A new Preclinical DIPG Consortium

A new Preclinical DIPG Consortium has been unveiled at-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

One of the spectacular things is that this clearly identifies some of the researchers that are truly placing significant emphasis is trying to unravel DIPG.  There are 5 US sites and one each in Canada, France and Amsterdam.  A main requirement to be a site currently seems to have a cell line as well as a funding source.

The DIPG Consortium includes:

• Oregon Health and Science University-  Charles Keller MD, Kellie Nazemi MD, Nate Selden MD, PhD and Dan Guillaume MD, PhD

• Duke University- Oren Becher MD

• Stanford- Michelle Monje, MD, PhD

• Cincinnati Children’s Hospital Medical Center- Maryam Fouladi, DM

• Baylor College of Medicine- Xiao Nan Li, MD,PhD

• University of Toronto- Cynthia Hawkins, MD, PhD

• VU Cancer Center of Amsterdam- Dannis G. van Vuuren, ND MSc and Ester Hulleman

• Institut Gustave-Roussy, Villejuif France- Jacques Grill

The current study is called "Rapid Preclinical Development of a Targeted Therapy Combination for DIPG" which has a goal of attempting rapidly to test agents against cell lines and then animal models to hopefully rapidly translate into clinical trials over the next two years.

 It does seem that this trial is a novel approach in that it will treat DIPG specifically and not rely on adult models or cell lines.  This is important in that pediatric DIPG is molecularly distinct from adult gliomas.

Another interesting thing is that the high throughput screening of agents seems like it is to be limited specifically to 60 already available drugs.  This sounds quite reasonable as why test against agents that might not be available for some time. 

 In addition, combinations of agents will also be tested.  This also seems to be significant as many researchers have said that a single agent is unlikely to be effective against DIPG.

 It seems that after the best agents and combinations are found in vitro (against cells alone) that they will be tested in animal models- likely both xenografts and Oren Becher’s  GEMM (genetically engineered mouse model).  

Note- Xenografts are made when human cells lines are injected into animal to create a tumor.  GEMMs make tumors on their own and are not from human cell lines

People can check back to the website at that entry to check the progress of the study (mid page)-

http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

Funding for this study has been through parent founded organizations.   The Cure Starts Now provided $100,000 for the North American Institutions.  Also listed were those involved in the DIPG Symposium Collaboration including Reflections of Grace Foundation, The Jeffrey Thomas Hayden Foundation, Cancerfree Kids, Carly’s Crusaders, The Max Lacewell Foundation, Smiles for Sophie Forever Foundation and Benny’s World Foundation for making our project possible.

http://kellerlabblog.blogspot.com/2011/11/thecurestartsnow-funds-dipg.html

Additionally, a $28,000 grant from The Lyla Nsouli Foundation for Children’s Brain Cancer Research in the UK allowed for expansion for  the two participating European collaborators.

http://kellerlabblog.blogspot.com/2011/11/lyla-nsouli-foundation-funds-supplement.html

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma

The NIH based study lead by Kathy Warren utilizing low dose pegylated interferon for children with newly diagnosed DIPGs recently was published on line ahead of print in the journal Cancer.  The rationale behind this study was the finding that low dose administration of interferon alfa produced” more significant inhibition of angiogenesis-regulating genes, tumor vascularization, and tumor growth compared with the higher intermittent dose schedule. These effects were lost at higher doses, suggesting that metronomic administration of IFNs may have a more robust antitumor effect.”

In this study, 32 children between the ages of 1.8 and  14.8 years (mean 5.3 years) were given pegylated interferon subcutaneously (a shot under the skin) weekly starting 2-10 weeks after radiation until disease progression or unacceptable toxicity.  The idea was to try to have a continuous low dose of inferferon.

There were no grade 4 toxicities and no child stopped interferon because of toxicity.

The overall survival at 2 years was 14.3%  The median time to progression from diagnosis was 235 days, and the median OS from diagnosis was 351 days. 

The authors concluded, “Although low-dose PEG-Intron therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.”

The narrowness of the eligibility criteria in this study is particularly interesting as it shows the advancement in understanding that not all brainstem tumors are the same.   This stricter eligibility criterion seems to be trying to eliminate those tumors that might have an underlying aspect giving it a better prognosis and thus skew the data.  The eligibility criteria defined as:

• Age less than 21 years
• Diffuse intrinsic tumor with epicenter presumed in the pons
• Signal abnormality involving 50% or more of the pons on T2-weighed sequence at diagnosis
• Involvement of the ventral pons
• No expophytic component
• No patients with known or suspected neurofibromatosis type 1

The paper pointed out that the increasing delineation of a DIPG tumor can make it very difficult to compare results with past papers that did not define the patient population in this way.   Those that previously included focal tumors and those with exophytic components might have mistakenly high overall survival statistics.  For those interested in comparing studies analysis of the eligibility criteria is going to be important.

