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\begin{document}

\title{Impact of Diagnostic and End-Induction Curie Scores with Tandem
Autologous Transplants for Metastatic High-Risk Neuroblastoma: A Report
from the Children's Oncology Group}



\author[1]{Keri Streby}%
\author[2]{Meg Parisi}%
\author[3]{Barry Shulkin}%
\author[4]{Brian LaBarre}%
\author[5]{Rochelle Bagatell}%
\author[6]{Lisa Diller}%
\author[5]{Stephan A. Grupp}%
\author[7]{Katherine Matthay}%
\author[8]{Stephan Voss}%
\author[9]{Alice Lin Tsing Yu}%
\author[6]{Wendy London}%
\author[10]{Julie Park}%
\author[11]{Gregory Yanik}%
\author[4]{Arlene Naranjo}%
\affil[1]{Nationwide Children's Hospital Hematology Oncology \& Blood and Marrow Transplant}%
\affil[2]{University of Washington Department of Radiology}%
\affil[3]{St Jude Children's Research Hospital}%
\affil[4]{University of Florida Department of Biostatistics}%
\affil[5]{The Children's Hospital of Philadelphia}%
\affil[6]{Dana-Farber/Boston Children's Cancer and Blood Disorders Center}%
\affil[7]{University of California San Francisco Department of Pediatrics}%
\affil[8]{Boston Children's Hospital}%
\affil[9]{University of California San Diego}%
\affil[10]{University of Washington Department of Pediatrics}%
\affil[11]{University of Michigan Department of Pediatrics}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{BACKGROUND:} Diagnostic mIBG (meta-iodobenzylguanidine) scans
are an integral component of response assessment in children with
high-risk neuroblastoma. The role of end of induction (EOI) Curie Scores
(CS) was previously described in patients undergoing a single autologous
hematopoietic cell transplant (AHCT) as consolidation therapy.
\textbf{OBJECTIVE:} We now examine the prognostic significance of CS in
patients randomized to tandem AHCT on the Children's Oncology Group
(COG) trial ANBL0532. \textbf{STUDY DESIGN:} A retrospective analysis of
mIBG scans obtained from patients enrolled in COG ANBL0532 was
performed. Evaluable patients had mIBG-avid, International Neuroblastoma
Staging System (INSS) stage 4 disease, did not progress during induction
therapy, consented to consolidation randomization, and received a tandem
AHCT (n=80). Optimal CS cut points maximized the outcome difference ([?]
vs \textgreater{}CS cut-off) according to the Youden index.
\textbf{RESULTS:} For recipients of tandem AHCT, the optimal cut point
at diagnosis was CS=12, with superior EFS from study enrollment for
patients with CS\textless{}12 (3-year EFS 74.2\selectlanguage{ngerman}±7.9\%) vs
CS\textgreater{}12 (59.2±7.1\%) (p=0.002). At EOI, the optimal cut point
was CS=0, with superior end-induction EFS for patients with CS=0
(72.9±6.4\%) vs CS\textgreater{}0 (46.5±9.1\%) (p=0.002).
\textbf{CONCLUSION:} In the setting of tandem transplantation for
children with high-risk neuroblastoma, Curie scores at diagnosis and
end-induction may identify a more favorable patient group. Patients
treated with tandem AHCT who exhibited a CS\textless{}12 at diagnosis or
CS=0 at EOI had superior EFS compared to those with CS above these cut
points.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{INTRODUCTION}

Outcomes for children with high-risk neuroblastoma have improved over
the past two decades with the addition of immunotherapy and tandem
autologous hematopoietic cell transplantation
(AHCT).\textsuperscript{1-3} Park et al demonstrated a significant
improvement in survival for patients treated with tandem AHCT vs single
AHCT on the Children's Oncology Group (COG) trial ANBL0532, ``A Phase
III Randomized Trial of Single versus Tandem Myeloablative Consolidation
Therapy for High-Risk Neuroblastoma'', with 3-year EFS 61.6\% vs 48.4\%,
respectively.\textsuperscript{3} Preparative regimens for tandem AHCT
included cyclophosphamide/thiotepa and dose-reduced
carboplatin/etoposide/melphalan (CEM); while single AHCT utilized
CEM.\textsuperscript{3-5} Despite the current multimodal approach,
approximately 10-15\% of patients develop disease progression during
induction therapy and another 40\% relapse after an initial response to
induction therapy.\textsuperscript{4,6} For patients who develop
relapsed disease, specifically those who relapse 6-18 months from
initial diagnosis, 5-year overall survival (OS) is less than
20\%.\textsuperscript{7} The ability to identify both clinical and/or
biologic prognostic markers of response earlier in a patient's treatment
course may guide subsequent treatment decision-making.

