Working Questions
These are all the questions we are trying to work to answer. Some of them or well developed, others need much more thought. We have partial answers to many of the questions.
Disease Origins and Pathogenesis Questions
What causes JXG? Is the cause 'reactive' (immune system reacting to disease, failure of the immune system) or neo-plastic?Given that a cause might not be easy to find, what is the mechanism that produces lesions?
What perpetuates the disease? Keeps it growing?
Are their any areas the disease prefers in the body? Flat bones? Bone marrow producing bones? Why?
Why does this disease prefer youth? How is a child's body different that would make the disease more likely?
Are these immune system disorders?
How is JXG different from or similar to LCH?
Are the cells involved in LCH really Langerhans cells (epidermal dendritic cells)? How are they dysfunctional?
Are the cells involved in JXG really dermal dendritic cells? How are they dysfunctional?
What is the normal function of a dendritic cell?
How do dendritic cells grow? age? change? morph?
What can go wrong with the immune system? Are any of these dysfunctions similar to histiocytosis?
What can cause the immune system to react in ways similar to histiocytosis?
Is there a common thread in all the histiocytic diseases? Are they related by some precursor cell? Or are they really several different diseases?
What is the true relationship between macrophages and the dendritic cells? What chemicals cause these cells to change back and forth? When and why?
How is the operation of macrophages different from and similar to dendritic cells?
What about the roll of cytokines? Is this process just caused by cytokines gone wrong?
What does a JXG lesion consist of?
What does a LCH lesion consist of?
Are LCH and JXG the same mechanism?
Should all the histiocytoses really be lumped together? Should macrophages and dendritic cells be together? Are they really related or are they separate dysfunctions and/or processes?
Are there several different causes for JXG?
Is the disease a result of histiocyte cells (dendritic cells and macrophages) going amiss or is it something else and the cells just show up or are called there by some source (functional or dysfunctional)?
What are the most likely foreign causes (bacteria, virus, a toxin)?
Is this process like a typical granuloma? Is it a delayed type hypersensitivity?
How are the lesions changing as they 'age' or mature?
What makes these diseases sometimes spontaneously regress?
What makes these diseases to go into remission and then reoccur? Why in different areas?
Why do both LCH and JXG lesions commonly show up in the brain? Are these perhaps another type of dendritic cell?
Why would there be three different 'types' of LCH brain involvement? Are these different mechanisms?
Could some cases of LCH (or JXG) be neoplastic or cancerous while others are reactive?
Is the relative rarity of JXG compared to LCH just the result of the lower number of DDC vs. LC cells? i.e. is the amount of disease proportional to the number of cells present in the body?
How are LCH cells different from correctly functioning LC's? How are JXG cells different from correctly functioning DDC's?
What is the function of Birbeck Granules?
How are Lymphoid dendritic cells different from myeloid dendritic cells?
Which chemokines are responsible for calling a dendritic cell (or even a macrophage) to a certain area?
What are the life cycle stages of a Langerhans cell? (veiled, interdiginating, dermal, others...)
What do we know for sure, what do we not know for sure?
What cells are present in the lesions? What correlation is there to age of the lesion?
Do the LCH and DDC cells reproduce at the lesion? Or are they all called to that location from surrounding tissue or other areas?
How is JXG different than LCH? Why might different chemotherapies work differently on the two diseases?
Does JXG not reoccur to the extent LCH does? Or is that observation just a result of lack of data?
Is JXG 'worse' than LCH or is it just less understood?
What is the life cycle of lesions? How do they change over time? Could a lesion effectively be dead but still be visible and present?
Does clonal mean cancerous or is it normal to see clonal proliferations of these types of cells?
Small & Large Lesion JXG, are they different diseases (Micro vs. Macronoduler)
How does JXG get into the brain?
Is JXG different in the brain as opposed to elsewhere?
Why is JXG most frequently on the head and neck?
What does it mean when the lesions get fibrostic?
What is the life cycle of a lesion?
When we see a different type of dendritic cell, is it really a different type or has it changed due to environmental stimulus (i.e. does a dermal dendritic cell normally change into a Langerhans cell and visa versa)?
Can trauma or tissue damage cause, exacerbate or accelerate this disease? Cause a single lesion?
There seems to be some kind of switch that is thrown, which results in an end state of a collection of dendritic-like cells. What could go wrong with the immune system or the body to produce this state? Tissue damage, virus, foreign material, reaction to some chemical signal, lack of a apoptosis (death) signal for the cell...? What could we us to stop the collection of cells (besides the traditional surgery, radiation & chemotherapy)? Some kind of chemical signal or some kind of immune system regulation?
At what level is this process going wrong? Is there truly something in the body that the immune system is reacting to? Is the immune system reacting to false signals? Is the immune system failing to produce a signal to shut the process off? Are the dendritic (lesional) cells reacting incorrectly? Are the lesional cells cancerous?
Are the dendritic cells really the key players in the process, our just a numerous result?
Instead of killing the cells via chemo, radiation or surgery, can we use other chemicals to modify the response?
Is this an inflamatory response?
Treatment and Chemotherapy Questions
What drugs cross the blood-brain barrier?Why are the chemotherapy doses so low compared to other cancers?
Why do we not give intrathecal chemo (chemo into the spine) to facilitate crossing of the blood-brain barrier?
What are the best treatments for the disease? How do some of the chemotherapies work to stop the disease?
How long is it safe to be on Prednisone, vinblastine and methotrexate? What would be the long term impact?
Why are the dosages for MTX so much lower? Why not increase the dosages?
Why would Etoposide (VP16) work for JXG but not LCH?
Is there any evidence of MTX working on JXG?
Why do only 40% of LCH patients respond to 2CdA?
What research fields or treatments out there could be considered but have not been considered yet?
What about the use of Immune Response Modifiers that 3M has produced? Is there potential to develop any of these into something that could help curb the immune response (instead of wiping out the immune system almost entirely)? I am envisioning something more targeted - with traditional chemotherapy we run into the issue of having to stop giving medicine to let the immune system recover, unfortunately, this is time out that the disease can use to grow. We we had a more targeted treatment that just turned off certain aspects of the immune system, we may be more successful.
What about screening what type of chemotherapy may be most effective on an individual by using sample tissue in a laboratory environment (in vitro drug resistance and therapy selection testing)? Currently we are only able to test one drug at a time on a patient, this method is severely time limited.
Why has increase dosage or more agressive therapy not shown any improvement in outcomes? What could be responsible for this?