Purpose in a bubble

Yesterday, I met with a researcher that was working on lipoproteins in neuroblastoma. The idea is really simple enough. Lipoproteins are essentially tiny little fat bubbles that can be used to carry chemotherapy to tumors. Why do we care, you ask? Well, part of the problem that we all have in treating neuroblastoma (any cancer really) is the issue of toxicity. In fact, in most cases, toxicity is the factor that limits the amount of tumor we can kill and the amount of treatment our children can receive. You see, every time chemotherapy is given it has a very long journey to actually kill the neuroblastoma. It has to make it out of the bag, down the IV line, into the vein, through the body, and finally to the tumor. Sometimes, the chemotherapy even has to be metabolized by the liver before it becomes useful. The problem is that chemotherapy is not particular smart. It can effect everything it passes through. It can affect the heart, the liver, or just about anything in the body it passes. In fact, many of them can even hurt you on the way out as they are filtered by the kidneys. This is a major factor in most drugs that our children receive for treatment. We are only able to get so much of the potentially life saving drug because of the very real fear that any more would drug create significant damage to their little organs.

What if you could take all of these chemotherapies and put them in a bubble? What if this bubble could make it out of the bag, down the IV line, into a vein, and throughout the body without effecting a single organ? What if these bubbles had little magnets that could actually seek out tumors? What if it was the tumor that was the only thing that could pop the bubble and release the drug?

If this was the case we, would be able to spare a tremendous amount of toxicity. It is likely that we could even significantly increase the dose of drug given, increasing its efficacy. Just as importantly, we would be able to reduce, if not almost entirely obliterate, toxicity. That means no hearing loss with cisplatin and no heart damage with doxorubicin. Potentially, this could also mean less hematological toxicity leading to fewer transfusions, infections, and risks.

There are actually several versions of liposomes and lipoproteins in trial today. There is even a formulation with irinotecan that had great responses in adults which we have been trying to get into neuroblastoma for some time. There are several being tested with paclitaxel in adults and even a few with cisplatin. There is no doubt that this "bubble" technology is on its way.

While understanding the concept is pretty simple, actually doing it is quite another. It is no easy feat and it was this meeting that was on this very subject. Getting the drug into the bubble for the most part is pretty easy. That has been mastered with many lipophilic drug (drugs that dissolve in fat) The trick is keeping the bubble stable as it makes its journey, helping it find its target, and ensuring the tumor has the ability to pop the bubble. It was these topics in the framework of neuroblastoma that we discussed yesterday.

It was an interesting lunch and I think we both came out with some new ideas on how we could borrow from some of the successes seen with these types of drugs in other cancers and manipulate them to work well for children with neuroblastoma. The good news is that the technology is there. This can be done. The struggle will be in coming up with the funds to get research like this moved forward. I truly believe it to be a very large part of the future of chemotherapy.

It is another example of purpose in a bubble.

Another fake relapse?

Good morning! I am happy to report that yesterday went splendidly. There were no yellow stickers in school, all of our cats can account for their tails, and CPS did not come for me. That is a pretty good day in my book. I also wanted to thank everyone who wrote and offered help regarding the medical journal, Pediatric Blood and Cancer. It turns out that the head librarian at the medical school actually read my diary. Too funny. Well, it turns out that he was as surprised as I was to find out that they did not carry Pediatric Blood and Cancer. He said he would look into it. He was true to his word. Unfortunately, the subscription for the library is roughly $4500 per year and they are not able to justify the addition at this time. Go figure, I am not an employee or student. So, that means, for the time being, I am out of luck. Thankfully, I had several messages from many who read my blog offering to help me out with articles whenever I needed them. I genuinely appreciate the offers and I will take you up on them. In fact, I already have. I am currently reading over several articles as we speak.

One of the articles from this journal that was so graciously supplied to me was for my own selfish curiosity. It turns out that there was yet another case study of a child with osteoblastic lesions following therapy. You may remember that this was the very thing that happened to Sydney. Since her first relapse was never proven and her second is seemingly resolving itself on its own, it would lead someone to believe that something else must be at play. As we all know by now, neuroblastoma does not typically act that way. What if these "relapses" were something else? We know something has gone on in her legs. We just don't know what it is.

