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   D.I.P.G Treatment

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The Basics of D.I.P.G. Treatment

Surgery D.I.P.G. tumours cannot be removed surgically because the tumour grows into healthy tissue & throughout the supportive tissues of the pons.  D.I.P.G. tumours have undefined edges so there is no way to avoid cutting out healthy brain tissue which is necessary for survival. a) Endoscopic Third Ventriculostomy (ETV) and Shunts Some children with D.I.P.G. develop Hydrocephalus, a build-up of fluid on the brain, and your medical team may decide that relieving the pressure with an ETV or shunt is an option. ETV’s are the preferred method but not all medical facilities will preform this procedure for D.I.P.G. because the risk is high and it will not change the outcome of D.I.P.G. Many parents will need to push and advocate or seek a facility that offers ETV for D.I.P.G. children. Helpful links: http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/cerebral- fluid/procedures/shunts  http://weillcornellbrainandspine.org/condition/diffuse-intrinsic-pontine-glioma-dipg/surgery-dipg  b) Stereotactic Biopsies Have been instrumental in discovering more about the biology of DIPG (ex. DNA mutations & deletions). Small amounts of tumour tissue are removed for diagnostic testing when MRIs are inconclusive.  Are seen as a feasible and safe way to personalize treatment for each of the 3 D.I.P.G. subgroups (each has different genes mutations). Have been standard D.I.P.G. care in Europe for a decade but have yet to become standard care protocol for D.I.P.G. in Canada & the US. Smart Needle Article: http://www.ibtimes.co.uk/how-smart-needle-could-revolutionise-brain-surgery- make-it-safer-1603021 
Radiation is seen as the only viable treatment option for D.I.P.G. and is simply part of palliative care: Helps ‘stabilize’ or stop tumour growth in 70% of DIPG tumours Regrowth, on average, occurs after 3 months Clinical trials & studies have experimented with RT dose & hyper-fractionated RT with no benefits found Average RT Schedule for DIPG: 6 weeks of RT; 5 days/week Children wear a stabilization shell (full face mask) that is bolted to the table to prevent movement for optimal results Younger children are usually sedated at each RT treatment 
Radiation Therapy
Risks of Radiation:  May cause more swelling which leads to the rapid progression of DIPG symptoms Radiation Necrosis   Neurocognitive problems, renal impairment and subsequent cancers, etc. due to its location on the brainstem and the areas of the brain it passes through. Permanent cognitive, social, emotional and physical structure damage because children’s brains are still developing and their bodies are still growing
Over 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy, newer biologic agents, molecularly targeted agents and/or anti-angiogenic agents have all failed to improve symptom-free survival time and the overall survival time of D.I.P.G. patients. There are different ways in which chemotherapy drugs are administered but the biggest inhibiter to chemotherapy for D.I.P.G. is the location behind the blood brain barrier. Therefore, the BBB requires that chemotherapy drugs for D.I.P.G. tumours have a delivery system that is able to bring the drug to the pons area of the brain and straight to the tumour: Convection-Enhanced Delivery System (CED) CED involves the surgical implantation of very fine catheters into the brain with a 10 to 13-hour long surgery. It delivers chemotherapy drugs past the blood brain barrier directly into the tumour. CED is currently the only delivery system for chemotherapy drugs that has shown promise. CED in the UK: uses 4 semi-permanent catheters that provide a pathway to administer effective quantities of a drug more directly to the D.I.P.G. tumour CED in the US: uses a single catheter that is inserted and extracted at each administration CED Articles: Convection-enhanced Delivery in Diffuse Intrinsic Pontine Glioma Weill Cornell Brain and Spine Centre: CED explained Chronic, intermittent convection-enhanced delivery devices Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model Video of Professor Gill (2016) at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.: Convection enhanced delivery of chemotherapy to paediatric brain stem tumours 
