8 YO BOY FIGHTING RARE BRAIN CANCER
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Chandler has gone through brain surgery,port placement,2 lumbar punctures,6 weeks of proton radiation,gallbladder surgery,g tube Surgery,pelvic surgery on a mass found,and spinal surgery to remove as much as possible of a life threatening tumor that grew into the cord and causing him to be unable to speak,walk and much more. Chandler has had 8 months of intensive chemo in patient ATRT.
His tumors sadly returned with only 5 more treatments left. It started with a tumor in his spine then 3 now 4. We started a new chemo hoping this would help but after round 2 we did an mri of brain amd spine and unfortunaty we got terrible results. Chandlers spinal tumors didnt only grow but now had spread back to his brain and he was also diagnosed with leptimengeal disease meaning his entire linning of his brain was covered in a thick layer of cancer. He has 5 tumors in his brain along with the 4 in his spine . Chandlers oncologists now says he has approx 3 months to be with us. She said she checked on clinical trials but chaer did not quailify for any of them and Maine nor Boston would attempt to remove the spinal tumor that was so threatening to his life. I was just standing there all alone with my daughter during our mom and daughter fun day trying so hard not to upset her a d let her know there was something really bad happening. My little girl is such a good big sister and deserved my focus and attention on her. I went on with our next hour together trying to hold it together but was truely crushed by this news and i was shivering,trembling in fear for my little boy. I wanted to scream, pound on something. I needed to understand why my little boy why does he have to figbt so hard nust to continue being punished and feel pain,every single minute every single day. Why,how do i watch him deteriate, continue fighting for what?? To hear the words from his oncologists im putting a call into hospice and we wil make him as comfortable as possible was soul crushing. My daughter wanted to sit in the front seat with me but i knew icouldnt so i had her sit in the back to controll my emotions. I cried all the way home and just about 10 mins before getting home i lost it. I had a total breakdown and couldnt control the crying and anger i felt. My daughter jullianna came into the front seat and said mommy whats wrong? I said its ok baby im just really sad but ill be ok. She hugged me tight and said mom i know its chandler but he will be ok. I love you. I hugved her back my precious girl and told her to go see daddy. Just before i hung up with the oncologist she said kristin i want you to understand its not your fault there nothing you couldve done to prevent this and ive never seen a mom in all my years fight for there son and make calls all around the world telling chandlers story to all the best docs like u have. She said the research youve done and the love for your son is unbelievable. I responded i dont care because it was for nothing hes dying and theres nothing i can do. Then i begged her to help me. There was a long silence then she said im so so sorry i wish there was something i could do but this cancer is just to strong and we dont know how to treat it. I promise to make him as comfortable as i can. My husband came out and wanted to know what was going on and i could barely get the words out. I grabbed him tight and cried on his shoulder for quite sometime. I told him to go to chandler while
I got myself together. I sat there for hours trying so hard but couldnt. My husband came out and said chandler was crying for mommy but told me i had to pull it together for chandler because he couldnt see me like that. I got inside and see him on the couch with a huge smile on his face yelling mommy your finally back come look at my invention. I held him told him how much i loved him and how special he was. We were called in for an oncology appt the next day and we told the doctor we werent ready to give up on our son what can we do. She said there really isnt anything we havnt tried. This cancer is impossible to get rid of. If u really wanna put chandler through more treatment even though it wont help i can look into raduation again for the spine but his brain could not be treated till after the spine radiation was dine and a 6 week break in between and even then didnt think the radiation would work and the brain would shut down fast. My husband and i were beside our selves with fear and uncertainty then we got the call. I had called all around the world literally to all the best docs for opinions and options 2x and it payed off. Washington dc offered to enroll him into a clinical trial in dc to try and save him and there surgeon had agreed to remove as much as he could of the life threatening tumor. We had 24 hours to get there. With a little help from some wonderful organizations we were able to get him there. We traveled weekly to dc from maine for months being home just a couple days a week. Sadly we found out chandler didnt respond to the trial at all and was taken off and now that brings us to here. My husband has done alot of research as well and found a drug used on one child ever in germany with some promise for stopping this cancer. This is a huge risk not knowing what interacts with this med or how he will respond and could end his life if something goes wrong. What choice do we have though?? He will die if we dont and doesnt have long. This medicine is $1000 perday 1 pill per day. Wow how were we gonna do this. What toxisities may it have. We are hopeful but also scared so scared. Chandler right now can barely sit up or walk with excruciating pain. His tumor behind his eye is swelling and he cant see anything up close now just far away and if he tilts his head. He still has numbness down his entire side from the spinal surgery and his cancer is spreading rapidly. Tomorrow is the day we start this new treatment in hopes that he will respond quickly and get the miracle he deserves so much. Make all his fighting ,pain and determination worth it. When i told him we were starting his new chemo tomorrow u know what he said to me. Chandler just 9 years old fighting almost 2 years now said mom its ok i know. I just wanna go see the grand canyon quick. What a precious gift from god he is. Please pray for us. For chandler that he gets his miracle he so deserves.
My guy posseses more strength than anyone could ever imagine and backs it up with a positive attitude and a huge smile and a kind heart. He has an incredible love for life and everything good it has to offer. His determination to survive this is endless.
https://www.facebook.com/chandler8cancer/videos/1906968366265505/
Chandlers results were heart breaking today. A mothers worst fear.
Hi, i want to tell u all about chandler but dont want to answere ?s or calls now. Today chandler had a brain mri and they found the cancer is back but instead of a tumor its everywhere throughout his brain. Mostly in his brain stem and one in his spine. His heart rate was only 50 to 60 which is extreamly low. The oncologists said chemo will only prolong his life a tiny bit if at all and radiation in his spine make him him a little bit more comfortable. She said the inflammation is no dont causing him so much pain. She said he will get worse and worse fast everyday. He was supposed to start radiation tomorrow and pallitive care. They want hospice and medical equipment in the house asap. I look at him and still see that big bright smile and sassy behavior with dreams for his future and just keep asking why? He doesnt look like he is in as bad of condition as they say. Im so broken. He doesnt know and no way can i tell him. I love him with all my heart and soul. I want to wrap my arms around him and never let go telling him how much i love him but he wont let me close or to say i love u. He says hes to big for that. I have streams of tears running down my face and cant control them so im sitting here all alone but wanna go be with him but dont want him upset. Im trying to get my mom and boyfriend back up from florida. Ive asked justin to stay with us and not work because he needs to here. We need to be together every minute. I dont care if we fall behind on bills, loose things whatever chandler needs to know how loved he is and that we wont leave him at all. How do i watch him go through this? How does he with stand this and the pain. How do i keep telling him i will help him with all his big dreams and plans. I wish god would take me instead. I cant loose him..
This is what chandler has. I thought his speech slurring, eyes rolled up and very droopy, moodiness,and exhaustion was from meds but apparently its all part of this. The oncologist is now putting him on seizure meds because they will start due to intercranial pressure.
A cancer can metastasize (or spread) to a single location or to multiple locations in the brain. It can also spread to the cerebrospinal fluid or to the leptomeninges, the outer lining of the brain and spinal cord. This type of metastasis is known as leptomeningeal disease (LMD), or leptomeningeal carcinomatosis.
Since LMD cancer cells float in the cerebrospinal fluid, they can quickly spread throughout the central nervous system. As a result, LMD has a poor prognosis
HIS STORY FROM THE BEGINNING
My 7 year old little boy Chandler was life flighted from emmc hospital in Maine to the children's Boston Hospital to get removal of a life threatening brain tumor removed on sat.
He was given a small chance of survival by many but his surgeon was hopeful. It was successfully removed Monday evening but he will have a long road ahead of him.
He is facing chemotherapy and radiation and I'd like to continue his care in Boston with his doctors that know him best. We will be starting this as soon as possible to try and ensure no regrowth of the brain tumor. He will be followed for years.
He is not completely out of the woods yet but he looks a lot better. He is still in a lot of pain and on morphine and lots of other meds. We are still very scared what will tomorrow and the future holds for him.
We have another son in a residential hospital as well out of state for 8 months now and have lots of traveling expense with this as well.
My husband will be out of work for some time and thier will be a lot of financial that come along with this. We have four kiddos and would like to have the family together through this so any help is greatly appreciated.
My little boy has had a smile on his face through all of this and a positive attitude and he's been an incredible strong little guy.
Chandler will need the best possible care. The docs stated this is the worst brain tumor ever seen in the pediactic Boston Hospital in his 30 years and in a terrible spot being in the brain stem. It's been removed but thiers a lot of follow up care and dangers.
Today by far is the best out of the past 4 days by far and huge relief after speaking to the neurology team for a brief few mins.
The doc outright said Chandler is a pure miracle and nothing less. He forwardly said no one thought Chandler would pull through this surgery and if he did there would be no way he would ever recover fully without significant damage and dissabilities.
He said the top MRI imaging showed everything completely normal and undamaged with complete removal and absoloutly incredible. He said it was never imagined to have a result and recovery ever with a condition like his and he was an incredibly amazing strong child to come through like he has.
Those words are something I'd never think I'd hear. I can't even express how much I dreamed about hearing those exact words and to actually hear them well....
As a mother your worst fear in the entire world is your child is sick. Four days ago
Chandler went downhill very quickly after showing symptoms and signs that something was off for about a year. At first it was just bloody noses and balance which i thought was clumbsiness. Then not eating well and dragging all the time with little energy and very tired. Next it was he was having muscle cramps and pain in his legs then arms. After that it was neck pain,back pain,headaches. Lastly his headaches got so severe nothing was helping and when ever he got up and did any sort of physical exercise he would immediately get on his hands and knees and cup his hands around his face and push his face into the floor, pillow ect and cry rocking back and fourth .
He said to me mom whats wrong with me i cant even play and just cried so hard. I had him to the docs over a year with different symptoms and told he was fine.
They did a lot of bw and all was fine. The next day i couldn't keep him awake and every time he moved at all he'd scream and was puking like crazy so i rushed him to the hospital.
When i got him there the doc was told about a fall on the trampoline three weeks prior and that he hit his face and head pretty hard but symptoms were increasing and really bad now. The doc said he thought it was just a concussion and there wasn't anything they could do. I demanded on a scan so he said he would do a ct scan. 30 mins later he said the scan was normal. I told him i wasn't taking chandler home.
He came in and said the radiologist said just in case as a procausion he should have a MRI but that id have to wait till next week because they would not have a machine till tues or fri.
I told them i refused to wait to find one now . I then headed down to the kitchen for drinks for Chandler and i and was met there about 10 mins after.
The doc had a very bad look on his face and put his hand on my shoulder and said i'm so sorry but the radiologist sent the ct scan down to Bangor for a second look and your son is getting a high dose of steroids because his brain is under a lot of pressure from hydrocephilous. Fluid all around the brain. He said he has to get to Bangor immediately and admitted to ICU because they think its a brain tumor.
I lost my footing and felt numb.
Once the steroids was injected in 30 mins he was completely normal and pain free.
This was mistaken by docs for other medical or normal child hood things going on.
Hearing your child needs to go by ambulance to ICU immediately to Bangor for studies sucked the life right outta me. We went from four days ago thinking Chandler had migraines to he has a concussion to he's got the worst imaginable brain tumor he could possibly have.
