mIBG – We are back on!

This entry is part 3 of 3 in the series "Radiation" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 
MetaIodoBenzylGuanidine

MetaIodoBenzylGuanidine


[Prologue]

For those avid followers of all of the science that I have introduced during all of this, you will recognize that this post is a rehash, but an exciting rehash.

Early on, Liam was initially slated to participate in a mIBG (MetaIodoBenzylGuanidine) trial.  The trial wasn’t supposed to happen until after the induction period of chemotherapy.  The catch is that only 80-85% of neuroblastomas absorb mIBG.  This is why fairly soon after diagnoses, while there is still a lot of cancer in concentrated pockets throughout the body, an mIBG scan is given to see if the particular variety of neuroblastoma picks it up. This is done with [123]- mIBG (see below.)

When this scan was performed on Liam back in September, there had been problems and the scan was not performed right away.  The doctors and hospital staff were having difficulty stabilizing Liam.  In fact, that first session in the hospital lasted over 21 days.  He had been started on  a fantastic chemotherapy drug called Topotecan (which is a TopoIsomerase I inhibitor that is so darn cool, it deserves its own post and I will not discuss it here.)  The problem was that Liam was spiraling out of control while he was on it. He started having trouble breathing, and he ended up with a plural effusion (yep… that was a bad couple of days. Click here for the post from that day).  After all was said and done, the mIBG scan was pushed off until he was admitted for chemo round 2.

When the [123] mIBG scan was finally performed, it came back negative. We were bummed, but the chemo seemed to be going so well that we really didn’t give it much thought. Liam was feeling better.

After 6 rounds of chemotherapy, a follow up PET scan was performed. No cancer showed up on the scan. He had a remarkable response, and we thought we were doing pretty well.  In reviewing all that had happened over the course of 6 rounds of chemo, I wondered if most of the cancer had vanished just after the first round of chemotherapy.  If it did, it would have skewed the mIBG test to a negative result.

Looking back at the sudden improvement after round 1- the plural effusion (now believed to be caused by cancer dying his lungs) and all of the immediate weight loss (now believed to be the cancer dying in his abdomen)…. he looked normal for the first time in months; I contend that the Topotecan chemotherapy made most of the cancer disappear quickly.  His response even astonished his doctors.

Now that the cancer has come back,  it was suggested by the doctors at CookChildren’s that we look one more time at the mIBG.  So, we did, and it gave a positive response to mIBG.  It can clearly be seen in the left tibia and the pelvis.

mIBG Liam 24July2015

123-mIBG Scan of Liam on 24July2015. His neuroblastoma has soaked up the mIBG compound, and due to its radioactivity is exposing the film. His trouble spots in his left leg and pelvis can clearly be seen.

So what does this mean? It means that we now have a really awesome tool in our tool chest to fight this. It won’t cure the neuroblastoma, but hopefully we can knock it down and coupled with other therapies, we can get this disease under control for Liam.  This is an option that a week ago we did not have.

[End of Prologue]

So, how does it work? It turns out that Neuroblastoma has a strong affinity for mIBG in about 85% of cases.[1] In a very high percentage, the Neuroblastoma cells will take this compound up while the normal cells will not. This is called ‘selectivity’. (i.e. the Neuroblastoma soaks this compound up selectively over normal cells).  mIBG in itself, however, doesn’t do anything. It is taken into the cell, and then is excreted from the cell at a later time.  This means that the Neuroblastoma cells are not sensitive to the compound. 

A clever and ingenious pupil of chemistry can already see what to do next.  Swapping out the Iodine atom on this compound with the radioactive version  makes this molecule very useful.


[123]-Iodine

123 Iodine will decay by electron capture to form 123 Tellurium which will then emit a Gamma ray with an energy of 159 keV. This is useful for imaging.  This is like having an x-ray performed, but rather than having an x-ray source shining high energy light through Liam, the light will be generated inside him!  Since this radioactive atom is attached to a compound which is only selective to Neuroblastoma, Gamma rays (like x-rays) will be generated only at the Neuroblastoma sites.  With the correct detector, the Neuroblastoma will light up like a Christmas tree.