Chemotherapy 
Intra-arterial Delivery This method of delivery has been around for quite some time, however, it has recently (Spring 2017) become a topic of great discussion in the D.I.P.G. community. In particular, amongst parents/guardians of children who do not qualify for a CED trial, who are in progression and can no longer participate in their current clinical trial, and/or who are out of treatment options. Intra-arterial Chemotherapy for the Treatment of Progressive Diffuse Intrinsic Pontine Gliomas Intra-Arterial Chemotherapy for Malignant Gliomas: a Critical Analysis Highly selective intra-arterial chemotherapy for the treatment of progressive diffuse intrinsic pontine gliomas (dipg) Learn more about the Intra-arterial delivery system for chemotherapy by watching this video Advisory: There is debate about how IA measures up to CED in quality and safety, please do your own research and do not rely strictly on personal testimonies Chemotherapy Drugs Chemotherapy drugs have been used along with radiation therapy and other biologic agents in many D.I.P.G. trials with minimal changes to symptom-free survival time and no changes in overall survival time of D.I.P.G. patients. As mentioned above, a delivery system that better targets the tumour is needed to make any drugs or immunotherapy antibodies more effective. Whatever your opinion is about chemotherapy and D.I.P.G., research is showing that the only way we are going to make progress is with a multi-pronged treatment.  Chemotherapy Drugs being used for D.I.P.G. (non-exclusive list)
D.I.P.G. Tumour Banking D.I.P.G. tumour tissue left over from surgical biopsies and tumour tissue donated by families after children with D.I.P.G. have died have been instrumental in the recent breakthroughs in D.I.P.G. research. See DIPG Research>Tumour Banks for more information.
Clinical Trials D.I.P.G. children take part in clinical trials because there is presently no treatment that significantly extends symptom-free survival time or overall survival time and there is no cure.  Please keep in mind that some trials require the child to be stabilized with radiation treatments first to qualify, while others only take in newly diagnosed with D.I.P.G. Do your research. Depending on where you live and the speed of progression, children with D.I.P.G. often have to travel, if medically stable, to participate in clinical trials which adds to the emotional and financial strain of a terminal diagnosis. See DIPG Research>Clinical Trials for more information.
Immunotherapy Is described as “the prevention or treatment of disease with substances that stimulate the immune response” by Oxford Dictionaries. Essentially, immunotherapy uses parts of a person’s immune system to work harder at attacking the cancer cells. Many D.I.P.G. families have utilized immunotherapy treatments for D.I.P.G. symptom management. More information: What Is Cancer Immunotherapy? A Brain Tumor Kept at Bay by Immunotherapy Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy Antibody fights pediatric brain tumors in preclinical testing What Makes Immunotherapy a Promising Treatment for Brain Cancer? Immunotherapy for glioma: promises and challenges Canadian Cancer Immunotherapy Consortium Fight Cancer with Immunotherapy Understanding Immunotherapy
Chemotherapy Drugs and D.I.P.G. There are three key parts to the successfulness of treating D.I.P.G. with chemotherapy drugs : 1. Delivery System (how they are administered) 2. Dose (volume and concentration) 3. Dosage (frequency)
DIPG Hilfe Koln FaceBook page created to help kids with DIPG and their families when coming to Cologne for immunotherapy treatment. - Sara Werr & Xenia Bagusche
Topotecan Avastin Methotrexate Doxorubicin Cisplatin Erlotinib   Desatinib Everolimus  **List from DIPG Research Facebook Group
Panobinostat Serolimus Vinorelbine Nimotuzumab Trametinib Bevacizumab Mebendazole/Vermox/Mebex Zaltrap
The Cancer Research Institute  The CRI offers information about Cancer Immunotherapy, and details about current Immunotherapy clinical trials for both childhood cancers and brain tumours. They focus on cancer immunology research and have a clinical development program which includes the Clinical Accelerator and Cancer Immunotherapy Consortium.
