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\begin{document}

\title{DIFFUSE PONTINE INTRINSIC GLIOMAS: FIRST REGISTRY EFFORT IN MEXICO}



\author[1]{Julieta Castro}%
\author[2]{Ana Niembro-Zúñiga}%
\author[3]{Yadira Betanazos-Cabrera}%
\author[4]{FARINA ARREGUIN GONZALEZ}%
\author[4]{Gabriela Barrera-Villegas}%
\author[5]{Daniel Ortiz-Morales}%
\author[6]{Arroyo Acosta}%
\author[7]{Marta Zapata Tarres}%
\affil[1]{Hospital Central Sur de Alta Especialidad}%
\affil[2]{Instituto Nacional de Pediatria}%
\affil[3]{Hospital de Especialidades Centro Medico Nacional Siglo XXI}%
\affil[4]{Centro Medico Nacional 20 de Noviembre}%
\affil[5]{Hospital General de Mexico Dr Eduardo Liceaga}%
\affil[6]{Hospital CIMA Hermosillo}%
\affil[7]{Fundacion IMSS AC}%


\vspace{-1em}



  
  \date{May 07, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Brain tumors in children are the main cause of cancer
related death in the pediatric population. Brainstem tumors incidence
comprises 10.9\% of all brain tumors having the Pediatric Diffuse
Intrinsic Pontine Gliomas (DIPG) a fatal prognosis. Some countries have
developed a national and international register database, to
characterize their population. This study provides a retrospective
population-based data to describe the epidemiology of children with DIPG
in M\selectlanguage{ngerman}éxico from 2001-2021, and assesses the proposed prognostic factors
previously described for survival outcome. Methods: Health Institutions
from México were invited to fill in a retrospective registry of DIPG
patients. Epidemiological, clinical, diagnostic, histopathologic and
treatment variables were described. Fisher exact test was used to
compare long, and short-term survivors and overall survival was
estimated using the Kaplan-Meier Method. Differences between survival
curves were evaluated using the Log-rank test and Cox proportional
hazards regression analysis. Results: One-hundred and ten patients were
included in the analysis. Median age at diagnosis was 7 years. Sixty
patients (54.5\%) presented with symptoms in less than 6 months being
the most frequent ataxia (56.4\%). Treatment was offered to 90 patients
(81.8\%), overall survival at 160 weeks (4 years) was 11.4\%, and 16
patients (14.5\%) arrived at clinical centers to die. We found no
significant survival differences in any of the prognostic factors.
Conclusion: This study highlights the need to develop improvement
strategies to streamline healthcare processes and enhance quality of
care to strengthen our situational diagnosis in Mexico.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{DIFFUSE PONTINE INTRINSIC GLIOMAS: FIRST REGISTRY EFFORT IN
MEXICO}

Julieta Robles-Castro\textsuperscript{1} M.D., M.Sc., Ana
Niembro-Z\selectlanguage{ngerman}úñiga\textsuperscript{2} M.D., Yadira
Betanzos-Cabrera\textsuperscript{3} M.D., Farina
Arreguín-González\textsuperscript{4} M.D., Gabriela
Barrera-Villegas\textsuperscript{4} M.D., Daniel
Ortiz-Morales\textsuperscript{5} M.D., M.Sc., José Benjamín
Arroyo-Acosta\textsuperscript{6} M.D, Marta
Zapata-Tarrés\textsuperscript{7} M.D., Ph.D.

\textsuperscript{1} Hospital Central Sur de Alta Especialidad de
Petróleos Mexicanos, Ciudad de México, México

\textsuperscript{2} Instituto Nacional de Pediatría, Ciudad de México,
México

\textsuperscript{3} Hospital Siglo XXI, Instituto Mexicano del Seguro
Social (IMSS), Ciudad de México, México

\textsuperscript{4} Centro Médico Nacional 20 de Noviembre, Instituto de
Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE),
Ciudad de México, México

\textsuperscript{5} Hospital Eduardo Liceaga, Hospital General de
México, Ciudad de México, México

\textsuperscript{6} Hospital CIMA, Hermosillo, Sonora, México

\textsuperscript{7} Coordinación de Investigación, Fundación IMSS, A.C.