Even though my baby wasn't expected to make it through and I was completely loosing hope and faith and felt like a piece of my own heart was cut out and life would never be the same I knew I had no choice but to make him as happy as possible no matter how much I was falling apart and didn't know what tomorrow was gonna bring but forced myself to smile while giving him answeres to keep him positive and as stress free as possible.
This little guy never had anything but a smile on his face and a positive attitude to the very second we we're holding hands in the ICU operating room while being put under to go through a very risky life threatening surgery for many hours to come.
I had a mask on and tears we're flowing down my face being hidden but talking to my baby and hugging and giving kisses knowing maybe that would be the last time but also knowing this was the most incredible little boy ever created and the strongest kid of all time and if anyone could get through this I knew he could.
I held onto that as I walked away waiting for an answere. It wasn't easy and I found myself questioning everything I've done over the last year trying to find something i missed or should've done differently but it didn't matter now.
Now I just sat and starred at the door in anticipation and fear for when the doctor showed up and what the expression would be on his face.
Many hours later he walked in with the most incredible smile on his face and sat down saying a few more hours maybe days we would not have been sitting here at all to your son is out of surgery and it went the best it could've possibly went and I think I got everything.
It was a true miracle and I won't lie there will be a long Rd ahead but I'm so excited his surgery turned out with these results. He made sure we knew how special Chandler was and that my boy may be the only one that could push through something like this.
I will forever be greatful for him. He not only saved his life but was encouraging,supportive but also honest and took the time to answer all our questions being honest but encouraging all at the same time also lightening the situation while talking with Chandler telling bad jokes.
I will never take tomorrow for granted and be so thankful for every minute I have with every one of my children but hold hope even when life is uncertain and things are at it's worst there's always hope.
I can keep a smile on my face knowing he get through anything I know he can and watching him walk and talk and be a grumpy independent little boy this morning is the best feeling in the world.
Hold the ones u love close and never think tomorrow is promised because it may not be. Always hold faith and never give up.   
We finally got back the Diagosis. CNS HGNET-BCOR.
Central nervous system high grade neuro epithelial tumor BCOR.
The diagnosis is an extremly rare brain cancer only discovered two years ago and thier has only been 7 reported cases in the us. Out of the 7 there has been 2 survivors in remission. The longest 18 months. All others lost there lives .
We are trying to stay positive and know how strong our little guy is and praying our hardest he makes it through I don't know how to get through this watching him go through this.
Daddy has had to give up 2 jobs to be with us during treatement and to care for our other children.
We have relocated to Boston for 7 weeks during his treatment.
We are working with three different teams but no one has any idea how to treat this or what will work if anything.
THESE ARE THE CHOICES WE WERE GIVEN FOR TREATMENT
https://m.facebook.com/story.php?story_fbid=342828593192025&id=332889224185962
We have started ATRT
Update...
I think were going with ATRT but just having a really hard time saying yes for sure. The bad downfalls of this treatment is..
1. Causing leukemia
2. No children later
3. Effects hearing badly
4. Effects eye sight
5. Needs a gtube so surgery
6. In patient for 12 months
7. Lots of muscle pain
8. More risk for infection
9. Higher risk of loosing him
10. More blood transfusions
11. Longer treatment time
Benefits
1. Treats both types of cancer they think he has
2. Better life expectency treating both
3. Hopfully cures him treating both
4. Less risk of it returning
5. Tumor is less agressive treating then if it goes away and comes back
6. Goes through treatment once if it works
7. Other docs are now going towards this treatment after patients relasped with just embryonic for this cancer.
8. Two of the best docs in the world are saying its his only chance through this. Dana farber and canada.
Yesterday was a scary,heart breaking day for myself and justin. I've been spending every available minute to talk to researchers and docs and differant referral people for weeks now all around the world trying to get any info on chandlers type of cancer and others opinions on our chemo choice. We have 5 opinions which are described in detail attatched.
1. (St judes plan) do embryonic chemo for 4 cycles. They have had all young with this and one in remission for 18 months now.
2. (Danafarber plan) ATRT which is very intense in patient for 12 months
3. (National doc) Treat it embryonic like st judes but one for 6 months instead of 4.
4. (Another doc) has had a patient in remission doing the embryonic for almost a year and a half before relapse and now doing treatment on a simular line of ATvRT.
5. (Canada doc) said go with the arrt because she believes after looking at the pathology he has sarcoma cells and the ATRT is the only one that will treat sarcoma and embryonic.
His oncologists says she would go the embryonic 6 months and if it comes back then treat like ATRT.
My concern is if it is sarcoma cells it will go untreated and it comes back because those cells arent treated he has to undergo treatment again and his tumor would be alot more resistant and angry. Also cant be radiated again or have embryonal treatment again. Will his body beable to handle a intense treatment then a very intense after??
Justin agrees with oncologists.
Chandlers blood level was low and his doc expects it to fall lower from radiation so watching close incase he needs blood transfusion.
Chaner is at a very big risk of developing seizures because of the brain surgery which i was never aware of till yesterday. She also said his hearing will be effected badly about 4 months after proton from the radiation.
Side effects he will have with all treatments.
Will require placing an NG tube. He will develop septisemia multiple times. Get a fever,lots of hospital time,nausea,vomiting,medicine to force his body to make new white cells to fight infection,lots of blood transfusions.
The ATRT treatment requires 12 months of in patient hospital treatment.
It would would treat everything if he does have sarcoma cells as well but a lot riskier and long term effects. Ver dangerous but may save his life. The only way to tell if his tumor has sarcoma cells is to test his live fresh tumor cells but does not has any left.
This treatment has never been tried yet.
The embryonic one has failed many times with one patient we know of in remission for 18 months and another in remission for year and a 1 13 and just relapsed with embryonic.
Im so upset,confused and frustrated. How do i make a decision like this. I was told we have one chance to cure him. If it comes back it will be very resistant and they could only keep him comfortable and could try things but it may be to resistant.
I cried myself to sleep just thinking about my baby going through these horrible treatments and more surgery along with living in a hospital and then it coming back and having to do it all over again and loosing his life anyway.
I feel as though if he has to endure all this pain and suffering i need to be too. Its my place as aparent. I feel i HAVE to FIX this somehow someway and save my baby's life.
If thier is a god then why make a child suffer this way and fight for his own life before its barely began?? There is no greater plan and thats why this is happening because to me my babys future and life is the greatest only plan.
I have just 2 weeks to be with him before all this starts and just want to fly away from here and give him the best vacation
This chandlers diagnosis
CNS HGNET-BCOR BRAIN TUMOR
Due to the noted radiosensitivity of the tumor, re-irradiation with 44 Gy (5 x 2 Gy/week) of the former position of the metastatic skull lesions was performed (high parietal/frontal and occipital) (Figure 4C and 4D). Re-irradiation was done with 3 cm safety margin and included the newly formed dural lesion which was re-irradiated to 44 Gy (Figure 4D, circle). ATO w
Radiographic follow-up using magnetic resonance imaging (MRI) revealed a continuous treatment response with the patient achieving complete remission (CR) with no measurable disease activity seven weeks after the initiation of relapse therapy (calculated starting from the first ICE block) including four weeks of targeted therapy with intravenous ATO (Figure 5A-5). CR was confirmed by a further MRI nearly two months later. Five months after the initiation of the relapse therapy (and 6 months after the resection of the metastases) the patient developed cranial and extra cranial metastases in lung, liver, spinal column and bones (Supplementary Figure 1). Notably, the former site of relapse in the skull was not involved.
The target lesion is sensitive to the targeted therapy.
Figure 5: The target lesion is sensitive to the targeted therapy. MRI showing the dural lesion developed under the first line therapy (A-B), before the start of the targeted therapy (C) and at the time of CR (D).
Following the diagnosis of progressive, systemic disease, we switched to an oral ATO formulation in order to forgo hospitalization of the patient. To increase the plasma arsenic concentration, we extended the oral formula dosage of ATO to 0.3 mg/kg (ATO III). The oral ATO formulation was prepared in our hospital pharmacy based on the publication of Kumana et al. [26]. The administration of parenteral ATO is well established in the therapy of acute promyelocytic leukemia (APL) and the oral formulation of ATO appears to have a comparable efficiency [26, 27] although, the clinical use of oral ATO in pediatric patients is less common. ATO was well tolerated intravenously and orally. No adverse cardiac effects, in particular, QT prolongation [28] or any skin reactions were observed. Furthermore, P1 did not develop any electrolyte disturbances with oral substitution of potassium. The oral ATO was given continuously for a period of four weeks. Due to the highly malignant nature of the disease, P1 died 22 months after initial diagnosis and 10 months after relapse.
The concentration of arsenic in plasma and CSF samples of P1 didn’t reach the IC50
The total amount of arsenic at the end of each cycle was 48.3 μg/l (ATO I) and 46.9 μg/l (ATO II) in plasma and 9.1 μg/l (ATO I) and 6.5 μg/l (ATO II) in CSF. After 2 weeks of ATO III, the concentration was 45.3 μg/l in plasma and 9.7 μg/l in CSF. In accordance with several reports [29], we observed a linear correlation (r =0.854; p <0.05) between the two compartments, with CSF levels at 16.5% of the plasma level. This was equivalent with a plasma/CSF ratio around 6:1. Regarding the systemic bioavailability of ATO, parenteral and enteral administration provided comparable concentrations in the plasma and CSF compartements. These results coincide with findings from adult APL patients treated with intravenous and oral ATO [26]. In conclusion, the maximal arsenic concentration achieved in P1 was of 48.3 μg/l in plasma and of 9.7 μg/l in CSF corresponding to a maximum arsenic concentration of 645 nM and 129 nM respectively, a concentration that was below the IC50.
The BCOR ITD is maintained in the systemic metastases
Because tissue biopsies of the systemic metastases at the time of the second relapse were not performed, we used peripheral blood to monitor the tumor status in P1, especially the persistence of the BCOR ITD under the targeted therapy. First we established primers for the detection of the BCOR ITD. The sequence of the BCOR ITD of P1 has been already described [4]. The primers detected the BCOR ITD in the genomic DNA extracted from the primary tumor and a metastasis from P1 but not the BCOR wild type (wt) in the genomic DNA extracted from the blood of P1 (Figure 6A) and had an efficiency of 100% (Figure 6B). We extracted the ctDNA from four samples of peripheral blood at different points of time after the detection of CR by MRI. One sample was collected 24 days after the radiographic detection of CR and three further samples were collected prior to the radiographic appearance of systemic metastatic disease. The concentration of the ctDNA ranged from 0.338 ng/μl to 5.820 ng/μl. The ctDNA was highly fragmented as expected [30] with a median size of about 160 bps (Figure 6C). Twenty-four days after the CR, the concentration of the BCOR ITD was at the limit of detection of our assay (Figure 6D). After circa two months, a clear increase in the concentration of the BCOR ITD was detectable and reached the maximum four days before the radiographic detection of the systemic metastases by MRI (Figure 6D, day 108). These data indicate that the BCOR ITD is still present in the lesions that developed after the systemic spread of the disease and that the liquid biopsy of peripheral blood represents a powerful method for the early detection of systemic metastasis in these patients.
The BCOR ITD is maintained in the systemic metastases of P1.
