Staging Of Neuroblastoma Research Articles

Recommendations for the use of nuclear medicine imaging in patients with neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid cancer in children. Despite intensive multimodality treatment, long-term survival of patients with high-risk NB, which comprises more than half of all cases, remains poor. Nuclear medicine is key in diagnosis, staging, response assessment and long-term follow-up of NB. The emergence of novel tracers and the increasing complexity of studies require updated guidelines for nuclear medicine imaging in NB. Standardising diagnostic techniques are essential for improving study comparability and ensuring test quality. This article aims to provide a comprehensive review of NB radionuclide diagnostic imaging, including its characteristics, accuracy, advantages, and limitations. It offers practical recommendations to multidisciplinary teams responsible for treating patients with NB. This review summarises the opinions of leading experts from the Neuroblastoma Spanish Group within the Spanish Society of Paediatric Haematology and Oncology (SEHOP) and the Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM).

Image-defined risk factors associated with MYCN oncogene amplification in neuroblastoma and their association with overall survival.

The MYCN oncogene is a critical factor in the development and progression of neuroblastoma, and image-defined risk factors (IDRFs) are radiological findings used for the preoperative staging of neuroblastoma. This study aimed to investigate the specific categories of IDRFs associated with MYCN amplification in neuroblastoma and their association with overall survival. A retrospective analysis was conducted on a cohort of 280 pediatric patients diagnosed with neuroblastoma, utilizing a combination of clinical and radiological data. MYCN amplification status was ascertained through molecular testing, and the assessment of IDRFs was conducted using either contrast-enhanced computed tomography or magnetic resonance imaging. The specific categories of IDRFs associated with MYCN amplification and their association with overall survival were analyzed. MYCN amplification was identified in 19.6% (55/280) of patients, with the majority of primary lesions located in the abdomen (53/55, 96.4%). Lesions accompanied by MYCN amplification exhibited significantly larger tumor volume and a greater number of IDRFs compared with those without MYCN amplification (P < 0.001). Both univariate and multivariate analyses revealed that coeliac axis/superior mesenteric artery encasement and infiltration of adjacent organs/structures were independently associated with MYCN amplification in abdominal neuroblastoma (P < 0.05). Patients presenting with more than four IDRFs experienced a worse prognosis (P = 0.017), and infiltration of adjacent organs/structures independently correlated with overall survival in abdominal neuroblastoma (P = 0.009). The IDRFs are closely correlated with the MYCN amplification status and overall survival in neuroblastoma.

Pediatric imaging of neuroblastoma-From classic to atypical

Neuroblastoma (NB) is the most common extracranial solid tumour in children, accounting for approximately eight percent of paediatric cancer and fifteen percent of pediatric cancer deaths. Reaching a correct and timely diagnosis is extremely important, especially in aggressive NB. Prognosis and treatment are based on tumour biology and genetics, patient age and perhaps most importantly, disease stage. The current staging system relies heavily on imaging, and this pictorial essay provides a description of the radiological features of NB, from classic to atypical, and the modalities used to help confirm the diagnosis and staging of NB. Our aim is to provide radiologists with a comprehensive collection of presentations of NB, to help improve diagnostic accuracy and decrease time to diagnose.

The quest to develop an effective therapy for neuroblastoma.

Neuroblastoma (NB) is a common solid extracranial tumor developing in pediatric populations. NB can spontaneously regress or grow and metastasize displaying resistance to therapy. This tumor is derived from primitive cells, mainly those of the neural crest, in the sympathetic nervous system and usually develops in the adrenal medulla and paraspinal ganglia. Our understanding of the molecular characteristics of human NBs continues to advance documenting abnormalities at the genome, epigenome, and transcriptome levels. The high-risk tumors have MYCN oncogene amplification, and the MYCN transcriptional regulator encoded by the MYCN oncogene is highly expressed in the neural crest. Studies on the biology of NB has enabled a more precise risk stratification strategy and a concomitant reduction in the required treatment in an expanding number of cases worldwide. However, newer treatment strategies are mandated to improve outcomes in pediatric patients who are at high-risk and display relapse. To improve outcomes and survival rates in such high-risk patients, it is necessary to use a multicomponent therapeutic approach. Accuracy in clinical staging of the disease and assessment of the associated risks based on biological, clinical, surgical, and pathological criteria are of paramount importance for prognosis and to effectively plan therapeutic approaches. This review discusses the staging of NB and the biological and genetic features of the disease and several current therapies including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy for NB.