[131]-Iodine

If 131 Iodine is used, different results will be observed.  131 Iodine decays in the follow two manners (statistically a 90% Beta(-) Decay and a 10% Gamma decay):

(Beta(-) Decay ~90%) {^{131}_{53}\mathrm{I}} \rightarrow \beta + \bar{\nu_e} + {^{131}_{54}\mathrm{Xe}^*}  + 606 keV 

(Gamma Decay ~10%) {^{131}_{54}\mathrm{Xe}^*}  \rightarrow {^{131}_{54}\mathrm{Xe}} + \gamma  + 364 keV

The Beta(-) decay produces a very energetic electron and an Antineutrino which have a tissue penetration of about 0.6 to 2 mm. This is enough energy to destroy cells. (i.e. a cell sized atomic bomb) So in essence, this gives a pathway for the mIBG, which is very selective to the Neuroblastoma, to blow up the cells (and leave the good cells alone).


This mIBG scan that was performed today only involved 123 Iodine for gamma ray imaging (see above images). This indicates all of the places that the Neuroblastoma is, with a few exceptions. There are false readings in some of the places like the thyroid (which regulates Iodine containing compounds).    In the coming weeks, it’ll be time to bring out the [131] Iodine and give this cancer the radioactive punch it deserves.

  1. According to NationWideChildrens.org “…Roughly 80-85% of neuroblastomas will absorb MIBG. There are really 2 ways in which MIBG treatment is used. In both methods, the MIBG chemical is attached to an iodine molecule that has been made radioactive. The radioactivity can be either a low-dose or a high-dose…. ”

Gene Blues and MYCN Amplification

This entry is part 9 of 10 in the series "Liam's Battle" --

WARNING: Science Content


As with all my posts, I try to include some thought provoking science, as well as interesting water cooler talk.  Good luck.
 

Neuroblastoma Genetic Testing

There is a lot of stuff that is not known about Neuroblastoma, but there are a few key markers on the genetic sequence that have had some statistics gathered and can provide an inkling of whether or not the particular breed (or genetic makeup) of the Neuroblastoma is going to be more (or less) difficult to fight. The list I have here is not comprehensive. I am not a medical doctor. So, I offer my own interpretation, which I may find later to be inaccurate. If I do find inaccuracies, I will correct them. I am a chemist, but biochemistry is not my specialty. I am a material scientist, so there is a good chance I will get some of this wrong. I have approached this with the background that I have and with the attitude that I am a dad who needs to understand what the heck is going on, and I am learning as fast as I can!

I have included a *brief* reminder on the genetics of the human body for those audience members who have (ahem) forgotten some of their high school biology.  Also, there is a lot of blockquotes in this post. Feel free to follow the references and see just how deep the rabbit hole goes. 🙂

What are genes?

BY-SA 3.0 Zephyris

Genes are like the lines on a blueprint for living things.  Your genes are in-fact what make you distinctly a human and not a cat, dog, or dinosaur. All living things have genes. Genes are the sequences of DNA that instruct the cell on how to build protein or peptide sequences. Genes (DNA sequences) are all lined-up into libraries called chromosomes. The human body has 23 chromosome pairs (46 chromosomes, half from mom and half from dad).  No matter which cell you look at within one individual, whether it be from the big toe or the liver, each cell in a body has a copy of all of the chromosomes.  There are approximately 3 billion base pairs (Yes…~3,000,000,000) required to make the 46 chromosomes in each cell. That is a lot of copying of base pairs that is going on all the time. It is quite phenomenal that it happens correctly once, much less regularly in the ~37 trillion cells in an adult human.

Neuroblastoma Genes – As far as we know, what can go wrong?

Well, I think that it is pretty clear that there is a lot that is not known about what goes wrong in cells that have turned into Neuroblastoma. There is currently no known link to any cause, and to make matters even more confusing, some kids can actually get Neuroblastoma cells, and at a later date be completely free of them without any treatment. (This only happens with Stage 1 low risk Neuroblastoma. There are no known cases of Stage 4 high risk Neuroblastoma suddenly disappearing.)

Given all of this, however, there are some things that can be determined from a genetic test of the Neuroblastoma cells. The primary reason for testing the cells is to estimate how challenging the fight will be for a patient’s particular Neuroblastoma.

