Paul Kent | Rush University Medical Center (original) (raw)

Papers by Paul Kent

Research paper thumbnail of External beam and stereotactic radiation in the treatment of fibrolamellar carcinoma

Journal of Clinical Oncology

e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (< 50 cases/year US), di... more e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (< 50 cases/year US), distinct type of primary liver cancer, unrelated to hepatocellular carcinoma (HCC), affecting healthy children and young adults that often presents at an advanced stage. Surgery is the only known cure, but is only possible in half of patients, and, even with surgery, there is an 80% relapse rate. Loco-regional therapies can make surgery possible or replace surgery, allow systemic therapy time to work, and prolong life. However because of the paucity of data and the common misunderstanding of treating FLC as a “variant of hepatocellular carcinoma (HCC)” it is often assumed to be radio-resistant. For example, the 2021 NCCN Guidelines give no specific recommendations for radiation in FLC but classifying FLC as a “variant of HCC'' recommend 25 1.8Gy fractions (45Gy) with a boost to 50-60 Gy for external beam radiation(EBRT) and 3-5 10Gy fractions for stereotactic body radiation (SBRT)....

Research paper thumbnail of Treatment a nd O utcome o f 8 3 C hildren W ith I ntraspinal Neuroblastoma: T he P ediatric O ncology G roup E xperience

Purpose: To investigate whether the rate of neurologic recovery or the incidence of long-term seq... more Purpose: To investigate whether the rate of neurologic recovery or the incidence of long-term sequelae differed for children with neuroblastoma (NB) initially treated with chemotherapy versus surgical decompression with laminectomy, we reviewed the Pediatric Oncology Group (POG) experience. Patients and Methods: A retrospective review of children diagnosed with intraspinal NB registered on POG NB Biology Protocol 9047 was performed. Survival, neurologic outcome, and orthopedic sequelae were evaluated according to age of the patient at diagnosis, stage of disease, duration and severity of neurologic symptoms, and therapeutic intervention. Results: Between May 1990 and January 1998, 83 children with intraspinal NB were entered onto the study. Five-year survival for this cohort of patients was 71% 6 9%. Forty-three (52%) of the patients had neurologic symptoms at diagnosis. After treatment, six of 15 severely affected patients, who presented with paralysis, completely recovered neurolo...

Research paper thumbnail of Harlequin syndrome following microwave ablation in a child with a symptomatic paraspinal mass

BMJ Case Reports, 2020

Our goal is to describe a case of Harlequin syndrome associated with microwave ablation in the tr... more Our goal is to describe a case of Harlequin syndrome associated with microwave ablation in the treatment of a symptomatic paraspinal mass in a child, along with a summary of the literature. Our patient is the only known case of persistent Harlequin syndrome associated with microwave ablation treatment of a symptomatic paraspinal mass. Harlequin syndrome is a rare neurological condition characterised by unilateral sweating and flushing of the face, neck and/or upper chest. The specific mechanism is unclear, but the majority of cases are believed to be a result of contralateral lesions along the sympathetic chain. CT-guided microwave ablation therapy is a minimally invasive technique used as an alternative to surgery in this case due to the risk and morbidity associated with excision of the mass. There is limited literature assessing the use and inherent risk of developing complications following microwave ablation to the paraspinal region in the paediatric population.

Research paper thumbnail of The Risk of Tumor Contamination Associated With Thoracic Instrumentation in Patients With Osteosarcoma

Journal of Pediatric Hematology/Oncology, 2020

Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteos... more Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteosarcoma. However, tumor contamination in patients with osteosarcoma associated with thoracic instrumentation is not well described. The authors summarize 2 reported cases in addition to the 2 cases at their institution of this phenomenon. Knowledge of tumor contamination and preventative measures against tumor contamination is sparse in the literature, especially pertaining to patients with osteosarcoma undergoing thoracic instrumentation. In this report, the authors hope to increase awareness of these cases and suggest preventative measures to mitigate against tumor contamination in patients with osteosarcoma. The authors report that the median time between thoracic instrumentation and the visible detection of tumor migration to local sites was 5 months. They conclude that tumor contamination associated with thoracic instrumentation is characterized by patients with multiple sites of relapse and aggressive, fatal disease.

Research paper thumbnail of Docetaxol, bevacizumab, gemcitabine “TAG” chemotherapy for high risk and relapsed adolescent and young adult (AYA) sarcoma patients

Journal of Clinical Oncology, 2016

10518Background: Adolescent and young adult (AYA) patients with high-risk recurrent / metastatic ... more 10518Background: Adolescent and young adult (AYA) patients with high-risk recurrent / metastatic sarcomas have very poor prognosis, with few living 2 years. There are currently no standard treatmen...

Research paper thumbnail of Improving Accrual of Adolescents and Young Adults and Underrepresented Minorities with Leukemia to Children's Oncology Group Clinical Trials: A Novel Collaborative Approach to Address Disparities in Leukemia

Blood, 2016

Background: It is accepted that the dramatic historical decrease in mortality from ALL and AML in... more Background: It is accepted that the dramatic historical decrease in mortality from ALL and AML in children and more recently AYAs is directly related to improved participation in NCI sponsored COG clinical trials. It is also known that African-American (AA) and Hispanic children, Hispanic females, and particularly AYAs 15 to 39 years are under-represented in COG clinical trials and may benefit from targeted attention. AA and Hispanic children with ALL and AML have worse survival than white and Asian children even with modern therapy where cure rates have improved drastically. Access to standard accepted chemotherapy for leukemia, socio-economic status and insurance status, differences in disease phenotype and pharmacogenetic variations play a role in these racial and ethnic disparities. AYAs with leukemia have experienced variable improvement in survival over the past two decades due partly to insufficient cancer clinical trial enrollment. Uninsured, older patients and those treated...