Meta-iodobenzylguanidine (mIBG) is a structural analogue of the
catecholamine norepinephrine. Approximately 90\% of neuroblastomas
concentrate mIBG within sites of disease including marrow, cortical
bone, and soft tissue.\textsuperscript{8-10} In 1995, a semiquantitative
mIBG scoring system (Curie scoring; CS) was developed to describe the
extent of mIBG uptake within individual patients, and serve as an
imaging biomarker for outcome prediction.\textsuperscript{11} The role
of Curie scoring as a prognostic indicator for high-risk neuroblastoma
has been reported in several institutional and cooperative group trials,
including trials within the COG and the International Society of
Paediatric Oncology European Neuroblastoma (SIOPEN) Research
Network.\textsuperscript{12-14} In particular, a CS\textgreater{}2 at
the end of induction (EOI) was associated with inferior outcomes in two
independent, cooperative group trials, the European high-risk
neuroblastoma trial SIOPEN/HR-NBL1 and the COG high-risk neuroblastoma
study COG A3973.\textsuperscript{12,13}

To date, the prognostic significance of Curie scoring has been reported
within the context of patients who underwent induction followed by
consolidation therapy with a single AHCT, with either busulfan/melphalan
or CEM given as AHCT conditioning,\textsuperscript{12,13} although few
patients received post-transplant anti-disialoganglioside (GD2)
immunotherapy which is now considered standard of
care.\textsuperscript{1,15} The aim of our current study was to
investigate the prognostic significance of CS at diagnosis and at EOI
for patients with newly diagnosed high-risk neuroblastoma treated with
tandem AHCT on COG ANBL0532, including those who also received anti-GD2
immunotherapy.

\textbf{MATERIALS AND METHODS}

\textbf{Patient Population}

Six hundred sixty-five patients with newly diagnosed high-risk
neuroblastoma were assessed for eligibility for COG ANBL0532 from
November 2007 through February 2012.\textsuperscript{3} Of these 665,
355 patients with newly diagnosed high-risk neuroblastoma who were
enrolled on COG ANBL0532, did not receive prior systemic therapy, did
not progress or die of toxicity during induction, and underwent
randomization to either single or tandem transplant were assessed for
inclusion in our Curie Score analysis \textbf{(Supplemental FIGURE S1)}
.\textsuperscript{3} Among the 355 randomized patients, 228 had paired
evaluable \textsuperscript{123}I-mIBG or\textsuperscript{131}I-mIBG
scans available at diagnosis and EOI. Patients with mIBG non-avid
disease (n=10) at diagnosis, International Neuroblastoma Staging System
(INSS) non-Stage 4 disease (n=19), and those who did not undergo their
assigned transplant (n=20) were excluded from the final analysis. The
resulting cohort of 179 patients, including 80 patients randomized to
tandem and 99 randomized to single AHCT, was examined. Written informed
consent was obtained from all patients (or legal guardians) before entry
onto ANBL0532 and prior to consolidation randomization. The trial was
registered on ClinicalTrials.gov (NCT00567567).

\textbf{Treatment}

Therapy on COG ANBL0532 consisted of six cycles of induction
chemotherapy, surgical resection of residual soft-tissue disease
following the 5th cycle of induction, randomization to single or tandem
AHCT, and post-AHCT radiotherapy \textbf{(Supplemental FIGURE S2)}
.\textsuperscript{3} Following radiotherapy, patients either a) received
6 monthly cycles of isotretinoin or b) were enrolled onto COG ANBL0032
(NCT00026312) or its successor trial, COG ANBL0931 (NCT01041638).
Patients enrolled on ANBL0032 were randomized to receive either
immunotherapy including chimeric anti-GD2 antibody (dinutuximab) and
cytokines of granulocyte colony stimulating factor and interleukin-2
plus isotretinoin or 6 monthly cycles of
isotretinoin.\textsuperscript{1} Following preliminary results of
superior outcomes with immunotherapy, subsequent patients were
non-randomly assigned to receive dinutuximab plus cytokine immunotherapy
with isotretinoin on ANBL0032 or ANBL0931.\textsuperscript{1,3,16}

\textbf{Diagnostic Imaging: mIBG Scans}

Diagnostic imaging was performed with either \textsuperscript{123}I-mIBG
or \textsuperscript{131}I-mIBG scanning techniques \textbf{(Figure 1C)}
.\textsuperscript{8,17} For thyroid protection, supersaturated potassium
iodide was given 16-24 hours before the diagnostic mIBG dose, and
several days post-imaging, per institutional
guidelines.\textsuperscript{123}I-mIBG or \textsuperscript{131}I-mIBG
planar images, with or without single photon emission tomography
(SPECT), were acquired using protocol recommended
guidelines.\textsuperscript{8,17}

\textbf{mIBG Semiquantitative Scoring: Modified Curie Scoring Method}

Curie scoring was performed from diagnostic and EOI mIBG scans as
previously described.\textsuperscript{12,13} SPECT was utilized only if
available and as needed for clarification of questionable sites of mIBG
uptake. An absolute score, calculated by summating the scores from the
ten individual anatomic sites, was determined. As in previous analyses,
relative score reductions were obtained by dividing the difference in
absolute score at EOI and diagnosis by the corresponding absolute score
at diagnosis.\textsuperscript{18} Curie scoring was performed by a
central scan review team, without knowledge of patient response or
outcome.