This is now the 5th or 6th documented case of these bony anomalies that I have seen. All of which have occurred in children that have had Accutane and monoclonal antibodies - either ch14.18 or 3F8. Some had treatment and some did not but all of the children have survived and they were never able to prove the existence of disease in any of them. No disease was ever identified by biopsy and none of the spots were ever verified by MIBG. The lesions showed up on bone scans and were usually confirmed by either CT, MRI or both.

I was hoping that this particular article would give me some more insight into what was occurring. However, like others I have read, there was little definitive information and much of it was speculatory. I am happy to see more cases, but I still wish there was something more definitive.

What is the moral of the story?

If your child has had Accutane and/or antibodies for treatment of neuroblastoma and presents with bone pain and osteoblastic lesions on bone scan, take a deep breath. Yes, these are signs of relapse but they are also a sign of this unknown condition. If these lesions can not be confirmed by MIBG or biopsy this may very well be a time for caution. I can not tell you when it is or is not an appropriate time to treat your child, but it may be something worthwhile to discuss with your doctor. There are now several published cases where children have had these symptoms and it has turned out not to be a relapse. In most cases the issues resolved on their own. Only enough, in many of these cases, they also reappeared in different parts of the body.
As I have said before, purpose is sometimes grey. Regardless, this does happen. Proceed carefully, you may end up with years of treatment that may have been unnecessary.

Purpose is not always crystal clear.

Kitty Cat Tails

Wow, a 3 day weekend and my kiddos made it through without much more than a hint of bickering. I am amazed at the change that has been brought about by school. It seems like the time that they are separated from each other at school is a good thing. What a loving wonderful gaggle of siblings. At the time I did not realize it. However, I now realize that it does seem logical that if they are not using there energies against each other they still have the capacity for evil. They still have the pent up energy. It still must go somewhere.

It makes sense enough now. I probably should have seen it coming. School brought harmony. That just meant they weren't using their powers against each other. Of course, that does not mean they lost there powers entirely. They just changed who they were using them on.

By Labor Day I was complacent. Happy kids. Happy wife. I will tell you, I was one happy Daddy. The kids had been spectacular all weekend. Incredible. The planets were aligned. I had been lulled into a false sense of security. As I sat while Sydney read a book to me, I heard silence from the ceiling above me head. I am clever. I knew that was potentially a bad thing. Kids and silence don't generally mix well. Thankfully, that was quickly followed by some footsteps and some giggles. Ah, I was back to relaxing. Graham and Ainsley were happily playing.

This went on for quite a while. I had become complacent. My kiddos, for all practical purposes, sounded perfectly. I was happy. Basking in the aura of a perfect family afternoon. After the next chapter in Sydney's book I decided to make my way upstairs. At the foot of the stairs I found a few globs of white hair.

Hmm. Is Boo, the cat, shedding? As I continued to make my way upstairs and into our room I continued to find little tufts of white hair. By the time I made it to our room I found Ainsley with Boo, cat tail in hand. Graham was nowhere to be found, but I would later find him hiding in the closet. I discovered that they had been pulling Boo around by his -hmmm - tail. Why they did it I still have not been able to figure out. They readily admit to doing it but, as most know, getting to the bottom of the question why? with a 4 or 5 year old can be elusive at best. I also never found an explanation for the tufts of hair. I can only imagine the worst.

It was the end of my perfect holiday weekend. As a lesson I decided to spend the next few minutes dragging the kiddos around by the ears. Yes, I received some rather disapproving looks from my wife and mother who was visiting. However, I wanted the kiddos to understand how it felt to be drug around by an appendage. I did not pull them hard but simply grasped them with enough pressure to make the experience uncomfortable. It did not take the long for them to decide that the kitty must not have liked it very much.

I am pretty sure Graham will never pull another kitty by its tail.

Ainsley, well, I am not to sure and I don't think I ever will be. She is definitely the difficult one to impress. Only tomorrow will tell.

Kids are like purpose. Complacency is never a good thing.

Pediatric Blood and Cancer pretty please

How come every article I want to read is in Pediatric Blood and Cancer and that is the one medical journal that my medical library does not carry? It drives me crazy and I simply can't stand it anymore. Every single time I see an abstract and think "Wow, this is interesting, I want to read more." or "Wow, this is interesting, I bet Joe Bob would love to read this." or "Gee, this is the exact issue that Billy Sue is having, I bet her parents would love to read this." it turns out to be in the journal Pediatric Blood and Cancer. Oh sure, I can beg my wife to call in 10 favors and get a hold of it for me but it just doesn't seem right. Furthermore at $29.95 an article I can't afford too many on my own much less to send to somebody else. FRUSTRATING!