Research paper thumbnail of To Transplant or Not to Transplant? Late-Onset Primary HLH in a Patient

Journal of Pediatric Hematology/Oncology, 2019

Primary, or familial, hemophagocytic lymphohistiocytosis (P-HLH) is a rare inherited autosomal-re... more Primary, or familial, hemophagocytic lymphohistiocytosis (P-HLH) is a rare inherited autosomal-recessive immune deficiency which generally manifests during infancy or early childhood. Recent literature suggests an increased number of reports of late-onset P-HLH, especially in association with infection and underlying malignancy. The authors describe a case of subcutaneous T-cell lymphoma in a 8-year-old child that was complicated by primary, perforin-deficient HLH. In contrast, we examined retrospective data for 19 cases of late-onset P-HLH with available treatment data and compared the results of conservative medical therapy with hematopoietic stem cell transplant (HSCT) postremission therapy. Our patient displayed compound heterozygous mutations in PRF1 that have not been described in the literature previously: allele 1 [c.786_801del(p.Gln263fs)] and allele 2 [c.886T > C(p.Tyr296His)]. Of the 19 cases analyzed, 14 achieved remission. Postremission, 7 of 14 (50%) received HSCT and were reported alive at a median time of 24 months, 5 of 14 (36%) received medical therapy and were reported alive at a median time of 24 months, and 2 of 14 (14%) received medical therapy and died at a median of 73 months postremission. Our retrospective literature review suggests that some patients can survive late-onset, perforindeficient, P-HLH without the potential lifelong risks of HSCT when in the first remission.

Research paper thumbnail of Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature

Journal of Pediatric Hematology/Oncology, 2019

Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elemen... more Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elements, unpredictable course, and uncommon metastatic or fatal potential. Although systemic chemotherapy has been reported with variable success, generally accepted treatment is aggressive surgery with wide margins. Evidence-based treatment options are lacking, and lack of clear prognostic features poses a risk of undertreatment or overtreatment with associated morbidity and mortality. We report the use of initial systemic therapy with oral sirolimus (SIR) and IV zoledronic acid (ZA) to induce a sustained clinical response and avoidance of amputation in a 6-year-old boy. At 37 months after diagnosis, our patient remains in sustained clinical remission as documented by x-ray, MRI, and PET-CT with return of normal mobility/activity and resolution of swelling and pain. Literature review identified 20 cases of pediatric and young adult patients with PMH, of which 7 received some form of systemic therapy. To the best of our knowledge, our patient represents the youngest reported case of PMH and the first successful and limb-sparing utilization of systemic chemotherapy as primary treatment for PMH.

Research paper thumbnail of Young Adult With Osteosarcoma of the Mandible and the Challenge in Management: Review of the Pediatric and Adult Literatures

Journal of Pediatric Hematology/Oncology, 2018

Neoadjuvant chemotherapy for osteosarcoma of the jaw (OSJ) remains controversial despite being a ... more Neoadjuvant chemotherapy for osteosarcoma of the jaw (OSJ) remains controversial despite being a standardized treatment in osteosarcoma of the long bones. We present a case of a 22-yearold male with OSJ and performed a retrospective systemic review of previously published literatures of OSJ. We identified 27 articles: 7% recommended neoadjuvant chemotherapy, 22% recommended adjuvant chemotherapy, 19% recommended both neoadjuvant and adjuvant chemotherapy, 33% recommended against chemotherapy and 19% stated the role of chemotherapy is unknown. The lack of consensus regarding the use of chemotherapy in OSJ, despite its benefits, demonstrates the need to establish a standardized algorithm for OSJ.

Research paper thumbnail of Sickle Cell Trait Testing Should Not Be a Player in NCAA Athletics: Examining the Media's Role in Disseminating Awareness and Information

Journal of pediatric hematology/oncology, Jan 12, 2018

There are 4 million people in the United States and > 300 million people worldwide with sickle ce... more There are 4 million people in the United States and > 300 million people worldwide with sickle cell trait (SCT). 1 Since sickle hemoglobin was first described in 1949, misclassification of SCT-associated complications has occurred regularly. 2 In 1972, the US Department of Defense developed guidelines for SCT testing based on published case reports of sudden death occurring among soldiers with SCT. 2,3 By 1985, restrictions for SCT soldiers were withdrawn due to a lack of evidence for adverse events. 2,3 In 2010, the National Collegiate Athletic Association (NCAA)-approved mandatory SCT screening for Division I athletes in response to lawsuits regarding SCT-associated deaths. 2 In 2012, the NCAA extended this policy to its Division II and III athletes. 2 Despite implementation of this policy, the NCAA has not adopted a uniform policy regarding genetic counseling and utilization of positive test results. 1,2,4,5 Although several media reports discussed SCT testing and its negative psychosocial consequences for athletes, there has not been a report analyzing if media outlets disseminate information from evidence-based sources. The American Society of Hematology (ASH), Sickle Cell Disease Association of America, National Institutes of Health (NIH), American Academy of Pediatrics (AAP), and Centers for Disease Control and Prevention (CDC) are all evidence-based sources that unanimously support unrestricted athletic participation for athletes with SCT. 1,2 We performed a retrospective, observational review to determine if media outlets cited evidence-based guidelines in The authors declare no conflict of interest.