Figure 6: The BCOR ITD is maintained in the systemic metastases of P1. (A) BCOR ITD specific primers were used for PCR analysis of the genomic DNA extracted from the primary tumor (lane 1), a metastasis (lane 2) and the blood (lane 3) of P1. The expected product of BCOR ITD is 117 bps. (B) The genomic DNA extracted from the primary tumor was diluted at different concentrations. The –log of the concentration in ng/μl is shown on the x-axis. The threshold cycle (ct) is shown on the y axis. The slope of the standard curve was used to calculate the efficiency of the primers. (C) The size of the isolated ctDNA was analyzed using a Bioanalyzer. The y axis shows the signal intensity (FU) and the x axis the size distribution in bps. The circle indicates the purified ctDNA. (D) The concentration of the ctDNA was calculated based on the standard curve in B and reported as ng of ctDNA per μl of purified ctDNA (ng/μl) on the y axis. The x axis report the days of the plasma collection with respect to the time of the complete remission as assessed by MRI (x=0). To facilitate the comparison with the sketch in Figure 3, the datum of the plasma collection is also reported.
The SHH pathway is upregulated in a second CNS HGNET-BCOR patient (P2)
CNS HGNET-BCOR is characterized by tandem duplication in exon 15 of the BCOR gene. This tandem duplication can be of different sizes. We analyzed exon 15 in the genomic DNA extracted from the blood and the primary tumor of P1 and from the primary tumor of P2 by PCR (Figure 7A). Only the BCOR wt could be detected in the blood of P1, only the BCOR ITD could be detected in the tumor of P1 and the wt and the BCOR ITD could be both detected in the tumor of P2. This can be explained by the fact that BCOR is located on the X chromosome and therefore male individuals carry only one allele. We cloned and sequenced the BCOR ITD in P2 revealing an internal tandem duplication of 126 nucleotides (42 amino acids) (Figure 7B). If the presence of the wt BCOR allele in female patients can influence the severity of the disease remains to be elucidate. The insertion in P2 is larger than that detected in P1 and is one of the largest described at the time of this publication [1]. The ITD of P2 and P1 are both localized in a domain required for the binding of BCOR to a Polycomb proteins complex [31]. We validated the upregulation of the SHH pathway in P2 by qRT-PCR. Expression of BCOR in P2 was even stronger than in P1 (Figure 7C). To functionally validate the activation of the SHH pathway, we analyzed the expression of GLI1, GLI2 and PTCH1. All three genes were highly expressed in P2, even stronger than in P1. These results confirm the assumption that the upregulation of the SHH pathway is a common feature of HGNET-BCOR. However, while the expression of GLI2 was confirmed at the protein level in tumor material extracted from P1 (Supplementary Figure 2), no fresh frozen material was available to perform the analysis in P2 and we cannot conclude if the higher RNA expression in P2 corresponds to a higher protein expression.
The SHH pathway is upregulated in an additional CNS HGNET-BCOR case.
Figure 7: The SHH pathway is upregulated in an additional CNS HGNET-BCOR case. (A) The sequence of exon 15 of BCOR was analyzed by PCR in the genomic DNA extracted from the blood of P1 (lane 1), the primary tumor of P2 (lane 2) or from the primary tumor of P1 (lane 3). The sizes of the wt BCOR and of the BCOR ITDs are indicated. (B) Protein sequence of the BCOR allele of P2 carrying the ITD compared to the wild type BCOR and to the BCOR ITD detected in P1. (C) qRT-PCR analysis was performed using primers recognizing BCOR, GLI2, PTCH1 or GLI1. After normalization to the housekeeping gene HPRT1, the fold change of the expression of P2 with respect to P1 was calculated. Expression analysis was done in triplicates. Expression analysis was done on RNA extracted from FFPE material.
Treatment of P2 was given according to the Children’s Oncology Group ACNS 0334 protocol, in an attempt to delay or avoid radiotherapy [32–34]. Therapy consisted of three induction cycles of chemotherapy, including high-dose methotrexate, and three consolidation cycles of myeloablative chemotherapy with autologous hematopoietic stem cell rescue. However, as more information on the propensity of this tumor entity to relapse became available, a decision to treat with low-dose craniospinal irradiation (18 Gy) and tumor bed boost (54 Gy) was made. Treatment details of P2 can be found in the Supplementary Materials. To date, 20 months from diagnosis and 10 months from completing treatment, the patient remains in clinical and radiological remission.
DISCUSSION
HGNET-BCOR is a recently described rare tumor entity of the central nervous system for which optimal treatment protocols are yet to be defined. Because patients with HGNET-BCOR were previously diagnosed as other entities, several treatment protocols have been attempted. To date, protocols for the treatment of CNS-PNET, glioblastoma and ependymoma have been used, all of which have included high doses of chemotherapy and radiation. According to the available data on follow up, no protocol has been successful in the treatment of this tumor entity with most patients developing progressive disease [1]. A recent clinicopathologic and molecular characterization of 3 cases of HGNET-BCOR [35] confirmed the difficulty encountered in controlling this tumor entity using surgical resection of the primary tumor followed by radiation and chemotherapy. Here we show that the combination of conventional sarcoma-based chemotherapy, irradiation and ATO administration led to complete remission after extra-cerebral relapse with six months of progression-free survival.
Available microarray data suggest that the upregulation of the SHH pathway is a common feature of HGNET-BCOR. We have previously validated the activation of the SHH pathway in P1 [4] and in this work in P2. Thus, a targeted therapy against this pathway is of interest for HGNET-BCOR patients. The therapeutic effect of the SMO inhibitor itraconazole has been recently discussed in one HGNET-BCOR female pediatric patient [35]. Unfortunately no in vitro data on the sensitivity of the HGNET-BCOR cells to itraconazole were available for that patient. Moreover, SMO inhibition causes permanent defects in bone structure in young mice, and its use in young children has to be carefully considered with respect to long-term toxicities [36]. Our data suggest a partially SMO-independent GLI transcriptional activity in the PhKh1 cells which has been described in other tumor entities. A possible mechanism for the SMO-independent activation of GLI could rely on the presence of the ITD. BCOR enhances BCL6-mediated transcriptional repression by interacting with histone deacetylases (HDAC) [37]. Moreover, BCOR forms a complex with Polycomb proteins and can act as an epigenetic repressor [38]. BCOR wt can repress the expression of GLI1 and GLI2 [39]. The ITD is localized in a region required for the binding to the Polycomb complex and required for the full activity of BCOR [31]. Thus the ITD may interfere with the repressor function of BCOR leading to the upregulation of GLI1 and GLI2. This hypothesis has to be validated but it is in line with the observed upregulation of GLI transcripts in clear cell sarcoma of the kidney which also express the BCOR ITD [2]. Thus, targeting the SHH pathway downstream of SMO at the level of the GLI transcripts using ATO is a particularly attractive approach in HGNET-BCOR. Here we show that ATO reduced the transcription of GLI target genes in a primary culture of HGNET-BCOR. In APL, ATO triggers the degradation of the PML–RARα fusion protein, probably by binding to a cysteine-rich region [40]. However, no cysteine-rich regions are created by the presence of the ITD. Thus, the effect of ATO on GLI in HGNET-BCOR is probably direct and not via BCOR. Indeed ATO has been shown to reduce GLI activity by direct binding to GLI proteins [7]. Moreover, the upregulation of GLI itself seemed to be responsible for the ineffectiveness of conventional chemotherapy [41, 42] and earlier studies demonstrated additive effects of ATO with conventional chemotherapeutic agents such as cisplatin, adriamycin, and etoposide [43, 44]. The down-regulation of GLI transcription factors via ATO to sensitize HGNET-BCOR cells to conventional chemotherapy, particularly to the sarcoma-based chemotherapy applied in the relapse protocol warrants further investigation.
The radiosensitivity of HGNET-BCOR is suggested by the growth of the skull metastases outside of the high dosage area. The relevance of postoperative craniospinal irradiation in patients suffering from CNS HGNET-BCOR has been recently discussed [35]. However, irradiation alone was not able to control the progression of the disease in P1. Indeed, the target lesion developed in a region that was irradiated with 59.4 Gy during the irradiation of the primar
Update: Central nervous system high grade neuroepithelial tumor with BCOR alteration
June 1, 2018 by neurosurgery.directory
Central nervous system high grade neuroepithelial tumor with BCOR alteration
Central nervous system high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3′ end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features.
CNS HGNET-BCOR display pathological overlap with CNS-PNET and other histological entities 1).
The high expression of IGF-2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity 2).
High expression of altered BCOR transcripts in CNS HGNET-BCOR tumors suggests a different mechanism from BCOR loss-of-function mutations reported in other malignancies, such as medulloblastoma 3) 4).
Yoshida et al., performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS 5).
Kirkman et al., describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor.
This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques 6).
Appay et al., reported in 2017, 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of “embryonal tumors” or within the category of “mesenchymal, nonmeningothelial tumors” remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity 7).
. T, Kohashi K, Oda Y, Hirato J, Yokoo H. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol. 2017 Dec 11. doi: 10.1111/bpa.12585. [Epub ahead of print] PubMed PMID: 29226988.
Kirkman MA, Pickles JC, Fairchild AR, Avery A, Pietsch T, Jacques TS, Aquilina K. Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report. World Neurosurg. 2018 May 30. pii: S1878-8750(18)31112-4. doi: 10.1016/j.wneu.2018.05.158. [Epub ahead of print] PubMed PMID: 29859355.
Abstract
The central nervous system (CNS) high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a recently described molecular entity. We report 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of "embryonal tumors" or within the category of "mesenchymal, nonmeningothelial tumors" remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity.7xxx xxx''x
Identification of Four New Molecular CNS Tumor Entities
Our initial clustering analysis of CNS-PNETs identified four new molecular entities designated “CNS NB-FOXR2”, “CNS EFT-CIC”, “CNS HGNET-MN1”, and “CNS HGNET-BCOR”. To explore whether these molecular entities were also diagnosed other than CNS-PNET, we compared DNA methylation patterns of each entity with an in-house collection of > 10,000 profiles from a broad variety of pediatric and adult CNS tumors (data not shown). Subsequent clustering analysis identified 59 tumors with diverse histological diagnoses that now grouped with one of the four new CNS tumor entities (Figures 3 and S3A-C, Table S3). While the enlarged CNS NB-FOXR2 (n = 46) and CNS EFT-CIC (n = 15) clusters represented entities with almost exclusive CNS-PNET histology (Figure 3), the CNS HGNET-MN1 cluster (n = 41) included 16 tumors histologically diagnosed as astroblastoma (ABM) – rare WHO-defined glial tumors – supporting the concept that they are distinct from conventional diffuse glial neoplasms (Louis et al., 2007). The CNS HGNET-BCOR cluster (n = 34) was expanded by a variety of CNS tumor histologies. Again, molecular subgroup assignment by transcriptomic profiling recapitulated DNA methylation-based clusters (Figures 3A and S3A) and allowed the identification of three additional tumors included in further gene expression analyses.
Identification of New CNS Tumor Entities Across Histologies
We correlated each of the four novel CNS tumor entities with available basic clinical parameters (Figures 3C-F). Noticeably, the gender ratio was strongly shifted towards females in the CNS HGNET-MN1 (p < 0.001), as also observed for ABM (Louis et al., 2007). Patient age at diagnosis in CNS HGNET-MN1 was higher compared with other entities (p < 0.001). There were no clear differences in tumor site of occurrence, although occasional cerebellar location was restricted to tumors of the CNS HGNET-MN1 and CNS HGNET-BCOR entities. Infratentorial, non-cerebellar location was not associated with a specific molecular CNS tumor entity. Surgical and pathological reports of four CNS EFT-CIC tumors did not indicate meningeal or osseous origin. Available survival data suggested differences between the novel CNS tumor entities, with significantly better overall survival observed for patients from the CNS HGNET-MN1 compared to the CNS HGNET-BCOR entity (Figure S3D).
