Publications by authors named "Stephan D Voss"

78 Publications

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.

Histopathology 2022 Aug 29;81(2):215-227. Epub 2022 May 29.

Department of Pathology, Boston Children's Hospital, Boston, MA, USA.

Aims: Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors.

Methods And Results: Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases).

Conclusion: Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.
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http://dx.doi.org/10.1111/his.14680DOI Listing
August 2022

Ga-DOTATATE PET and functional imaging in pediatric pheochromocytoma and paraganglioma.

Pediatr Blood Cancer 2022 08 29;69(8):e29740. Epub 2022 Apr 29.

Department of Radiology, Boston Children's Hospital, Boston, USA.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Up to 40% of PPGL are currently thought to be associated with a hereditary predisposition. Nuclear medicine imaging modalities such as fluorodeoxyglucose positron emission tomography ( F-FDG PET), Ga-DOTATATE PET, and I-metaiodobenzylguanidine ( I-MIBG) scintigraphy play an essential role in the staging, response assessment, and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these functional imaging modalities targets a different cellular characteristic and as such can be complementary to anatomic imaging and to each other. With the recent US Food and Drug Administration approval and increasing use of Ga-DOTATATE for imaging in children, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it is compared to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, as well as other neuroendocrine malignancies.
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http://dx.doi.org/10.1002/pbc.29740DOI Listing
August 2022

Development and autoregulation of kidney function in children: a retrospective study using Tc-MAG3 renography.

Pediatr Nephrol 2022 Sep 28;37(9):2157-2166. Epub 2022 Jan 28.

Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Both the development of kidney function in healthy children and autoregulation ability of kidney function in patients with asymmetric kidneys are important in clinical diagnosis and treatment of kidney-related diseases, but there are however only limited studies. This study aimed to investigate development of kidney function in normal children with healthy symmetric kidneys and autoregulation of the healthy kidney compensating the functional loss of a diseased one in children with asymmetric kidneys.

Methods: Two hundred thirty-seven children (156 male, 81 female) from 0 to 20y (average 4.6y ± 5.1) undergoing Tc-MAG3 renography were included, comprising 134 with healthy symmetrically functioning kidneys and 103 with asymmetric kidneys. Clearance was calculated from kidney uptakes at 1-2 min. A developmental model between MAG3 clearance (CL) and patient age in normal group was identified (CL = 84.39Age ml/min, r = 0.957, p < 0.001). The clearance autoregulation rate in abnormal group with asymmetric kidneys was defined as the ratio of the measured MAG3 clearance and the normal value predicted from the renal developmental model of normal group.

Results: No significant difference of MAG3 clearance (p = 0.723) was found between independent abnormal group and normal group. The autoregulation rate of kidney clearance in abnormal group was 94.2% on average, and no significant differences were found between two age groups (p = 0.49), male and female (p = 0.39), and left kidney and right kidney (p = 0.92) but two different grades of asymmetric kidneys (p = 0.02).

Conclusions: The healthy kidney of two asymmetric kidneys can automatically regulate total kidney function up to 94% of two symmetric kidneys in normal children.
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http://dx.doi.org/10.1007/s00467-022-05446-zDOI Listing
September 2022

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Juvenile Granulosa Cell Tumor as the Presenting Feature of McCune-Albright Syndrome.

J Endocr Soc 2021 Sep 8;5(9):bvab098. Epub 2021 Jul 8.

Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.

Introduction: mutations have been reported in both McCune-Albright syndrome (MAS) and juvenile granulosa cell tumors (JGCT) but have never been reported simultaneously in the same patient.

Case Presentation: A 15-year-old girl developed secondary oligomenorrhea. Laboratory studies revealed suppressed gonadotropin levels with markedly elevated estradiol and inhibin B levels. Pelvic ultrasound showed a 12-cm heterogeneous right adnexal mass; pelvic magnetic resonance imaging to further characterize the mass displayed heterogeneous bilateral femoral bone lesions initially concerning for metastatic disease. Positron emission tomography/computed tomography showed minimal F-fluorodeoxyglucose (FDG) uptake in the pelvic mass but unexpectedly revealed FDG uptake throughout the skeleton, concerning for polyostotic fibrous dysplasia in the context of MAS. The adnexal mass was excised and pathology confirmed a JGCT. The patient's affected bone and JGCT tissue revealed the same pathogenic p.R201C mutation, while her peripheral blood contained wild-type arginine at codon 201.

