Publications by authors named "William S Ferguson"

19 Publications

  • Page 1 of 1

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Cancer Res 2021 12 5;81(23):5818-5832. Epub 2021 Oct 5.

Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1033DOI Listing
December 2021

50 Years Ago in The Journal of Pediatrics: A Study of "Total Therapy" of Acute Lymphocytic Leukemia in Children.

J Pediatr 2018 03;194:115

Division of Pediatric Hematology-Oncology Saint Louis University of Medicine St Louis, Missouri.

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http://dx.doi.org/10.1016/j.jpeds.2017.09.042DOI Listing
March 2018

Iron deficiency in adolescence.

J Pediatr 2017 08;187

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http://dx.doi.org/10.1016/j.jpeds.2017.06.025DOI Listing
August 2017

Red cell antibody formation in the newborn.

J Pediatr 2017 02;181:3-4

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http://dx.doi.org/10.1016/j.jpeds.2016.12.014DOI Listing
February 2017

Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.

Biol Blood Marrow Transplant 2014 Nov 10;20(11):1847-51. Epub 2014 Jul 10.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.
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http://dx.doi.org/10.1016/j.bbmt.2014.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194244PMC
November 2014

A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma.

J Pediatr Hematol Oncol 2011 Jan;33(1):25-30

Department of Pediatrics, Vermont Children's Hospital, Burlington, VT, USA.

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.
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http://dx.doi.org/10.1097/MPH.0b013e3181f47061DOI Listing
January 2011

Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group.

J Clin Oncol 2008 Feb;26(4):633-8

Children's Oncology Group, Arcadia, CA, USA.

Purpose: To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma.

Patients And Methods: Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival.

Results: In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96).

Conclusion: The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.
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http://dx.doi.org/10.1200/JCO.2008.14.0095DOI Listing
February 2008

A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency.

Pediatr Blood Cancer 2008 May;50(5):1070-2

Department of Pediatrics, Saint Louis University, St. Louis, Missouri.

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder of cytotoxic cell function that results in abnormal proliferation of benign lymphocytes and histiocytes in response to infectious stimuli. FHLH generally occurs in very young children, and typically presents with fever, cytopenias, coagulopathy, lymphadenopathy, and hepatosplenomegaly. Central nervous system involvement occurs frequently and may precede the development of systemic symptoms by months to years. We report a case of an 18-year-old male with a 2-year history of symptoms attributed to a demyelinating disorder, who succumbed to rapidly progressive hemophagocyte lymphohistiocytosis. Post-mortem, two distinct perforin mutations were identified. We discuss the central nervous system and genetic findings in this unusual presentation of familial hemophagocytic lymphohistiocytosis.
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http://dx.doi.org/10.1002/pbc.21438DOI Listing
May 2008

Vinblastine and methotrexate for desmoid fibromatosis in children: results of a Pediatric Oncology Group Phase II Trial.

J Clin Oncol 2007 Feb;25(5):501-6

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Purpose: To determine the efficacy and safety of using vinblastine (Vbl) and methotrexate (Mtx) in children with desmoid-type fibromatosis that is recurrent or not amenable to treatment with radiation or surgery.

Patients And Methods: A phase II study was conducted within the Pediatric Oncology Group. Patients were treated using Vbl (5 mg/m2/dose) and Mtx (30 mg/m2/dose), both administered by intravenous injection weekly for 26 weeks and every other week for an additional 26 weeks. Response was assessed by bidimensional measurements of tumor on axial imaging (magnetic resonance imaging or computed tomography).

Results: Over 35 months, 28 patients were enrolled; 27 were eligible, and 26 were assessable for response. A measurable response was documented in eight patients (31%), and 10 patients had stable disease documented as the best response to treatment. Eighteen patients had disease progression at a median time of 9.1 months. Eight patients remain free of disease progression at a median of 43.4 months from study entry. Nine patients reported no to moderate toxicity. Neutropenia was the most common toxicity (n = 22) and the most common grade 4 toxicity (n = 5). Anemia, nausea, vomiting, and elevations in hepatic transaminases were also common and were reversible with interruption of chemotherapy.

Conclusion: Vbl and Mtx are well tolerated in children with desmoid-type fibromatosis. Furthermore, this combination can promote tumor regression or block tumor growth in most children.
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http://dx.doi.org/10.1200/JCO.2006.08.2966DOI Listing
February 2007

Combined computed tomography-guided radiofrequency ablation and brachytherapy in a child with multiple recurrences of Wilms' tumor.