Histopathology of New CNS Tumor Entities
Histopathological review was performed on 30 CNS NB-FOXR2, 14 CNS HGNET-BCOR, 10 CNS HGNET-MN1, and four CNS EFT-CIC tumors (Tables S2A-C). The CNS NB-FOXR2 entity displayed embryonal architectural and cytological features with a small-cell phenotype (Figures 4A-C). Areas of differentiation in the form of neuropil, neurocytic cells, or ganglion cells were observed in a high proportion of tumors (Figure 4C). Frequent perivascular anuclear zones (“vascular pseudorosettes”), nuclear palisades, and Homer Wright rosettes were encountered in individual samples (Figure S4A, Tables S2B/C). This group encompassed tumors that would be classified as CNS neuroblastoma or CNS ganglioneuroblastoma in the 2007 WHO classification scheme (Louis et al., 2007) (Figures 4A-C). CNS NB-FOXR2 tumors nearly uniformly expressed OLIG2 and the neuronal antigen synaptophysin (Figures S4A/B).
Histopathological Patterns of New CNS Tumor Entities
The CNS EFT-CIC entity was also characterized by a small-cell phenotype but with variable histology (Figures 4D-F). The tumor architecture included both alveolar and fascicular patterns of growth. Although tumors were uniformly high-grade, this group lacked defining histological features and failed to express markers of differentiation.
The CNS HGNET-MN1 entity (Figures 4G-I) consisted of circumscribed high-grade tumors containing a mixture of solid and pseudopapillary patterns. Dense pericellular hyalinization was frequently present in this group. Some had the typical pathology of the tumor termed astroblastoma (ABM) in the current WHO classification system, whereas others were harder to align with that diagnosis. The majority of tumors (16/23) from our current database histologically diagnosed as ABM belonged to this molecular entity. Thus, we consider it unlikely that there is an additional true ‘astroblastoma’ entity other than the MN1-altered entity outlined here.
The CNS HGNET-BCOR entity consisted of relatively compact tumors with a combination of spindle to oval cells. They often exhibited perivascular pseudorosettes, giving the tumors an ependymoma-like appearance (Figures 4J-L). Tumors frequently demonstrated fibrillary processes, typical of glial differentiation, and only in rare instances exhibited true embryonal morphology.
Tumors from CNS HGNET-MN1 and CNS HGNET-BCOR entities frequently expressed GFAP, but neuronal antigen expression was either focal or absent. In comparison, mitotic counts were high for CNS NB-FOXR2 and CNS EFT-CIC tumors, but lower for the other two entities (Figure S4C).
Genetic Alterations Define New CNS Tumor Entities
For each of the four new CNS tumor entities, we next inspected copy-number profiles derived from DNA methylation arrays. Gain of chromosome arm 1q was characteristic for the CNS NB-FOXR2 entity (43/44, 98 %; p < 0.001) (Figure S5A). Further broad aberrations included loss of 16q in CNS NB-FOXR2 (21/42, 50 %) and CNS HGNET-MN1 (12/37, 32 %), and gain of chromosome 8 in CNS NB-FOXR2 (14/44, 32 %), CNS EFT-CIC (3/13, 23 %), and CNS HGNET-MN1 (6/38, 16 %) tumors. Most tumors from the CNS HGNET-BCOR entity displayed balanced copy-number profiles. We only detected high-level focal oncogene amplifications of MYC and CDK4, each in one CNS NB-FOXR2 sample, and EGFR and CDK4 in one CNS HGNET-MN1 sample (Table S4). Homozygous deletions of CDKN2A were found in two CNS HGNET-BCOR and one CNS HGNET-MN1 tumors.
In order to identify genetic alterations that underlie each of the four new, molecularly defined CNS tumor entities in greater detail, we performed genome-wide DNA and RNA sequencing of all cases with available fresh-frozen tissue (Table S4). As outlined below, we found that each entity was characterized by a recurrent genetic alteration.
CNS Neuroblastoma with FOXR2 Activation (CNS NB-FOXR2)
Genome-wide sequencing revealed complex inter- and intrachromosomal re-arrangements converging on forkhead box R2 (FOXR2) in 6/8 samples with available data, leading to increased FOXR2 gene expression levels in CNS NB-FOXR2 tumors compared with other CNS tumor entities (Figure 5A-C). Three of the detected events resulted in fusion transcripts retaining the full coding sequence of FOXR2, with upstream non-coding exons forming a novel transcript variant fused to different fusion partners (Figures S5B/C). These included JMJD1C as a result of a complex interchromosomal translocation involving chromosome 10, and LOC550643 and JPX as products of tandem duplications on chromosome X. These duplications were also detectable by characteristic copy-number changes in three samples without available sequencing data (Figure S5D). We further identified a recurrent deletion between full-length FOXR2 and MAGEH1 in two samples. Copy-number data indicated additional alterations targeting the FOXR2 locus in seven samples (Figure S5D), with a deletion reaching ~ 500 kb upstream of FOXR2 as the most frequent event (4/46, 9 %), potentially fusing FOXR2 to the MAGED2 gene. Moreover, we identified a mitochondrial DNA insertion within USP51 that led to the formation of a novel FOXR2 promoter (Figure S5E). Mitochondrial-nuclear genome fusions have been recently reported to occur frequently in cancer (Ju et al., 2015), but this is the first example where such an event induces oncogene expression. Since FOXR2 is not expressed in other CNS tumor types (Figure 5C) or normal brain tissues, these events are suggestive of FOXR2 activation facilitated by promoters of active genes (Figure S5F), thus instigating oncogenic activity (Rahrmann et al., 2013). One exceptional tumor that did not show elevated gene expression of FOXR2 was the only one to harbor a focal amplification of MYC, resulting in upregulated MYC gene expression compared with FOXR2-activated tumors (Figure S5F). The FOXR2 homologue FOXR1 is recurrently activated in peripheral neuroblastoma counterparts by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts (Santo et al., 2012).
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Abstract
High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity which was formerly diagnosed with diverse histological diagnoses, for example as ependymoma. This tumor predominantly affects children and has a dismal prognosis. No standard therapies for this entity exist so far. Recently we described the activation of the Sonic hedgehog (SHH) and the WNT signaling pathway in this tumor and described a primary cell culture (PhKh1) isolated from a skull metastasis of a seven years old patient. We also detected a high expression of IGF2, which is known to be required for SHH signaling in medulloblastoma. IGF2 signals through IGF1R leading to cell growth via the downstream PI3K/Akt pathway. In pediatric brain tumors high expression of IGF2 has been described in ependymoma and may acts as a molecular target. Here we analyzed the expression of IGF2 in our transcriptome data of 12 pediatric brain tumors patients (6 medulloblastoma, 2 glioblastoma, 2 anaplastic astrocytoma, 1 HGNET-BCOR and 1 ependymoma relapse). The highest expression of IGF2 was detected in the HGNET-BCOR and ependymoma samples. The high expression of IGF2 was maintained in the PhKh1 cell line and was similar to the expression detected in a primary cell culture isolated from the ependymoma relapse. Incubation with increasing concentrations of an antibody that blocks IGF1R resulted in a great reduction of the cell proliferation of the PhKh1 cell line but not of an IGF2-negative control cell line. In conclusion, the high expression of IGF2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity
Latest update..
So today has been terrible. Chandlers oncologists is back from vacation and looked over the scans ect and said shes extreamly concerned the mass is cancer and from the brain tumor. She said there is a very slight chance its something else. No one has seen this in this area and its floating around near his back wall near the hips and probably is giving him pain amd definately the feeling he has to pee all the time even after going. The two surgeons here dont know how to get at it or dare to try and even touch this so the doc sent everything to boston and there trying to figure out which surgeon team can attempt this. They also will have to radiate the area as well so he will need to go through that again as well. We are waiting for a day to leave for boston again. We havnt even got feeds worked out yet. He is on his way home for the night and awaiting the call. Im trying my best to hold hope and have faith hes got this but honestly i will never understand. All my baby wants is to hang out with a friend and not to feel bad for one day. I dont know how but chandlers still smiles. Its beyond me after all this he still is. Again my little girl will have both parents away and shes alone to deal with all this and not have us to talk to. Its so hard on her. Please donate if u can to help with dads time from work. Its been a few weeks since hes worked at all and will be a while before he goes back. There will be alot of expenses that will go along with this trip and surgery too. Please share
Ok so the latest update on Chandler is he had 6 1/2 hours of laying completely still on a table for testing. We found out all the belly pain and nausea was from his gallbladder completely failing him. He needed help with nutrition now because hes lost two much weight and has been unable to drink or eat at all on his own without causing him horrible pain. 4 days ago Chandler again went into surgery for 2 surgeries this time. Gallbladder removal and to put a g tube in place ..Poor chandler had a very rough night and pain control was extreamly difficult . The next day he cried alot and was very sensitive to any touch or pressure and wouldn't move because it hurt to bad. The 3rd day he was able to stay awake more and move around a bit . He was a very happy guy to go home. He is still extreamly sore and cant stand up straight while walking or sit up much because it causes pain but refuses pain meds. He wont drink or eat at all and docs think its because hes getting to much through the g tube but hes only half way to what the docs want him at and not tolerating that. We are lowering his feed again tonight and we will see what happens tomorrow and decide next steps. I can say my baby boy is still smiling and has got a positive attitude and says he feels so much better now. It broke my heart to hear him scream in pain all the time. Monday we start in patient ATRT chemo for 12 months. Please keep him in your prayers and share this as much as possible to find other patients and info that might save his life from this very rare cancer.
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Chandlers make a wish cant fill his wish till a little while after hes done treatment and cant start the garden before because the whole wish needs to be done together. He wont be done chemo for over a year. Anyone who knows chandler knows his favorite thing in the whole world is flowers. Id love to give him a real big beautiful garden, water statue things,fountain,lights. Whatever we can do to make it nice for him. We couldnt get make a wish to do a pond because of ground work and such but if they had it wouldve been a long process. He has a big long list of flowers he wants in his garden. Anyone that could volunteer for ground work,plans for a garden ect or donate things for his garden would be most appreciated. Please let me know if u can help make this happen this spring. I dont have much time and cant do it on my on.
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Im having a particularly hard time tonight. Im getting ready to give chandler his chemo myself and getting all dressed up and laying my special chemo stuff out gloves,mask,proper disposal to make sure to protect myself the nurse said i have to but i cant stop thinking about myself putting poison into my baby. Something i cant even get on my skin. Something thats killing good and bad inside his little body. Im told i cant wipe his tears away without gloves on one medication then the same one makes his pee and tears red. All take many cautious actions to inject. All make him sick and cause some sort of pain. Im about to do it but feel so sad,and guilty knowing hes gonna wake up sick and i put that yucky, terrible medicine in him. I dont know how moms do this cause im having such a hard time bringing myself too. I wish i had my mom here with me in a time like this. Im sure some are thinking its for his own good to fight this cancer and yes i know that but how did this happen to my baby. I'll never stop asking that and wondering whyú6hiyou*&in him. Look at my precious boy sleeping so peacful right now happy to be home.