\textbf{Statistical Analysis}

Survival analysis was performed by transplant type (single or tandem) at
each mIBG scan time point (diagnosis or EOI). The primary endpoint was
an EFS event; death was a secondary endpoint. An optimum cut point for
total Curie score was determined for each combination (transplant type
and time of mIBG scan) by maximizing the Youden index with respect to
how well the Curie score differentiated patients who did and did not
have an EFS event. The Youden index represents the maximum value
(sensitivity + specificity -- 1) over all CS threshold
values.\textsuperscript{19}Event-free survival (EFS) time was calculated
with two different starting points, from enrollment or from the EOI mIBG
scan, until the occurrence of an event; or, if no event, until the date
of last follow-up. Events included death from any cause, disease relapse
or progression, or the development of a secondary malignancy. Overall
survival (OS) time was calculated with two different starting points,
from enrollment, or from the EOI scan to death from any cause or, if the
patient was still alive, the date of last follow-up. Three-year EFS and
OS estimates,\textsuperscript{20} with standard errors per Peto et
al.,\textsuperscript{21} were computed for all patients for each
variable investigated at the corresponding time point and transplant
group. Log-rank tests were performed to compare EFS and OS, with a
p-value \textless{}0.05 considered statistically significant. The data
used for this analysis were current as of June 30, 2020.

Several variables were investigated for their effect on outcome,
including an optimal CS cut point from the initial diagnostic and EOI
mIBG scans. Outcomes based on a relative reduction in Curie scores from
diagnosis to EOI were determined, using reductions of 50\% and 75\% as
in previous analyses.

To determine the independent prognostic strength of the Curie score for
survival in the presence of various prognostic factors, including age
(\textless{}18 vs. [?]18 months), \emph{MYCN} status (non-amplified vs.
amplified), end-induction response (CR/VGPR vs. PR vs. MR/NR), and
immunotherapy (yes vs. no), Cox proportional hazards (PH) models with
the Efron method of handling tied event times were fit. Tests for
violations of the PH assumption were performed. Backward selection was
used to determine the most parsimonious model, with a threshold
p-value\textless{}0.05 to remain in the model.

\textbf{RESULTS}

Eighty patients underwent tandem AHCT on ANBL0532 and had MIBG scans
obtained at both diagnosis and end-induction. Demographics and disease
characteristics for these 80 patients are shown in \textbf{TABLE 1} .
Fifty-six tandem AHCT recipients (70\%) subsequently received
immunotherapy with dinutuximab and cytokines, either on ANBL0032 (n=50)
or ANBL0931 (n=6). Patients who did not receive immunotherapy either did
not enroll on ANBL0032 or ANBL0931, or were enrolled on ANBL0032 but
were not randomized to receive immunotherapy. Patient and disease
characteristics for the subset of patients that underwent tandem AHCT
(n=80) in our CS analysis were consistent with those of the larger
cohort of patients (n=355) randomized on ANBL0532 \textbf{(Supplemental
TABLE S1)} .\textsuperscript{3}

\textbf{Curie Scores at Initial Diagnosis}

For tandem transplant recipients (n=80), the 3-year EFS and OS from
diagnosis were 65.0\selectlanguage{ngerman}±5.4\% and 73.5±5.0\% respectively. The median Curie
score at diagnosis was 20 (range 1-28) \textbf{(FIGURE 1A)} . The
optimal cut point at diagnosis was a CS=12. Three-year EFS was
significantly higher for patients with a CS\selectlanguage{english}[?]12 at diagnosis (74.2+-7.9\%)
when compared to patients with a CS\textgreater{}12 (59.2+-7.1\%),
p=0.002\textbf{(TABLE 2) (FIGURE 2A)} . The 3-year OS was likewise
significantly higher for patients with a CS\selectlanguage{english}[?]12 vs \textgreater{}12 at
diagnosis, 87.1+-6.0\% vs 64.6+-7.0\%, p=0.017.