68Ga-DOTATATE PET/CT for Neuroblastoma Staging: Utility for Clinical Use

Metaiodobenzylguanidine (MIBG) imaging has been the standard for neuroblastoma staging for many decades. Novel agents such as 18F-DOPA and 68Ga-DOTATATE are being used nowadays in academic centers. During the coronavirus disease 2019 (COVID-19) pandemic, procurement of 123I-MIBG has proved particularly challenging, necessitating the use of 68Ga-DOTATATE PET. 68Ga-DOTATATE is Food and Drug Administration-approved for imaging of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Methods: 68Ga-DOTATATE PET/CT imaging was performed for staging of 3 pediatric patients with neuroblastoma at our institution. Areview of the literature was also completed. Results: 68Ga-DOTATATE PET/CT scans were successfully performed on all patients. All patients showed 68Ga-DOTATATE-avid disease. PET scans showed an excellent spatial resolution and demonstrated high accuracy in concordance with current European Association of Nuclear Medicine guidelines. Conclusion: We have presented 68Ga-DOTATATE PET/CT imaging for staging of neuroblastoma and believe it can reliably be used as an alternative to 123I-MIBG. It has technical, clinical, and practical advantages making it an attractive option. Further multicenter studies are required before it can be recommended for standard clinical use.

Nuclear Medicine Imaging in Neuroblastoma: Current Status and New Developments.

Neuroblastoma is the most common extracranial solid malignancy in children. At diagnosis, approximately 50% of patients present with metastatic disease. These patients are at high risk for refractory or recurrent disease, which conveys a very poor prognosis. During the past decades, nuclear medicine has been essential for the staging and response assessment of neuroblastoma. Currently, the standard nuclear imaging technique is meta-[123I]iodobenzylguanidine ([123I]mIBG) whole-body scintigraphy, usually combined with single-photon emission computed tomography with computed tomography (SPECT-CT). Nevertheless, 10% of neuroblastomas are mIBG non-avid and [123I]mIBG imaging has relatively low spatial resolution, resulting in limited sensitivity for smaller lesions. More accurate methods to assess full disease extent are needed in order to optimize treatment strategies. Advances in nuclear medicine have led to the introduction of radiotracers compatible for positron emission tomography (PET) imaging in neuroblastoma, such as [124I]mIBG, [18F]mFBG, [18F]FDG, [68Ga]Ga-DOTA peptides, [18F]F-DOPA, and [11C]mHED. PET has multiple advantages over SPECT, including a superior resolution and whole-body tomographic range. This article reviews the use, characteristics, diagnostic accuracy, advantages, and limitations of current and new tracers for nuclear medicine imaging in neuroblastoma.

Submandibular Swelling: Initial Presentation of Metastatic Neuroblastoma

Abstract Casestudy: Neuroblastoma is the most common solid tumor in the pediatric population. It is derived from neural crest cells and can arise from anywhere along the sympathetic chain. Fifty-to-sixty percent of patients with neuroblastoma present with disseminated disease. However, neuroblastoma rarely presents with metastasis to the submandibular gland or head and neck region. We present a case of a 3-year-old male with a one-month history of left submandibular swelling, lower back pain, fever, decreased urine output and constipation. An abdominal ultrasound demonstrated hydronephrosis. The ultrasound of the left mandible showed an echogenic mass with prominent Doppler flow. An excisional biopsy was performed on the left submandibular mass revealing small round blue cells with syncytial pattern, scant pink cytoplasm, and dark blue nuclei. Tumor cells were strongly positive for synaptophysin immunohistochemical stain. His urine vanillylmandelic acid and homovanillic acid were 121.7 and 79.3, respectively. Subsequent imaging revealed multifocal metastatic lesions involving the cervical, thoracic and lumbar vertebrae as well as the sacrum and bilateral iliac bones and posterior epidural soft tissue on MRI. While, CT scan demonstrated a right adrenal calcified mass that was presumed to be the primary malignancy site for his metastatic neuroblastoma. He was treated with chemotherapy and follow up was recommended. Although an initial presentation of neuroblastoma as a sub-mandibular mass is rare, diagnostic workup by way of radiography, bone marrow biopsy, and laboratory investigations is crucial in the accurate diagnosis, staging, and treatment of metastatic neuroblastoma.