Corresponding Author:

Marta Zapata-Tarrés

Address: Reforma 476 mezzanine poniente. Colonia Juárez, Delegación
Cuauhtémoc, Ciudad de México

Phone: (+52) 5554184099 Email: mzapatatarres@gmail.com

Text Word Count: 2751

Abstract Word Count: 240

Number of tables 1

Number of figures: 2

Brief running title: DIPG Registry in México

Keywords: DPIG, pediatrics, cancer, survival, palliative care

Abbreviation key table:\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
DPIG & Diffuse pontine intrinsic glioma\tabularnewline
OS & Overall survival\tabularnewline
EFS & Event free survival\tabularnewline
SIOPE & Soci\selectlanguage{ngerman}été Internationale d'Oncologie Pédiatrique Europe
(International Society of Pediatric Oncology Europe)\tabularnewline
PET/CT & Positron emission tomography/computed tomography\tabularnewline
MRI & Magnetic resonance image\tabularnewline
\bottomrule
\end{longtable}

TITLE

DIFFUSE PONTINE INTRINSIC GLIOMAS: FIRST REGISTRY EFFORT IN MEXICO

Julieta Robles-Castro, Ana Niembro-Z\selectlanguage{ngerman}úñiga, Yadira Betanzos-Cabrera,
Farina Arreguín-González, Gabriela Barrera-Villegas, Daniel
Ortiz-Morales, José Benjamín Arroyo-Acosta, Marta Zapata-Tarrés.

ABSTRACT (240 words)

Introduction: Brain tumors in children are the main cause of cancer
related death in the pediatric population. Brainstem tumors incidence
comprises 10.9\% of all brain tumors having the Pediatric Diffuse
Intrinsic Pontine Gliomas (DIPG) a fatal prognosis. Some countries have
developed a national and international register database, to
characterize their population. This study provides a retrospective
population-based data to describe the epidemiology of children with DIPG
in México from 2001-2021, and assesses the proposed prognostic factors
previously described for survival outcome.

Methods: Health Institutions from México were invited to fill in a
retrospective registry of DIPG patients. Epidemiological, clinical,
diagnostic, histopathologic and treatment variables were described.
Fisher exact test was used to compare long, and short-term survivors and
overall survival was estimated using the Kaplan-Meier Method.
Differences between survival curves were evaluated using the Log-rank
test and Cox proportional hazards regression analysis.

Results: One-hundred and ten patients were included in the analysis.
Median age at diagnosis was 7 years. Sixty patients (54.5\%) presented
with symptoms in less than 6 months being the most frequent ataxia
(56.4\%). Treatment was offered to 90 patients (81.8\%), overall
survival at 160 weeks (4 years) was 11.4\%, and 16 patients (14.5\%)
arrived at clinical centers to die. We found no significant survival
differences in any of the prognostic factors.

Conclusion: This study highlights the need to develop improvement
strategies to streamline healthcare processes and enhance quality of
care to strengthen our situational diagnosis in Mexico.

MAIN TEXT (2751 words)

Introduction

Brain tumors in children are the main cause of cancer related death in
the pediatric population. The overall incidence of brain tumors is
around 23.41 per 100 000 population in the United States, and 6.06 per
100,000 population among children and adolescents aged 0-19
years\textsuperscript{1}. Brainstem tumors incidence comprises 10.9\% of
all brain tumors in this population. Pediatric Diffuse Intrinsic Pontine
Gliomas (DIPG) is a malignant brain tumor with a median overall survival
of 9 months\textsuperscript{2}. Symptoms appear in a short time, and
include cranial nerve involvement, long tract signs and cerebral
deficits. A magnetic resonance imaging (MRI) with and without gadolinium
administration is the study of choice and can confirm the diagnosis when
biopsy is not possible due to the anatomical location and high morbidity
rate associated with the procedure. Actual therapeutic strategies
include radiotherapy with or without chemotherapy with a palliative care
approach and only a few months of increase
insurvival\textsuperscript{3}. Treatment strategies have not improved
survival and since DIPG is a rare tumor, non-randomized trials with a
low number of patients constitute most of the available information.
Some countries have developed national and international register
databases of pediatric patients with DIPG. In 2011, the International
Society of Pediatric Oncology Europe (SIOPE) formed the SIOP DIPG
Network to create an online resource of comprehensive data on DIPG
patients to initiate collaborative clinical trials with uniform criteria
and share information on diagnosis, treatment, ongoing clinical trials,
and additional care for DIPG patients\textsuperscript{4}. From these
data base registries, some characteristics, both clinical and
radiological, have become possible prognostic factors for survival,
including duration of symptoms prior to diagnosis for more than 12
months, age less than 3 years at diagnosis, use of chemotherapy, and the
presence of ring-enhancement on MRI as an unfavorable
factor\textsuperscript{5}. These predictors have been validated in a
SIOP DIPG Registry cohort\textsuperscript{6}.