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma Cancer.  2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print] 
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Call To Action: Criminals Stealing From Our Families Whose Children have Died

This is shocking…..    There are criminals out there just looking around for kids who have died and then claim them as dependents before some families can file.   Those families that have been targeted must then have to prove that their child was actually their child. 

How can something so appalling happen?  How can people get the social security number? 

Well, actually for those in the know it is very easy.   It is the government who made it mandatory for this data to be rapidly available after an individual’s death.  The thought was not bad or evil.   The Death Master File (yes, that is what is called) was meant particularly for financial institutions to try to prevent others from using a dead person’s SSN to gain credit.   In addition, there was a movement toward more transparency.   What wasn’t considered at that time was the ease of information transfer that would come years later with the internet.   Likely it wasn’t considered how genealogy sites would used the Death Master File. 

So, how easily available is this Death Master File available?   Well, one can even get it as a app- http://itunes.apple.com/us/app/ssdmf/id453279465?ls=1&mt=8

Or if you don’t want to go to all that trouble one can just use one of the genealogy sites.

It seems that the DIPG community has been particularly hard hit  with a dozen or more families being hit this year.   Here is an article from Nov 17 the Huffington Post…..  http://www.huffingtonpost.com/2011/11/17/why-thieves-are-stealing-childhood-cancer-victims-identities_n_1093481.html

On Nov 18, Representative Sam Johnson (R- TX) along with seven co-sponsors introduced a bill  to try to curtail this fraud perpetrated on our grieving families.: 

H.R.3475 -- Keeping IDs Safe Act of 2011 
http://thomas.loc.gov/cgi-bin/query/z?c112:H.R.3475:

Please consider calling and writing your Representative to bring awareness to this issue.  
http://www.house.gov/ 

Unfortunately, it might not be possible to close this loophole before the next tax cycle in 2012 so it is likely that many families will continue to be vulnerable to this fraud.

Clinical Trials for the Newly Diagnosed Child with DIPG

A review of  www.clinicaltrials.gov was done on October 20, 2011 to identify which therapeutic trials are currently listed as open for the newly diagnosed child with DIPG.   The following is information on the ten (10) listed trials that were listed as accruing patients as well as one vaccine trial that is yet to open.  Clinicaltrials.gov seems to be often not be up to date on trial status.  If you have interest or questions it might be wise to contact the primary investigator.  Contact information is listed at the bottom of each clinical trial site.  Most US clinical trials for DIPG can be found with the key word “pontine glioma” but some are still listed under “brainstem glioma”. 

*Note- many, if not most clinical trials will not allow you to enter a trial if you have already started treatment. 

 

PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma

Phase 1
ligible age- 18 months- 21 years
Study Chair- Cynthia Wetmore
Location- St Jude (Memphis, TN)
http://clinicaltrial.gov/ct2/show/NCT01393912?term=pontine+glioma&recr=Open&rank=1

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma

Phase 2
Eligible age- 3-18 years
Study Chair- Mark Kieran
Location- when open up to 20 locations- only Boston open on 10/20/11
http://clinicaltrial.gov/ct2/show/NCT01182350?term=pontine+glioma&recr=Open&rank=3

Lenalidomide and Radiation Therapy in High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas 

Phase 1
Eligible age- 1-18 years
Location- NIH (Bethesda, MD)
http://clinicaltrial.gov/ct2/show/NCT01222754?term=pontine+glioma&recr=Open&rank=4


A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Glioma 
Phase- not listed
Eligible age- 3-30 years
Study Chair- Maryam Fouladi
Location- Cincinnati and Chicago
http://clinicaltrial.gov/ct2/show/NCT00890786?term=pontine+glioma&recr=Open&rank=5

Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma 

Phase 1
Eligible age- 6 months-21 years
Study Chair. Pierre Leblond
Location- France
http://clinicaltrial.gov/ct2/show/NCT01165333?term=pontine+glioma&recr=Open&rank=7

Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas 

Phase 1
Eligible age- 3 to 18
Study Chair- Paul Fisher
Location- Stanford (Palo Alto, CA)
http://clinicaltrial.gov/ct2/show/NCT01058850?term=pontine+glioma&recr=Open&rank=8

Vorinostat and Radiation Therapy Followed By Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Pontine Glioma 