Non-invasive prediction of an unfavorable histological variant in patients with neuroblastic tumors using the quantitative and semiquantitative assessment of ¹²³I-MIBG uptake

¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy is widely used for the detection and staging of neuroblastoma. Risk-adapted treatment in patients with neuroblastic tumors is based on many clinical and genetic factors including histopathology. Purpose: non-invasive prediction of an unfavorable histological variant in patients with neuroblastic tumors using quantitative assessment of ¹²³I-MIBG uptake. This study was approved by the Independent Ethical Committee and the Academic Council of Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation. 96 patients were included in this retrospective study. ¹²³I-MIBG-scintigraphy including whole body planner images and SPECT/CT were performed for all patients before any type of treatment. Semiquantitative and quantitative assessment of ¹²³I-MIBG uptake were calculated and analyzed. Out of 96 patients: 54 with neuroblastoma (NB), 28 with ganglioneuroblastoma (GNB) and 14 with ganglioneuroma (GN). The average values of TLCRR and SUVmax for NB were 5.67 and 7.5, for GNB – 2.58 and 3.1 and for GN – 1.48 and 1.85, respectively. A centile analysis was carried out for all groups. SPECT/CT in combination with modern software allows semiquantitative and quantitative assessment of ¹²³I-MIBG uptake in neuroblastic tumor. The TLCRR and SUVmax can be used separately as well as in combination with NSE for prediction of histological variant.

LncRNA SNHG16 is associated with proliferation and poor prognosis of pediatric neuroblastoma.

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children, which has complex molecular mechanisms. Increasing evidence has suggested that long noncoding RNAs (lncRNAs) account for NB pathogenesis. However, the function of small nucleolar RNA host gene 16 (SNHG16) in NB is currently unclear. In the present study, publically available data and clinical specimens were employed to verify the expression of SNHG16 in NB. Colony formation, real-time cell proliferation and migration assays were performed to demonstrate the status of cellular proliferation and migration. Flow cytometry was used to examine cell cycle progression in SH-SY5Y cells, and acridine orange/ethidium bromide staining and caspase-3/7 activity measurements were applied to study cell apoptosis. To explore the underlying mechanism of SNHG16 function, an online database was used to identify potential RNA-binding proteins that bind SNHG16. The expression of SNHG16 was revealed to be in line with the clinical staging of NB, and high SNHG16 expression was positively associated with poor clinical outcome. Furthermore, SNHG16 silencing inhibited cell proliferation, repressed migration, and induced cell cycle arrest at the G0/G1 phase in SH-SY5Y cells. Additionally, apoptosis was undetectable in SH-SY5Y cells following SNHG16 silencing. Bioinformatics analysis revealed that SNHG16 regulated cell proliferation in NB through transcriptional and translational pathways. These results suggested that SNHG16 may serve important roles in the development and progression of NB, and could represent a potential target for NB therapy.

Guidelines on nuclear medicine imaging in neuroblastoma.

Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18F-FDG, 18F-DOPA and 68Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.

Role of Multi-Slice CT in Staging of Neuroblastoma

Background: The International Neuroblastoma Risk Group Staging System (INRGSS) is a recent pretreatment staging system for neuroblastoma (NB), based on imaging by CT before surgery. Purpose: this study aimed to stage NB cases using CT scan, in relation to available clinicopathologic data. Patients and Methods: Twenty pathologically proven NB cases were included. All were reviewed for patients' characteristics, includingage; sex, clinical picture, LN status and metastatic spread. All cases underwent CT scan for diagnosis. Stagingwas done using IDRFs, LN status and metastatic spread according to the INRGSS and INSS when available. Results: an abdominal mass was found in 85% of cases and the suprarenal gland was the most common site of primary tumor (50% of cases). Concerning tumor grade, 85 % of cases were poorly differentiated. LNs were positive in 70%, and metastatic spread was found in 35% of patients respectively. Staging according to the INRGSS showed that L2 was the most common stage (45% of cases), followed by M stage (35%). L1 and MS stages were found in 15% and 5% of cases respectively. Only 7 cases had postsurgical CT scans, and were staged according to the INSS. Conclusion: it was concluded that the use of the INRGSS using CT scan, is a recent valuable pretreatment staging system, allowing accurate classification of neuroblastoma.

