Our laboratory focuses on investigating molecular mechanisms of oncogene-induced tumorigenesis and tumor suppressor pathways, and oncogenic signaling in the pediatric solid tumor rhabdomyosarcoma. Our earlier work identified the tumor suppressors p53 and p18Ink4c as inhibitors of Cyclin D1-driven tumorigenesis in a pineoblastoma model, through senescence induction, and highlighted distinct roles for the the RB and p53 pathways in induction and maintenance of oncogene-induced senescence. We also identified CDK2 as a potential target for inducing senescence in premalignant lesions to inhibit tumor progression.
Our current focus is on studying oncogenic signaling and tumor suppression in the childhood tumor rhabdomyosarcoma, to identify key mediators of invasion and metastasis, which is the most common cause of treatment failure clinically. We use preclinical in vitro and in vivo models, including murine and human cell lines, and mouse models of disease.
We have recently uncovered a paracrine role for rhabdomyosarcoma-secreted exosomes in impacting biology of stromal cells. Rhabdomyosarcoma-derived exosomes carry specific miRNA cargo that imparts an invasive and migratory phenotype on normal recipient fibroblasts, and proteomic analysis revealed specific and unique pathways relevant to the two different molecular rhabdomyosarcoma subtypes that are driven by distinct oncogenic pathways. We identified that the driver oncogene in fusion-positive rhabdomyosarcoma, PAX3-FOXO1, modulates exosome cargo to promote invasion, migration, and angiogenic properties, and identified specific microRNA and protein cargo acting as effectors of PAX3-FOXO1 exosome-mediated signaling, including modulation of oxidative stress response and cell survival signaling.
Our ongoing work is focused on interrogating specific paracrine signaling pathways and molecular mechanisms of metastatic disease progression in rhabdomyosarcoma, for potential therapeutic targeting.
- Pediatric Hematology-Oncology
- Pediatric solid tumors
- Global Health
Director,, Bass Center Tissue Biorepository (2023 - Present)
Section Chief, Oncology, Lucile Packard Children's Hospital, Stanford University, CA, USA (2022 - Present)
Acting Director, Children's Cancer Institute, American University of Beirut Medical Center (2017 - 2021)
Associate Director for Administrative and Academic Affairs, Children’s Cancer Institute, American University of Beirut Medical Center (2014 - 2016)
Director, Pediatric Cancer Research Program and Data Management Unit, Children’s Cancer Institute, American University of Beirut Medical Center (2012 - 2021)
Residency: Duke University School of Medicine (2003) NC
Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (2017)
Fellowship: St Jude Children's Research Hospital (2007) TN
Fellowship: University of Tennessee Pediatric Hematology and Oncology Fellowship (2006) TN
Board Certification: American Board of Pediatrics, Pediatrics (2003)
Internship: American University of Beirut Office of the Registrar (2000) Lebanon
Medical Education: American University of Beirut Office of the Registrar (1999) Lebanon
Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.
Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.
View details for DOI 10.1007/s00439-023-02530-8
View details for PubMedID 36790526
Addressing the Gap in Research Methodologies Education in Pediatric Oncology in the Eastern Mediterranean Region.
JCO global oncology
2023; 9: e2200295
Formal training in clinical research methodologies is limited in limited-resource countries. Through collaboration among high- and middle-resource settings and in response to an identified need verbalized by regional pediatric oncology practitioners, Pediatric Oncology East & Mediterranean Group and St Jude Global developed a workshop focused on capacity building in research skills. Here, we describe its structure, implementation, and early results.Leveraging virtual capabilities, the format included lectures and small group breakout exercise sessions, for 3 hours per day on 2 consecutive days per week for 2 consecutive weeks. Topics included basics of study design, introduction to health care statistics, research ethics, data registries, and scientific writing. Applicants were required to submit an abstract for a potential research project. Each breakout group selected one abstract for further development and presented the final version in a groupwide session. The participants' experience was evaluated through an online survey.Attendance included 29 registrants from 12 countries and six disciplines. Each breakout group was assigned a themed category: cohort studies, clinical trials, or registries. Critical feedback from the breakout sessions helped strengthen the selected projects, which included a retrospective study, a prospective observational study, a prospective interventional study, and a registry proposal. After the workshop, participants were invited to further develop their original abstracts, and three proposals received additional mentoring, one of which was a multi-institutional prospective study that was subsequently submitted through the Pediatric Oncology East & Mediterranean Group network for implementation. The postworkshop survey revealed an overall highly positive experience, and feedback provided potential themes for future workshops.This workshop demonstrated the potential for collaborative network partnerships in targeting research training gaps in pediatric oncology. Lessons learned will be applied to future workshops to strengthen research in limited-resource settings.
View details for DOI 10.1200/GO.22.00295
View details for PubMedID 36780591
A temporal in vivo catalogue of chromatin accessibility and expression profiles in pineoblastoma reveals a prevalent role for repressor elements.
Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations in RB1 and DICER1, the role of epigenetic deregulation and cis-regulatory regions in PB pathogenesis and progression is largely unknown. Here, we generated genome-wide gene expression, chromatin accessibility, and H3K27ac profiles covering key time-points of PB initiation and progression from pineal tissues of a mouse model of Ccnd1-driven pineoblastoma. We identified PB-specific enhancers and super-enhancers and found that, in some cases, the accessible genome dynamic precedes the transcriptome, a characteristic that is underexplored in tumor progression. During progression of PB, newly acquired open chromatin regions lacking H3K27ac signal become enriched for repressive state elements and harbor motifs of repressor transcription factors like HINFP, GLI2, and YY1. Copy number variant analysis identified deletion events specific to the tumorigenic stage, affecting among others the histone genes cluster and Gas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples demonstrating the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivo cis-regulatory, expression, and accessibility maps in PB.