End of life care is complex for patients with DIPG, requiring surgical
procedures and other medical treatments to minimize or alleviate
symptoms like pain, seizures, dysphagia, constipation, or urinary
retention, and to make everyday tasks easier for their families. Most
families still pursue chemotherapy treatment to improve quality of life.
Planning the place of death is also important to all families with
children with DIPG\textsuperscript{7}.

The availability of tumor tissue for accurate diagnosis and research
purposes is a difficult task due to anatomical location or tumor size at
diagnosis. Routine tumor biopsy is still under debate, considering
diagnosis can be made with radiological studies\textsuperscript{8}, and
it is recommended before treatment if molecular targeted therapies are
planned under a clinical trial\textsuperscript{9}. The collection of
post-mortem tumor tissue can be an alternate approach to understand the
biology of this group of tumors, but autopsies cannot always be
performed. Families must consent for a brain autopsy and pathologists
need to include unfixed brain tissue for molecular
studies\textsuperscript{10}. An informed consent for research analysis
must be signed as well. These procedures are not always possible to
achieve if the patient dies at home.

With some difficulties due to lack of registries in the past, Mexico has
worked to establish a national registry. In 2016, a group of pediatric
oncologists reported a significant number of patients with brainstem
gliomas, where the main symptom was ataxia and the overall survival at 5
years was 68\%. All patients with DIPG died\textsuperscript{11}.

The purpose of this study is to provide a retrospective population-based
data to characterize the descriptive epidemiology of children with DIPG
in México from 2001-2021, and assess proposed prognostic factors
previously described for survival outcomes.

Methods

Health Institutions from Mexico were invited to fill in a retrospective
registry of patients with DIPG. All patients were included. The study
was approved by the Institutional Review Board of six institutions.
Demographic variables included, age, sex, duration of before admission,
clinical signs at admission, image studies for diagnosis and treatment.
Histopathological diagnosis and type of surgery was described when
available. Overall Survival (OS) was defined as the time from diagnosis
to death or last follow-up. Survival at 9 and 12 months was calculated.
The value of 9 and 12 months was chosen as an arbitrary cutoff
considering the average survival of DIPG patients, and the cut-off
chosen at clinical trials. Short-term survivors were defined as those
with an OS \textless{}12 months and long-term survivors as those with an
OS of \textgreater{}12 months.

Patients' demographic, clinical and diagnostic characteristics and
treatment variables were summarized using frequencies and percentages or
median ranges. Cause of death or palliative care treatment was described
when available. Fisher's exact test was used to compare long, and
short-term survivors and OS was estimated using the Kaplan-Meier
estimate. Differences between survival curves were evaluated using the
Log-rank test with a P-value \textless{} 0.05 indicating a significant
difference. Also, the Cox proportional hazards regression analysis was
performed for univariate and multivariate hazard ratios for all
variables of interest.

Prognostic variables used for survival were age (cutoff at 3 years),
duration of symptoms at diagnosis (cutoff at 6 months), and chemotherapy
plus radiotherapy at any time during the disease course. Radiological
data on diagnostic imaging was not used due to missing data.