\emph{MYCN} amplification data were available for 68 of the 80 patients
in the tandem transplant cohort, including 29 patients with\emph{MYCN}
-amplified and 39 patients with \emph{MYCN} non-amplified (\emph{MYCN-}
NA) disease \textbf{(TABLE 3)} . At diagnosis, median Curie scores were
higher for patients with \emph{MYCN} -NA {[}CS=22 (range 1-26){]} vs
\emph{MYCN} -amplified disease {[}CS=7 (range 1-27){]}. A survival
advantage was noted for a small cohort of patients with\emph{MYCN}
-amplified disease who exhibited a CS\emph{\textless{}} 12 at diagnosis,
when compared to those with a CS\textgreater{}12\textbf{(FIGURE 2B)} .
No survival advantage by diagnostic CS was noted for a similar cohort of
patients with \emph{MYCN} -NA disease

\textbf{(FIGURE 2C).}

\textbf{End of Induction (EOI) Curie Scores}

For patients undergoing tandem AHCT, the median Curie score at EOI was 0
(range 0 to 23) and the median change in Curie score was -11.5 (range
-27 to 0) from diagnosis to EOI \textbf{(FIGURE 1B)} . The optimal CS
cut point at EOI was 0 for recipients of tandem AHCT. Three-year EFS was
significantly greater in patients with a CS=0 (n=48) vs \textgreater{}0
(n=32) at EOI, 72.9+-6.4\% vs 46.5+-9.1\%, p=0.002. Similarly, 3-year OS
was superior in patients with a CS=0 vs \textgreater{}0 at EOI,
83.1+-5.5\% vs 55.9+-9.0\%, p=0.015 \textbf{(TABLE 2) (FIGURE 3A)} . When
restricting the analysis to the 56 patients who received tandem
transplant and immunotherapy, EOI CS remained significant, with 3-year
EFS 81.1+-6.4\% vs 57.9+-11.3\% for those with a CS=0 (n=37) vs
CS\textgreater{}0 (n=19) respectively; p=0.016. No statistical
difference was noted in OS for this same population, p=0.06.

Outcomes based upon CS at EOI are shown by \emph{MYCN}
status\textbf{(TABLE 3) (FIGURE 3B-C)} . In this small cohort of
patients with either \emph{MYCN-} amplified or \emph{MYCN-} NA disease,
3-year EFS was superior in patients with a CS=0 (vs \textgreater{}0) at
EOI.

Relative Curie scores, including either a 50\% or 75\% reduction in CS
from diagnosis to EOI, were not associated with a statistically
significant difference in EFS or OS in recipients of tandem
AHCT\textbf{(TABLE 2)} .

\textbf{Multivariable Cox models}

Using a CS cut point of 12 at diagnosis and 0 at EOI, a
backward-selected Cox model showed that CS at diagnosis, EOI CS,
\emph{MYCN} status, and receipt of immunotherapy were each independently
prognostic of EFS. CS \textgreater{}12 at diagnosis was associated with
a \textgreater{}14-fold higher risk of an event (n=68;
p\textless{}0.0001), while EOI CS \textgreater{}0 was associated with a
3-fold higher risk of an event (p=0.0149), \emph{MYCN}amplification was
associated with a 21-fold higher risk of an event (p\textless{}0.0001),
and non-receipt of immunotherapy was associated with a 4-fold higher
risk of an event (p=0.0008).

For OS, using the same factors as for EFS, a backward-selected Cox model
indicated that CS at diagnosis, \emph{MYCN} status, and immunotherapy
were prognostic of OS, with CS \textgreater{}12 at diagnosis,\emph{MYCN}
amplification, and no immunotherapy corresponding to an increase in the
risk of death of 12.821 (n=68; P\textless{}0.0001), 15.167
(P\textless{}0.0001), and 4.557 (P=0.0006), respectively.

\textbf{Single transplant: CS at diagnosis and end of induction}

Though the focus of this report is on recipients of tandem transplant, a
sub-analysis was performed to permit assessment of the CS cut point in a
contemporaneously treated group of patients randomized to undergo a
single AHCT (n=99) on ANBL0532 (\textbf{Supplemental TABLE S1)} . The
optimal CS cut point at diagnosis was 21, with a median CS of 15 (range
1-28) \textbf{(Supplemental Table S2)} . The 3-year EFS for patients
with CS\emph{\textless{}} 21 (n=72) vs \textgreater{}21 (n=27) at
diagnosis was 51.0+-6.0\% vs 34.9+-9.4\%; p=0.04 \textbf{(Supplemental
FIGURE S3A-C)} .

At EOI, the optimal EOI CS cut point was 2, with a median CS=0 (range
0-21). However, the difference in EFS for patients with
CS\emph{\textless{}} 2 (n=81) vs CS\textgreater{}2 (n=18) at EOI was not
statistically significant, with 3-year EFS 46.5+-5.6\% vs 29.5+-11.1\%;
p=0.29 \textbf{(Supplemental Figure S3D-F)} .