Phase 1/2
Eligible age- 3 to 21 years
Study Chair- Jack Su
Location- COG trial- multiple locations
http://clinicaltrial.gov/ct2/show/NCT01189266?term=pontine+glioma&recr=Open&rank=11


Pilot Study of  Glioma Associated Antigen Vaccines in Conjunction With Poly-ICLC in Pediatric Gliomas
Phase- none listed (listed as a pilot)
Eligible age- 19 months – 20 years
Study Chair- Regina Jakacki
Location- Pittsburgh
http://clinicaltrial.gov/ct2/show/NCT01130077?term=pontine+glioma&recr=Open&rank=13

External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas

Phase
Eligible age-
Study Chair-
Location-
http://clinicaltrial.gov/ct2/show/NCT01012609?term=pontine+glioma&recr=Open&rank=15

Valproic Acid and Radiation Followed by Maintenance Valproic Acid and Bevacizumab in Children With High Grade Gliomas 
Phase 2
Eligible age- 3-21 years
Study Chair- Ira Dunkel
Location- POETIC study- several locations
http://clinicaltrial.gov/ct2/show/NCT00879437?term=brainstem+glioma&recr=Open&rank=9

 Not Yet Open-

Imiquimod/Brain Tumor Initiating Cell (BTIC) Vaccine in Brain Glioma 

Phase 1
Eligible age- 3 to 25 years
Study Chair- Christopher Moetel
Location- Minneapolis. MN
http://clinicaltrial.gov/ct2/show/NCT01400672?term=pontine+glioma&recr=Open&rank=6

DIPG - Current Status and Future Strategies

The September 27^th issue of journal Child’s Nervous System included a review article evaluating where we are with the treatment and research of diffuse intrinsic pontine gliomas.  These authors performed an extensive literature review particularly looking at clinical trials, evolving molecular biology and new therapeutics.

 In their review they found-

• Radiation is the only treatment that has consistently shown clinical and radiographic improvement.  Approximately 70% of the children receiving radiation will have clinical improvement and 30-70% will have radiographic improvement.
• Multiple studies using a combination of radiation and another agent with generally unimpressive results.  Such agents have included RMP-7/carboplatin, topetecan/cisplatin, tamoxifen,  vincristine/vp-16, cisplatin, temozolomide,  vandetanib, and tipifarnib.  However, the vandetanib study showed that those patients that had a higher plasma VEGF level to start had a longer progression free survival whereas those patients that has increasing levels of VEGF with treatment had a shorter progression free survival. (Original vandetanib study- http://www.ncbi.nlm.nih.gov/pubmed/20921456 )
• “No single chemotherapeutic agent alone or in combination, either in a neoadjuvant oradjuvant setting, has proven to increase disease-free survival or alter overall survival in these children with primary or progressive disease.”  This has included avastin and irinotecan which has had some success in adults. 

The prognosis has remained dismal for more than two decades.   This ‘virtual standstill’ for improved prognosis is leveled at:

•  The lack of biologic knowledge about these tumors.
•  Assumptions that adult and pediatric high grade gliomas are the same.
•  The poor drug access to the tumor because of the blood brain barrier.  
•  The lack of experimental models.

Recommendations included:

1. A shift in treatment paradigm to include a diagnostic biopsy to “identify key molecules of unique signaling pathways which could provide clues to potential targets.
2. Development of preclinical (i.e., mouse) models.
3.  “The need to design phase I study with routine sampling along with CED of therapeutic agents is imperative in these fatal tumors.”
4. “Further exploration of these different imaging modalities needs to be continued, and should facilitate better understanding of tumor architecture and metabolic profile as well as to provide more accurate prediction of extent and duration of response following radiation and adjuvant  therapies.”
5. Evaluation of immunotherapy, gene therapy and other innovative techniques.

Diffuse intrinsic pontine glioma-current status and future strategies.

Childs Nerv Syst. 2011 Sep;27(9):1391-7. Epub 2011 Apr 30.
http://www.ncbi.nlm.nih.gov/pubmed/21533575

Prados Predicted Paradigm Shift for DIPG (diffuse intrinsic pontine glioma)

Three years ago, Dr. Michael Prados was interviewed by Accelerated Brain Cancer Cure on his thoughts of advancements coming for pediatric brain tumors.   Dr Prados immediately focused on the paradigm shift occurring in the medical community to develop unique strategies to fight DIPG though analysis of individual biopsy samples predicting things may change quickly for DIPG.

Why did that paradigm shift occur in the prior year?  Well, French physicians published in the Journal of Neurosurgery 4 years of biopsy results for diffuse pontine lesions.  All 24 children survived the procedure and only 2 suffered some sequela from the intervention developing transient cranial nerve palsies.   One of the two has a worsening of a previous hemiparesis.   Two children had their treatment plan altered because of the biopsy results.