Imagerie fonctionnelle et métabolique du neuroblastome en 2016

Neuroblastoma is the most common extracranial neoplasm in children. This disease has a great heterogenity in his presentation and prognosis. 123I-MIBG remains currently a key and reference exam for diagnosis, initial staging, prognosis and follow-up of neuroblastoma. SPECT/CT increased the diagnostic certainty of 123I-MIBG scintigraphy interpretation and help to reduce false negative and false positive results. Bone scan is yet not indicated. 18FDG-PET/CT is not superior to 123I-MIBG in stages 3 and 4. 18FDG-PET/CT is recommended in case of non-avid 123I-MIBG neuroblastoma. 18F-FDOPA PET/CT could represent an alternative exam to 123I-MIBG scintigraphy because of better spatial resolution and no interference with therapy. Other PET radiopharmaceuticals as 124I-MIBG or 18F-MFBG could be interesting and particularly 68Ga-peptides PET/CT as a theranostic agent in providing valuable information for pretherapeutic staging of neuroblastoma.

Abstract B61: Targeting glycolysis and compensatory mitochondrial metabolism in neuroblastoma with FDA-approved ritonavir and metformin

Abstract One of the hallmarks of cancer cell development is increased dependence on glucose to fuel aerobic glycolysis for the increased production of cellular metabolites required for rapid cell division. [1] PET with fluorine-18 fluorodeoxyglucose (18F-FDG) exploits this increased aerobic glycolysis of malignant as compared with most normal cells. There is increasing literature to support the utility of PET scans in the diagnosis, staging and monitoring response of neuroblastoma (NBL) to treatment. Glucose is transported via a family of ATP-independent transporters (GLUTs). GLUTs 1, 3 and 4 are high affinity glucose transporters which have been shown to play roles in normal B cell glucose transport [2]. GLUT4 plays a critical role in facilitating glucose transport in hematological malignancies such as multiple myeloma [3]. This study focuses on identifying glucose transporters that may be aberrantly expressed in NBL cells. We have further used HIV protease inhibitor (ritonavir) that has an off-target inhibitory effect on GLUT4 to inhibit glucose transport in these cells. In addition we hypothesized that the cells, which are resistant to ritonavir, are sensitized upon treatment with a complex 1 inhibitor (metformin) that targets compensatory mitochondrial metabolism. Methods: We tested the dependence of NBL cells on glucose by culturing six different cell lines under aerobic conditions in the presence and absence of glucose. These cell lines included both N-myc amplified and non-amplified cell lines. To determine the transporters involved in transport of glucose across the cell membrane we performed PCR and Western Blot for GLUT 1, 4 and 3, the major high affinity glucose transporters in various NBL cell lines. Based on the results of these tests and preliminary data we used lentivirus sh-RNA and knocked down GLUT 4 in the IMR 5 cell line. To further prove our hypothesis, we cultured cell lines in the presence and absence of metformin, ritonavir and both metformin and ritonavir both and determined viability using flow-cytometry analysis. Results: The number of live cells in all the cell lines decreased considerably when deprived of glucose. Western Blot and PCR for various glucose transporters showed that GLUT 4 was highly expressed across all cell lines while the expression of GLUT 1 was variable. On knocking down GLUT 4 using lentivirus sh-RNA in the IMR 5 cell line we observed a large difference between the morphology of the 2 groups ( control sh-RNA and the ones with GLUT 4 knocked down). The cells where GLUT 4 had been knocked down were found to be more vacuolated and failed to form any neural processes which is a characteristic of this cell line at the end of 72 hours. We also observed that the cell line IMR5 (NMYC amplified) showed marked cell death in the presence of metformin and ritonavir compared to SHY5Y ( single copy of NMYC) where the cell death was not so remarkable. Conclusions: NBL cells are highly dependent on glycolysis for their metabolism and to maintain viability. Inhibition of glycolysis through the inhibition of glucose flux into the cells via glucose transporters results in cell death. Further studies to validate this hypothesis and to test in in vivo are underway in our laboratory.