\textbf{DISCUSSION}

This is the first COG study to examine the impact of CS in the setting
of tandem AHCT. Our study identified optimal CS cut points with
prognostic significance at diagnosis (CS=12) and EOI (CS=0) in a subset
of patients with INSS stage 4 disease who received tandem AHCT on COG
ANBL0532. Patients with a CS\emph{\textless{}} 12 at diagnosis had a
statistically significantly higher 3-year EFS and OS when compared to
those with a CS\textgreater{}12 at the same timepoint. Patients with a
CS=0 at EOI also had a statistically significantly higher 3-year EFS and
OS than those with CS\textgreater{}0 at EOI.

The role of CS as a prognostic indicator in high-risk neuroblastoma has
been reported within the context of clinical trials utilizing single
AHCT, both within COG and European cooperative
groups.\textsuperscript{12,13,22-24} In a prior COG study, we found no
correlation between CS at diagnosis and subsequent outcome following a
single AHCT.\textsuperscript{12} In contrast, a prior SIOPEN study noted
the prognostic impact of skeletal-only mIBG scores at initial diagnosis,
using either a SIOPEN-specific or a CS system for
analysis.\textsuperscript{13,14} Within both COG and SIOPEN, an optimal
mIBG cut point at EOI was described for single AHCT recipients, with EOI
CS\selectlanguage{english}[?]2 associated with improved outcomes in patients treated on COG
A3973\textsuperscript{12} or SIOPEN-HR-NBL-1.\textsuperscript{13} Our
current study confirmed this optimal CS cut point (CS=2) in single AHCT
recipients, though the differences in EFS (CS\emph{\textless{}} 2 vs
CS\textgreater{}2) were not significant.

Important distinctions should be noted between the CS performed on
tandem AHCT recipients on COG ANBL0532 and the scoring performed on
single AHCT recipients on COG A3973. Curie scoring in ANBL0532 involved
a more contemporary group of patients, with 70\% of patients receiving
immunotherapy with dinutuximab and cytokines following tandem AHCT. In
contrast, less than 20\% of patients with Curie scoring performed in COG
A3973 received similar immunotherapy. Whereas CS from patients treated
on COG A3973 identified an ultra-high-risk group of patients with poor
outcomes (3-year EFS=15\%), our current CS analysis of ANBL0532 tandem
AHCT recipients did not identify an ultra-high-risk group, but instead
identified a potentially more favorable risk group (CS=0 at EOI) with
promising 3-year EFS (73\%) and 3-year OS (83\%). Conversely, tandem
AHCT recipients with a CS\textgreater{}0 at EOI in our current analysis
had similar 3-year EFS as the ``favorable'' risk group (CS\textless{}2)
identified in our prior COG A3973 analysis, with 3-year EFS of 46.5\%
and 44.9\% respectively.\textsuperscript{12}

The current practice for disease response evaluation has changed since
the COG A3973 analysis, with the revision of the INRC in
2017.\textsuperscript{18} The revised INRC include assessment of
response in the primary tumor, bone marrow and metastatic disease sites,
with CS now incorporated into the metastatic response assessment. In
particular, INRC currently define a metastatic response as a 50\%
reduction in Curie scores from diagnosis to the evaluation timepoint.
However, based upon our current analysis, the absolute score should be
considered instead of a ``relative reduction in score'' for assessing
response in metastatic sites. We found no difference in outcomes based
upon the relative reduction of CS from diagnosis to EOI \textbf{(TABLE
2)} . Several previous studies also reported that relative reductions in
CS did not provide additional prognostic information when compared with
absolute scores alone, including results from COG
A3973,\textsuperscript{12} the German Neuroblastoma Trial
NB97,\textsuperscript{22} and SIOPEN HR-NBL1.\textsuperscript{13} In
future studies, we will prospectively examine the CS cut points at
diagnosis and EOI using both an absolute CS and a 50\% relative
reduction in CS, to determine if the INRC definition of metastatic
response should be redefined for EOI response.

The outcome differences noted in our study were most striking in
patients with \emph{MYCN} -amplified disease, in which patients with a
diagnostic CS\textgreater{}12, or CS\textgreater{}0 at EOI had extremely
poor outcomes. Definitive conclusions regarding the impact of CS in
patients with \emph{MYCN} -amplified disease are difficult to make,
given the small sample size of the \emph{MYCN} -amplified cohort in our
current study. Further analysis of the impact of CS in patients
with\emph{MYCN} -amplified disease will be performed in upcoming COG
high-risk neuroblastoma therapy trials.

One major limitation of this study is the potential for selection bias,
as a more favorable group of patients may have comprised the subset that
underwent randomization and completed consolidation treatment on
ANBL0532. Our study excluded patients with neuroblastoma progression
during induction (or prior to consolidation therapy), patients who
refused randomization, and patients who died and/or had organ toxicity
that precluded continuation on protocol therapy during induction. The
small sample size of the patient cohort in the current analysis was also
a limitation, particularly for those with \emph{MYCN-} amplified tumors.