All statistical tests were performed using SPSS, version 25 (IBM Corp-
Released 2017. IBM SPSS Statistics for Mac, Armonk, NY: IBM Corp)

Results

Twenty-three institutions that are members of the Mexican Agrupation of
Pediatric Hemato-Oncology were invited to participate in a survey. The
survey consisted of a database with epidemiological information of
patients with high-grade brainstem gliomas from 2001 to 2021. Six
institutions answered the registry and submitted the protocol to the
research and ethics committee. All patients with complete information
were included. The health institutions that participated were the
Instituto Nacional de Pediatría, Hospital Siglo XXI from the Instituto
Mexicano del Seguro Social (IMSS), Centro Médico Nacional 20 de
Noviembre, from the Instituto de Seguridad y Servicios Sociales de los
Trabajadores del Estado (ISSSTE), Hospital General de México Dr. Eduardo
Liceaga from México City, and the Hospital CIMA from Sonora, México.

We analyzed 110 patients with DIPG (Table 1). Annual variations were
observed; 14 patients were registered in 2014 and only 1 registered in
2003, 2006 and 2009.

Forty-seven patients (42.7\%) were males, and 63 (57.3\%) females.
Median age at diagnosis was 7.0 years (1 -- 17 years). Only 17 patients
(15.5\%) were 3 or less years old. The most frequent age at diagnosis
was at 6 years with 16 patients, and 51 patients were diagnosed at 4-7
years (46.3\%).

Sixty patients (54.5\%) presented with symptoms in less than 6 months.
Behavioral disturbances were reported in 8 patients, with somnolence and
irritation being the most frequent. The most common clinical symptoms at
diagnosis were paresis 31 (28.2\%) and abnormal eye movement (diplopia)
25 (22.7\%).

The most frequent signs reported were ataxia 62 (56.4\%), cranial nerve
palsies 57 (51.8\%) with compromise of cranial nerve VI in 35 (31.8\%),
VII in 32 (29.1\%), III in 25 (22.7\%) and IV in 14 (12.7\%). Other
signs reported were facial asymmetry 32 (29.1\%), dysmetria 17 (15.5\%),
hyperreflexia 24 (21.8\%), the Babinsky sign in 18 (16.4\%) and
hemiplegia in 28 (25.5\%). Hydrocephalus was present in 37 patients
(33.6\%) and 24 (21.8\%) received a shunt.

Spectroscopy was available in 22 patients (20\%) and positron emission
tomography/computed tomography (PET-CT) in 6 (5.5\%). Tomography was
used for initial diagnosis in 74 (67.3\%) and magnetic resonance image
was used to complete it in 100 (90.9\%). Descriptive image diagnosis was
not available in all patients.

Ninety patients (81.8\%) received treatment. Radiotherapy was reported
in 76 (69.1\%). Among these patients, the total dose used was 54 Gy
(49.1\%) followed by 55 Gy and 50.4 Gy (10\% each). Of these 76
patients, 35 (31.8\%) underwent normofractioned radiotherapy.

Histological diagnosis was available in 58 patients (52.7\%), 3 of whom
(2.7\%) were not conclusive and 1 (0.9\%) was unknown. The most frequent
diagnosis was pilocytic astrocytoma 19 (17.3\%) and anaplastic
astrocytoma 15 (13.6\%). Chemotherapy was used in 67 patients (60.9\%),
being concomitant with radiotherapy in 36 (32.7\%), neoadjuvant in 9
(8.2\%) and adjuvant in 22 (20\%). Steroids were used in 44 patients
(40\%).

Surgery performed to ameliorate symptoms or to improve quality of life
were shunt 24 (21.8\%), gastrostomy 15 (13.6\%), tracheostomy 7 (6.4\%)
and port-catheter 8 (6.3\%).

Ten patients survived (9.1\%) and the longest survivor was reported at
16 years from diagnosis, 90 patients (81.8\%) died, and 10 (9\%) were
lost to follow-up. Considering the cutoff points of 9 and 12 months, 72
patients (65.5\%) patients died in less than 9 months and 79.1\% in less
than 12 months. Thirty patients died at home (27.3\%) and 28 at the
hospital (25.5\%). Only 2 (1.8\%) autopsies were performed. Palliative
care was given in 22 patients (20\%). Only 88 patients had a complete
registry to determine survival. Of these 88 patients, overall survival
was 11.4\% and event free survival was 19.3\% at 160 weeks (4 years)
(Fig 1). Sixteen patients (14.5\%) died at medical centers at diagnosis,
and 33 (30\%) died within one month of diagnosis

Progression was documented with an image report in 40 patients (36.4\%).
Only 50 patients had a date of death. Median time to death was 172.32
days (range 0-3660).