Stereotactic biopsy of diffuse pontine lesions in children

http://www.ncbi.nlm.nih.gov/pubmed/17647306

Neurosurgeon Stefanie Puget has come to North America several times to discuss there ongoing work.   It appears she was just at the Bethesda Consensus Conference earlier this month.

However, it seems that events have moved beyond the discussion stage.   The new multi-institution, 4-armed molecular stratification study is listed as open on clinicaltrials.gov opening first at Dana Farber Boston.   The other institutions slated to collaborate in this trial include -

• University of California, San Francisco
• Children's Hospital Boston
• Children's Memorial Hospital
• Children's Hospital Los Angeles
• University of Utah
• Memorial Sloan-Kettering Cancer Center
• Seattle Children's Hospital
• The Children's Hospital, Denver
• Doernbecher Children's Hospital
• Washington University Children's Hospital
• Miami Children's Hospital
• Johns Hopkins University
• University of Florida
• Children's Hospitals and Clinics of Minnesota
• Southwestern Regional Medical Center
• New York University
• University of Rochester
• University of Mississippi Medical Center
• Louisville Children's Hospital
• Children's Healthcare of Atlanta

http://clinicaltrials.gov/ct2/show/NCT01182350?term=pontine+glioma&rank=4

Accelerate Brain Cancer Cure (ABC²) is a U.S. brain tumor foundation started in 2001 by Dan and Steve Case with the mission to accelerate a cure for brain cancer by increasing the number of potential therapies and moving them rapidly into the clinic for patients.  Since inception,  ABC²  has raised more than 16 million dollars investing in each stage of the development pipeline in pushing for a cure.   It is worth taking a look at the diversity of funding they have engaged in striving for a cure.
http://www.abc2.org/smarter-research

PBTC Phase 2 Study Results for Temozolomide/06-Benzylguanine

An abstract was released ahead of print for a phase 2 Pediatric Brain  Tumor Consortium study on recurrent/progressive high-grade gliomas and brainstem gliomas utilizing the combination of temozolomide and 06-benzylguanine (06 BG).  The study was initially put up on clinicaltrials.gov in January 2006.

O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

http://clinicaltrial.gov/ct2/show/NCT00275002?term=06+temozolomide&rank=10

The thought was that the two agents may work differently to stop tumor growth and that combined chemotherapy might kill more cells.   Temozolomide is an alkylating agent that interferes with DNA replication.  This mechanism of action has seemed dependant on the ability to methylate DNA primarily at the N7 of 0-6 position on guanine.  Some cells were found to be able to repair this DNA damage.  The hope that O6 BG might overcome some of that repair issue.

Of the 41 children evaluated, 16 had brainstem gliomas.  There were no sustained objective responses with any in the brainstem glioma group, however, one patient had long term stable disease of more than 6 courses (28 day course). 

It was concluded that this combination “did not achieve target response rate for pediatric patients with recurrent or progressive high grade glioma or brainstem glioma.”

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study   
http://www.ncbi.nlm.nih.gov/pubmed/21968943

Columbia’s new treatment for DIPG - CED Topotecan

In September, Columbia University announced that neurosurgeons Richard Anderson and Jeffrey Bruce have successfully used convection enhanced delivery (CED) with the agent topotecan for two pediatric DIPG patients.
http://www.columbianeurosurgery.org/2011/09/anderson-and-bruce-beating-the-odds-with-new-cancer-treatment/

CED requires fine catheters to be placed directly into the tumor.  This approach allows for therapy to be placed directly in the tumor avoiding systemic toxicity and higher dosages.

Dr Bruce has worked for more than a decade in development of CED for malignant gliomas.   His initial publications were in 2000 with a rat glioma model.  In 2011, Bruce has authored three publications regarding CED with topotecan for malignant glioma. 

Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model
http://www.ncbi.nlm.nih.gov/pubmed/11126910

Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors
www.ncbi.nlm.nih.gov/pubmed/21464045

Regression of Recurrent Malignant Gliomas with Convection-Enhanced Delivery of Topotecan
http://www.ncbi.nlm.nih.gov/pubmed/21562434

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump
http://www.ncbi.nlm.nih.gov/pubmed/21750007

In addition to Columbia, the NIH also has a CED trial open for recurrent DIPG children utilizing a different agent -
An Open Label Dose Escalation Safety Study of Convection-Enhanced Delivery of IL13-PE38QQR in Patients With Progressive Pediatric Diffuse Infiltrating Brainstem Glioma and Supratentorial High-grade Glioma
http://clinicaltrial.gov/ct2/show/NCT00880061?term=pontine+glioma&rank=20