Conclusion: This mutation has been previously reported in cases of MAS and JGCT but never simultaneously in the same patient. This demonstration of a mutation underlying both JGCT and MAS in the same patient raises questions about appropriate surveillance for patients with these conditions.
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http://dx.doi.org/10.1210/jendso/bvab098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282215PMC
September 2021

Response to Febo-Rodriguez et al.

Am J Gastroenterol 2021 07;116(7):1553

Joint Program in Nuclear Medicine, Department of Radiology, Brigham and Women's' Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.14309/ajg.0000000000001214DOI Listing
July 2021

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912).

Clin Cancer Res 2021 07 10;27(13):3543-3548. Epub 2021 Feb 10.

Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration.

Patients And Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study.

Results: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%-34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count.

Conclusions: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254744PMC
July 2021

Pediatric Solid Gastric Emptying Scintigraphy: Normative Value Guidelines and Nonstandard Meal Alternatives.

Am J Gastroenterol 2020 11;115(11):1830-1839

Joint Program in Nuclear Medicine, Department of Radiology, Brigham and Women's' Hospital, Harvard Medical School, Boston, Massachusetts.

Introduction: Adult standards for gastric emptying scintigraphy, including the type of meal and range of normative values for percent gastric emptying, are routinely used in pediatric practice, but to date have not been validated. The purpose of this study is to determine whether the use of adult criteria for gastric emptying scintigraphy is valid for children and whether alternative nonstandard meals can also be offered based on these criteria.

Methods: This retrospective study analyzed patients (n = 1,151 total) who underwent solid-phase gastric emptying scintigraphy. Patients were stratified into normal and delayed gastric emptying cohorts based on adult criteria, i.e., with normal gastric emptying defined as ≤10% gastric retention at 4 hours. Patients were further stratified based on the type of meal, namely complete or partial adult standard meals or alternative cheese-based meals. Percent gastric retention values at 1, 2, 3, and 4 hours were compared.

Results: The median (95% upper reference limit) percentage gastric retention values for the complete standard meal were 72% (93%) at 1 hour, 39% (65%) at 2 hours, 15% (33%) at 3 hours, and 6% (10 %) at 4 hours. By comparison, the values for cheese-based meals were 60% (87%) at 1 hour, 29% (61%) at 2 hours, 10% (30%) at 3 hours, and 5% (10%) at 4 hours. Consumption of at least 50% of the standard meal yielded similar retention percentages; 68% (89%) at 1 hour, 32% (57%) at 2 hours, 10% (29%) at 3 hours, and 5% (10%) at 4 hours. There were no significant age- or sex-specific differences using the adult criteria.

Discussion: The adult normative standards for gastric emptying scintigraphy are applicable for use in the pediatric population. These same standards can be also be applied to nonstandard meal options, including cheese-based alternative meals and partial standard meals.
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http://dx.doi.org/10.14309/ajg.0000000000000831DOI Listing
November 2020

Expert consensus statements for Waldeyer's ring involvement in pediatric Hodgkin lymphoma: The staging, evaluation, and response criteria harmonization (SEARCH) for childhood, adolescent, and young adult Hodgkin lymphoma (CAYAHL) group.

Pediatr Blood Cancer 2020 09 16;67(9):e28361. Epub 2020 Jul 16.

Division of Haematology/Oncology, Department of Paediatrics, SickKids Hospital and University of Toronto, Toronto, Canada.

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.
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http://dx.doi.org/10.1002/pbc.28361DOI Listing
September 2020

Neck CT angiography examinations for pediatric oropharyngeal trauma: diagnostic yield and proposal of a new targeted technique.

Pediatr Radiol 2020 10 3;50(11):1602-1609. Epub 2020 Jul 3.

Department of Radiology, Boston Children's Hospital, 300 Longwood Ave., Boston, MA, 02115, USA.

Background: Neck computed tomography (CT) angiography is commonly ordered for pediatric patients with soft palate trauma to exclude vascular injury. Debate exists regarding what type of imaging is indicated in this setting, particularly amid growing concern that standard neck CT angiography results in considerable radiation exposure.