\textbf{CONCLUSION}

The role of CS as a prognostic marker in high-risk neuroblastoma
patients undergoing tandem AHCT was examined in our study. We identified
an optimal CS cut point both at diagnosis (CS\selectlanguage{english}[?]12 vs\textgreater{}12) and
EOI (CS=0 vs CS\textgreater{}0), and demonstrated that patients with CS
at or below those cut points have potentially more favorable outcomes.
The role of CS as a prognostic indicator in tandem AHCT patients will
require validation in future COG high-risk neuroblastoma trials,
including the current COG trial, COG ANBL1531. Ultimately, further
improvements in outcome may depend on improved induction therapy
regimen, either with the addition of targeted agents
like\textsuperscript{131}I-mIBG (COG ANBL1531) or anti-GD2 antibody (COG
ANBL2131).

\textbf{ACKNOWLEDGMENTS}

We thank Thomas J. FitzGerald, MD, and the staff at the Quality
Assurance Review Center (QARC), especially Deirdre Logan, Sandy Kessel,
and Fran Laurie, for their tremendous support.

\textbf{Financial Disclosure Statement:}

\emph{Financial Support:} Supported by National Institutes of Health,
National Cancer Institute (Grant No. U10 CA180899 to Children's Oncology
Group Statistics and Data Center), National Clinical Trials Network
Operations Center (Grant U10 CA180886), and St Baldrick's Foundation.

\emph{Conflicts of interest} : Keri A. Streby is a consultant for
Innervate Radiopharmaceuticals LLC and YmAbs Therapeutics Inc. and Kate
Matthay is a consultant for Innervate Radiopharmaceuticals LLC.

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ANBL00P1.\emph{Bone Marrow Transplant} . Jul 2013;48(7):947-52.
doi:10.1038/bmt.2012.276

6. Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for
children with high-risk neuroblastoma treated on a randomized trial of
myeloablative therapy followed by 13-cis-retinoic acid: a children's
oncology group study. \emph{J Clin Oncol} . Mar 2009;27(7):1007-13.
doi:10.1200/JCO.2007.13.8925

7. London WB, Castel V, Monclair T, et al. Clinical and biologic
features predictive of survival after relapse of neuroblastoma: a report
from the International Neuroblastoma Risk Group project. \emph{J Clin
Oncol} . Aug 2011;29(24):3286-92. doi:10.1200/JCO.2010.34.3392

8. Shulkin BL, Shapiro B. Current concepts on the diagnostic use of MIBG
in children. \emph{J Nucl Med} . Apr 1998;39(4):679-88.

9. Lumbroso JD, Guermazi F, Hartmann O, et al. Meta-iodobenzylguanidine
(mIBG) scans in neuroblastoma: sensitivity and specificity, a review of
115 scans. \emph{Prog Clin Biol Res} . 1988;271:689-705.

10. Claudiani F, Stimamiglio P, Bertolazzi L, et al. Radioiodinated
meta-iodobenzylguanidine in the diagnosis of childhood
neuroblastoma.\emph{Q J Nucl Med} . Dec 1995;39(4 Suppl 1):21-4.

11. Ady N, Zucker JM, Asselain B, et al. A new 123I-MIBG whole body scan
scoring method--application to the prediction of the response of
metastases to induction chemotherapy in stage IV neuroblastoma.\emph{Eur
J Cancer} . 1995;31A(2):256-61. doi:10.1016/0959-8049(94)00509-4

12. Yanik GA, Parisi MT, Shulkin BL, et al. Semiquantitative mIBG
scoring as a prognostic indicator in patients with stage 4
neuroblastoma: a report from the Children's oncology group. \emph{J Nucl
Med} . Apr 2013;54(4):541-8. doi:10.2967/jnumed.112.112334

13. Yanik GA, Parisi MT, Naranjo A, et al. Validation of Postinduction
Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and
SIOPEN Group Report on SIOPEN/HR-NBL1. \emph{J Nucl Med} . 03
2018;59(3):502-508. doi:10.2967/jnumed.117.195883

14. Lewington V, Lambert B, Poetschger U, et al. I-mIBG scintigraphy in
neuroblastoma: development of a SIOPEN semi-quantitative reporting
,method by an international panel. \emph{Eur J Nucl Med Mol Imaging} .
Feb 2017;44(2):234-241. doi:10.1007/s00259-016-3516-0

15. Ladenstein R, Potschger U, Valteau-Couanet D, et al. Investigation
of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN
High-Risk Neuroblastoma 1 Trial (HR-NBL1). \emph{Cancers (Basel)} . Jan
28 2020;12(2)doi:10.3390/cancers12020309

16. Ozkaynak MF, Gilman AL, London WB, et al. A Comprehensive Safety
Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in
High-Risk Neuroblastoma Patients Following Myeloablative Therapy:
Children's Oncology Group Study ANBL0931. \emph{Front Immunol} .
2018;9:1355. doi:10.3389/fimmu.2018.01355