The NIH has piloted CED in the brainstem not only for DIPG but also for other issues.  In 2007, the NIH published technical notes on two children that received CED therapy.  One of these children had a DIPG and the other had Gaucher’s Disease.
Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note.
http://www.ncbi.nlm.nih.gov/pubmed/17639894

Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood

On September 25^th, YM Bioscience presented a poster presentation at the ECCO-EMSO meeting in Stockholm, Sweden regarding the combined use of Nimotuzamab and vinorelbine with radiation in pediatric DIPG entitled:
"Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood: Promising Results on a Series of 13 Patients"
http://www.news-medical.net/news/20110927/Data-from-YM-BioSciences-nimotuzumab-clinical-trials-to-be-reported-at-ECCO-ESMO-2011.aspx

This appears to a companion to the 2011 ASCO presentation in Chicago.   In this study, the Italian researchers reported on a series of 12 children.  They noted that all children were treated on an outpatient basis and none had suffered significant treatment related side effects.  For the 12 children (ages from 3-13), the progression free survival at 9 months was 69 ± 21% and the 12 month overall survival  was 81.5 ± 12 %.  The researchers believed this combination shows promise for DIPG

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77258

Many researchers feel that combination therapy is going to be important in combating DIPG.  It is exciting to see the combination therapy research.

DIPG Consensus Conference

On October 6 and 7^th in Bethesda, a potentially pivotal meeting took place.
http://web.ncifcrf.gov/events/DIPG/default.asp

This invitation-only conference brought together physicians that care for children with diffuse intrinsic pontine gliomas to talk about several key current issues facing DIPG research.  Some of the presentation titles include:

• A Death Sentence Without Tissue Diagnosis
• Translating Genomics Into Novel Therapeutic Strategies in Pediatric DIPG
• Using A Genetically Engineered Mouse Model of Brainstem Glioma as a Preclinical Tool
• Development of an International DIPG Registry
• Personalized Medicine in Translation: From the Tissue to Treatment in a Single trial
• Rapid Preclinical Development of Targeted Therapy Combinations for DIPG

Hopefully a Consensus Statement or White Paper will be issued as was done with the Toronto DIPG Think Tank.

http://www.ncbi.nlm.nih.gov/pubmed/21901544

The agenda and presenters can be found in the following link-
http://web.ncifcrf.gov/events/DIPG/agenda.pdf

JCO Releases St Jude DIPG Study Ahead of Print

On September 19^th, the Journal of Clinical Oncology published online a St Jude original report on the molecular analysis of diffuse intrinsic pontine gliomas entitled:

Genomic-Wide Analyses Identify Recurrent Amplification of Receptor Tyrosine Kinase and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma.

A press release from Memphis heralded this landmark event as “the largest study ever of a rare childhood brain tumor”. 

http://www.eurekalert.org/pub_releases/2011-09/sjcr-krg091911.php

Other news articles highlight “possible new treatment targets for diffuse intrinsic pontine gliomas” and speculates that (this research) “may tip the scales in the current debate about tumor biopsies.”  http://www.marketwatch.com/story/key-regulatory-genes-often-amplified-in-aggressive-childhood-tumor-of-the-brainstem-2011-09-19

So what is the big news from this study?

First, DIPGs are a distinct subclass of gliomas.  They are different from their counterparts not only in location but also in tumor molecular biology in some ways.  In comparing DIPGs to other pediatric and adult gliomas they found “higher expression of particular HOX gene family members in DIPGs compared to non-brainstem gliomas.”   These HOX genes play an important part in the development of the hindbrain.    Suzanne Baker, St Jude senior developmental biologists said “those differences offer clues about where DIPGs begin and suggest the HOX family of genes might be involved.”

What does this mean?

Well, it would seem to explain the reason that other high grade glioma (HGG) research can not be reliably translated to DIPGs as we have seen with the recurrent dismal results with temozolomide in DIPGs despite it being a first line treatment with adult glioblastoma.     Even HGG pediatric studies might not be comparable.   Thus, DIPG will need to have its own research and clinical trials.

Secondly, it gives another point to start in trying to unravel the development of DIPGs… the HOX genes.  This seems somewhat novel in DIPG literature; however, there are researchers in other areas that are working on HOX genes and hindbrain development.

Thirdly, this is only the beginning.   To truly understand DIPG, there will need to be more samples and more studies.  

Please join us on September 17, 2011 as we celebrate Childhood Cancer Awareness Month along with the life of Alicia Marie Martin