Objective: To assess the diagnostic yield and estimated dose reduction of a novel targeted protocol extending from the skull base to the hyoid bone to evaluate pediatric oropharyngeal trauma.

Materials And Methods: A retrospective imaging and medical chart review was performed of patients for whom a neck CT angiography was obtained for an indication of oropharyngeal trauma between 2008 and 2018. Effective dose and size-specific dose estimates (SSDEs) were estimated for standard and targeted neck CT angiography protocols with calculation of percent dose reduction of the targeted exams.

Results: Ninety-eight CT angiography examinations were reviewed. No cases were positive for neurological or major vessel injury; one case was positive for small vessel extravasation. Clinically significant nonvascular findings included phlegmonous change, retained foreign body, retropharyngeal/mediastinal air and pterygoid process fracture. With the exception of mediastinal air, all findings would have been included in the targeted protocol. Effective dose and SSDE were calculated for all cases where CTDI (volume CT dose index) had been reported (n=72). There was a statistically significant reduction in dose for the targeted protocol with an effective dose decrease of 69.7%±10.5% (P=0.009) and SSDE decrease of 53.9%±14.7% (P=0.01). Limiting ionizing radiation to the lung apices, esophagus and thyroid gland provided the greatest dose savings.

Conclusion: Based on low diagnostic yield and high radiation dose associated with standard neck CT angiography for evaluating oropharyngeal trauma, a targeted protocol is recommended, resulting in significantly less dose to the neck, while preserving diagnostic yield.
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http://dx.doi.org/10.1007/s00247-020-04737-7DOI Listing
October 2020

Prospective Evaluation of Radiation Dose Escalation in Patients With High-Risk Neuroblastoma and Gross Residual Disease After Surgery: A Report From the Children's Oncology Group ANBL0532 Study.

J Clin Oncol 2020 08 12;38(24):2741-2752. Epub 2020 Jun 12.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Purpose: A primary objective of the Children's Oncology Group (COG) ANBL0532 phase III study was to assess the effect of increasing local dose of radiation to a residual primary tumor on the cumulative incidence of local progression (CILP) in patients with high-risk neuroblastoma.

Patients And Methods: Newly diagnosed patients with high-risk neuroblastoma were randomly assigned or assigned to receive single or tandem autologous stem-cell transplantation (SCT) after induction chemotherapy. Local control consisted of surgical resection during induction chemotherapy and radiotherapy after last SCT. Patients received 21.6 Gy to the preoperative primary tumor volume. For patients with incomplete surgical resection, an additional boost of 14.4 Gy was delivered to the gross residual tumor, for a total dose of 36 Gy. CILP (primary end point) and event-free (EFS) and overall survival (OS; secondary end points) were compared with the COG A3973 historical cohort, in which all patients received single SCT and 21.6 Gy without a boost.

Results: For all patients in ANBL0532 receiving radiotherapy (n = 323), 5-year CILP, EFS, and OS rates were 11.2% ± 1.8%, 56.2% ± 3.4%, and 68.4% ± 3.2% compared with 7.1% ± 1.4% ( = .0590), 47.0% ± 3.5% ( = .0090), and 57.4% ± 3.5% ( = .0088) for all patients in A3973 receiving radiotherapy (n = 328), respectively. Five-year CILP, EFS, and OS rates for patients in A3973 with incomplete resection and radiotherapy (n = 47) were 10.6% ± 4.6%, 48.9% ± 10.1%, and 56.9% ± 10.0%, respectively. In comparison, 5-year CILP, EFS, and OS rates for patients in ANBL0532 who were randomly assigned or assigned to single SCT and received boost radiotherapy (n = 74) were 16.3% ± 4.3% ( = .4126), 50.9% ± 7.0% ( = .5084), and 68.1% ± 6.7% ( = .2835), respectively.

Conclusion: Boost radiotherapy to gross residual tumor present at the end of induction did not significantly improve 5-year CILP. These results highlight the need for new strategies to decrease the risk of locoregional failure.
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http://dx.doi.org/10.1200/JCO.19.03316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430214PMC
August 2020

Liver involvement in pediatric Hodgkin lymphoma: A systematic review by an international collaboration on Staging Evaluation and Response Criteria Harmonization (SEARCH) for Children, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL).