Research paper thumbnail of Osteosarcoma Metastases With Direct Cardiac Invasion

Journal of Pediatric Hematology/Oncology, 2017

Metastatic osteosarcoma with direct cardiac involvement is an exceptionally rare finding, with on... more Metastatic osteosarcoma with direct cardiac involvement is an exceptionally rare finding, with only 63 total reported cases in the English literature over the past 123 years. Although the precise incidence is unknown, we estimate that direct cardiac involvement currently occurs in <2% of metastatic osteosarcoma cases. We also find that before the adoption of adjuvant chemotherapy as a standard of care therapy for osteosarcoma, metastatic osteosarcoma to the heart was much more common than it is today, as cardiac involvement occurred in B20% of cases of metastatic osteosarcoma before the 1980s. This suggests that adjuvant chemotherapy has not only improved the overall prognosis of osteosarcoma, but also altered the metastatic pattern of disease. In this paper we present the case of an 11-year-old boy with metastatic osteosarcoma to the cardiac interventricular septum, as well as review 20 other previously reported pediatric cases of metastatic osteosarcoma to the heart. We also analyzed the cardiac surgical outcomes for 11 pediatric patients with metastatic osteosarcoma to the heart. The median disease-free survival time was 12 months, demonstrating that metastatic osteosarcoma to the heart is currently a rare occurrence with a poor prognosis.

Research paper thumbnail of Docetaxel, bevacizumab, and gemcitabine for very high risk sarcomas in adolescents and young adults: A single-center experience

Pediatric Blood & Cancer, 2016

Background: Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outc... more Background: Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outcomes and are in need of novel therapies.

Research paper thumbnail of Abstract B38: F317i mutation-associated nilotinib resistance in a child with CML: A first report

Clinical Cancer Research, 2015

Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) a... more Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) accounts for only 2-2.5% of childhood leukemia cases or about 60 cases per year in the US. Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis and treatment of CML in adults and children. Failure of TKIs is often due to mutations. In adult CML, the F317i mutation has been implicated in resistance to first and second line TKIs (imatinib/dasatinib) without affecting sensitivity to the third line TKI, nilotinib. The F317i mutation has been documented a handful of times in adult CML and in childhood Ph+ALL cases. We describe what we believe to be a first report of F317i mutation in a child with Ph+ CML who, after initial major molecular responses, rapidly developed resistance to first, second and third line TKIs. The current Childrens Oncology Group trial of oral nilotinib (COG AAML1321) does not recognize F317i as a mutation associated with nilotinib resistance. Case: A...

Research paper thumbnail of Pulmonary Micronodules Do Not Impact Survival in Young Sarcoma Patients

Research paper thumbnail of Insights into the genetic basis of familal hemophagocytic lymphohistiocytosis

Pediatric Blood & Cancer, 2014

I n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease... more I n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease affecting male and female siblings aged 2 months, causing fever, cytopenia, hepatosplenomegaly, and rapidly leading to death despite treatment with antibiotics and steroids [1]. In the 6 decades since we have evolved an understanding of familial hemophagocytic lymphohistiocytosis (FHL) that has also greatly enhanced our understanding of the immune system. In this issue of Pediatric Blood and Cancer, Qian et al. extend our knowledge of the genetic underpinnings of this rare and deadly disease [2].As recently asDecember 1999, the first FHL-related gene was described [3,4]. Over the subsequent decade we have learned that FHL is a very heterogeneous autosomal recessive disorder. To date, OMIM lists, five genetic lesions in four genes: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5). Current knowledge allows a genetic defect to be identified in variable proportions of patients, depending on ethnic origin. For example, bi-allelic mutations in FHL-3 are identified in approximately 50% of North American patients. Specifically the subject of Qian’s review, the FHL-3 mutations in UNC13D are found in 30% of Caucasion, 90% of Koreans, but is rare in patients of African descent [5–8]. The authors point out that although FHL-3 is an autosomal recessive disorder, several symptomatic patients have been described who have a mutation identified on only 1 allele [6,7]. Zhang et al. postulate that this can occur if a second allele is mutated in the promoter region, a non-coding region, on a different gene or there exists a complex rearrangement that is undetectable by current methods [6]. In this issue Qian et al. report their findings from a study in which they performed genetic testing of the UNC13D gene, including DNA sequencing of three recently reported non-coding mutations to investigate the prevalence of these mutations in a large North American cohort of 1709 patients with clinical diagnosis of HLH. This study uncovers familial cases not previously recognized allowing for counselling after screening. In addition, the authors identify mutations that cannot be detected by conventional testing in a North American cohort which may explain genetic basis in several patients who were thought to be heterozygous, or carriers. Furthermore, they report 8 new mutations in UNC13D for the first time and together with previously diagnosed FHL3 patients in their registry, these lesions account for nearly a 1/3 of the FHL3 patients. Indeed, recent work on the deep intronic (c.118-308C>T) and inversion mutations of UNC13D in Northern European and Korean patients revealed founder effects [4,8]. The expanded panel of identifiable lesions offered by Qian et al. can identify bi-allelic mutations, raising important questions pertaining to follow up, treatment, preemptive transplant, and genetic and antenatal counselling. Currently the indications of genetic testing for familial HLH are for confirmation of diagnosis in a symptomatic individual, pre-symptomatic testing of at-risk siblings, carrier identification in individuals with a family history of FHL and prenatal diagnosis of an at-risk fetus, after confirmation of bi-allelic mutations in the parents [6]. In addition, even though the typical age of presentation for familial HLH is within infancy, some affected individuals may present later in life [9]. An attempt at identification of a complete genotype achieved by this type of testing may aid consideration of pre-symptomatic bonemarrow transplantation and timely treatment in at risk genetically affected siblings and children with an atypical phenotype (for example acute liver failure, acute encephalopathy) [10]. The decision to prophylactically transplant asymptomatic affected individuals is complex, but, at the least such individuals may be monitored carefully and a suitable stem cell donor identified. Additionally such screeningmay have value in that, mutations in the FHL related genes have shown an increased frequency of lymphoma, leukemia, diabetes mellitus, multiple sclerosis, and juvenile arthritis [3]. More FHL data on correlations between genotype and phenotype in a large cohort of patients are needed to inform clinicians about screening asymptomatic individuals in a cost effective manner. Qian et al. have taken an important step towards this goal.