 MYCN Amplification

The  MYCN protein regulates fundamental cellular processes from proliferation to apoptosis (cell death). If the cell has more than 10 copies of this protein, it is bad. So bad, in fact, if Neuroblastoma cells have this, then it is automatically classified as high-risk (even if it were discovered early and would otherwise be classified as low-risk). The MYCN protein genetic information is located on chromosome 2p24.3 between base pairs 15,940,560 and 15,947,006. [Ref]

MYCN is a protein and a member of the MYC family of proto-oncogenes.  A proto-oncogene is a normal gene that has the potential to become cancer because of mutations or some type of increased expression (expression is how information from a gene is utilized to create another genetic product such as a protein).  “Like many other MYC proteins, MYCN is a transcription factor that controls expression of many target genes, which in turn regulate fundamental cellular processes including proliferation, cell growth, protein synthesis, metabolism, apoptosis and differentiation” [Ref]

Having too many copies of the MYCN protein makes this type of cancer hard to fight, but some interesting findings actually show that the MYCN protein may in fact be involved in the creation of the Neuroblastoma [Ref], although this is disputed other places [Ref]. It is possible that there is a system of checks and balances with some of the genetic information on chromosomes 1 and 11, which may help regulate over duplication of the MYCN protein, and the amplification of MYCN is closely related to  “missing” information on these Chromosomes. (Also called a ‘deletion’)

Deletion From Chromosome 1 and Chromosome 11

The deletion of a chromosome implies that there are areas of the genetic code, which we know are typically present in the DNA, that are missing from the sequence of the person whose DNA is being examined. Deletion from chromosomes 1 and 11 seem to be linked to to Neuroblastoma:

… Researchers believe the deleted regions in these chromosomes could contain a gene that keeps cells from growing and dividing too quickly or in an uncontrolled way, called a tumor suppressor gene. When a tumor suppressor gene is deleted, cancer can occur. The KIF1B gene is a tumor suppressor gene located in the deleted region of chromosome 1, and mutations in this gene have been identified in some people with familial neuroblastoma, indicating it is involved in neuroblastoma development or progression. There are several other possible tumor suppressor genes in the deleted region of chromosome 1. No tumor suppressor genes have been identified in the deleted region of chromosome 11. [Ref]

About 25 percent of people with neuroblastoma have a deletion of 1p36.1-1p36.3, which is associated with a more severe form of neuroblastoma. Researchers believe the deleted region could contain a gene that keeps cells from growing and dividing too quickly or in an uncontrolled way, called a tumor suppressor gene. When tumor suppressor genes are deleted, cancer can occur. Researchers have identified several possible tumor suppressor genes in the deleted region of chromosome 1, and more research is needed to understand what role these genes play in neuroblastoma development. [Ref]

The Gene List: (Changes in These Genes are Associated with Neuroblastoma)

 

Liam’s Results

Fluorescence in-situ hybridization (FISH)

When Liam was in the hospital the first time, a sample of the neuroblastoma was collected from his bone marrow before he began chemotherapy. This sample was sent off and analyzed by the FISH method. (Specifically the report says “FISH for MYCN (2p23-24) gene amplification,” which we know from above is one of the important mutations that predicts poor prognosis.)

Out of the 200 cells probed for MYCN Amplification by the FISH technique, 16 showed to be abnormal, and 184 showed to be normal. Indeed, his Neuroblastoma cells show MCYN amplification.

Chromosome Analysis by Karyotyping

Karyotyping is a way of analyzing the chromosomes for number and completeness. The results from Liam’s test are as follows:

  • 21 cells were counted and analyzed, and 3 of the cells were karyotyped.
  • 19/21 cells were of normal male chromosome compliment
  • 2/21 cells showed a gain on Chromosome 7 and multiple “double minutes

The gain on Chromosome 7 and extra fragments of DNA material are likely a direct cause of the amplification of MYCN gene.

Further Discussion

Now, this is discouraging news, and the words “poor prognosis” have bounced around my cortex for a while. What do we make of this? How can we put this all in perspective?