Pediatr Blood Cancer 2020 08 3;67(8):e28365. Epub 2020 Jun 3.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Hepatic involvement in Hodgkin lymphoma (HL) is uncommon (∼5% of patients) but always implies stage IV disease. Accurate staging is mandatory for making the appropriate risk assignment and treatment decisions. The Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) international working group conducted a systematic literature review of liver involvement in HL patients with the aim to propose a universally acceptable definition for liver involvement in pediatric HL. Thirty-three articles describing 6985 pediatric and adult HL patients were reviewed, of which 539 (7.7%) mentioned liver involvement. The literature did not provide a uniform definition of hepatic involvement and we propose consensus criteria derived from the EuroNet and Children's Oncology Group protocols, where liver involvement is defined as any hepatic lesion on computed tomography scan that correlates with F-FDG uptake greater than background liver. A clear definition of liver lesions is necessary to consistently identify liver involvement and compare its impact on outcomes among protocols worldwide.
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http://dx.doi.org/10.1002/pbc.28365DOI Listing
August 2020

Definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma: A report from the International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH).

Pediatr Blood Cancer 2020 04 22;67(4):e28142. Epub 2019 Dec 22.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: The International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH) seeks to provide a universally acceptable definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma.

Procedure: A comprehensive literature search was performed using PubMed and Google Scholar with the search terms "Hodgkin lymphoma," "osseous lesions," "bony involvement," and "pediatric." Publications reviewed included case reports, retrospective analyses, and literature reviews. Each was evaluated for study design, number of participants, median age and age range at diagnosis, percentage of pediatric patients, criteria of interest definition, diagnostic tools, study objectives, and level of evidence. The final definition was based on the available data and consensus of the SEARCH working group.

Results: Twenty-five papers specifically addressing cortical bone involvement in Hodgkin lymphoma met the inclusion criteria. Eighteen papers were case reports with literature reviews; the remainder were observational cohort studies. Of these, 14 included pediatric patients (aged 0-21 years). The criteria for cortical bone involvement were not clearly defined in any paper, often varied within a study, and were inconsistent between publications.

Conclusions: The SEARCH group for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) proposes the following criteria as defining cortical bone involvement: any cortical bone biopsy-proven lesion; a positive bony window lesion on computer tomography (CT), with an FDG-PET positive correlate in a patient with biopsy-proven Hodgkin lymphoma, if there is no other typical skeletal pathology; auspicious skeletal lesions on FDG-PET or magnetic resonance imaging should be confirmed by CT or Tc-99m scan to distinguish cortical lesions from bone marrow involvement. Nodal masses that extend into bone with bony destruction are considered extranodal extension or "E" lesions and do not represent metastatic or stage IV disease.
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http://dx.doi.org/10.1002/pbc.28142DOI Listing
April 2020

Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312).

Clin Cancer Res 2020 03 19;26(6):1213-1219. Epub 2019 Dec 19.

University of Minnesota, Minneapolis, Minnesota.

Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.

Patients And Methods: Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m/day) delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.

Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m) in combination with irinotecan (90 mg/m) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.

Conclusions: Adavosertib (85 mg/m) in combination with irinotecan (90 mg/m) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073289PMC
March 2020

Surveillance imaging in pediatric lymphoma.

Pediatr Radiol 2019 10 16;49(11):1565-1573. Epub 2019 Oct 16.

Department of Pediatric Hematology,Oncology, and Stem Cell Transplantation, Maria Fareri Children's Hospital, Westchester Medical Center, New York Medical College, Valhalla, NY, USA.

Current therapies used in treating children with Hodgkin lymphoma and many histological subtypes of non-Hodgkin lymphoma have resulted in overall survival rates exceeding 90% in many instances. With increasing concerns related to the cost of radiologic imaging, exposure to ionizing radiation, and potential false-positive results, the role of routine off-therapy surveillance imaging has been called into question. Although radiologic imaging plays an important role in diagnosing and assessing treatment response, in these children - the majority of whom have an excellent outcome following completion of therapy - there is an opportunity to dramatically reduce the number of off-therapy imaging evaluations. This review summarizes several recent studies in both Hodgkin and non-Hodgkin lymphoma providing evidence to support these efforts. In addition, we propose a surveillance imaging strategy that uses a novel risk-adapted and response-based approach to determine which children would most benefit from off-therapy imaging surveillance.
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http://dx.doi.org/10.1007/s00247-019-04511-4DOI Listing
October 2019

Functional and anatomical imaging in pediatric oncology: which is best for which tumors.