There are 6 broad categories of Immunotherapy which may help with your research: Monoclonal Antibodies Oncolytic Virus Therapies Adoptive Cell Therapy
Cancer Vaccines Checkpoint Inhibitors Adjuvant Immunotherapies From the Cancer Research Institute
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The Basics of D.I.P.G. Treatment

Surgery  D.I.P.G. tumours cannot be removed surgically because the tumour grows into healthy tissue & throughout the supportive tissues of the pons.  D.I.P.G. tumours have undefined edges so there is no way to avoid cutting out healthy brain tissue which is necessary for survival. a) Endoscopic Third Ventriculostomy (ETV) and Shunts Some children with D.I.P.G. develop Hydrocephalus, a build-up of fluid on the brain, and your medical team may decide that relieving the pressure with an ETV or shunt is an option. ETV’s are the preferred method but not all medical facilities will preform this procedure for D.I.P.G. because the risk is high and it will not change the outcome of D.I.P.G. Many parents will need to push and advocate or seek a facility that offers ETV for D.I.P.G. children. Helpful links: http://www.hopkinsmedicine.org/neurology _neurosurgery/centers_clinics/cerebral- fluid/procedures/shunts  http://weillcornellbrainandspine.org/conditio n/diffuse-intrinsic-pontine-glioma- dipg/surgery-dipg  b) Stereotactic Biopsies Have been instrumental in discovering more about the biology of DIPG (ex. DNA mutations & deletions). Small amounts of tumour tissue are removed for diagnostic testing when MRIs are inconclusive.  Are seen as a feasible and safe way to personalize treatment for each of the 3 D.I.P.G. subgroups (each has different genes mutations). Have been standard D.I.P.G. care in Europe for a decade but have yet to become standard care protocol for D.I.P.G. in Canada & the US. Smart Needle Article: http://www.ibtimes.co.uk/how-smart-needle- could-revolutionise-brain-surgery-make-it- safer-1603021  Liquid Biopsies Although they are not available for D.I.P.G. yet, keep your eye out for them: The Liquid Biopsy: A Noninvasive Tumor Tracker PDTB-13. DETECTION OF HISTONE H3 MUTATIONS IN PEDIATRIC GLIOMA VIA TUMOR DNA DERIVED FROM CEREBROSPINAL FLUID World-first liquid biopsy for blood cancers to improve treatment
Radiation Therapy Radiation is seen as the only viable treatment option for D.I.P.G. and is simply part of palliative care: Helps ‘stabilize’ or stop tumour growth in 70% of DIPG tumours Regrowth, on average, occurs after 3 months Clinical trials & studies have experimented with RT dose & hyper-fractionated RT with no benefits found Average RT Schedule for DIPG: 6 weeks of RT; 5 days/week Children wear a stabilization shell (full face mask) that is bolted to the table to prevent movement for optimal results Younger children are usually sedated at each RT treatment   Risks of Radiation:  May cause more swelling which leads to the rapid progression of DIPG symptoms Radiation Necrosis   Neurocognitive problems, renal impairment and subsequent cancers, etc. due to its location on the brainstem and the areas of the brain it passes through. Permanent cognitive, social, emotional and physical structure damage because children’s brains are still developing and their bodies are still growing  New Research: PET/CT helps predict therapy effectiveness in pediatric brain tumors Re-irradiation: Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group Palliative reirradiation for progressive diffuse intrinsic pontine glioma Re-irradiation for Recurrent Primary Brain Tumors Chemotherapy Over 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy, newer biologic agents, molecularly targeted agents and/or anti-angiogenic agents have all failed to improve symptom-free survival time and the overall survival time of D.I.P.G. patients. There are different ways in which chemotherapy drugs are administered but the biggest inhibiter to chemotherapy for D.I.P.G. is the location behind the blood brain barrier. Therefore, the BBB requires that chemotherapy drugs for D.I.P.G. tumours have a delivery system that is able to bring the drug to the pons area of the brain and straight to the tumour: Convection-Enhanced Delivery System (CED) CED involves the surgical implantation