Chandlers oncologist in maine called and said the preliminary frozen results of the mass in his pelvis are saying it is scar tissue. Thank god and we are so relieved. We won't know for positive till the real pathology comes back but its great news!!
yu
His tumors sadly returned with only 5 more treatments left. It started with a tumor in his spine then 3 now 4. We started a new chemo hoping this would help but after round 2 we did an mri of brain amd spine and unfortunaty we got terrible results. Chandlers spinal tumors didnt only grow but now had spread back to his brain and he was also diagnosed with leptimengeal disease meaning his entire linning of his brain was covered in a thick layer of cancer. He has 5 tumors in his brain along with the 4 in his spine . Chandlers oncologists now says he has approx 3 months to be with us. She said she checked on clinical trials but chaer did not quailify for any of them and Maine nor Boston would attempt to remove the spinal tumor that was so threatening to his life. I was just standing there all alone with my daughter during our mom and daughter fun day trying so hard not to upset her a d let her know there was something really bad happening. My little girl is such a good big sister and deserved my focus and attention on her. I went on with our next hour together trying to hold it together but was truely crushed by this news and i was shivering,trembling in fear for my little boy. I wanted to scream, pound on something. I needed to understand why my little boy why does he have to figbt so hard nust to continue being punished and feel pain,every single minute every single day. Why,how do i watch him deteriate, continue fighting for what?? To hear the words from his oncologists im putting a call into hospice and we wil make him as comfortable as possible was soul crushing. My daughter wanted to sit in the front seat with me but i knew icouldnt so i had her sit in the back to controll my emotions. I cried all the way home and just about 10 mins before getting home i lost it. I had a total breakdown and couldnt control the crying and anger i felt. My daughter jullianna came into the front seat and said mommy whats wrong? I said its ok baby im just really sad but ill be ok. She hugged me tight and said mom i know its chandler but he will be ok. I love you. I hugved her back my precious girl and told her to go see daddy. Just before i hung up with the oncologist she said kristin i want you to understand its not your fault there nothing you couldve done to prevent this and ive never seen a mom in all my years fight for there son and make calls all around the world telling chandlers story to all the best docs like u have. She said the research youve done and the love for your son is unbelievable. I responded i dont care because it was for nothing hes dying and theres nothing i can do. Then i begged her to help me. There was a long silence then she said im so so sorry i wish there was something i could do but this cancer is just to strong and we dont know how to treat it. I promise to make him as comfortable as i can. My husband came out and wanted to know what was going on and i could barely get the words out. I grabbed him tight and cried on his shoulder for quite sometime. I told him to go to chandler while
I got myself together. I sat there for hours trying so hard but couldnt. My husband came out and said chandler was crying for mommy but told me i had to pull it together for chandler because he couldnt see me like that. I got inside and see him on the couch with a huge smile on his face yelling mommy your finally back come look at my invention. I held him told him how much i loved him and how special he was. We were called in for an oncology appt the next day and we told the doctor we werent ready to give up on our son what can we do. She said there really isnt anything we havnt tried. This cancer is impossible to get rid of. If u really wanna put chandler through more treatment even though it wont help i can look into raduation again for the spine but his brain could not be treated till after the spine radiation was dine and a 6 week break in between and even then didnt think the radiation would work and the brain would shut down fast. My husband and i were beside our selves with fear and uncertainty then we got the call. I had called all around the world literally to all the best docs for opinions and options 2x and it payed off. Washington dc offered to enroll him into a clinical trial in dc to try and save him and there surgeon had agreed to remove as much as he could of the life threatening tumor. We had 24 hours to get there. With a little help from some wonderful organizations we were able to get him there. We traveled weekly to dc from maine for months being home just a couple days a week. Sadly we found out chandler didnt respond to the trial at all and was taken off and now that brings us to here. My husband has done alot of research as well and found a drug used on one child ever in germany with some promise for stopping this cancer. This is a huge risk not knowing what interacts with this med or how he will respond and could end his life if something goes wrong. What choice do we have though?? He will die if we dont and doesnt have long. This medicine is $1000 perday 1 pill per day. Wow how were we gonna do this. What toxisities may it have. We are hopeful but also scared so scared. Chandler right now can barely sit up or walk with excruciating pain. His tumor behind his eye is swelling and he cant see anything up close now just far away and if he tilts his head. He still has numbness down his entire side from the spinal surgery and his cancer is spreading rapidly. Tomorrow is the day we start this new treatment in hopes that he will respond quickly and get the miracle he deserves so much. Make all his fighting ,pain and determination worth it. When i told him we were starting his new chemo tomorrow u know what he said to me. Chandler just 9 years old fighting almost 2 years now said mom its ok i know. I just wanna go see the grand canyon quick. What a precious gift from god he is. Please pray for us. For chandler that he gets his miracle he so deserves.
My guy posseses more strength than anyone could ever imagine and backs it up with a positive attitude and a huge smile and a kind heart. He has an incredible love for life and everything good it has to offer. His determination to survive this is endless.
https://www.facebook.com/chandler8cancer/videos/1906968366265505/
Chandlers results were heart breaking today. A mothers worst fear.
Hi, i want to tell u all about chandler but dont want to answere ?s or calls now. Today chandler had a brain mri and they found the cancer is back but instead of a tumor its everywhere throughout his brain. Mostly in his brain stem and one in his spine. His heart rate was only 50 to 60 which is extreamly low. The oncologists said chemo will only prolong his life a tiny bit if at all and radiation in his spine make him him a little bit more comfortable. She said the inflammation is no dont causing him so much pain. She said he will get worse and worse fast everyday. He was supposed to start radiation tomorrow and pallitive care. They want hospice and medical equipment in the house asap. I look at him and still see that big bright smile and sassy behavior with dreams for his future and just keep asking why? He doesnt look like he is in as bad of condition as they say. Im so broken. He doesnt know and no way can i tell him. I love him with all my heart and soul. I want to wrap my arms around him and never let go telling him how much i love him but he wont let me close or to say i love u. He says hes to big for that. I have streams of tears running down my face and cant control them so im sitting here all alone but wanna go be with him but dont want him upset. Im trying to get my mom and boyfriend back up from florida. Ive asked justin to stay with us and not work because he needs to here. We need to be together every minute. I dont care if we fall behind on bills, loose things whatever chandler needs to know how loved he is and that we wont leave him at all. How do i watch him go through this? How does he with stand this and the pain. How do i keep telling him i will help him with all his big dreams and plans. I wish god would take me instead. I cant loose him..
This is what chandler has. I thought his speech slurring, eyes rolled up and very droopy, moodiness,and exhaustion was from meds but apparently its all part of this. The oncologist is now putting him on seizure meds because they will start due to intercranial pressure.
A cancer can metastasize (or spread) to a single location or to multiple locations in the brain. It can also spread to the cerebrospinal fluid or to the leptomeninges, the outer lining of the brain and spinal cord. This type of metastasis is known as leptomeningeal disease (LMD), or leptomeningeal carcinomatosis.
Since LMD cancer cells float in the cerebrospinal fluid, they can quickly spread throughout the central nervous system. As a result, LMD has a poor prognosis
HIS STORY FROM THE BEGINNING
My 7 year old little boy Chandler was life flighted from emmc hospital in Maine to the children's Boston Hospital to get removal of a life threatening brain tumor removed on sat.
He was given a small chance of survival by many but his surgeon was hopeful. It was successfully removed Monday evening but he will have a long road ahead of him.
He is facing chemotherapy and radiation and I'd like to continue his care in Boston with his doctors that know him best. We will be starting this as soon as possible to try and ensure no regrowth of the brain tumor. He will be followed for years.
He is not completely out of the woods yet but he looks a lot better. He is still in a lot of pain and on morphine and lots of other meds. We are still very scared what will tomorrow and the future holds for him.
We have another son in a residential hospital as well out of state for 8 months now and have lots of traveling expense with this as well.
My husband will be out of work for some time and thier will be a lot of financial that come along with this. We have four kiddos and would like to have the family together through this so any help is greatly appreciated.
My little boy has had a smile on his face through all of this and a positive attitude and he's been an incredible strong little guy.
Chandler will need the best possible care. The docs stated this is the worst brain tumor ever seen in the pediactic Boston Hospital in his 30 years and in a terrible spot being in the brain stem. It's been removed but thiers a lot of follow up care and dangers.
Today by far is the best out of the past 4 days by far and huge relief after speaking to the neurology team for a brief few mins.
The doc outright said Chandler is a pure miracle and nothing less. He forwardly said no one thought Chandler would pull through this surgery and if he did there would be no way he would ever recover fully without significant damage and dissabilities.
He said the top MRI imaging showed everything completely normal and undamaged with complete removal and absoloutly incredible. He said it was never imagined to have a result and recovery ever with a condition like his and he was an incredibly amazing strong child to come through like he has.
Those words are something I'd never think I'd hear. I can't even express how much I dreamed about hearing those exact words and to actually hear them well....
As a mother your worst fear in the entire world is your child is sick. Four days ago
Chandler went downhill very quickly after showing symptoms and signs that something was off for about a year. At first it was just bloody noses and balance which i thought was clumbsiness. Then not eating well and dragging all the time with little energy and very tired. Next it was he was having muscle cramps and pain in his legs then arms. After that it was neck pain,back pain,headaches. Lastly his headaches got so severe nothing was helping and when ever he got up and did any sort of physical exercise he would immediately get on his hands and knees and cup his hands around his face and push his face into the floor, pillow ect and cry rocking back and fourth .
He said to me mom whats wrong with me i cant even play and just cried so hard. I had him to the docs over a year with different symptoms and told he was fine.
They did a lot of bw and all was fine. The next day i couldn't keep him awake and every time he moved at all he'd scream and was puking like crazy so i rushed him to the hospital.
When i got him there the doc was told about a fall on the trampoline three weeks prior and that he hit his face and head pretty hard but symptoms were increasing and really bad now. The doc said he thought it was just a concussion and there wasn't anything they could do. I demanded on a scan so he said he would do a ct scan. 30 mins later he said the scan was normal. I told him i wasn't taking chandler home.
He came in and said the radiologist said just in case as a procausion he should have a MRI but that id have to wait till next week because they would not have a machine till tues or fri.
I told them i refused to wait to find one now . I then headed down to the kitchen for drinks for Chandler and i and was met there about 10 mins after.
The doc had a very bad look on his face and put his hand on my shoulder and said i'm so sorry but the radiologist sent the ct scan down to Bangor for a second look and your son is getting a high dose of steroids because his brain is under a lot of pressure from hydrocephilous. Fluid all around the brain. He said he has to get to Bangor immediately and admitted to ICU because they think its a brain tumor.
I lost my footing and felt numb.
Once the steroids was injected in 30 mins he was completely normal and pain free.
This was mistaken by docs for other medical or normal child hood things going on.
Hearing your child needs to go by ambulance to ICU immediately to Bangor for studies sucked the life right outta me. We went from four days ago thinking Chandler had migraines to he has a concussion to he's got the worst imaginable brain tumor he could possibly have.
Even though my baby wasn't expected to make it through and I was completely loosing hope and faith and felt like a piece of my own heart was cut out and life would never be the same I knew I had no choice but to make him as happy as possible no matter how much I was falling apart and didn't know what tomorrow was gonna bring but forced myself to smile while giving him answeres to keep him positive and as stress free as possible.
This little guy never had anything but a smile on his face and a positive attitude to the very second we we're holding hands in the ICU operating room while being put under to go through a very risky life threatening surgery for many hours to come.