Research paper thumbnail of The pathophysiology of primary bone tumors in young adults and children

Current Problems in Cancer, 2013

The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone recognizes 12... more The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone recognizes 12 categories of primary skeletal tissue-derived malignancies. Diagnosis is a multidisciplinary task, and the role of the biopsy varies depending on the diagnosis. We anticipate an increased role for tissue biopsy as treatment decisions within the diagnostic categories listed later in the article become dependent on more precise immunophenotypic and genetic subtyping in the age of next generation sequencing. Our experience with the distribution of bone tumor types in this age group closely mirrors what has been reported in the literature. As previously noted, primary bone tumor diagnoses are far more common than that of metastasis for children and adolescents or young adults. As already stressed, the correct diagnosis usually requires coordinated care, such as a tumor board, among the radiologist, orthopedic oncologist, adult and pediatric oncologists, and pathologists. Adequate biopsy material is critical. Poor or inadequate samples and an uncertain diagnosis should lead to a repeat open biopsy. The most commonmalignant bone tumor in this age group is OS (Fig 1). Figure 2A shows the distribution of histologies for malignant bone tumors in children and adolescents or young adults at our institution. Up to age 50 Figure 2B shows the subtypes of OS, Figure 2C shows the subtypes of CS, and Figure 2D shows the subtypes of tumors of lymphoid lineage.

Research paper thumbnail of Future directions for pediatric and young adult bone sarcoma

Current Problems in Cancer, 2013

Current treatment options for advanced pediatric and young adult bone sarcomas are limited. Altho... more Current treatment options for advanced pediatric and young adult bone sarcomas are limited. Although aggressive multimodality therapy can relieve pain, prolong the progression-free interval, and provide long-term relapse-free survival (and possible cure) in some patients, the likelihood of these outcomes is usually very low. New approaches and strategies are desperately needed. In this section, we present an overview of some new strategies and research initiatives for young patients with bone tumor with high-risk disease (Fig 1A and B).

Research paper thumbnail of Clinical presentation of bone tumors in children and young adults

Current Problems in Cancer, 2013

Research paper thumbnail of Introduction: Malignant primary bone tumors in children and young adults

Current Problems in Cancer, 2013

Osteosarcoma, Ewing sarcoma, chondrosarcoma, and primary bone lymphoma account for greater than 9... more Osteosarcoma, Ewing sarcoma, chondrosarcoma, and primary bone lymphoma account for greater than 95% of all primary bone tumors occurring in the first 50 years of life. These diseases are the primary focus of this review. 1 Today, most patients younger than 50 years of age with primary bone tumors are cured (Fig 1), but most are affected by some late effects of their treatment. The outlook for recurrent and metastatic bone cancer is still very poor. The need for clinical research and new treatment options is self-evident. This paper is a collaborative work from our institution's multidisciplinary sarcoma tumor board. Our pediatric and adult oncology specialists care for more than 300 patients a year in a seamless approach focusing on the disease processes without the arbitrary separation of age. Under the leadership of Dr Steven Gitelis, we have been treating adolescents and young adults (AYA, defined as individuals who are 15-39 years of age) with bone tumors using the same approach and protocols as children for the last 30 years. This successful paradigm was ahead of its time. In this review, we discuss the presentation, workup, treatment strategies, new directions, late effects, and clinical and laboratory advances in the treatment of primary malignant bone cancers in young people and the need for all patients to be given the opportunity to be treated by a multidisciplinary team and participate in clinical research.

Research paper thumbnail of Metastatic and recurrent bone primary bone cancers

Current Problems in Cancer, 2013

With current multimodal treatment regimens, approximately two-thirds or more of patients with loc... more With current multimodal treatment regimens, approximately two-thirds or more of patients with localized ES or OS can be cured; however, survival rates of patients with metastatic disease and those with early relapse remain very poor. Ironically, as adjuvant regimens used in front-line therapy of children and Adolescents and Young Adults with ES and OS are intensified, the number of patients surviving without ever developing recurrence increases, but the proportion who are likely to be salvageable after relapse may decrease, because they are more likely to have drug-resistant disease. To date, there is no effective way to overcome this problem. The one exception is the isolated, late, resectable pulmonary nodule in OS and to a lesser degree ES, when there can be a reasonable chance of long-term survival and even cure. We therefore recommend that any patient with relapsed or metastatic OS or ES strongly consider enrollment on a clinical trial. This section of the review strives to describe the strategies that are considered reasonable as secondor third-line approaches and those that are more experimental for those unfortunate young people with high-risk OS and ES.