17. Matthay KK, Shulkin B, Ladenstein R, et al. Criteria for evaluation
of disease extent by (123)I-metaiodobenzylguanidine scans in
neuroblastoma: a report for the International Neuroblastoma Risk Group
(INRG) Task Force. \emph{Br J Cancer} . Apr 27 2010;102(9):1319-26.
doi:10.1038/sj.bjc.6605621

18. Park JR, Bagatell R, Cohn SL, et al. Revisions to the International
Neuroblastoma Response Criteria: A Consensus Statement From the National
Cancer Institute Clinical Trials Planning Meeting. \emph{J Clin Oncol} .
Aug 2017;35(22):2580-2587. doi:10.1200/JCO.2016.72.0177

19. YOUDEN WJ. Index for rating diagnostic tests. \emph{Cancer} . Jan
1950;3(1):32-5.
doi:10.1002/1097-0142(1950)3:1\textless{}32::aid-cncr2820030106\textgreater{}3.0.co;2-3

20. Kaplan E, Meier P. Nonparametric estimation from incomplete
observations. \emph{Journal of American Statistics} . 1958;(53):457-481.

21. Peto R, Pike MC, Armitage P, et al. Design and analysis of
randomized clinical trials requiring prolonged observation of each
patient. II. analysis and examples. \emph{Br J Cancer} . Jan
1977;35(1):1-39. doi:10.1038/bjc.1977.1

22. Decarolis B, Schneider C, Hero B, et al. Iodine-123
metaiodobenzylguanidine scintigraphy scoring allows prediction of
outcome in patients with stage 4 neuroblastoma: results of the Cologne
interscore comparison study. \emph{J Clin Oncol} . Mar 01
2013;31(7):944-51. doi:10.1200/JCO.2012.45.8794

23. Ladenstein R, Lambert B, Potschger U, et al. Validation of the mIBG
skeletal SIOPEN scoring method in two independent high-risk
neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973
trials.\emph{Eur J Nucl Med Mol Imaging} . Feb 2018;45(2):292-305.
doi:10.1007/s00259-017-3829-7

24. Schmidt M, Simon T, Hero B, Schicha H, Berthold F. The prognostic
impact of functional imaging with (123)I-mIBG in patients with stage 4
neuroblastoma \textgreater{}1 year of age on a high-risk treatment
protocol: results of the German Neuroblastoma Trial NB97. \emph{Eur J
Cancer} . Jul 2008;44(11):1552-8. doi:10.1016/j.ejca.2008.03.013

TABLES

\textbf{TABLE 1} Patient characteristics at diagnosis\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Variable} & \textbf{Characteristic} & \textbf{Tandem (n
(\%))}\tabularnewline
\midrule
\endhead
Number of patients & & 80\tabularnewline
Sex & Female & 36 (45.0\%)\tabularnewline
& Male & 44 (55.0\%)\tabularnewline
Age (median, range), in years & & 3.5 (0.87,17.39)\tabularnewline
Tumor \emph{MYCN} status & Amplified & 29 (42.6\%)\tabularnewline
& Nonamplified & 39 (57.4\%)\tabularnewline
& Unknown & 12\tabularnewline
Tumor Histology & Favorable & 1 (1.3\%)\tabularnewline
& Unfavorable & 74 (98.7\%)\tabularnewline
& Unknown & 5\tabularnewline
Tumor Cell Ploidy & Hyperdiploid & 32 (52.5\%)\tabularnewline
& Diploid & 29 (47.5\%)\tabularnewline
& Unknown & 19\tabularnewline
Immunotherapy & Immunotherapy & 56 (70.0\%)\tabularnewline
& No immunotherapy & 24 (30.0\%)\tabularnewline
EOI Response & Complete or very good partial response & 33
(41.2\%)\tabularnewline
& Partial response & 37 (46.3\%)\tabularnewline
& No or mixed response & 10 (12.5\%)\tabularnewline
\bottomrule
\end{longtable}

*\textsuperscript{123}I-mIBG was used in 94.8\% (73/77)
and\textsuperscript{131}I-mIBG used in 5.2\% (4/77) of scans, with the
same radioisotope used for imaging at both time points. 2 patients were
missing scan type and 1 patient reported different scan types at
diagnosis and end of induction.