There was no significant survival difference (PFS or OS) according to
the 3 years of age cutoff (Log-rank PFS p=0.310 and OS p=0.399),
oncologic treatment (Log-rank PFS p=0.523 and OS p=0.679), or steroids
use (Log-rank PFS p=0.384 and OS p=0.462). There was a significant
difference in PFS between sexes but not with OS (Log-rank PFS p=0.035
and OS p=0.091).

Fisher's exact test was used to compare long and short-term survivors in
terms of certain variables of interest. Accordingly, hyperreflexia,
onset of symptoms in less than six months, and use of radiotherapy with
concomitant radiotherapy differed significantly (p= 0.028, p= 0.009 and
p=0.007, respectively). According to our logistic regression analysis on
these variables, the best model to predict survival was hyperreflexia
and radiotherapy with concomitant chemotherapy (p= 0.001) where
hyperreflexia and concomitant treatment had a protector prognostic
factor (OR 0.225 p=0.012 (95\%CI 0.070-0.720) and OR 0.231 p=0.009
(95\%CI 0.077-0.690) respectively). Onset of symptoms in less than six
months showed no significance between the groups (p= 0.061)

A Cox proportional hazards regression analysis was performed for
univariate and multivariate hazard ratios without any significance for
all variables of interest. Considering the 3 rears of age cutoff, onset
of symptoms in less than six months or concomitant treatment showed no
significance (p= 0.888).

Discussion

The prognosis for children with DIPG has remained dismal. The low
incidence of these tumors makes clinical trials hard to perform and data
from different health institutions and countries are difficult to
compare due to a lack of consensus in inclusion, exclusion, and response
criteria. Another issue is the number of specialists who care for these
patients. Pediatric oncologists, neurosurgeons, neurologists, emergency
doctors and pediatricians are an important part of a large team of
specialists. Considering treatments, new pharmacological strategies are
used randomly without randomized controlled clinical trials.
Historically, another variable is the possibility of performing a tumor
biopsy and neurosurgeons' criteria for a tumor biopsy. This surgical
limitation has resulted in lack of knowledge on the histology and
malignancy grade of tumors, forcing medical doctor to sometimes
overtreat some patients. The variability of access to medical attention,
differences in patient and family care choices, performance of the
surgery, classification of disease risk, indication of radiotherapy,
decision to start palliative care, and magnitude of medical and surgical
interventions to give nutritional support or to avoid intracranial
hypertension among other issues have made the medical approach to this
problematic disease very heterogeneous. Hence, it has become difficult
to come to a consensus and establish standardized diagnostic and
treatment strategies\textsuperscript{12}.

In 2011, the International Society of Pediatric Oncology in Europe
(SIOPE) created a DIPG Registry with the aim to collect epidemiological,
clinical, diagnostic, histopathological, treatment, and prognosis data
to allow collaborative and structured analysis studies among every
participating country\textsuperscript{4}.

Mexico is one of the countries participating in this DIPG Registry. The
first section of this registry is a retrospective analysis and the
second a prospective inclusion of new cases. Our aim was at first to
start a collaborative initiative in Mexico for a registry based on the
International DIPG Registry. As a second point, we made a situational
diagnosis of patients' clinical characteristics and quality of clinical
care and analyzed the Mexican hospitals that participated. The analysis
of signs and symptoms at diagnosis match with the epidemiological data
reported in other countries\textsuperscript{13, 14, 15. 16}. Some
interesting data from our cohort is that 45.5\% of patients are
diagnosed after six months, which may not change the final prognosis but
could delay symptom relief. We report 9.1\% of the patients survived and
one of these patients was 16 years old at the time of this report.
Considering the median time to survival, 65.5\% of the patients died in
less than 9 months.