I had a mask on and tears we're flowing down my face being hidden but talking to my baby and hugging and giving kisses knowing maybe that would be the last time but also knowing this was the most incredible little boy ever created and the strongest kid of all time and if anyone could get through this I knew he could.
I held onto that as I walked away waiting for an answere. It wasn't easy and I found myself questioning everything I've done over the last year trying to find something i missed or should've done differently but it didn't matter now.
Now I just sat and starred at the door in anticipation and fear for when the doctor showed up and what the expression would be on his face.
Many hours later he walked in with the most incredible smile on his face and sat down saying a few more hours maybe days we would not have been sitting here at all to your son is out of surgery and it went the best it could've possibly went and I think I got everything.
It was a true miracle and I won't lie there will be a long Rd ahead but I'm so excited his surgery turned out with these results. He made sure we knew how special Chandler was and that my boy may be the only one that could push through something like this.
I will forever be greatful for him. He not only saved his life but was encouraging,supportive but also honest and took the time to answer all our questions being honest but encouraging all at the same time also lightening the situation while talking with Chandler telling bad jokes.
I will never take tomorrow for granted and be so thankful for every minute I have with every one of my children but hold hope even when life is uncertain and things are at it's worst there's always hope.
I can keep a smile on my face knowing he get through anything I know he can and watching him walk and talk and be a grumpy independent little boy this morning is the best feeling in the world.
Hold the ones u love close and never think tomorrow is promised because it may not be. Always hold faith and never give up.   
We finally got back the Diagosis. CNS HGNET-BCOR.
Central nervous system high grade neuro epithelial tumor BCOR.
The diagnosis is an extremly rare brain cancer only discovered two years ago and thier has only been 7 reported cases in the us. Out of the 7 there has been 2 survivors in remission. The longest 18 months. All others lost there lives .
We are trying to stay positive and know how strong our little guy is and praying our hardest he makes it through I don't know how to get through this watching him go through this.
Daddy has had to give up 2 jobs to be with us during treatement and to care for our other children.
We have relocated to Boston for 7 weeks during his treatment.
We are working with three different teams but no one has any idea how to treat this or what will work if anything.
THESE ARE THE CHOICES WE WERE GIVEN FOR TREATMENT
https://m.facebook.com/story.php?story_fbid=342828593192025&id=332889224185962
We have started ATRT
Update...
I think were going with ATRT but just having a really hard time saying yes for sure. The bad downfalls of this treatment is..
1. Causing leukemia
2. No children later
3. Effects hearing badly
4. Effects eye sight
5. Needs a gtube so surgery
6. In patient for 12 months
7. Lots of muscle pain
8. More risk for infection
9. Higher risk of loosing him
10. More blood transfusions
11. Longer treatment time
Benefits
1. Treats both types of cancer they think he has
2. Better life expectency treating both
3. Hopfully cures him treating both
4. Less risk of it returning
5. Tumor is less agressive treating then if it goes away and comes back
6. Goes through treatment once if it works
7. Other docs are now going towards this treatment after patients relasped with just embryonic for this cancer.
8. Two of the best docs in the world are saying its his only chance through this. Dana farber and canada.
Yesterday was a scary,heart breaking day for myself and justin. I've been spending every available minute to talk to researchers and docs and differant referral people for weeks now all around the world trying to get any info on chandlers type of cancer and others opinions on our chemo choice. We have 5 opinions which are described in detail attatched.
1. (St judes plan) do embryonic chemo for 4 cycles. They have had all young with this and one in remission for 18 months now.
2. (Danafarber plan) ATRT which is very intense in patient for 12 months
3. (National doc) Treat it embryonic like st judes but one for 6 months instead of 4.
4. (Another doc) has had a patient in remission doing the embryonic for almost a year and a half before relapse and now doing treatment on a simular line of ATvRT.
5. (Canada doc) said go with the arrt because she believes after looking at the pathology he has sarcoma cells and the ATRT is the only one that will treat sarcoma and embryonic.
His oncologists says she would go the embryonic 6 months and if it comes back then treat like ATRT.
My concern is if it is sarcoma cells it will go untreated and it comes back because those cells arent treated he has to undergo treatment again and his tumor would be alot more resistant and angry. Also cant be radiated again or have embryonal treatment again. Will his body beable to handle a intense treatment then a very intense after??
Justin agrees with oncologists.
Chandlers blood level was low and his doc expects it to fall lower from radiation so watching close incase he needs blood transfusion.
Chaner is at a very big risk of developing seizures because of the brain surgery which i was never aware of till yesterday. She also said his hearing will be effected badly about 4 months after proton from the radiation.
Side effects he will have with all treatments.
Will require placing an NG tube. He will develop septisemia multiple times. Get a fever,lots of hospital time,nausea,vomiting,medicine to force his body to make new white cells to fight infection,lots of blood transfusions.
The ATRT treatment requires 12 months of in patient hospital treatment.
It would would treat everything if he does have sarcoma cells as well but a lot riskier and long term effects. Ver dangerous but may save his life. The only way to tell if his tumor has sarcoma cells is to test his live fresh tumor cells but does not has any left.
This treatment has never been tried yet.
The embryonic one has failed many times with one patient we know of in remission for 18 months and another in remission for year and a 1 13 and just relapsed with embryonic.
Im so upset,confused and frustrated. How do i make a decision like this. I was told we have one chance to cure him. If it comes back it will be very resistant and they could only keep him comfortable and could try things but it may be to resistant.
I cried myself to sleep just thinking about my baby going through these horrible treatments and more surgery along with living in a hospital and then it coming back and having to do it all over again and loosing his life anyway.
I feel as though if he has to endure all this pain and suffering i need to be too. Its my place as aparent. I feel i HAVE to FIX this somehow someway and save my baby's life.
If thier is a god then why make a child suffer this way and fight for his own life before its barely began?? There is no greater plan and thats why this is happening because to me my babys future and life is the greatest only plan.
I have just 2 weeks to be with him before all this starts and just want to fly away from here and give him the best vacation
This chandlers diagnosis
CNS HGNET-BCOR BRAIN TUMOR
Due to the noted radiosensitivity of the tumor, re-irradiation with 44 Gy (5 x 2 Gy/week) of the former position of the metastatic skull lesions was performed (high parietal/frontal and occipital) (Figure 4C and 4D). Re-irradiation was done with 3 cm safety margin and included the newly formed dural lesion which was re-irradiated to 44 Gy (Figure 4D, circle). ATO w
Radiographic follow-up using magnetic resonance imaging (MRI) revealed a continuous treatment response with the patient achieving complete remission (CR) with no measurable disease activity seven weeks after the initiation of relapse therapy (calculated starting from the first ICE block) including four weeks of targeted therapy with intravenous ATO (Figure 5A-5). CR was confirmed by a further MRI nearly two months later. Five months after the initiation of the relapse therapy (and 6 months after the resection of the metastases) the patient developed cranial and extra cranial metastases in lung, liver, spinal column and bones (Supplementary Figure 1). Notably, the former site of relapse in the skull was not involved.
The target lesion is sensitive to the targeted therapy.
Figure 5: The target lesion is sensitive to the targeted therapy. MRI showing the dural lesion developed under the first line therapy (A-B), before the start of the targeted therapy (C) and at the time of CR (D).
Following the diagnosis of progressive, systemic disease, we switched to an oral ATO formulation in order to forgo hospitalization of the patient. To increase the plasma arsenic concentration, we extended the oral formula dosage of ATO to 0.3 mg/kg (ATO III). The oral ATO formulation was prepared in our hospital pharmacy based on the publication of Kumana et al. [26]. The administration of parenteral ATO is well established in the therapy of acute promyelocytic leukemia (APL) and the oral formulation of ATO appears to have a comparable efficiency [26, 27] although, the clinical use of oral ATO in pediatric patients is less common. ATO was well tolerated intravenously and orally. No adverse cardiac effects, in particular, QT prolongation [28] or any skin reactions were observed. Furthermore, P1 did not develop any electrolyte disturbances with oral substitution of potassium. The oral ATO was given continuously for a period of four weeks. Due to the highly malignant nature of the disease, P1 died 22 months after initial diagnosis and 10 months after relapse.
The concentration of arsenic in plasma and CSF samples of P1 didn’t reach the IC50
The total amount of arsenic at the end of each cycle was 48.3 μg/l (ATO I) and 46.9 μg/l (ATO II) in plasma and 9.1 μg/l (ATO I) and 6.5 μg/l (ATO II) in CSF. After 2 weeks of ATO III, the concentration was 45.3 μg/l in plasma and 9.7 μg/l in CSF. In accordance with several reports [29], we observed a linear correlation (r =0.854; p <0.05) between the two compartments, with CSF levels at 16.5% of the plasma level. This was equivalent with a plasma/CSF ratio around 6:1. Regarding the systemic bioavailability of ATO, parenteral and enteral administration provided comparable concentrations in the plasma and CSF compartements. These results coincide with findings from adult APL patients treated with intravenous and oral ATO [26]. In conclusion, the maximal arsenic concentration achieved in P1 was of 48.3 μg/l in plasma and of 9.7 μg/l in CSF corresponding to a maximum arsenic concentration of 645 nM and 129 nM respectively, a concentration that was below the IC50.
The BCOR ITD is maintained in the systemic metastases
Because tissue biopsies of the systemic metastases at the time of the second relapse were not performed, we used peripheral blood to monitor the tumor status in P1, especially the persistence of the BCOR ITD under the targeted therapy. First we established primers for the detection of the BCOR ITD. The sequence of the BCOR ITD of P1 has been already described [4]. The primers detected the BCOR ITD in the genomic DNA extracted from the primary tumor and a metastasis from P1 but not the BCOR wild type (wt) in the genomic DNA extracted from the blood of P1 (Figure 6A) and had an efficiency of 100% (Figure 6B). We extracted the ctDNA from four samples of peripheral blood at different points of time after the detection of CR by MRI. One sample was collected 24 days after the radiographic detection of CR and three further samples were collected prior to the radiographic appearance of systemic metastatic disease. The concentration of the ctDNA ranged from 0.338 ng/μl to 5.820 ng/μl. The ctDNA was highly fragmented as expected [30] with a median size of about 160 bps (Figure 6C). Twenty-four days after the CR, the concentration of the BCOR ITD was at the limit of detection of our assay (Figure 6D). After circa two months, a clear increase in the concentration of the BCOR ITD was detectable and reached the maximum four days before the radiographic detection of the systemic metastases by MRI (Figure 6D, day 108). These data indicate that the BCOR ITD is still present in the lesions that developed after the systemic spread of the disease and that the liquid biopsy of peripheral blood represents a powerful method for the early detection of systemic metastasis in these patients.
The BCOR ITD is maintained in the systemic metastases of P1.
Figure 6: The BCOR ITD is maintained in the systemic metastases of P1. (A) BCOR ITD specific primers were used for PCR analysis of the genomic DNA extracted from the primary tumor (lane 1), a metastasis (lane 2) and the blood (lane 3) of P1. The expected product of BCOR ITD is 117 bps. (B) The genomic DNA extracted from the primary tumor was diluted at different concentrations. The –log of the concentration in ng/μl is shown on the x-axis. The threshold cycle (ct) is shown on the y axis. The slope of the standard curve was used to calculate the efficiency of the primers. (C) The size of the isolated ctDNA was analyzed using a Bioanalyzer. The y axis shows the signal intensity (FU) and the x axis the size distribution in bps. The circle indicates the purified ctDNA. (D) The concentration of the ctDNA was calculated based on the standard curve in B and reported as ng of ctDNA per μl of purified ctDNA (ng/μl) on the y axis. The x axis report the days of the plasma collection with respect to the time of the complete remission as assessed by MRI (x=0). To facilitate the comparison with the sketch in Figure 3, the datum of the plasma collection is also reported.