\textbf{TABLE 2} EFS and OS by optimal CS at diagnosis, end of
induction, and relative reduction in CS in tandem transplant recipients
(n=80)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{CS}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{3-year EFS ± std error (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{EFS} \textbf{p-value}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{3-year OS ± std error (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{OS} \textbf{p-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Diagnostic}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\emph{\textless{}} 12\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
31 (39\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
74.2 \selectlanguage{ngerman}± 7.9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.002\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
87.1 \selectlanguage{ngerman}± 6.0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.017\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{} 12\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
49 (61\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
59.2 \selectlanguage{ngerman}± 7.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
64.6 \selectlanguage{ngerman}± 7.0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{End of Induction}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
48 (60\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
72.9 \selectlanguage{ngerman}± 6.4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.002\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
83.1 \selectlanguage{ngerman}± 5.5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.015\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{} 0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
32 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
46.5 \selectlanguage{ngerman}± 9.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
55.9 \selectlanguage{ngerman}± 9.0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Relative Reduction*}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}75\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
16 (20\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50.0 \selectlanguage{ngerman}± 12.5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.21\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
62.5 \selectlanguage{ngerman}± 12.1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.51\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?]75\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
64 (80\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
65.6 \selectlanguage{ngerman}± 6.0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
74.6 \selectlanguage{ngerman}± 5.5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}50\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12 (15\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50.0 \selectlanguage{ngerman}± 14.4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.45\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
58.3 \selectlanguage{ngerman}± 14.2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.67\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?]50\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
68 (85\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
64.7 \selectlanguage{ngerman}± 5.9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
74.7 \selectlanguage{ngerman}± 5.4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*Refers to relative reduction in CS from diagnosis to end-induction.

\textbf{TABLE 3} Impact of tumor \emph{MYCN} amplification and Curie
Score cut point in tandem transplant recipients (n=68 with
known\emph{MYCN} status)\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Time Point}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\emph{MYCN} \textbf{status}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Curie Score}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{N (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{3-year EFS ± std error (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{EFS} \textbf{p-value}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{3-year OS ± std error (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{OS} \textbf{p-value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Diagnosis\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Amplified n=29\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textgreater{}12\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
11 (38\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
9.1 \selectlanguage{ngerman}± 8.7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}.0001\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10.4 \selectlanguage{ngerman}± 9.8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}.0001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
[?]12\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18 (62\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
72.2 \selectlanguage{ngerman}± 10.6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
77.8 \selectlanguage{ngerman}± 9.8\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NA n=39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textgreater{}12\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
28 (72\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
71.4 \selectlanguage{ngerman}± 8.8\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.1137\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
78.4 \selectlanguage{ngerman}± 8.0\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.1754\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
[?]12\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11 (28\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
81.8 \selectlanguage{ngerman}± 11.6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
100.0 \selectlanguage{ngerman}± 0.0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
End of Induction\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Amplified n=29\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textgreater{}0\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 (28\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12.5 \selectlanguage{ngerman}± 11.7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.0079\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
12.5 \selectlanguage{ngerman}± 11.7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.0056\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21 (72\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
61.9 \selectlanguage{ngerman}± 10.6\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
70.2 \selectlanguage{ngerman}± 10.2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NA n=39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textgreater{}0\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19 (49\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
63.2 \selectlanguage{ngerman}± 11.6\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.0096\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
73.3 \selectlanguage{ngerman}± 10.5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.1870\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20 (51\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
85.0 \selectlanguage{ngerman}± 8.0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
95.0 \selectlanguage{ngerman}± 4.9\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{Key: NA, non-amplified}



\textbf{FIGURE LEGENDS}

FIGURE 1. Distribution of Curie Scores (CS) at (A) diagnosis, and (B) at
EOI for patients treated with tandem transplants. (C) Representative
mIBG scan at diagnosis and EOI.

FIGURE 2. EFS by CS at Diagnosis in Patients Treated with Tandem
Transplants. EFS by diagnostic CS using: A) Optimal cut point of 12 in
all patients. (B) Optimal cut point of 12 in patients with\emph{MYCN}
-amplified neuroblastoma. (C) Optimal cut point of 12 in patients with
\emph{MYCN-} NA neuroblastoma.

FIGURE 3. EFS by CS at EOI in Patients Treated with Tandem Transplants.
EFS by EOI CS using: (A) Optimal cut point of 0 in all patients. (B)
Optimal cut point of 0 in patients with \emph{MYCN} -amplified
neuroblastoma. (C) Optimal cut point of 0 in patients with\emph{MYCN-}
NA neuroblastoma.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig2-diag-EFS-tandem-vfinal-001/Fig2-diag-EFS-tandem-vfinal-001}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig3-EOI-EFS-tandem-final-001/Fig3-EOI-EFS-tandem-final-001}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1C/Figure-1C}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Streby-Fig-1-PBC-001/Streby-Fig-1-PBC-001}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig2-diag-EFS-tandem-vfinal-002/Fig2-diag-EFS-tandem-vfinal-002}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig3-EOI-EFS-tandem-final-002/Fig3-EOI-EFS-tandem-final-002}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig2-diag-EFS-tandem-vfinal-003/Fig2-diag-EFS-tandem-vfinal-003}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig3-EOI-EFS-tandem-final-003/Fig3-EOI-EFS-tandem-final-003}

\end{center}
\end{figure}

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