Considering the parameters for quality of standard care, we found that
almost 90\% of patients were diagnosed with a magnetic resonance image
and only 20\% with spectroscopy. Though the conventional use of magnetic
resonance imaging over computed tomography has become the standard
method of diagnosis, many health institutions have still not made
further use of spectroscopy or other new techniques due to availability,
where patients must travel in delicate conditions to get
one\textsuperscript{17}. Six patients had a PET-CT which is not a
standard tool, and we documented these cases were not in a research
protocol. Interestingly, tumor tissue was available in almost half of
the patients, but no molecular studies were performed. This is a very
important point in which neurosurgery has the surgical skill and
attitude to take oriented decisions. Even if molecular studies are not
available, discriminating between low and high-grade cases is
fundamental for understanding the clinical course and considering the
use of chemotherapy in a reasoned way.

Treatment with radiotherapy was used in 91 patients, which makes a
standpoint observation because it is at this moment the standard option
of treatment. Some patients could not receive it because they arrived at
a hospital and died in the first week after diagnosis. Use of steroids
as part of initial treatment was observed in 40 patients, which
elucidates that not all health centers use them as part of their
treatment, as it has been documented that side effects can be important,
and the health benefits and risks remain
controversial\textsuperscript{18}.

Only a small proportion of patients were evaluated by a palliative care
team, and some were treated with a gastrostomy and/or tracheostomy as
part of end-of-life care. However, no information was available on the
use, type, or dose of steroids and pain treatment in any of the
patients. Not all hospitals have a palliative care team, or end-of-life
guidelines for pediatric patients with DIPG; the initial treatment is
given by the oncology department. There is still scarce information
about what specific special needs are appropriate for palliative and
end-of-life care in these patients\textsuperscript{19, 20}.

Two autopsies were performed, though 16 patients died at a hospital.
Collecting postmortem tumor tissue can be of great importance in
countries like ours where molecular analysis cannot always be performed,
to begin understanding, along with tumor tissue from alive patients,
histopathology, and immunochemistry patterns\textsuperscript{21}.

Our study has several strengths and limitations. The strengths include
the national collaboration, and effort to show and understand a partial
situational diagnosis of the country in the DIPG problem, its diagnosis,
and treatment strategies, as well as standard of end-of-life care. Latin
America has not gathered information on DIPG pediatric patients to date.
The main limitation was the lack of national collaboration. This is such
an issue that the Mexican Society of Pediatric Onco-Hematology is
working on it through clinical research courses and presentation of
initiatives among other things.

This study highlights the need to develop improvement strategies to
streamline healthcare processes and improve quality of care in DIPG. We
could not perform multivariate analysis due to the number of patients
studied and the lack of information available. Further research must be
done to show data that can be compared to international patient series.
Still, in our country, not all risk factors can be measured, collected,
analyzed, and compared with high-income countries; therefore, we may
need to adapt other clinical, diagnostic and treatment related factors
to our population. Still, as members of the SIOPE Registry for patients
with DIPG, the repository and description of images are of great
importance and must be applied to our database as a prospective goal,
along with the molecular analysis of tumor tissue and standard of
treatment care.

Conflict of Interest statement

There is no conflict of interest by any of the authors in this
manuscript

Acknowledgments

We thank CONACYT (CV596782) and the Doctorate program in Medical, Dental
and Health Sciences, recognized by the CONACYT National Quality Graduate
Program, for their support for the realization of this Project.