Research paper thumbnail of External beam and stereotactic radiation in the treatment of fibrolamellar carcinoma

Journal of Clinical Oncology

e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (< 50 cases/year US), di... more e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (< 50 cases/year US), distinct type of primary liver cancer, unrelated to hepatocellular carcinoma (HCC), affecting healthy children and young adults that often presents at an advanced stage. Surgery is the only known cure, but is only possible in half of patients, and, even with surgery, there is an 80% relapse rate. Loco-regional therapies can make surgery possible or replace surgery, allow systemic therapy time to work, and prolong life. However because of the paucity of data and the common misunderstanding of treating FLC as a “variant of hepatocellular carcinoma (HCC)” it is often assumed to be radio-resistant. For example, the 2021 NCCN Guidelines give no specific recommendations for radiation in FLC but classifying FLC as a “variant of HCC'' recommend 25 1.8Gy fractions (45Gy) with a boost to 50-60 Gy for external beam radiation(EBRT) and 3-5 10Gy fractions for stereotactic body radiation (SBRT)....

Research paper thumbnail of Treatment a nd O utcome o f 8 3 C hildren W ith I ntraspinal Neuroblastoma: T he P ediatric O ncology G roup E xperience

Purpose: To investigate whether the rate of neurologic recovery or the incidence of long-term seq... more Purpose: To investigate whether the rate of neurologic recovery or the incidence of long-term sequelae differed for children with neuroblastoma (NB) initially treated with chemotherapy versus surgical decompression with laminectomy, we reviewed the Pediatric Oncology Group (POG) experience. Patients and Methods: A retrospective review of children diagnosed with intraspinal NB registered on POG NB Biology Protocol 9047 was performed. Survival, neurologic outcome, and orthopedic sequelae were evaluated according to age of the patient at diagnosis, stage of disease, duration and severity of neurologic symptoms, and therapeutic intervention. Results: Between May 1990 and January 1998, 83 children with intraspinal NB were entered onto the study. Five-year survival for this cohort of patients was 71% 6 9%. Forty-three (52%) of the patients had neurologic symptoms at diagnosis. After treatment, six of 15 severely affected patients, who presented with paralysis, completely recovered neurolo...

Research paper thumbnail of Harlequin syndrome following microwave ablation in a child with a symptomatic paraspinal mass

BMJ Case Reports, 2020

Our goal is to describe a case of Harlequin syndrome associated with microwave ablation in the tr... more Our goal is to describe a case of Harlequin syndrome associated with microwave ablation in the treatment of a symptomatic paraspinal mass in a child, along with a summary of the literature. Our patient is the only known case of persistent Harlequin syndrome associated with microwave ablation treatment of a symptomatic paraspinal mass. Harlequin syndrome is a rare neurological condition characterised by unilateral sweating and flushing of the face, neck and/or upper chest. The specific mechanism is unclear, but the majority of cases are believed to be a result of contralateral lesions along the sympathetic chain. CT-guided microwave ablation therapy is a minimally invasive technique used as an alternative to surgery in this case due to the risk and morbidity associated with excision of the mass. There is limited literature assessing the use and inherent risk of developing complications following microwave ablation to the paraspinal region in the paediatric population.

Research paper thumbnail of The Risk of Tumor Contamination Associated With Thoracic Instrumentation in Patients With Osteosarcoma

Journal of Pediatric Hematology/Oncology, 2020

Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteos... more Orthopedic surgeons are well aware of tumor contamination at the site of initial biopsy in osteosarcoma. However, tumor contamination in patients with osteosarcoma associated with thoracic instrumentation is not well described. The authors summarize 2 reported cases in addition to the 2 cases at their institution of this phenomenon. Knowledge of tumor contamination and preventative measures against tumor contamination is sparse in the literature, especially pertaining to patients with osteosarcoma undergoing thoracic instrumentation. In this report, the authors hope to increase awareness of these cases and suggest preventative measures to mitigate against tumor contamination in patients with osteosarcoma. The authors report that the median time between thoracic instrumentation and the visible detection of tumor migration to local sites was 5 months. They conclude that tumor contamination associated with thoracic instrumentation is characterized by patients with multiple sites of relapse and aggressive, fatal disease.

Research paper thumbnail of Docetaxol, bevacizumab, gemcitabine “TAG” chemotherapy for high risk and relapsed adolescent and young adult (AYA) sarcoma patients

Journal of Clinical Oncology, 2016

10518Background: Adolescent and young adult (AYA) patients with high-risk recurrent / metastatic ... more 10518Background: Adolescent and young adult (AYA) patients with high-risk recurrent / metastatic sarcomas have very poor prognosis, with few living 2 years. There are currently no standard treatmen...

Research paper thumbnail of Improving Accrual of Adolescents and Young Adults and Underrepresented Minorities with Leukemia to Children's Oncology Group Clinical Trials: A Novel Collaborative Approach to Address Disparities in Leukemia

Blood, 2016

Background: It is accepted that the dramatic historical decrease in mortality from ALL and AML in... more Background: It is accepted that the dramatic historical decrease in mortality from ALL and AML in children and more recently AYAs is directly related to improved participation in NCI sponsored COG clinical trials. It is also known that African-American (AA) and Hispanic children, Hispanic females, and particularly AYAs 15 to 39 years are under-represented in COG clinical trials and may benefit from targeted attention. AA and Hispanic children with ALL and AML have worse survival than white and Asian children even with modern therapy where cure rates have improved drastically. Access to standard accepted chemotherapy for leukemia, socio-economic status and insurance status, differences in disease phenotype and pharmacogenetic variations play a role in these racial and ethnic disparities. AYAs with leukemia have experienced variable improvement in survival over the past two decades due partly to insufficient cancer clinical trial enrollment. Uninsured, older patients and those treated...