So here I sit.

Stupid.

Yes, I could be smart. But no, I am stupid because I can't get to the holy grail of neuroblastoma medical articles.

(Hmm. Maybe this will motivate my wife to talk to the head librarian and talk them into a subscription to benefit all of the medical students that are studying pediatrics and to help Dr. Bowman who no doubtedly needs access to this journal.)

I am quite sure lives are at stake.

I know my sanity is.

I have no ammo for my purpose gun.

What a kick in the backside.

Aargh! Yesterday, Graham came home with yet another yellow sticker. That makes 2. I was in complete and utter disbelief. Sure enough, the boy kicked another kindergartner in the hiney. Not hard, mind you, just enough to gain the attention of the teacher. This is a tough one for me. I really don't exactly know how to handle this situation. Here is my conundrum.

First, you should know, Graham is not doing this maliciously. That is not Graham style. These episodes are in jest - not anger. He is trying to be funny and, if he is anything like his dad, these are the first episodes in a lifetime journey of trying to identify what is funny and what is not. There is not a mean bone in Graham's body. This is simply a way for him to grab a little acceptance and to be cool in a world full of 5 year olds. He is trying to figure out how to fit in.

I have insight into this. I was exactly the same way. To tell you the truth, I think part of me struggles with this to this very day. There is something special about making people laugh. It is like a drug and there is no high better. I am serious. There is no greater gift than making one of the kiddos laugh in one of those deep guttural uncontrollable laughs. It is what life is all about. Humor is an incredible tool. Not only can it bring joy and laughter but it can also disarm tense situations, bring perspective and comfort, and even curb pain. Furthermore, I learned early on that acceptance amongst my peers could be achieved through making people laugh. It has been in the learning of what is and what is not appropriate that has been the challenge.

Graham is doing the exact same thing. He is trying to gain acceptance my making others laugh.

The question is how do I help him learn? I don't want him kicking or slapping other children in the hiney. However, I also don't want him to stop experimenting with humor. In this case, it is a fine line and I have to give him the tools to differentiate.

I have been very stern with him regarding these two incidents. He has been punished significantly. He knows that it is not appropriate behavior. I have also sat down and began to talk to him about his humor and what he is trying to achieve. I have been about as effective as I can be in talking to a 5 year old about the subtleties of a sense humor. It is no easy task. Let's be honest, at that age, comedy isn't subtle. We are on different levels. He is young. He still buys into the silliness of passing gas. I, on the other hand, gave that up weeks ago. (Please know that I am kidding. I don't do fart humor. I am married to Lynley. Do you think I could get away with that - and live?)

Bottom line, I want to help Graham through this learning experience. I don't want him doing what he is doing but I do want him to experiment. That is how you learn. I just have to figure out how to help him drawn the line between what could be funny and what is absolutely unacceptable.

Sometimes purpose is a kick in the behind.

Hooting with the owls

Good morning! Well, last night I was at the Texas Rangers double header and did not get home until roughly midnight. So, this morning, I am a bit tired and my clever meter does not seem to be registering. I suppose that is the price you pay for being out with the boys until late hours instead of at home with the family.

Last night was also Grammie's birthday dinner. We all had a great time at Macaroni Grill. This has been one of my favorite places because the kiddos seem to absolutely love it. I have learned over the years that, when it comes to dining out, the happier they are, the happier we are. Add on the fact that they all like the kid's macaroni and cheese and you have a true winner. With the twerplets, there is rarely a single place or meal that meets all of their needs. This however, fit the bill. My only complaint was that the portion sizes have appeared to shrink over the last 6 months or so. Oddly enough, the prices had not. Regardless, it was still a successful outing and Grammie seemed to have a wonderful time. By 7:30 they were all heading home and I was off to see the Rangers.

Well I had best be off. We have two canine guests staying with us and the kiddos are already up and playing with them. There is some corralling that is needed if we have any hope of getting to school on time this morning.

I am off to chase purpii.

What is the skinny on tandem tranplants in neuroblastoma?