of very fine catheters into the brain with a 10 to 13-hour long surgery. It delivers chemotherapy drugs past the blood brain barrier directly into the tumour. CED is currently the only delivery system for chemotherapy drugs that has shown promise. CED in the UK: uses 4 semi-permanent catheters that provide a pathway to administer effective quantities of a drug more directly to the D.I.P.G. tumour CED in the US: uses a single catheter that is inserted and extracted at each administration CED Articles: Convection-enhanced Delivery in Diffuse Intrinsic Pontine Glioma Weill Cornell Brain and Spine Centre: CED explained Chronic, intermittent convection-enhanced delivery devices Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model Video of Professor Gill (2016) at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.: Convection enhanced delivery of chemotherapy to paediatric brain stem tumours  Intra-arterial Delivery This method of delivery has been around for quite some time, however, it has recently (Spring 2017) become a topic of great discussion in the D.I.P.G. community. In particular, amongst parents/guardians of children who do not qualify for a CED trial, who are in progression and can no longer participate in their current clinical trial, and/or who are out of treatment options. Intra-arterial Chemotherapy for the Treatment of Progressive Diffuse Intrinsic Pontine Gliomas Intra-Arterial Chemotherapy for Malignant Gliomas: a Critical Analysis Highly selective intra-arterial chemotherapy for the treatment of progressive diffuse intrinsic pontine gliomas (dipg) Learn more about the Intra-arterial delivery system for chemotherapy by watching this video Advisory: There is debate about how IA measures up to CED in quality and safety, please do your own research and do not rely strictly on personal testimonies Chemotherapy Drugs Chemotherapy drugs have been used along with radiation therapy and other biologic agents in many D.I.P.G. trials with minimal changes to symptom-free survival time and no changes in overall survival time of D.I.P.G. patients. As mentioned above, a delivery system that better targets the tumour is needed to make any drugs or immunotherapy antibodies more effective. Whatever your opinion is about chemotherapy and D.I.P.G., research is showing that the only way we are going to make progress is with a multi-pronged treatment.  Chemotherapy Drugs being used for D.I.P.G. (non-exclusive list) Panobinostat Serolimus Vinorelbine Nimotuzumab Trametinib Bevacizumab Mebendazole/Vermox/Mebex Zaltrap Topotecan Avastin Methotrexate Doxorubicin Cisplatin Erlotinib   Desatinib Everolimus **List from DIPG Research Facebook Group New Research: ‘Team examines use of antiparasitic drug as new treatment for brain tumors’ Immunotherapy Is described as “the prevention or treatment of disease with substances that stimulate the immune response” by Oxford Dictionaries. Essentially, immunotherapy uses parts of a person’s immune system to work harder at attacking the cancer cells. Many D.I.P.G. families have utilized immunotherapy treatments for D.I.P.G. symptom management. More information: What Is Cancer Immunotherapy? A Brain Tumor Kept at Bay by Immunotherapy Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy Antibody fights pediatric brain tumors in preclinical testing What Makes Immunotherapy a Promising Treatment for Brain Cancer? Immunotherapy for glioma: promises and challenges Canadian Cancer Immunotherapy Consortium Fight Cancer with Immunotherapy Understanding Immunotherapy DIPG Hilfe Koln FaceBook page created to help kids with DIPG and their families when coming to Cologne for immunotherapy treatment. - Sara Werr & Xenia Bagusche
The Cancer Research Institute offers information about: Cancer Immunotherapy Current Immunotherapy clinical trials for both childhood cancers and brain tumours Cancer immunology research Clinical development program which includes the Clinical Accelerator and Cancer Immunotherapy Consortium. There are 6 broad categories of Immunotherapy which may help with your research: Monoclonal Antibodies Oncolytic Virus Therapies Adoptive Cell Therapy Cancer Vaccines Checkpoint Inhibitors Adjuvant Immunotherapies From the Cancer Research Institute