Authors:
Stephan D Voss

Pediatr Radiol 2019 10 16;49(11):1534-1544. Epub 2019 Oct 16.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.

Functional imaging techniques are playing an increasingly important role in the management of pediatric cancer. Technological advances have pushed the development of hybrid imaging techniques, including positron emission tomography (PET)/CT, PET/MR and single-photon emission computed tomography (SPECT)/CT. Together with an increasing need to identify surrogate biomarkers for response to novel therapies, the use of functional imaging techniques, which had been reserved primarily for lymphoma patients, is now being recognized as standard of care for the management of many other pediatric solid tumors. The purpose of this review is to summarize recent data describing the use of functional and metabolic imaging strategies for the staging and response assessment of common pediatric solid tumors, and to offer some guidance as to which techniques are most appropriate for which tumor types.
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http://dx.doi.org/10.1007/s00247-019-04489-zDOI Listing
October 2019

Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial.

JAMA 2019 08;322(8):746-755

Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Importance: Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low.

Objective: To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant.

Design, Setting, And Participants: Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017.

Interventions: Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179).

Main Outcomes And Measures: The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant.

Results: Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%).

Conclusions And Relevance: Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT00567567.
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http://dx.doi.org/10.1001/jama.2019.11642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714031PMC
August 2019

Multicenter pre-operative assessment of pediatric ovarian malignancy.

J Pediatr Surg 2019 Sep 25;54(9):1921-1925. Epub 2019 Feb 25.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer Center and Harvard Medical School, Boston, MA.

Purpose: The purpose of this study was to develop a pre-operative risk assessment tool for childhood and adolescent ovarian malignancy, in order to guide operative management of pediatric ovarian masses.

Methods: We conducted a retrospective analysis of patients <18 years old who underwent ovarian surgery at two quaternary care pediatric centers over 4 years (1/1/13-12/31/16). Probability of malignancy was estimated based on imaging characteristics (simple cyst, heterogeneous, or solid), maximal diameter, and tumor markers (α-fetoprotein, β-human chorionic gonadotropin).

Results: Among 188 children with ovarian masses, 11% had malignancies. For simple cysts, there were no malignancies (0/24, 95% CI = 0-17%). Among solid lesions, 44% (15/34, 95% CI = 28-62%) were malignant. Among marker-elevated heterogeneous masses, 40% (2/5, 95% CI = 12-77%) were malignant. Conversely, small (≤10 cm) and large (>10 cm) marker-negative heterogeneous lesions had malignancy proportions of 0% (0/39, 95% CI = 0-11%) and 5% (2/40, 95% CI = 1-18%), respectively.

Conclusions: Given the malignancy estimates identified from these multi-institutional data, we recommend an attempt at ovarian-sparing resection for simple cysts or tumor marker-negative heterogeneous lesions ≤10 cm. Oophorectomy is recommended for solid masses or heterogeneous lesions with elevated markers. Finally, large (>10 cm) heterogeneous masses with non-elevated markers warrant a careful discussion of ovarian-sparing techniques. Complete surgical staging is mandatory regardless of operative procedure.

Type Of Study: Study of Diagnostic Test.

Level Of Evidence: Level I.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.02.019DOI Listing
September 2019

A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921).

Clin Cancer Res 2019 06 18;25(11):3229-3238. Epub 2019 Feb 18.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816).

Patients And Methods: Alisertib (80 mg/m/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle.

Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed.

Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897379PMC
June 2019

Staging and following common pediatric malignancies: MRI versus CT versus functional imaging.

Authors:
Stephan D Voss

Pediatr Radiol 2018 08 4;48(9):1324-1336. Epub 2018 Aug 4.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115, USA.