REFERENCES

\begin{enumerate}
\tightlist
\item
  Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS Statistical Report:
  Primary Brain and Other Central Nervous System Tumors Diagnosed in the
  United States in 2012-2016.~\emph{Neuro Oncol} . 2019;21(Suppl
  5):v1-v100. doi:10.1093/neuonc/noz150
\item
  Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in
  children: critical review of clinical trials.~\emph{Lancet Oncol} .
  2006;7(3):241-248. doi:10.1016/S1470-2045(06)70615-5
\item
  Cage TA, Samagh SP, Mueller S, et al. Feasibility, safety, and
  indications for surgical biopsy of intrinsic brainstem tumors in
  children.~\emph{Childs Nerv Syst} . 2013;29(8):1313-1319.
  doi:10.1007/s00381-013-2101-0
\item
  Veldhuijzen van Zanten SEM, Baugh J, Chaney B, et al. Development of
  the SIOPE DIPG network, registry and imaging repository: a
  collaborative effort to optimize research into a rare and lethal
  disease.~\emph{J Neurooncol} . 2017;132(2):255-266.
  doi:10.1007/s11060-016-2363-y
\item
  Jansen MH, Veldhuijzen van Zanten SE, Sanchez Aliaga E, et al.
  Survival prediction model of children with diffuse intrinsic pontine
  glioma based on clinical and radiological criteria.~\emph{Neuro Oncol}
  . 2015;17(1):160-166. doi:10.1093/neuonc/nou104
\item
  Veldhuijzen van Zanten SEM, Lane A, Heymans MW, et al. External
  validation of the diffuse intrinsic pontine glioma survival prediction
  model: a collaborative report from the International DIPG Registry and
  the SIOPE DIPG Registry.~\emph{J Neurooncol} . 2017;134(1):231-240.
  doi:10.1007/s11060-017-2514-9
\item
  Hasan F, Weingarten K, Rapoport A, Bouffet E, Bartels U. End-of-life
  care of children with diffuse intrinsic pontine glioma.~\emph{J
  Neurooncol} . 2018;138(1):147-153. doi:10.1007/s11060-018-2781-0
\item
  Tejada S, Aquilina K, Goodden J, et al. Biopsy in diffuse pontine
  gliomas: expert neurosurgeon opinion-a survey from the SIOPE brain
  tumor group.~\emph{Childs Nerv Syst} . 2020;36(4):705-711.
  doi:10.1007/s00381-020-04523-8
\item
  Infinger LK, Stevenson CB. Re-Examining the Need for Tissue Diagnosis
  in Pediatric Diffuse Intrinsic Pontine Gliomas: A Review.~\emph{Curr
  Neuropharmacol} . 2017;15(1):129-133.
  doi:10.2174/1570159x14666160425114024
\item
  Ahrendsen JT, Filbin MG, Chi SN, et al. Increasing value of autopsies
  in patients with brain tumors in the molecular era.~\emph{J
  Neurooncol} . 2019;145(2):349-355. doi:10.1007/s11060-019-03302-z
\item
  Murray-Cota AE, Zapata-Tarres M, Arreguín-González FE, et al. Brain
  Stem Glioma National Registry: Pilot program. Neuro-Oncology
  18:iii48-iii77, 2016
\item
  El-Khouly FE, Veldhuijzen van Zanten SEM, Santa-Maria Lopez V, et al.
  Diagnostics and treatment of diffuse intrinsic pontine glioma: where
  do we stand?. \emph{J Neurooncol} . 2019;145(1):177-184.
  doi:10.1007/s11060-019-03287-9
\item
  Patil N, Kelly ME, Yeboa DN, et al. Epidemiology of brainstem
  high-grade gliomas in children and adolescents in the United States,
  2000-2017. \emph{Neuro Oncol} . 2021;23(6):990-998.
  doi:10.1093/neuonc/noaa295
\item
  Fonseca A, Afzal S, Bowes L, et al. Pontine gliomas a 10-year
  population-based study: a report from The Canadian Paediatric Brain
  Tumour Consortium (CPBTC). \emph{J Neurooncol} . 2020;149(1):45-54.
  doi:10.1007/s11060-020-03568-8
\item
  Vallero SG, Bertin D, Basso ME, Pittana LS, Mussano A, Fagioli F.
  Diffuse intrinsic pontine glioma in children and adolescents: a
  single-center experience. \emph{Childs Nerv Syst} .
  2014;30(6):1061-1066. doi:10.1007/s00381-014-2359-x
\item
  Veldhuijzen van Zanten SE, Jansen MH, Sanchez Aliaga E, van Vuurden
  DG, Vandertop WP, Kaspers GJ. A twenty-year review of diagnosing and
  treating children with diffuse intrinsic pontine glioma in The
  Netherlands. \emph{Expert Rev Anticancer Ther} . 2015;15(2):157-164.
  doi:10.1586/14737140.2015.974563
\item
  Rashed WM, Maher E, Adel M, Saber O, Zaghloul MS. Pediatric diffuse
  intrinsic pontine glioma: where do we stand?. \emph{Cancer Metastasis
  Rev} . 2019;38(4):759-770. doi:10.1007/s10555-019-09824-2
\item
  Veldhuijzen van Zanten SE, Cruz O, Kaspers GJ, Hargrave DR, van
  Vuurden DG; SIOPE DIPG Network. State of affairs in use of steroids in
  diffuse intrinsic pontine glioma: an international survey and a review
  of the literature. \emph{J Neurooncol} . 2016;128(3):387-394.
  doi:10.1007/s11060-016-2141-x
\item
  Veldhuijzen van Zanten SE, van Meerwijk CL, Jansen MH, et al.
  Palliative and end-of-life care for children with diffuse intrinsic
  pontine glioma: results from a London cohort study and international
  survey. \emph{Neuro Oncol} . 2016;18(4):582-588.
  doi:10.1093/neuonc/nov250
\item
  Elhemaly A, Refaey OE, Rizkallah RS, Refaat A, Zaghloul MS. Palliative
  and end-of-life symptoms management for children with diffuse
  intrinsic pontine glioma. \emph{Future Oncol} . 2022;18(16):1943-1950.
  doi:10.2217/fon-2021-1455
\item
  Kambhampati M, Perez JP, Yadavilli S, et al. A standardized autopsy
  procurement allows for the comprehensive study of DIPG
  biology.\emph{Oncotarget} . 2015;6(14):12740-12747.
  doi:10.18632/oncotarget.3374
\end{enumerate}