I was encouraged by a Japanese article which investigated the use of blood stem-cell transplantation (SCT) to treat Neuroblastoma (SCT is a procedure that Liam is scheduled for early next year). It would appear that SCT increases the odds of survival of Neuroblastoma patients with MYCN Amplification significantly (from the low 20% to about 50% survival after 66 months). The article concludes with the following statement:

Not all patients with advanced neuroblastoma who have more than 10 copies of MYCN will die. The requisites for survival in such patients seem to be intensive induction chemotherapy, effective surgery, irradiation, and the use of SCT.  [Ref]

Positive things to consider:

  • This test did not show Chromosome 1 or 11 deletion.
  • The DNA gain was in Chromosome 7 and in double minutes. Chromosome 7 is not tied to anything normally seen with Neuroblastoma. So it is possible that the MYCN has amplified a part of the DNA that might be easier to fight than a Chromosome 1 or 11 deletion (which takes away some of the regulation of MYCN). We will have to wait and see.

Cancer is Wood

This entry is part 8 of 10 in the series "Liam's Battle" --

Fred and I met in the fall of 1995 at Southwest Texas University (now Texas State University). I was a 17 year old freshman and he was a senior. We met at the first chemistry club meeting. He told me I had cold hands (he asked to shake my hand after I was elected secretary of the new club), and I later told my roommate that I had met a really nice guy but he was way too old for me. A Friday night group movie night (planned by Fred just to have a way to ask me out without asking me out on a one on one date), a Saturday night group outing to listen to music and dance at Nephews (I walked down to the square in San Marcos to check to make sure I could actually get into the venue), and a Sunday morning “date” to attend church and Sunday school together, and I was smitten.

A year and a half later, we had been already been engaged to be married for 7 months and the plan was to wed when I graduated (scheduled for May 1998…I was on the “I took a bunch of AP classes in high school and am willing to work through the summers to complete this degree” program); however, Fred and I wanted to move the wedding up and start our happily ever after. My parents wanted me to finish school. So, Fred and I flew out to northern Virginia for Spring Break to discuss the possible change in plans.

My parents were preparing to put their house on the market. (My dad had been reassigned to Fort Sill, OK.) Unlike the previous trip that Fred had taken to visit my parents, the tenor of this visit did not involve sight seeing or national monument visitation. This trip involved a lot of work…together.

We stacked firewood. And my dad watched our interaction. The temperatures fell. And then dropped below freezing. And dad asked (told) us to power wash the large wooden deck. This was a task that neither Fred nor I had ever done before-alone or together, in good weather or bad. But we tackled it together and managed to enjoy a rather miserable time together. We took turns, we encouraged one another, we laughed, we borrowed a joke from the sitcom “Boy Meets World” that we still use, “This is the opposite of fun. This is wood.” And my dad watched.

At the end of Fred’s trip, my parents had a clean deck, we had the memory of a lifetime, and my dad gave his blessing for us to move our wedding to August of 1997…even though I wasn’t done with school, my sister was getting ready to finish high school/start college, and they were selling their home and moving halfway across the U.S.

What I didn’t fully appreciate at the time, but am starting to appreciate more fully after 17 years of marriage, is that character is revealed as well as developed during times of conflict. My dad had already figured that out and was resourceful in using tasks that needed to be accomplished to see how Fred and I would work together in challenging times.

Our first year of marriage was a borderline disaster, but we endured the conflict that arises when one person has a schedule crammed too full of graduation requirements and the other is waiting for said person to graduate. We endured all of the frustrations that go along with learning to share a life (and small apartment) with someone else. We endured the transition to graduate school and my realization that I didn’t want a Ph.D. because I knew I would feel compelled to use it in a job outside of the home once I had earned it. We endured 5 years of a commuting marriage when I took a job at Portland Community College, while Fred finished his degree in Eugene. (I had an apartment in Portland and lived there during the week and came “home” to Fred on the weekends.)

We endured the stillbirth of our first child, a daughter who we had named, talked to, hoped for, and love deeply. We have endured the wonder, blessing, sleeplessness, and general nuttiness that parenting 4 kids can entail. We endured a chemical pregnancy and a miscarriage.

We have walked an interesting journey together and we continue to grow together as two become one flesh, a head and a body learning to serve each other as we respect, love, and cherbish (we both mispronounced “cherish” in our wedding vows) each other (Ephesians 5).