Most pediatric malignancies require some form of cross-sectional imaging, either for staging or response assessment. The majority of these are solid tumors and this review addresses the role of MRI, as well as other cross-sectional and functional imaging techniques, for evaluating the most common pediatric solid tumors. The primary emphasis is on neuroblastoma, hepatoblastoma and Wilms tumor, three of the most common non-central-nervous-system (CNS) pediatric solid tumors encountered in young children. The initial focus will be a review of the imaging techniques and approaches used for diagnosis, staging and early post-treatment response assessment, followed by a discussion of the role surveillance imaging plays in pediatric oncology and a brief review of other emerging imaging techniques. The lessons learned here can be applied to most other pediatric tumors, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, as well as germ cell tumors, neurofibromatosis and other rare tumors. Although lymphoma, in particular Hodgkin lymphoma, represents one of the more common pediatric malignancies, this is not discussed in detail here. Rather, many of the lessons that we have learned from lymphoma, specifically with regard to how we integrate both anatomical imaging and functional imaging techniques, is applied to the discussion of the other pediatric solid tumors.
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http://dx.doi.org/10.1007/s00247-018-4162-4DOI Listing
August 2018

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

Cancer 2018 08 8;124(15):3210-3219. Epub 2018 May 8.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence.

Methods: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival.

Results: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary.

Conclusions: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097921PMC
August 2018

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

Pediatr Blood Cancer 2018 08 25;65(8):e27077. Epub 2018 Apr 25.

Department of Pediatrics, Hem/Onc/BMT/University of Minnesota/Masonic Cancer Center, Minneapolis, MN, USA.

Background: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors.

Methods: Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed.

Results: Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m /day. At 40 mg/m /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma).

Conclusions: A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m /day. A phase 2 study of cabozantinib is being conducted.
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http://dx.doi.org/10.1002/pbc.27077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082380PMC
August 2018

Correction to: Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations.

Pediatr Radiol 2018 03;48(3):454

Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The published version of this article incorrectly lists Dr. Joseph P. Cravero in the Department of Radiology at Boston Children's Hospital. Dr. Cravero's correct affiliation is given below.
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http://dx.doi.org/10.1007/s00247-017-4057-9DOI Listing
March 2018

Imaging Optimization in Children.

J Am Coll Radiol 2018 03 29;15(3 Pt A):440-443. Epub 2017 Dec 29.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacr.2017.10.017DOI Listing
March 2018

Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations.

Pediatr Radiol 2018 01 27;48(1):21-30. Epub 2017 Nov 27.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115, USA.

In the context of health care, risk assessment is the identification, evaluation and estimation of risk related to a particular clinical situation or intervention compared to accepted medical practice standards. The goal of risk assessment is to determine an acceptable level of risk for a given clinical treatment or intervention in association with the provided clinical circumstances for a patient or group of patients. In spite of the inherent challenges related to risk assessment in pediatric cross-sectional imaging, the potential risks of ionizing radiation and sedation/anesthesia in the pediatric population are thought to be quite small. Nevertheless both issues continue to be topics of discussion concerning risk and generate significant anxiety and concern for patients, parents and practicing pediatricians. Recent advances in CT technology allow for more rapid imaging with substantially lower radiation exposures, obviating the need for anesthesia for many indications and potentially mitigating concerns related to radiation exposure. In this review, we compare and contrast the potential risks of CT without anesthesia against the potential risks of MRI with anesthesia, and discuss the implications of this analysis on exam selection, providing specific examples related to neuroblastoma surveillance imaging.
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http://dx.doi.org/10.1007/s00247-017-4023-6DOI Listing
January 2018

How we read pediatric PET/CT: indications and strategies for image acquisition, interpretation and reporting.

Cancer Imaging 2017 Nov 7;17(1):28. Epub 2017 Nov 7.