TABLES

TABLE 1: Patient characteristics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Demographic / Clinical & n = 110\tabularnewline
\midrule
\endhead
Age, (median in years) & 7y\tabularnewline
[?] 3 a\selectlanguage{ngerman}ños & 17\tabularnewline
Gender, male & 47\tabularnewline
Symptom duration prior to presentation &\tabularnewline
\textless{} 6 weeks & 60\tabularnewline
6-12 weeks & 11\tabularnewline
12-24 weeks & 12\tabularnewline
\textgreater{}24 weeks & 6\tabularnewline
Unknown & 21\tabularnewline
Symptoms and signs at presentation &\tabularnewline
Conduct alterations & 8\tabularnewline
Ataxia & 62\tabularnewline
Hemiplegia & 28\tabularnewline
Quadriplegia & 5\tabularnewline
Dysmetria & 17\tabularnewline
Diplopia & 25\tabularnewline
Babinski & 18\tabularnewline
Papilledema & 3\tabularnewline
Cranial nerve palsy & 57\tabularnewline
Hydrocephalus & 37\tabularnewline
Diagnosis corroborated with imaging &\tabularnewline
Magnetic Resonance & 100\tabularnewline
Tomography & 74\tabularnewline
Spectroscopy & 22\tabularnewline
Treatment & 90\tabularnewline
Surgery (biopsy) & 58\tabularnewline
Radiotherapy & 76\tabularnewline
Chemotherapy & 67\tabularnewline
Neoadjuvant & 9\tabularnewline
Concomitant & 36\tabularnewline
Adjuvant & 22\tabularnewline
Steroids & 44\tabularnewline
Progression by image & 40\tabularnewline
Patient alive at 9 months & 38\tabularnewline
Place of death &\tabularnewline
Hospital & 28\tabularnewline
Other & 2\tabularnewline
Home & 30\tabularnewline
Unknown & 50\tabularnewline
Autopsy & 2\tabularnewline
Palliative care & 22\tabularnewline
\bottomrule
\end{longtable}

FIGURES:\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Fig 1. Overall survival (OS) and Event free Survival (EFS) for the
entire cohort. Blue line represents OS, red line represents EFS

\textbf{Hosted file}

\verb`Figuras GPID.docx`  available at \url{https://authorea.com/users/507119/articles/585645-diffuse-pontine-intrinsic-gliomas-first-registry-effort-in-mexico}

\textbf{Hosted file}

\verb`Tables GPID.docx`  available at \url{https://authorea.com/users/507119/articles/585645-diffuse-pontine-intrinsic-gliomas-first-registry-effort-in-mexico}

\selectlanguage{english}
\FloatBarrier
\end{document}