We celebrated our 17th wedding anniversary by indoor skydiving, a surprise my sweet husband knew I would love. We laughed and made memories as we experienced the wonder of being supported by a force we could not see, but could definitely feel. We cheered for each other as we learned how to relax into the wind. We compared sore muscles after our brief flights.

And on August 17, 2014, the day after our 17th wedding anniversary, our sweet two-year-old Liam was diagnosed with Neuroblastoma. It is a horrible disease and the treatment for it seems cruel and unusual in many ways. Honestly, at first I felt like we were in free fall. But as we continue to endure and walk this journey together, I have come to realize that just like when we were skydiving indoors, we are being supported by an invisible force. We can’t see it, but we can definitely feel it. This is an opportunity for our character to be revealed and shaped. It is an opportunity for us to grow together as a couple as well as for our family to be unified.

Just like power washing the deck in freezing temperatures, we are in a situation that neither Fred nor I have experienced before, we are tackling it together, and managing to enjoy a rather miserable time.

Our audience has grown. We are blessed to have our family here to help.  My dad has a front row seat to this adventure as the long term substitute in our homeschool this year.  My mom is wearing many hats as she shuttles kids, cooks, cleans, runs errands, etc.  My sister and brother-in-law (and their girls) are walking along side of us, watching, supporting, teaching. And our children are watching how we handle this situation, growing, and learning some character lessons early in life.  We are enjoying an extended family support system orchestrated by a God who listened to our prayers to relocate to Texas for six years before allowing us to move to within 2 miles of my parents and sister to a job that was a perfect fit for Fred’s skill set and personality type. We have been blessed and humbled with an army of people praying for us and our son, people providing meals, people sending care packages and encouragement, people showing us God’s love.

Cancer is the opposite of fun. Cancer is wood. And yet, it is fueling a refining fire. We are not the people or parents that we were before our son was diagnosed. We are still imperfect, flawed, and human; however, we are calling on the name of the Lord and we testify that He is our God (Zechariah 13:9). He is faithful and just to cleanse us of all unrighteousness (1 John 1:9). And He promises to use all things for the good of those who love Him…so that we can be conformed to the likeness of his Son (Romans 8:28-29). May our faith be proved genuine and result in praise, glory, and honor for Jesus Christ (1 Peter 1:7).

What does it mean to be Liam’s Shield Bearer?

Liam’s name means Beloved, Courageous Protector.  We remind him every time he goes to sleep because it’s part of his blessing song.  (Each of our kids has a personalized blessing that we sing over them before they go to sleep.  It’s a Harris-thing.)

After learning of Liam’s diagnosis, I kept hearing the words of Nehemiah 1:11 in my head, “I was a cupbearer to the king,” and I realized that what Liam the Protector needed was an army of Shield Bearers–people who would lift up the shield of faith and pray for our son.  It’s a similar image to Aaron and Hur raising up Moses’ weary hands and keeping them steady till sunset  as  Joshua battled the Amalekites in Exodus 17:8-15.  Liam is fighting a battle and needs the shield of faith to be raised on his behalf.

The verse on the bracelets is Ephesians 6:16, “In addition to all this, take up the shield of faith, with which you can extinguish all the flaming arrows of the evil one.”  It’s the ending verse to the Ephesians 6:10-16 Armor of God passage:

10 Finally, be strong in the Lord and in his mighty power. 11 Put on the full armor of God,so that you can take your stand against the devil’s schemes. 12 For our struggle is not against flesh and blood, but against the rulers, against the authorities, against the powers of this dark world and against the spiritual forces of evil in the heavenly realms.13 Therefore put on the full armor of God, so that when the day of evil comes, you may be able to stand your ground, and after you have done everything, to stand. 14 Stand firm then, with the belt of truth buckled around your waist, with the breastplate of righteousness in place, 15 and with your feet fitted with the readiness that comes from the gospel of peace. 16 In addition to all this, take up the shield of faith, with which you can extinguish all the flaming arrows of the evil one.

As you pray for Liam, we encourage you to put on the full armor of God before taking up the shield of faith to pray for our son.

We are so grateful for your prayers and humbled by the number of people who are praying for Liam.  People coast to coast and around the world are praying for our son.  We serve a big God and trust that regardless of the outcome that He will be glorified.