Research paper thumbnail of To Transplant or Not to Transplant? Late-Onset Primary HLH in a Patient

Journal of Pediatric Hematology/Oncology, 2019

Primary, or familial, hemophagocytic lymphohistiocytosis (P-HLH) is a rare inherited autosomal-re... more Primary, or familial, hemophagocytic lymphohistiocytosis (P-HLH) is a rare inherited autosomal-recessive immune deficiency which generally manifests during infancy or early childhood. Recent literature suggests an increased number of reports of late-onset P-HLH, especially in association with infection and underlying malignancy. The authors describe a case of subcutaneous T-cell lymphoma in a 8-year-old child that was complicated by primary, perforin-deficient HLH. In contrast, we examined retrospective data for 19 cases of late-onset P-HLH with available treatment data and compared the results of conservative medical therapy with hematopoietic stem cell transplant (HSCT) postremission therapy. Our patient displayed compound heterozygous mutations in PRF1 that have not been described in the literature previously: allele 1 [c.786_801del(p.Gln263fs)] and allele 2 [c.886T > C(p.Tyr296His)]. Of the 19 cases analyzed, 14 achieved remission. Postremission, 7 of 14 (50%) received HSCT and were reported alive at a median time of 24 months, 5 of 14 (36%) received medical therapy and were reported alive at a median time of 24 months, and 2 of 14 (14%) received medical therapy and died at a median of 73 months postremission. Our retrospective literature review suggests that some patients can survive late-onset, perforindeficient, P-HLH without the potential lifelong risks of HSCT when in the first remission.

Research paper thumbnail of Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature

Journal of Pediatric Hematology/Oncology, 2019

Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elemen... more Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elements, unpredictable course, and uncommon metastatic or fatal potential. Although systemic chemotherapy has been reported with variable success, generally accepted treatment is aggressive surgery with wide margins. Evidence-based treatment options are lacking, and lack of clear prognostic features poses a risk of undertreatment or overtreatment with associated morbidity and mortality. We report the use of initial systemic therapy with oral sirolimus (SIR) and IV zoledronic acid (ZA) to induce a sustained clinical response and avoidance of amputation in a 6-year-old boy. At 37 months after diagnosis, our patient remains in sustained clinical remission as documented by x-ray, MRI, and PET-CT with return of normal mobility/activity and resolution of swelling and pain. Literature review identified 20 cases of pediatric and young adult patients with PMH, of which 7 received some form of systemic therapy. To the best of our knowledge, our patient represents the youngest reported case of PMH and the first successful and limb-sparing utilization of systemic chemotherapy as primary treatment for PMH.

Research paper thumbnail of Young Adult With Osteosarcoma of the Mandible and the Challenge in Management: Review of the Pediatric and Adult Literatures

Journal of Pediatric Hematology/Oncology, 2018

Neoadjuvant chemotherapy for osteosarcoma of the jaw (OSJ) remains controversial despite being a ... more Neoadjuvant chemotherapy for osteosarcoma of the jaw (OSJ) remains controversial despite being a standardized treatment in osteosarcoma of the long bones. We present a case of a 22-yearold male with OSJ and performed a retrospective systemic review of previously published literatures of OSJ. We identified 27 articles: 7% recommended neoadjuvant chemotherapy, 22% recommended adjuvant chemotherapy, 19% recommended both neoadjuvant and adjuvant chemotherapy, 33% recommended against chemotherapy and 19% stated the role of chemotherapy is unknown. The lack of consensus regarding the use of chemotherapy in OSJ, despite its benefits, demonstrates the need to establish a standardized algorithm for OSJ.

Research paper thumbnail of Sickle Cell Trait Testing Should Not Be a Player in NCAA Athletics: Examining the Media's Role in Disseminating Awareness and Information

Journal of pediatric hematology/oncology, Jan 12, 2018

There are 4 million people in the United States and > 300 million people worldwide with sickle ce... more There are 4 million people in the United States and > 300 million people worldwide with sickle cell trait (SCT). 1 Since sickle hemoglobin was first described in 1949, misclassification of SCT-associated complications has occurred regularly. 2 In 1972, the US Department of Defense developed guidelines for SCT testing based on published case reports of sudden death occurring among soldiers with SCT. 2,3 By 1985, restrictions for SCT soldiers were withdrawn due to a lack of evidence for adverse events. 2,3 In 2010, the National Collegiate Athletic Association (NCAA)-approved mandatory SCT screening for Division I athletes in response to lawsuits regarding SCT-associated deaths. 2 In 2012, the NCAA extended this policy to its Division II and III athletes. 2 Despite implementation of this policy, the NCAA has not adopted a uniform policy regarding genetic counseling and utilization of positive test results. 1,2,4,5 Although several media reports discussed SCT testing and its negative psychosocial consequences for athletes, there has not been a report analyzing if media outlets disseminate information from evidence-based sources. The American Society of Hematology (ASH), Sickle Cell Disease Association of America, National Institutes of Health (NIH), American Academy of Pediatrics (AAP), and Centers for Disease Control and Prevention (CDC) are all evidence-based sources that unanimously support unrestricted athletic participation for athletes with SCT. 1,2 We performed a retrospective, observational review to determine if media outlets cited evidence-based guidelines in The authors declare no conflict of interest.