The SHH pathway is upregulated in a second CNS HGNET-BCOR patient (P2)
CNS HGNET-BCOR is characterized by tandem duplication in exon 15 of the BCOR gene. This tandem duplication can be of different sizes. We analyzed exon 15 in the genomic DNA extracted from the blood and the primary tumor of P1 and from the primary tumor of P2 by PCR (Figure 7A). Only the BCOR wt could be detected in the blood of P1, only the BCOR ITD could be detected in the tumor of P1 and the wt and the BCOR ITD could be both detected in the tumor of P2. This can be explained by the fact that BCOR is located on the X chromosome and therefore male individuals carry only one allele. We cloned and sequenced the BCOR ITD in P2 revealing an internal tandem duplication of 126 nucleotides (42 amino acids) (Figure 7B). If the presence of the wt BCOR allele in female patients can influence the severity of the disease remains to be elucidate. The insertion in P2 is larger than that detected in P1 and is one of the largest described at the time of this publication [1]. The ITD of P2 and P1 are both localized in a domain required for the binding of BCOR to a Polycomb proteins complex [31]. We validated the upregulation of the SHH pathway in P2 by qRT-PCR. Expression of BCOR in P2 was even stronger than in P1 (Figure 7C). To functionally validate the activation of the SHH pathway, we analyzed the expression of GLI1, GLI2 and PTCH1. All three genes were highly expressed in P2, even stronger than in P1. These results confirm the assumption that the upregulation of the SHH pathway is a common feature of HGNET-BCOR. However, while the expression of GLI2 was confirmed at the protein level in tumor material extracted from P1 (Supplementary Figure 2), no fresh frozen material was available to perform the analysis in P2 and we cannot conclude if the higher RNA expression in P2 corresponds to a higher protein expression.
The SHH pathway is upregulated in an additional CNS HGNET-BCOR case.
Figure 7: The SHH pathway is upregulated in an additional CNS HGNET-BCOR case. (A) The sequence of exon 15 of BCOR was analyzed by PCR in the genomic DNA extracted from the blood of P1 (lane 1), the primary tumor of P2 (lane 2) or from the primary tumor of P1 (lane 3). The sizes of the wt BCOR and of the BCOR ITDs are indicated. (B) Protein sequence of the BCOR allele of P2 carrying the ITD compared to the wild type BCOR and to the BCOR ITD detected in P1. (C) qRT-PCR analysis was performed using primers recognizing BCOR, GLI2, PTCH1 or GLI1. After normalization to the housekeeping gene HPRT1, the fold change of the expression of P2 with respect to P1 was calculated. Expression analysis was done in triplicates. Expression analysis was done on RNA extracted from FFPE material.
Treatment of P2 was given according to the Children’s Oncology Group ACNS 0334 protocol, in an attempt to delay or avoid radiotherapy [32–34]. Therapy consisted of three induction cycles of chemotherapy, including high-dose methotrexate, and three consolidation cycles of myeloablative chemotherapy with autologous hematopoietic stem cell rescue. However, as more information on the propensity of this tumor entity to relapse became available, a decision to treat with low-dose craniospinal irradiation (18 Gy) and tumor bed boost (54 Gy) was made. Treatment details of P2 can be found in the Supplementary Materials. To date, 20 months from diagnosis and 10 months from completing treatment, the patient remains in clinical and radiological remission.
DISCUSSION
HGNET-BCOR is a recently described rare tumor entity of the central nervous system for which optimal treatment protocols are yet to be defined. Because patients with HGNET-BCOR were previously diagnosed as other entities, several treatment protocols have been attempted. To date, protocols for the treatment of CNS-PNET, glioblastoma and ependymoma have been used, all of which have included high doses of chemotherapy and radiation. According to the available data on follow up, no protocol has been successful in the treatment of this tumor entity with most patients developing progressive disease [1]. A recent clinicopathologic and molecular characterization of 3 cases of HGNET-BCOR [35] confirmed the difficulty encountered in controlling this tumor entity using surgical resection of the primary tumor followed by radiation and chemotherapy. Here we show that the combination of conventional sarcoma-based chemotherapy, irradiation and ATO administration led to complete remission after extra-cerebral relapse with six months of progression-free survival.
Available microarray data suggest that the upregulation of the SHH pathway is a common feature of HGNET-BCOR. We have previously validated the activation of the SHH pathway in P1 [4] and in this work in P2. Thus, a targeted therapy against this pathway is of interest for HGNET-BCOR patients. The therapeutic effect of the SMO inhibitor itraconazole has been recently discussed in one HGNET-BCOR female pediatric patient [35]. Unfortunately no in vitro data on the sensitivity of the HGNET-BCOR cells to itraconazole were available for that patient. Moreover, SMO inhibition causes permanent defects in bone structure in young mice, and its use in young children has to be carefully considered with respect to long-term toxicities [36]. Our data suggest a partially SMO-independent GLI transcriptional activity in the PhKh1 cells which has been described in other tumor entities. A possible mechanism for the SMO-independent activation of GLI could rely on the presence of the ITD. BCOR enhances BCL6-mediated transcriptional repression by interacting with histone deacetylases (HDAC) [37]. Moreover, BCOR forms a complex with Polycomb proteins and can act as an epigenetic repressor [38]. BCOR wt can repress the expression of GLI1 and GLI2 [39]. The ITD is localized in a region required for the binding to the Polycomb complex and required for the full activity of BCOR [31]. Thus the ITD may interfere with the repressor function of BCOR leading to the upregulation of GLI1 and GLI2. This hypothesis has to be validated but it is in line with the observed upregulation of GLI transcripts in clear cell sarcoma of the kidney which also express the BCOR ITD [2]. Thus, targeting the SHH pathway downstream of SMO at the level of the GLI transcripts using ATO is a particularly attractive approach in HGNET-BCOR. Here we show that ATO reduced the transcription of GLI target genes in a primary culture of HGNET-BCOR. In APL, ATO triggers the degradation of the PML–RARα fusion protein, probably by binding to a cysteine-rich region [40]. However, no cysteine-rich regions are created by the presence of the ITD. Thus, the effect of ATO on GLI in HGNET-BCOR is probably direct and not via BCOR. Indeed ATO has been shown to reduce GLI activity by direct binding to GLI proteins [7]. Moreover, the upregulation of GLI itself seemed to be responsible for the ineffectiveness of conventional chemotherapy [41, 42] and earlier studies demonstrated additive effects of ATO with conventional chemotherapeutic agents such as cisplatin, adriamycin, and etoposide [43, 44]. The down-regulation of GLI transcription factors via ATO to sensitize HGNET-BCOR cells to conventional chemotherapy, particularly to the sarcoma-based chemotherapy applied in the relapse protocol warrants further investigation.
The radiosensitivity of HGNET-BCOR is suggested by the growth of the skull metastases outside of the high dosage area. The relevance of postoperative craniospinal irradiation in patients suffering from CNS HGNET-BCOR has been recently discussed [35]. However, irradiation alone was not able to control the progression of the disease in P1. Indeed, the target lesion developed in a region that was irradiated with 59.4 Gy during the irradiation of the primar
Update: Central nervous system high grade neuroepithelial tumor with BCOR alteration
June 1, 2018 by neurosurgery.directory
Central nervous system high grade neuroepithelial tumor with BCOR alteration
Central nervous system high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3′ end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features.
CNS HGNET-BCOR display pathological overlap with CNS-PNET and other histological entities 1).
The high expression of IGF-2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity 2).
High expression of altered BCOR transcripts in CNS HGNET-BCOR tumors suggests a different mechanism from BCOR loss-of-function mutations reported in other malignancies, such as medulloblastoma 3) 4).
Yoshida et al., performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS 5).
Kirkman et al., describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor.
This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques 6).
Appay et al., reported in 2017, 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of “embryonal tumors” or within the category of “mesenchymal, nonmeningothelial tumors” remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity 7).
. T, Kohashi K, Oda Y, Hirato J, Yokoo H. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol. 2017 Dec 11. doi: 10.1111/bpa.12585. [Epub ahead of print] PubMed PMID: 29226988.
Kirkman MA, Pickles JC, Fairchild AR, Avery A, Pietsch T, Jacques TS, Aquilina K. Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report. World Neurosurg. 2018 May 30. pii: S1878-8750(18)31112-4. doi: 10.1016/j.wneu.2018.05.158. [Epub ahead of print] PubMed PMID: 29859355.
Abstract
The central nervous system (CNS) high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a recently described molecular entity. We report 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of "embryonal tumors" or within the category of "mesenchymal, nonmeningothelial tumors" remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity.7xxx xxx''x
Identification of Four New Molecular CNS Tumor Entities
Our initial clustering analysis of CNS-PNETs identified four new molecular entities designated “CNS NB-FOXR2”, “CNS EFT-CIC”, “CNS HGNET-MN1”, and “CNS HGNET-BCOR”. To explore whether these molecular entities were also diagnosed other than CNS-PNET, we compared DNA methylation patterns of each entity with an in-house collection of > 10,000 profiles from a broad variety of pediatric and adult CNS tumors (data not shown). Subsequent clustering analysis identified 59 tumors with diverse histological diagnoses that now grouped with one of the four new CNS tumor entities (Figures 3 and S3A-C, Table S3). While the enlarged CNS NB-FOXR2 (n = 46) and CNS EFT-CIC (n = 15) clusters represented entities with almost exclusive CNS-PNET histology (Figure 3), the CNS HGNET-MN1 cluster (n = 41) included 16 tumors histologically diagnosed as astroblastoma (ABM) – rare WHO-defined glial tumors – supporting the concept that they are distinct from conventional diffuse glial neoplasms (Louis et al., 2007). The CNS HGNET-BCOR cluster (n = 34) was expanded by a variety of CNS tumor histologies. Again, molecular subgroup assignment by transcriptomic profiling recapitulated DNA methylation-based clusters (Figures 3A and S3A) and allowed the identification of three additional tumors included in further gene expression analyses.
Identification of New CNS Tumor Entities Across Histologies
We correlated each of the four novel CNS tumor entities with available basic clinical parameters (Figures 3C-F). Noticeably, the gender ratio was strongly shifted towards females in the CNS HGNET-MN1 (p < 0.001), as also observed for ABM (Louis et al., 2007). Patient age at diagnosis in CNS HGNET-MN1 was higher compared with other entities (p < 0.001). There were no clear differences in tumor site of occurrence, although occasional cerebellar location was restricted to tumors of the CNS HGNET-MN1 and CNS HGNET-BCOR entities. Infratentorial, non-cerebellar location was not associated with a specific molecular CNS tumor entity. Surgical and pathological reports of four CNS EFT-CIC tumors did not indicate meningeal or osseous origin. Available survival data suggested differences between the novel CNS tumor entities, with significantly better overall survival observed for patients from the CNS HGNET-MN1 compared to the CNS HGNET-BCOR entity (Figure S3D).
