This single-center, open-label diagnostic imaging study investigates the clinical utility
of somatostatin receptor (SSTR) and norepinephrine transporter (NET) targeted molecular
imaging for detection, staging, and treatment planning in patients with neuroblastoma and
pheochromocytoma/paraganglioma (PPGL). The biological rationale rests on the frequent
overexpression of NET in sympathoneuronal tumors and SSTR in neuroendocrine-derived
neoplasms, enabling high-contrast visualization of primary and metastatic disease,
including bone and bone marrow involvement. The protocol emphasizes harmonized
acquisition and reconstruction parameters, quantitative analysis, and rigorous comparison
against a composite reference standard comprising histopathology when available and
multidisciplinary clinical adjudication.
The imaging strategy purposefully includes a broad spectrum of tracers within the SSTR
and NET classes to capture complementary biology and to accommodate variability in
patient phenotype, prior therapies, and local availability. For NET-targeted imaging, the
study may employ 123I-metaiodobenzylguanidine (123I-MIBG) with planar and SPECT/CT
techniques, 131I-MIBG as a legacy diagnostic alternative where appropriate,
18F-meta-fluorobenzylguanidine (18F-MFBG) for PET/CT or PET/MRI with improved resolution
and logistics, 18F-LMI1195 as an investigational PET agent subject to site availability,
11C-hydroxyephedrine (11C-HED) PET where a cyclotron is accessible, and
18F-fluorodopamine (18F-FDA) PET in centers with established protocols. For SSTR-targeted
imaging, the protocol allows 68Ga-DOTATATE, 68Ga-DOTATOC, and 68Ga-DOTANOC PET/CT or
PET/MRI as contemporary standards; 64Cu-DOTATATE to leverage its longer half-life and
extended imaging window; 18F-labeled SSTR agents such as 18F-SiTATE and
18F-AlF-NOTA-octreotide where available; and legacy SPECT agents including
111In-pentetreotide (Octreoscan) and 99mTc-HYNIC-TOC or 99mTc-EDDA/HYNIC-TOC depending on
local practice. Tracer selection is individualized based on clinical indication, age,
renal and hepatic function, concomitant medications, and logistical factors; when
clinically justified and feasible, intra-patient multi-tracer imaging within and across
SSTR and NET classes may be performed to enable head-to-head comparisons.
FDG and CXCR4 PET/CT or PET/MRI may be performed solely as optional comparator imaging at
investigator discretion and contingent on site capability and local approvals. Optional
comparators include 18F-FDG and CXCR4-targeted agents such as 68Ga-Pentixafor (and
64Cu-Pentixafor where permitted). These scans are not required for enrollment or primary
analyses but may support exploratory comparisons in predefined subgroups.
Radiopharmaceutical preparation follows good manufacturing practice with predefined batch
release specifications, including radiochemical purity (typically ≥95% for PET peptides),
acceptable pH range, sterility, endotoxin limits, and specific activity as applicable.
Each batch is accompanied by a certificate of analysis, lot traceability, and temperature
and transport documentation, and any deviations are handled under corrective and
preventive action procedures. Handling, storage, and administration comply with
institutional radiation safety policies and national regulations. For optional comparator
agents, applicable pharmacopeial or investigator's brochure specifications are followed.
Patient preparation adheres to tracer-specific guidance. For NET imaging, medications
that interfere with catecholamine transport or storage (for example, labetalol and
certain antidepressants) are reviewed and managed per site standard operating procedures,
and thyroid blockade is implemented when indicated for radioiodine-labeled agents. For
SSTR imaging, somatostatin analogues are managed to minimize receptor blockade when
clinically appropriate. Hydration and frequent voiding are encouraged to reduce
background activity. When optional 18F-FDG imaging is performed, patients fast for at
least 4-6 hours, non-glucose-containing hydration is encouraged, strenuous exercise is
avoided for 24 hours, and blood glucose is checked and documented prior to injection;
insulin correction, if used, follows site policy to avoid altered biodistribution. When
optional CXCR4 imaging is performed, no specific dietary restrictions apply; recent
exposure to hematopoietic growth factors (for example, G-CSF) is recorded, and imaging
may be deferred when clinically safe to mitigate confounding marrow uptake.
Acquisition timing follows established windows, such as approximately 90-180 minutes
post-injection for 18F-MFBG, about 20-24 hours for 123I-MIBG planar/SPECT-CT (with
optional early or delayed views), roughly 45-90 minutes for 68Ga-DOTA-peptides,
approximately 60-180 minutes for 64Cu-DOTATATE, and around 60-120 minutes for 18F-labeled
SSTR agents. For optional comparator scans, the recommended uptake times are
approximately 50-70 minutes for 18F-FDG (acceptable range 45-90 minutes, time-stamped)
and approximately 45-75 minutes for 68Ga-Pentixafor. Whole-body coverage typically spans
from the skull vertex to mid-thigh, extended as clinically indicated; PET imaging uses 3D
acquisition with attenuation and scatter correction, and SPECT employs iterative
reconstruction with CT-based attenuation and scatter correction when available. Pediatric
protocols prioritize dose optimization and motion mitigation, including sedation per
institutional policy when required.