Department of Radiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

PET/CT plays an important role in the diagnosis, staging and management of many pediatric malignancies. The techniques for performing PET/CT examinations in children have evolved, with increasing attention focused on reducing patient exposure to ionizing radiation dose whenever possible and minimizing scan duration and sedation times, with a goal toward optimizing the overall patient experience. This review outlines our approach to performing PET/CT, including a discussion of the indications for a PET/CT exam, approaches for optimizing the exam protocol, and a review of different approaches for acquiring the CT portion of the PET/CT exam. Strategies for PACS integration, image display, interpretation and reporting are also provided. Most practices will develop a strategy for performing PET/CT that best meets their respective needs. The purpose of this article is to provide a comprehensive overview for radiologists who are new to pediatric PET/CT, and also to provide experienced PET/CT practitioners with an update on state-of-the art CT techniques that we have incorporated into our protocols and that have enabled us to make considerable improvements to our PET/CT practice.
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http://dx.doi.org/10.1186/s40644-017-0130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678769PMC
November 2017

Role of imaging in the diagnosis of parotid infantile hemangiomas.

Int J Pediatr Otorhinolaryngol 2017 Nov 4;102:61-66. Epub 2017 Sep 4.

Vascular Anomalies Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Vascular and Interventional Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Objectives: To review the clinical presentation, imaging and follow-up of parotid infantile hemangiomas (IH).

Methods: Over a 15-year period, all patients with a clinical diagnosis of parotid IH were evaluated. Imaging was available in 35. The medical records, photographs, and radiology studies of these patients were reviewed.

Results: All patients presented at less than 4 months of age (M:F, 13:21). 19 (55)% of tumors were on the left and were bilateral in 2 patients. The majority (29 patients) presented due to localized swelling or palpable mass; the remainder had a cutaneous lesion, but no palpable mass at the time of presentation. The referring diagnosis was incomplete or incorrect in 9 patients (26%). The imaging studies all demonstrated a well-defined homogeneous mass, with no abnormality of the surrounding subcutaneous fat. Sonography showed a uniformly vascular lesion with pulsatile fast-flow seen on Doppler. On MRI, the lesion was hyperintense on T2-weighted images, isointense on T1, with intense enhancement post-contrast. Oral therapy (propranolol or corticosteroids) was prescribed in 15 (45%). Follow-up in 28 patients demonstrated stability of the lesion in 11, regression in size in 11 and complete involution in 6. After involution 2 patients underwent resection of residual tissue and/or excess skin.

Conclusions: Typical clinical presentation alone may be adequate to establish a diagnosis of parotid infantile hemangioma. However, in patients with no overlying cutaneous lesion, imaging can play a critical role in confirming the diagnosis. The sonographic findings are sufficiently characteristic to allow for a definitive diagnosis, obviating the need for further investigations. If diagnostic uncertainty remains or the full extent of the lesion cannot be appreciated, then MRI should be preferred over CT to avoid ionizing radiation.
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http://dx.doi.org/10.1016/j.ijporl.2017.08.035DOI Listing
November 2017

Liposuction for Swelling in Patients with Lymphedema.

N Engl J Med 2017 11;377(18):1788-1789

Boston Children's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc1709275DOI Listing
November 2017

Screening with whole-body magnetic resonance imaging in pediatric subjects with Li-Fraumeni syndrome: A single institution pilot study.

Pediatr Blood Cancer 2018 Feb 27;65(2). Epub 2017 Oct 27.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood-onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole-body magnetic resonance imaging (WB-MRI) may provide an acceptable method for early cancer detection.

Procedure: We conducted a prospective feasibility pilot study of pediatric subjects (age < 18 years) with LFS to determine return rates for annual WB-MRI scan. Secondary objectives included characterization of incident cancers (and how they were detected).

Results: Forty-five WB-MRI scans in 20 subjects were performed over 5 years; two patients enrolled without subsequently undergoing scans. Eighty-nine percent of participants scanned (95% confidence interval: 67-99%) returned for second examinations. Fifty-five percent of participants required general anesthesia, which was well tolerated in all cases. Six patients required dedicated follow-up imaging. One participant required biopsy of a detected brain lesion; pathology demonstrated reactive gliosis. Another participant, with prior choroid plexus carcinoma, had a new brain lesion detected on clinical follow-up MRI not seen on WB-MRI 6 months prior. All other participants remain well (median: 3 years, range: 0.08-4 years).

Conclusions: WB-MRI in pediatric subjects is a well-tolerated approach to cancer surveillance despite the need for general anesthesia in some patients. A large multicenter trial would determine true test characteristics and efficacy of this approach for early cancer detection in children at high cancer risk.
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http://dx.doi.org/10.1002/pbc.26822DOI Listing
February 2018
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