Research paper thumbnail of Osteosarcoma Metastases With Direct Cardiac Invasion

Journal of Pediatric Hematology/Oncology, 2017

Metastatic osteosarcoma with direct cardiac involvement is an exceptionally rare finding, with on... more Metastatic osteosarcoma with direct cardiac involvement is an exceptionally rare finding, with only 63 total reported cases in the English literature over the past 123 years. Although the precise incidence is unknown, we estimate that direct cardiac involvement currently occurs in <2% of metastatic osteosarcoma cases. We also find that before the adoption of adjuvant chemotherapy as a standard of care therapy for osteosarcoma, metastatic osteosarcoma to the heart was much more common than it is today, as cardiac involvement occurred in B20% of cases of metastatic osteosarcoma before the 1980s. This suggests that adjuvant chemotherapy has not only improved the overall prognosis of osteosarcoma, but also altered the metastatic pattern of disease. In this paper we present the case of an 11-year-old boy with metastatic osteosarcoma to the cardiac interventricular septum, as well as review 20 other previously reported pediatric cases of metastatic osteosarcoma to the heart. We also analyzed the cardiac surgical outcomes for 11 pediatric patients with metastatic osteosarcoma to the heart. The median disease-free survival time was 12 months, demonstrating that metastatic osteosarcoma to the heart is currently a rare occurrence with a poor prognosis.

Research paper thumbnail of Docetaxel, bevacizumab, and gemcitabine for very high risk sarcomas in adolescents and young adults: A single-center experience

Pediatric Blood & Cancer, 2016

Background: Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outc... more Background: Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outcomes and are in need of novel therapies.

Research paper thumbnail of Abstract B38: F317i mutation-associated nilotinib resistance in a child with CML: A first report

Clinical Cancer Research, 2015

Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) a... more Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) accounts for only 2-2.5% of childhood leukemia cases or about 60 cases per year in the US. Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis and treatment of CML in adults and children. Failure of TKIs is often due to mutations. In adult CML, the F317i mutation has been implicated in resistance to first and second line TKIs (imatinib/dasatinib) without affecting sensitivity to the third line TKI, nilotinib. The F317i mutation has been documented a handful of times in adult CML and in childhood Ph+ALL cases. We describe what we believe to be a first report of F317i mutation in a child with Ph+ CML who, after initial major molecular responses, rapidly developed resistance to first, second and third line TKIs. The current Childrens Oncology Group trial of oral nilotinib (COG AAML1321) does not recognize F317i as a mutation associated with nilotinib resistance. Case: A...

Research paper thumbnail of Pulmonary Micronodules Do Not Impact Survival in Young Sarcoma Patients

Research paper thumbnail of Insights into the genetic basis of familal hemophagocytic lymphohistiocytosis

Pediatric Blood & Cancer, 2014

I n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease... more I n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease affecting male and female siblings aged 2 months, causing fever, cytopenia, hepatosplenomegaly, and rapidly leading to death despite treatment with antibiotics and steroids [1]. In the 6 decades since we have evolved an understanding of familial hemophagocytic lymphohistiocytosis (FHL) that has also greatly enhanced our understanding of the immune system. In this issue of Pediatric Blood and Cancer, Qian et al. extend our knowledge of the genetic underpinnings of this rare and deadly disease [2].As recently asDecember 1999, the first FHL-related gene was described [3,4]. Over the subsequent decade we have learned that FHL is a very heterogeneous autosomal recessive disorder. To date, OMIM lists, five genetic lesions in four genes: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5). Current knowledge allows a genetic defect to be identified in variable proportions of patients, depending on ethnic origin. For example, bi-allelic mutations in FHL-3 are identified in approximately 50% of North American patients. Specifically the subject of Qian’s review, the FHL-3 mutations in UNC13D are found in 30% of Caucasion, 90% of Koreans, but is rare in patients of African descent [5–8]. The authors point out that although FHL-3 is an autosomal recessive disorder, several symptomatic patients have been described who have a mutation identified on only 1 allele [6,7]. Zhang et al. postulate that this can occur if a second allele is mutated in the promoter region, a non-coding region, on a different gene or there exists a complex rearrangement that is undetectable by current methods [6]. In this issue Qian et al. report their findings from a study in which they performed genetic testing of the UNC13D gene, including DNA sequencing of three recently reported non-coding mutations to investigate the prevalence of these mutations in a large North American cohort of 1709 patients with clinical diagnosis of HLH. This study uncovers familial cases not previously recognized allowing for counselling after screening. In addition, the authors identify mutations that cannot be detected by conventional testing in a North American cohort which may explain genetic basis in several patients who were thought to be heterozygous, or carriers. Furthermore, they report 8 new mutations in UNC13D for the first time and together with previously diagnosed FHL3 patients in their registry, these lesions account for nearly a 1/3 of the FHL3 patients. Indeed, recent work on the deep intronic (c.118-308C>T) and inversion mutations of UNC13D in Northern European and Korean patients revealed founder effects [4,8]. The expanded panel of identifiable lesions offered by Qian et al. can identify bi-allelic mutations, raising important questions pertaining to follow up, treatment, preemptive transplant, and genetic and antenatal counselling. Currently the indications of genetic testing for familial HLH are for confirmation of diagnosis in a symptomatic individual, pre-symptomatic testing of at-risk siblings, carrier identification in individuals with a family history of FHL and prenatal diagnosis of an at-risk fetus, after confirmation of bi-allelic mutations in the parents [6]. In addition, even though the typical age of presentation for familial HLH is within infancy, some affected individuals may present later in life [9]. An attempt at identification of a complete genotype achieved by this type of testing may aid consideration of pre-symptomatic bonemarrow transplantation and timely treatment in at risk genetically affected siblings and children with an atypical phenotype (for example acute liver failure, acute encephalopathy) [10]. The decision to prophylactically transplant asymptomatic affected individuals is complex, but, at the least such individuals may be monitored carefully and a suitable stem cell donor identified. Additionally such screeningmay have value in that, mutations in the FHL related genes have shown an increased frequency of lymphoma, leukemia, diabetes mellitus, multiple sclerosis, and juvenile arthritis [3]. More FHL data on correlations between genotype and phenotype in a large cohort of patients are needed to inform clinicians about screening asymptomatic individuals in a cost effective manner. Qian et al. have taken an important step towards this goal.