Histopathology of New CNS Tumor Entities
Histopathological review was performed on 30 CNS NB-FOXR2, 14 CNS HGNET-BCOR, 10 CNS HGNET-MN1, and four CNS EFT-CIC tumors (Tables S2A-C). The CNS NB-FOXR2 entity displayed embryonal architectural and cytological features with a small-cell phenotype (Figures 4A-C). Areas of differentiation in the form of neuropil, neurocytic cells, or ganglion cells were observed in a high proportion of tumors (Figure 4C). Frequent perivascular anuclear zones (“vascular pseudorosettes”), nuclear palisades, and Homer Wright rosettes were encountered in individual samples (Figure S4A, Tables S2B/C). This group encompassed tumors that would be classified as CNS neuroblastoma or CNS ganglioneuroblastoma in the 2007 WHO classification scheme (Louis et al., 2007) (Figures 4A-C). CNS NB-FOXR2 tumors nearly uniformly expressed OLIG2 and the neuronal antigen synaptophysin (Figures S4A/B).
Histopathological Patterns of New CNS Tumor Entities
The CNS EFT-CIC entity was also characterized by a small-cell phenotype but with variable histology (Figures 4D-F). The tumor architecture included both alveolar and fascicular patterns of growth. Although tumors were uniformly high-grade, this group lacked defining histological features and failed to express markers of differentiation.
The CNS HGNET-MN1 entity (Figures 4G-I) consisted of circumscribed high-grade tumors containing a mixture of solid and pseudopapillary patterns. Dense pericellular hyalinization was frequently present in this group. Some had the typical pathology of the tumor termed astroblastoma (ABM) in the current WHO classification system, whereas others were harder to align with that diagnosis. The majority of tumors (16/23) from our current database histologically diagnosed as ABM belonged to this molecular entity. Thus, we consider it unlikely that there is an additional true ‘astroblastoma’ entity other than the MN1-altered entity outlined here.
The CNS HGNET-BCOR entity consisted of relatively compact tumors with a combination of spindle to oval cells. They often exhibited perivascular pseudorosettes, giving the tumors an ependymoma-like appearance (Figures 4J-L). Tumors frequently demonstrated fibrillary processes, typical of glial differentiation, and only in rare instances exhibited true embryonal morphology.
Tumors from CNS HGNET-MN1 and CNS HGNET-BCOR entities frequently expressed GFAP, but neuronal antigen expression was either focal or absent. In comparison, mitotic counts were high for CNS NB-FOXR2 and CNS EFT-CIC tumors, but lower for the other two entities (Figure S4C).
Genetic Alterations Define New CNS Tumor Entities
For each of the four new CNS tumor entities, we next inspected copy-number profiles derived from DNA methylation arrays. Gain of chromosome arm 1q was characteristic for the CNS NB-FOXR2 entity (43/44, 98 %; p < 0.001) (Figure S5A). Further broad aberrations included loss of 16q in CNS NB-FOXR2 (21/42, 50 %) and CNS HGNET-MN1 (12/37, 32 %), and gain of chromosome 8 in CNS NB-FOXR2 (14/44, 32 %), CNS EFT-CIC (3/13, 23 %), and CNS HGNET-MN1 (6/38, 16 %) tumors. Most tumors from the CNS HGNET-BCOR entity displayed balanced copy-number profiles. We only detected high-level focal oncogene amplifications of MYC and CDK4, each in one CNS NB-FOXR2 sample, and EGFR and CDK4 in one CNS HGNET-MN1 sample (Table S4). Homozygous deletions of CDKN2A were found in two CNS HGNET-BCOR and one CNS HGNET-MN1 tumors.
In order to identify genetic alterations that underlie each of the four new, molecularly defined CNS tumor entities in greater detail, we performed genome-wide DNA and RNA sequencing of all cases with available fresh-frozen tissue (Table S4). As outlined below, we found that each entity was characterized by a recurrent genetic alteration.
CNS Neuroblastoma with FOXR2 Activation (CNS NB-FOXR2)
Genome-wide sequencing revealed complex inter- and intrachromosomal re-arrangements converging on forkhead box R2 (FOXR2) in 6/8 samples with available data, leading to increased FOXR2 gene expression levels in CNS NB-FOXR2 tumors compared with other CNS tumor entities (Figure 5A-C). Three of the detected events resulted in fusion transcripts retaining the full coding sequence of FOXR2, with upstream non-coding exons forming a novel transcript variant fused to different fusion partners (Figures S5B/C). These included JMJD1C as a result of a complex interchromosomal translocation involving chromosome 10, and LOC550643 and JPX as products of tandem duplications on chromosome X. These duplications were also detectable by characteristic copy-number changes in three samples without available sequencing data (Figure S5D). We further identified a recurrent deletion between full-length FOXR2 and MAGEH1 in two samples. Copy-number data indicated additional alterations targeting the FOXR2 locus in seven samples (Figure S5D), with a deletion reaching ~ 500 kb upstream of FOXR2 as the most frequent event (4/46, 9 %), potentially fusing FOXR2 to the MAGED2 gene. Moreover, we identified a mitochondrial DNA insertion within USP51 that led to the formation of a novel FOXR2 promoter (Figure S5E). Mitochondrial-nuclear genome fusions have been recently reported to occur frequently in cancer (Ju et al., 2015), but this is the first example where such an event induces oncogene expression. Since FOXR2 is not expressed in other CNS tumor types (Figure 5C) or normal brain tissues, these events are suggestive of FOXR2 activation facilitated by promoters of active genes (Figure S5F), thus instigating oncogenic activity (Rahrmann et al., 2013). One exceptional tumor that did not show elevated gene expression of FOXR2 was the only one to harbor a focal amplification of MYC, resulting in upregulated MYC gene expression compared with FOXR2-activated tumors (Figure S5F). The FOXR2 homologue FOXR1 is recurrently activated in peripheral neuroblastoma counterparts by intrachromosomal deletion/fusion events, resulting in overexpression of fusion transcripts (Santo et al., 2012).
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Abstract
High grade neuroepithelial tumor of the central nervous system with BCOR alteration (CNS HGNET-BCOR) is a recently described new tumor entity which was formerly diagnosed with diverse histological diagnoses, for example as ependymoma. This tumor predominantly affects children and has a dismal prognosis. No standard therapies for this entity exist so far. Recently we described the activation of the Sonic hedgehog (SHH) and the WNT signaling pathway in this tumor and described a primary cell culture (PhKh1) isolated from a skull metastasis of a seven years old patient. We also detected a high expression of IGF2, which is known to be required for SHH signaling in medulloblastoma. IGF2 signals through IGF1R leading to cell growth via the downstream PI3K/Akt pathway. In pediatric brain tumors high expression of IGF2 has been described in ependymoma and may acts as a molecular target. Here we analyzed the expression of IGF2 in our transcriptome data of 12 pediatric brain tumors patients (6 medulloblastoma, 2 glioblastoma, 2 anaplastic astrocytoma, 1 HGNET-BCOR and 1 ependymoma relapse). The highest expression of IGF2 was detected in the HGNET-BCOR and ependymoma samples. The high expression of IGF2 was maintained in the PhKh1 cell line and was similar to the expression detected in a primary cell culture isolated from the ependymoma relapse. Incubation with increasing concentrations of an antibody that blocks IGF1R resulted in a great reduction of the cell proliferation of the PhKh1 cell line but not of an IGF2-negative control cell line. In conclusion, the high expression of IGF2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity
Latest update..
So today has been terrible. Chandlers oncologists is back from vacation and looked over the scans ect and said shes extreamly concerned the mass is cancer and from the brain tumor. She said there is a very slight chance its something else. No one has seen this in this area and its floating around near his back wall near the hips and probably is giving him pain amd definately the feeling he has to pee all the time even after going. The two surgeons here dont know how to get at it or dare to try and even touch this so the doc sent everything to boston and there trying to figure out which surgeon team can attempt this. They also will have to radiate the area as well so he will need to go through that again as well. We are waiting for a day to leave for boston again. We havnt even got feeds worked out yet. He is on his way home for the night and awaiting the call. Im trying my best to hold hope and have faith hes got this but honestly i will never understand. All my baby wants is to hang out with a friend and not to feel bad for one day. I dont know how but chandlers still smiles. Its beyond me after all this he still is. Again my little girl will have both parents away and shes alone to deal with all this and not have us to talk to. Its so hard on her. Please donate if u can to help with dads time from work. Its been a few weeks since hes worked at all and will be a while before he goes back. There will be alot of expenses that will go along with this trip and surgery too. Please share
Ok so the latest update on Chandler is he had 6 1/2 hours of laying completely still on a table for testing. We found out all the belly pain and nausea was from his gallbladder completely failing him. He needed help with nutrition now because hes lost two much weight and has been unable to drink or eat at all on his own without causing him horrible pain. 4 days ago Chandler again went into surgery for 2 surgeries this time. Gallbladder removal and to put a g tube in place ..Poor chandler had a very rough night and pain control was extreamly difficult . The next day he cried alot and was very sensitive to any touch or pressure and wouldn't move because it hurt to bad. The 3rd day he was able to stay awake more and move around a bit . He was a very happy guy to go home. He is still extreamly sore and cant stand up straight while walking or sit up much because it causes pain but refuses pain meds. He wont drink or eat at all and docs think its because hes getting to much through the g tube but hes only half way to what the docs want him at and not tolerating that. We are lowering his feed again tonight and we will see what happens tomorrow and decide next steps. I can say my baby boy is still smiling and has got a positive attitude and says he feels so much better now. It broke my heart to hear him scream in pain all the time. Monday we start in patient ATRT chemo for 12 months. Please keep him in your prayers and share this as much as possible to find other patients and info that might save his life from this very rare cancer.
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Chandlers make a wish cant fill his wish till a little while after hes done treatment and cant start the garden before because the whole wish needs to be done together. He wont be done chemo for over a year. Anyone who knows chandler knows his favorite thing in the whole world is flowers. Id love to give him a real big beautiful garden, water statue things,fountain,lights. Whatever we can do to make it nice for him. We couldnt get make a wish to do a pond because of ground work and such but if they had it wouldve been a long process. He has a big long list of flowers he wants in his garden. Anyone that could volunteer for ground work,plans for a garden ect or donate things for his garden would be most appreciated. Please let me know if u can help make this happen this spring. I dont have much time and cant do it on my on.
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Im having a particularly hard time tonight. Im getting ready to give chandler his chemo myself and getting all dressed up and laying my special chemo stuff out gloves,mask,proper disposal to make sure to protect myself the nurse said i have to but i cant stop thinking about myself putting poison into my baby. Something i cant even get on my skin. Something thats killing good and bad inside his little body. Im told i cant wipe his tears away without gloves on one medication then the same one makes his pee and tears red. All take many cautious actions to inject. All make him sick and cause some sort of pain. Im about to do it but feel so sad,and guilty knowing hes gonna wake up sick and i put that yucky, terrible medicine in him. I dont know how moms do this cause im having such a hard time bringing myself too. I wish i had my mom here with me in a time like this. Im sure some are thinking its for his own good to fight this cancer and yes i know that but how did this happen to my baby. I'll never stop asking that and wondering whyú6hiyou*&in him. Look at my precious boy sleeping so peacful right now happy to be home.
Chandlers oncologist in maine called and said the preliminary frozen results of the mass in his pelvis are saying it is scar tissue. Thank god and we are so relieved. We won't know for positive till the real pathology comes back but its great news!!
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Kristin Frost-grey
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Enfield, ME