Quantitative analysis uses standardized regions of interest to derive SUVmax and SUVmean
for PET, lesion-to-background ratios, and optional volumetric metrics such as total
lesion uptake and metabolic or receptor-expressing tumor volume. For SPECT,
semi-quantitative indices such as lesion-to-liver or lesion-to-mediastinum ratios and
established MIBG scoring systems are applied where relevant. Optional comparator scans,
when performed, follow the same quantitative framework; for 18F-FDG,
lean-body-mass-normalized SUVs and metabolic tumor volume/total lesion glycolysis are
recommended, and for CXCR4, lesion-to-liver or lesion-to-blood pool ratios may be
recorded to assist harmonization. Image interpretation is performed by two blinded
readers with adjudication of discrepancies, and lesion mapping records locations by
compartment, including primary tumor, nodal stations, bone and bone marrow, soft tissue,
liver, lung, adrenal, and other sites.
The reference standard integrates histopathology, correlative cross-sectional imaging,
and clinical follow-up to adjudicate lesion truth status. In cases of modality
discordance, targeted biopsy or directed follow-up is prioritized when clinically
appropriate to refine the composite reference standard.
Data are captured in a validated electronic data capture environment with role-based
access controls and full audit trails. The database implements automated range checks,
temporal consistency checks for dose and acquisition timestamps, cross-form logic for
tracer-modality pairing and pediatric weight-based dosing, and site-level reconciliation
of imaging metadata (for example, DICOM headers) with case report forms. When optional
comparator scans are performed, additional fields capture FDG-specific variables (fasting
duration, pre-injection blood glucose, insulin use and timing, uptake time, ambient
warming status) and CXCR4-specific variables (recent growth factor exposure and timing,
white blood cell/absolute neutrophil counts when available, and timing of cytotoxic or
steroid therapy relative to imaging). Source data verification is conducted on a
predefined fraction of cases against medical records, radiopharmacy logs, imaging
archives, and pathology reports. A comprehensive data dictionary specifies variable
definitions, sources, units, coding standards such as MedDRA for adverse events, and
normal or reference ranges where applicable. Written standard operating procedures govern
study operations, including screening and consent, patient preparation and tracer
administration, acquisition and reconstruction parameters, image reading and
adjudication, data entry and query resolution, adverse event reporting, change control,
and archival.
The study is exploratory in size and designed to estimate diagnostic performance with
acceptable precision rather than to test a formal hypothesis. Primary analyses focus on
SSTR- and NET-based imaging and will report per-patient and per-lesion sensitivity,
specificity, accuracy, positive predictive value, and negative predictive value against
the reference standard. Secondary and exploratory objectives include comparative
effectiveness between NET and SSTR classes and within-class comparisons where intra- or
inter-patient data allow, as well as subgroup analyses by disease category, metastatic
distribution, and prior therapy. Where optional comparator scans are available,
incremental and added-value analyses will evaluate their yield beyond SSTR/NET imaging
using paired methods (for example, McNemar tests for sensitivity/specificity and
decision-impact rates where management recommendations are captured). Statistical methods
include exact confidence intervals for proportions, receiver operating characteristic
analysis with area under the curve estimation, agreement metrics such as Cohen's kappa,
and models that account for lesion-level clustering, for example generalized estimating
equations. Multiplicity will be managed via hierarchical analysis plans or false
discovery rate control for exploratory endpoints. Missing data are minimized
prospectively through time-stamped workflows and automated completeness checks;
missingness is categorized as missing, unavailable, non-reported, or not interpretable,
and the primary analyses use complete-case datasets with sensitivity analyses employing
appropriate imputation strategies when assumptions are defensible.
Safety oversight includes systematic collection of adverse events from tracer
administration through follow-up, graded according to CTCAE version 5.0, with expedited
reporting for serious and unexpected events per institutional and regulatory
requirements. Radiation dosimetry is tracked at the participant level by tracer and
modality, and cumulative exposure is maintained within diagnostic reference levels for
the relevant age group. For optional comparator imaging, risks specific to the agents
used are monitored and managed per protocol and local policy. The study is conducted in
accordance with ICH-GCP and the Declaration of Helsinki, with institutional review board
approval and written informed consent or assent obtained prior to any study procedures.
Periodic monitoring and audits, on-site or remote as appropriate, verify adherence to the
protocol, standard operating procedures, and the predefined data quality plan.