Research paper thumbnail of The pathophysiology of primary bone tumors in young adults and children

Current Problems in Cancer, 2013

The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone recognizes 12... more The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone recognizes 12 categories of primary skeletal tissue-derived malignancies. Diagnosis is a multidisciplinary task, and the role of the biopsy varies depending on the diagnosis. We anticipate an increased role for tissue biopsy as treatment decisions within the diagnostic categories listed later in the article become dependent on more precise immunophenotypic and genetic subtyping in the age of next generation sequencing. Our experience with the distribution of bone tumor types in this age group closely mirrors what has been reported in the literature. As previously noted, primary bone tumor diagnoses are far more common than that of metastasis for children and adolescents or young adults. As already stressed, the correct diagnosis usually requires coordinated care, such as a tumor board, among the radiologist, orthopedic oncologist, adult and pediatric oncologists, and pathologists. Adequate biopsy material is critical. Poor or inadequate samples and an uncertain diagnosis should lead to a repeat open biopsy. The most commonmalignant bone tumor in this age group is OS (Fig 1). Figure 2A shows the distribution of histologies for malignant bone tumors in children and adolescents or young adults at our institution. Up to age 50 Figure 2B shows the subtypes of OS, Figure 2C shows the subtypes of CS, and Figure 2D shows the subtypes of tumors of lymphoid lineage.

Research paper thumbnail of Future directions for pediatric and young adult bone sarcoma

Current Problems in Cancer, 2013

Current treatment options for advanced pediatric and young adult bone sarcomas are limited. Altho... more Current treatment options for advanced pediatric and young adult bone sarcomas are limited. Although aggressive multimodality therapy can relieve pain, prolong the progression-free interval, and provide long-term relapse-free survival (and possible cure) in some patients, the likelihood of these outcomes is usually very low. New approaches and strategies are desperately needed. In this section, we present an overview of some new strategies and research initiatives for young patients with bone tumor with high-risk disease (Fig 1A and B).

Research paper thumbnail of Clinical presentation of bone tumors in children and young adults

Current Problems in Cancer, 2013

Research paper thumbnail of Introduction: Malignant primary bone tumors in children and young adults

Current Problems in Cancer, 2013

Osteosarcoma, Ewing sarcoma, chondrosarcoma, and primary bone lymphoma account for greater than 9... more Osteosarcoma, Ewing sarcoma, chondrosarcoma, and primary bone lymphoma account for greater than 95% of all primary bone tumors occurring in the first 50 years of life. These diseases are the primary focus of this review. 1 Today, most patients younger than 50 years of age with primary bone tumors are cured (Fig 1), but most are affected by some late effects of their treatment. The outlook for recurrent and metastatic bone cancer is still very poor. The need for clinical research and new treatment options is self-evident. This paper is a collaborative work from our institution's multidisciplinary sarcoma tumor board. Our pediatric and adult oncology specialists care for more than 300 patients a year in a seamless approach focusing on the disease processes without the arbitrary separation of age. Under the leadership of Dr Steven Gitelis, we have been treating adolescents and young adults (AYA, defined as individuals who are 15-39 years of age) with bone tumors using the same approach and protocols as children for the last 30 years. This successful paradigm was ahead of its time. In this review, we discuss the presentation, workup, treatment strategies, new directions, late effects, and clinical and laboratory advances in the treatment of primary malignant bone cancers in young people and the need for all patients to be given the opportunity to be treated by a multidisciplinary team and participate in clinical research.

Research paper thumbnail of Metastatic and recurrent bone primary bone cancers

Current Problems in Cancer, 2013

With current multimodal treatment regimens, approximately two-thirds or more of patients with loc... more With current multimodal treatment regimens, approximately two-thirds or more of patients with localized ES or OS can be cured; however, survival rates of patients with metastatic disease and those with early relapse remain very poor. Ironically, as adjuvant regimens used in front-line therapy of children and Adolescents and Young Adults with ES and OS are intensified, the number of patients surviving without ever developing recurrence increases, but the proportion who are likely to be salvageable after relapse may decrease, because they are more likely to have drug-resistant disease. To date, there is no effective way to overcome this problem. The one exception is the isolated, late, resectable pulmonary nodule in OS and to a lesser degree ES, when there can be a reasonable chance of long-term survival and even cure. We therefore recommend that any patient with relapsed or metastatic OS or ES strongly consider enrollment on a clinical trial. This section of the review strives to describe the strategies that are considered reasonable as secondor third-line approaches and those that are more experimental for those unfortunate young people with high-risk OS and ES.