J Pediatr Hematol Oncol 2005 Jul;27(7):377-9

Department of Diagnostic Imaging, Rhode Island Hospital, Providence, RI 02903, USA.

Background: Treatment of relapsed Wilms' tumor remains a challenge. We describe a case of an 11-year-old girl with multiply relapsed Wilms' tumor in whom combined percutaneous computed tomography (CT)-guided radiofrequency ablation and brachytherapy directed at a retroperitoneal tumor mass resulted in pain palliation and local tumor control.

Observations: Over the course of few weeks, her requirement for narcotic pain medications dramatically decreased. A contrast-enhanced CT scan obtained at 8 months after the procedure showed no evidence for local tumor recurrence. However, she subsequently developed myelodysplasia with evolution into leukemia, presumably secondary to chemotherapy, and died 9.5 months after the procedure.

Conclusion: Combined CT-guided radiofrequency ablation and brachytherapy is a promising new minimally invasive palliative treatment of recurrent Wilms' tumor.
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http://dx.doi.org/10.1097/01.mph.0000173846.87539.a9DOI Listing
July 2005

Intracardiac yolk sac tumor and dysrhythmia as an etiology of pediatric syncope.

Pediatrics 2004 Apr;113(4):e374-6

Division of Pediatric Critical Care, Department of Pediatrics, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island 02903, USA.

This report describes a new etiology of pediatric syncope. Epilepsy, brain anomalies, infection, electrolyte abnormalities, and trauma are commonly identified etiologies of seizures in the pediatric population. We report here a child with third-degree heart block and right ventricular outflow tract obstruction related to an intracardiac tumor presenting with syncope and seizure-like activity. Echocardiography revealed a large (3 x 8-cm) intracardiac mass filling the right atrium, extending across the tricuspid valve into the right ventricle and crossing the atrial septum into the left atrium, extending into the left ventricular outflow tract. She underwent emergent cardiopulmonary bypass with removal of the majority of the tumor mass, clearing both the left and right ventricular outflow tracts of obstruction and repairing the tricuspid valve. Postoperative cardiac conduction remained blocked and required permanent pacing. The initial serum alpha-fetoprotein level was grossly elevated, and the tumor showed characteristic histopathologic features of a yolk sac tumor. Four years after the completion of her chemotherapy, she remains clinically well, with no evidence of recurrent tumor by echocardiography or radiographic studies, and her alpha-fetoprotein remains in the normal range. The clinical manifestations of tumor infiltration of the heart with complete heart block resulting in loss of consciousness with tonic-clonic movements are detailed. Although rare, cardiac syncope has multiple known causes and should be suspected in any patient with sudden loss of consciousness and pallor. In the pediatric population, cardiac rhythm disturbances are typically the result, rather than the cause, of acute cardiac emergencies. Pediatricians should be aware of depressed cardiac output and dysrhythmias as etiologies of new-onset syncope. Evaluation should include a cardiac assessment with electrocardiogram to exclude a life-threatening arrhythmia as a potential cause.
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http://dx.doi.org/10.1542/peds.113.4.e374DOI Listing
April 2004

Advances in the adjuvant treatment of infantile fibrosarcoma.

Expert Rev Anticancer Ther 2003 Apr;3(2):185-91

Division of Pediatric Hematology-Oncology, Rhode Island Hospital, Providence 02903, USA.

Infantile fibrosarcoma is a rare soft tissue tumor, predominately affecting young infants. It grows rapidly and is locally infiltrative but rarely metastases. Complete surgical removal is usually curative but is impossible in some patients and would result in significant functional or cosmetic consequences in many others. Neoadjuvant chemotherapy will cause many tumors to shrink significantly, allowing less mutilating surgical resections to be performed--this is the current recommendation where immediate surgical removal cannot be accomplished without unacceptable morbidity. In contrast, there is no defined role for adjuvant chemotherapy or radiation following complete surgical resection. Although there is a significant risk of local recurrence, most of these can be successfully treated with further surgery and the overall survival rate exceeds 90%.
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http://dx.doi.org/10.1586/14737140.3.2.185DOI Listing
April 2003

Childhood cancer: past successes, future directions.

Med Health R I 2002 Jan;85(1):17-22

Rhode Island Hospital, 593 Eddy St., Providence, RI 02903, USA.

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January 2002
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