I have been receiving a lot of email lately regarding the tandem transplant question in high risk neuroblastoma. While I can't blame anyone for having fear related to one transplant, much less two, I am seeing a higher degree of concern than I have in years past. Most of these discussions have focused on the toxicity related to the transplants. Parents often feel that if you have double the transplant you must also have double the risk. Fortunately, from published papers, that has not necessarily been the case. Regardless, I thought a more thorough discussion of why the COG is asking the tandem transplant question was worthwhile. There is a fairly large amount of science in this area. What does the research seem to indicate?

Not surprisingly there is actually some pretty strong data supporting the idea behind tandem transplants. First, the published data seems to indicate that the toxicity is tolerable. In other words, it does not seem to be adding much more toxicity than a single transplant. In fact, there is at least one study that actually seems to indicate that there is less toxicity. Go figure? While there is some somewhat long term data, a tandem transplant's effect in the long term (10, 20, 50 years) is relatively unknown. For that, we will have to wait and see. The main point to gain from all of the research is that while there is toxicity related to the second transplant it does not appear to double your risk.

From the standpoint of an increase in survival, the published studies seem to show a significant increase in survival. Now please realize that I say this also knowing that institutions like TXCCC went from tandem transplants back to single transplants because they did not see a difference in survival and, in their experience, saw an increase in toxicity. I have not seen that data published and only know that from personal communication. With that being said, the strongest published data still seems to indicate that a tandem transplant will increase survival. We just don't know if that will still hold true in a large randomized phase 3 trial such as the one being offered in the COG.

There have been some fairly decent sized studies that have looked into tandem transplants. While none are directly comparable to the current study offered by the COG they do offer some insight into the impact of the tandem transplant. In most cases the studies have included differing induction chemotherapy regimens, total body irradiation, and a difference in timing of local irradiation. However, one can make a strong argument that the difference in survival seen in these studies in probably due to the tandem transplant itself.

There are 3 published studies regarding tandem transplants that appear to be the most referenced. These are:

• High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006 Jun 20;24(18):2891-6.
• Tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma. Bone Marrow Transplant. 2007 Jul;40(1):37-45.
• Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study.J Clin Oncol. 2002 May 1;20(9):2284-92.

The earliest work attempting to answer the question of whether a double transplant might improve survival used a double harvest/double graft approach with purged bone marrow support, with an OS rate of 32% at 5 years in a high-risk group of patients. In an analysis of 546 patients with advanced neuroblastoma from the European Bone Marrow Transplantation Solid Tumor Registry, a 5-year progression free survival (PFS) rate of 24% was reported for 436 patients who underwent a single procedure compared with 33% for 110 patients who underwent double mega-therapy. In the Chicago Pilot II study (mentioned above) in which 17 high-risk neuroblastoma patients were treated with triple-tandem cycles of high-dose therapy with peripheral blood stem cell rescue (PBSCR) and local irradiation, the 3-year PFS rate was 57%. In the long term survival study mentioned above, patients who underwent double high-dose therapy had a 3-year PFS rate from time of first transplantation of 61%, and 5- and 7-year PFS rates of 54% and 52%, respectively. For reference, the 3 year PFS for a single transplant was 34% in a large randomized phase 3 study in the COG. While a tandem transplant certainly appears to be better than the results of a single transplant, the question as to whether or not two transplants is significantly better than single transplant regimens still requires a larger, phase III randomized study to prove. This is the rationale behind this COG's randomized tandem transplant trial.

From the standpoint of these studies it certainly appears that a tandem transplant would be the way to go. However, it isn't as clear as it may seem. As I pointed out, there are some differences in the studies. Secondly, in these smaller studies with single institutions or small groups of hospitals it is impossible to rule out patient bias and other factors. Many of these studies were completed at institutions known for their superior patient care and expertise in this area. Could the quality of care provided at these institutions impact survival - possibly? All of these are reasons why it is important to ask the tandem transplant question in a randomized phase 3 trial. We simply do not know the answer for sure. We certainly hope it significantly increases survival but the bottom line is that we do not know. It could go either way.

Many parents ask - "If it were you, what would you want?" My answer is no different than theirs. I want my child to live. There is no answer. That is what is so important about this trial. Frankly, if my child were randomized to a single transplant I would be very happy that we would not have to subject her to the added risk of a second transplant. If she were randomized to 2 transplants I would be happy that she had a chance at increased survival. No matter which way we went you could bet that I would be able to find an adequate amount of research supporting our direction.

We don't know the answer. But, it is because of our children that others will.

I wish there was an answer for all of our purpii but, as of this point in time, either side of the coin could be a winner.