Open versus needle biopsy in diagnosing neuroblastoma

BackgroundOpen surgical biopsy is traditionally advocated prior to initiating therapy in UKCCLG neuroblastoma protocols. We report a single centre experience comparing the utility of open biopsy vs image guided needle biopsy in aiding the definitive diagnosis and risk stratification of neuroblastoma – (Shimada classification, MYCN expression, cytogenetics – 1p 11q, 17 q). MethodsMedical records of all new cases of neuroblastoma presenting to a single UKCCLG centre during January 2002–July 2013 were examined. ResultsThirty nine patients underwent a biopsy of primary tumour for neuroblastoma during the study. Twenty one children had open biopsy and eighteen cases had a needle biopsy. Staging of neuroblastoma revealed - stage 4 (n=26), stage 3 (n=7), stage 2 (n=3) and stage 4S (n=3). Sites of primary tumour were adrenal gland (n=20), abdomen (n=12), thoracic (n=4), abdomino-thoracic (n=2) and abdomino pelvic regions (n=1). All patients (open vs needle) had adequate tissue retrieved for histological diagnosis of neuroblastoma. One needle and one open biopsy case did not have MYCN status determined despite adequate tissue sampling. Seventeen patients (7 open and 10 needle biopsies) had 1p and 17q status reported in MLPA testing (Multiplex Ligation-dependent Probe Amplification). No single patient required a repeat tumour biopsy. Morbidity in the series was minimal with only one child – open biopsy group, requiring emergent laparotomy to control bleeding from an abdominal primary tumour. No complications were recorded with needle biopsy. ConclusionsOpen and image guided needle biopsy appear to yield adequate tissue sampling for diagnosis, risk classification and staging of neuroblastoma. Further larger co-operative studies may usefully guide national and international protocols.

Validation of the MIBG SIOPEN scoring method in two independent high-risk neuroblastoma trials.

10029 Background: Harmonised evaluation standards of MIBG scintigraphy for (re)staging of neuroblastoma (NB) are an international aim. In the HR-NBL1/SIOPEN trial population a SIOPEN score (SISCO) ...

Adult versus Pediatric Neuroblastoma: The M.D. Anderson Cancer Center Experience.

Background. Staging and treatment of adult neuroblastoma has yet to be formalized. We sought to determine the utility of the pediatric classification system in adults and determine the efficacy of different treatment modalities. Methods. Medical records of 118 adults (patients >17 years old) and 112 pediatric patients (ages 2–17), who were treated for neuroblastoma at M.D. Anderson Cancer Center from January 1994 to September 2012, were reviewed. International neuroblastoma risk group (INRG) variables were abstracted. The primary outcome of interest was actuarial progression-free survival. Results. Median age of pediatric patients was 5 years (range 3–16) and 47 years (range 18–82) for adult patients. There were no differences in PFS or OS between stage-matched risk categories between pediatric and adult patients (L1-P = 0.40, L2-P = 0.54, and M-P = 0.73). In the treatment of L1 disease, median PFS for adults treated with surgery and radiation was 11.1 months compared with single modality local treatment ± chemotherapy (6.4 and 5.1 months, resp.; P = 0.07). Median PFS in L2 adult patients was 5.2 months with local therapy and 4 months with the addition of chemotherapy (P = 0.23). Conclusions. Adult and pediatric patients with neuroblastoma achieve similar survival outcomes. INRG classification should be employed to stratify adult neuroblastoma patients and help select treatment.

