up hope. merely acknowledging the enormity of what you and ed are dealing with, and that it is beyond my power to heal.I don' have the answers but I knew others would come forth with ideas.Miracles do not happen because of me but they do happen.love and prayers to both of you