Impact diagnostique de l’imagerie hybride TEMP/TDM dans la prise en charge des neuroblastomes. Expérience du service de médecine nucléaire du CHU Mohammed VI de Marrakech

IntroductionThe neuroblastoma is a malignant pediatric tumor of the peripheral sympathetic nervous system. This is the pediatric solid extracranial tumor most common and accounts for approximately 8 to 10% of childhood cancers. The diagnosis is based on imaging showing a tumor developed at the expense of the sympathetic nervous system, increased urinary catecholamines, increased uptake of meta-iodo-benzylguanidine (MIBG) and histology who finds a malignant proliferation of small round cells. An assessment of the tumor mass and its extension are required to assess the prognosis and adapt the treatment. The MIBG scintigraphy is a non-invasive imaging technique that can evaluate with a single review the totality of the tumor extension. The single-photon emission computed tomography/computed tomography (SPECT/CT) improves the sensitivity of the examination, it allows an anatomical and functional study and improves the anatomical localization of scintigraphic uptake observed. The purpose of our work is to illustrate the contribution of the SPECT/CT in addition to the planar MIBG scintigraphy in the diagnosis and staging of neuroblastoma about four cases. Case reportClinical case 1: a 4-year old child, presented for 2months abdominal pain. In the clinical examination, he presented a hard abdominal mass, painless and right paramedian. Abdominal ultrasound showed a right retroperitoneal mass with lymph nodes. The dosage of urinary catecholamines was increased. The 131I-MIBG scintigraphy showed an image for a right adrenal neuroblastoma measuring 8.6×4.5cm. Surgical excision of the adrenal mass revealed in the anatomopathologic study a malignant tumoral proliferation with round cells compatible with a neuroblastoma. Clinical case 2: a 10-month old infant, presented since 15 days an exophtalmia with poor general status. The clinical examination showed a right abdominal mass and a bilateral periorbital ecchymosis. The radiography of the thorax showed a widening mediastinal. Abdominal echography showed a tissular mass of the right adrenal gland with retroperitoneal lymph nodes and an ascites. The dosage of urinary catecholamines was increased. The 131I-MIBG scintigraphy showed a right adrenal neuroblastoma measuring 6.4×2.7cm with orbital bone metastases in favor of a Hutchinson syndrome. Clinical case 3: a 2-month old infant, followed since 1month for bilateral adrenal neuroblastoma. The clinical examination showed an important abdominal distension with bluish nodules under skin. The abdominal echography and the abdomino-pelvic TDM showed two adrenal masses corresponding to a bilateral neuroblastoma with liver metastases. The 131I-MIBG scintigraphy showed two adrenal masses measuring respectively 6.5×3.4cm and 8×6cm, with liver and skin metastases in favor of 4S neuroblastoma with bilateral adrenal tumors. Clinical case 4: a 3-year old child, followed for left adrenal neuroblastoma with multiple bone metastases. The clinical examination showed a left abdominal mass with exophtalmia and right palpebral ecchymosis. The radiography of the thorax showed a widening of the mediastin with repression of the paravertebral right line. Abdominal echography showed a left retroperitoneal tissular mass measuring 9.2×5.2cm. The abdomino-pelvic TDM showed a left adrenal tumor with lumbar vertebral bone metastases. A first 131I-MIBG scan showed a left neuroblastoma with multiple bone metastases in the right orbit, the right humerus, the occipital bone, the right scapula and spine (D10, D11, L1, L3, S1). The child was treated by 5 courses of chemotherapy (protocol HRNLB/10). The 131I-MIBG scan control showed a regression of neuroblastoma size (1.4×1.2cm) with loss of bone metastases of the occipital bone, the right scapula and spine. DiscussionThe MIBG scintigraphy is a simple, non-invasive examination that has excellent sensitivity and specificity in detection of neuroblastoma and especially in invasion bone marrow and in evaluation of the therapeutic response. The hybrid SPECT/CT imaging improve the performance of the scintigraphy as well in sensibility, toward the deep localization, as in specificity for images poorly defined in planar imaging.

64Cu-p-NH2-Bn-DOTA-hu14.18K322A, a PET Radiotracer Targeting Neuroblastoma and Melanoma

The hu14.18K322A variant of the GD2-targeting antibody hu14.18 has been shown to elicit a level of antibody-dependent cell-mediated cytotoxicity toward human neuroblastoma cells similar to that of the parent antibody. However, hu14.18K322A exhibited a decreased complement activation and associated pain, the dose-limiting toxicity in neuroblastoma immunotherapy. PET with a radiolabeled analog of the same antibody used in treatment will provide insight into the ability of hu14.18K322A to reach its target, as well as nontarget uptake that may cause side effects. Such antibody radiotracers might also provide a method for measuring GD2 expression in tumors, thus enabling the prediction of response to anti-GD2 therapy for individual patients. The conjugation of hu14.18K322A with p-NH(2)-Bn-DOTA was accomplished using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide with subsequent (64)Cu radiolabeling at 37°C for 30 min. Immunoreactivity of the conjugate was assessed by a dose-escalation blocking experiment measuring binding to purified GD2 versus GD1b as a negative control. Cell uptake and biodistribution studies in M21 (GD2-positive) and PC-3 (GD2-negative) tumor models were performed, as was small-animal PET/CT of M21 and PC-3 tumor-bearing mice. The labeling of (64)Cu-p-NH(2)-Bn-DOTA-hu14.18K322A was achieved at more than 95% radiochemical purity and a specific activity of 127-370 MBq/mg (3.4-10 mCi/mg) after chromatographic purification. Preliminary in vitro data demonstrated a greater than 6-fold selectivity of binding to GD2 versus GD1b and dose-dependent inhibition of binding by unmodified hu14.8K322A. In vivo data, including small-animal PET/CT, showed significant GD2-positive tumor-targeting ability, with a persistent 2-fold-higher uptake of radiotracer than in GD2-negative tumors. (64)Cu-p-NH(2)-Bn-DOTA-hu14.18K322A represents a novel PET radiotracer to facilitate clinical investigations of anti-GD2 immunotherapies and to complement other imaging modalities in the staging and treatment of neuroblastoma.

Imaging Features of Adult Neuroblastoma in F-18 FDG PET/CT

Neuroblastoma is an embryonal tumor from the neural crest cell, which generally occurs in young children with a median age of about 17 months. The incidence of adult was only 0.12 cases per million per year. Because metastatic disease was present in approximately one-third of all adult patients at diagnosis, accurate staging was necessary before the initial therapy. We report F-18 FDG PET/CT findings a case of adult neuroblastoma in the anterior mediastinum with skeletal and pulmonary metastasis, which demonstrates the utility of F-18 FDG PET/CT in the staging of adult neuroblastoma.

Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine

(68)Ga-DOTA-Tyr(3)-octreotide positron emission tomography ((68)Ga-DOTA-TOC PET) has proven to be superior to (111)In-DTPA-D-Phe(1)-octreotide ((111)In-octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard. Three male and eight female patients (age range 3 to 68years) with biochemically and histologically proven disease were included in this study. Three male and three female patients were suffering from phaeochromocytoma, and five female patients from neuroblastoma. Comparative evaluation included morphological imaging with CT or MRI, functional imaging with (68)Ga-DOTA-TOCPET and (123)I-MIBG imaging. Imaging results were analysed on a per-patient and on a per-lesion basis. On a per-patient basis, both (68)Ga-DOTA-TOC and (123)I-MIBG showed a sensitivity of 100%, when compared with anatomical imaging. In phaeochromocytoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 91.7% and that of (123)I-MIBG was 63.3%. In neuroblastoma patients, on a per-lesion basis, the sensitivity of (68)Ga-DOTA-TOC was 97.2% and that of (123)I-MIBG was 90.7%. Overall, in this patient cohort, (68)Ga-DOTA-TOC PET identified 257 lesions, anatomical imaging identified 216 lesions, and (123)I-MIBG identified only 184 lesions. In this patient group, the overall sensitivity of (68)Ga-DOTA-TOC PET on a lesion basis was 94.4% (McNemar p<0.0001) and that of (123)I-MIBG was 76.9% (McNemar p<0.0001). Our analysis in this relatively small patient cohort indicates that (68)Ga-DOTA-TOC PET may be superior to (123)I-MIBG gamma-scintigraphy and even to the reference CT/MRI technique in providing particularly valuable information for pretherapeutic staging of phaeochromocytoma and neuroblastoma.