View details for DOI 10.1101/gr.277037.122
View details for PubMedID 36650051
Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country
PEDIATRIC BLOOD & CANCER
Resource-limited settings often have financial barriers to genetic testing for heritable cancer. This retrospective study investigated the pattern of heritable cancer predisposition testing in a middle-income country over the period 2014-2021, excluding retinoblastoma. After establishing a specific fund in 2019, rate of tests increased from 1.1% to 10.9% of new diagnoses. Most common testing was for constitutional mismatch repair deficiency (CMMRD), rhabdoid predisposition syndrome, TP53 (tumor protein 53) mutation, and hereditary cancer panel. Of 33 patients, 13 (39%) tested positive, 12 (36%) negative, and eight (24%) had variants of unknown significance. Positivity rate was 43% for a clinical phenotype and 44% for a tumor type indication.
View details for DOI 10.1002/pbc.29982
View details for Web of Science ID 000853116100001
View details for PubMedID 36094320
Non-coding RNA in rhabdomyosarcoma progression and metastasis.
Frontiers in oncology
2022; 12: 971174
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma of skeletal muscle differentiation, with a predominant occurrence in children and adolescents. One of the major challenges facing treatment success is the presence of metastatic disease at the time of diagnosis, commonly associated with the more aggressive fusion-positive subtype. Non-coding RNA (ncRNA) can regulate gene transcription and translation, and their dysregulation has been associated with cancer development and progression. MicroRNA (miRNA) are short non-coding nucleic acid sequences involved in the regulation of gene expression that act by targeting messenger RNA (mRNA), and their aberrant expression has been associated with both RMS initiation and progression. Other ncRNA including long non-coding RNA (lncRNA), circular RNA (circRNA) and ribosomal RNA (rRNA) have also been associated with RMS revealing important mechanistic roles in RMS biology, but these studies are still limited and require further investigation. In this review, we discuss the established roles of ncRNA in RMS differentiation, growth and progression, highlighting their potential use in RMS prognosis, as therapeutic agents or as targets of treatment.
View details for DOI 10.3389/fonc.2022.971174
View details for PubMedID 36033507
View details for PubMedCentralID PMC9403786
The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries
LANCET GLOBAL HEALTH
2022; 10 (8): E1128-E1140
Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival.We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models.The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0-36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8-100·0) for children from high-income countries, 91·2% (89·5-93·0) for children from upper-middle-income countries, 80·3% (78·3-82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76-50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44-18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23-1·56). For children aged 3-7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope).This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.Queen Elizabeth Diamond Jubilee Trust.
View details for Web of Science ID 000863614200019
View details for PubMedID 35839812
View details for PubMedCentralID PMC9397647
CD147 Promotes Tumorigenesis via Exosome-Mediated Signaling in Rhabdomyosarcoma.
2022; 11 (15)
Rhabdomyosarcoma (RMS) is an aggressive childhood soft-tissue tumor, with propensity for local invasion and distant metastasis. Exosomes are secreted vesicles that mediate paracrine signaling by delivering functional proteins and miRNA to recipient cells. The transmembrane protein CD147, also known as Basigin or EMMPRIN, is enriched in various tumor cells, as well as in tumor-derived exosomes, and has been correlated with poor prognosis in several types of cancer, but has not been previously investigated in RMS. We investigated the effects of CD147 on RMS cell biology and paracrine signaling, specifically its contribution to invasion and metastatic phenotype. CD147 downregulation diminishes RMS cell invasion and inhibits anchorage-independent growth in vitro. While treatment of normal fibroblasts with RMS-derived exosomes results in a significant increase in proliferation, migration, and invasion, these effects are reversed when using exosomes from CD147-downregulated RMS cells. In human RMS tissue, CD147 was expressed exclusively in metastatic tumors. Altogether, our results demonstrate that CD147 contributes to RMS tumor cell aggressiveness, and is involved in modulating the microenvironment through RMS-secreted exosomes. Targeted inhibition of CD147 reduces its expression levels within the isolated exosomes and reduces the capacity of these exosomes to enhance cellular invasive properties.
View details for DOI 10.3390/cells11152267
View details for PubMedID 35892564
Pediatric oncology infrastructure and workforce training needs: a report from the Pediatric Oncology East and Mediterranean (POEM) Group.
Pediatric blood & cancer
BACKGROUND: Inadequate numbers of trained healthcare providers (HCPs), contribute to poor pediatric oncology (PO) outcomes, particularly in low- and lower middle-income countries (L/LMICs). An understanding of the characteristics of the workforce challenges are vital for addressing these problems.METHODS: The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of the North Africa, Middle East, Central Asia and Indian subcontinent on infrastructure and workforce capacity, service availability, and training opportunities for HCPs. Participating centers were categorized by the World Bank income levels for their countries and correlated with services, workload and staffing characteristics, and training needs.RESULTS: Fifty of 82 member-centers (61%) from 21 countries responded to the survey. 299 pediatric oncologists and 1,176 nurses treated 12,496 new PO patients/year, with a 1,451 beds utilization. The majority (71%) of new cases occurred in L/LMICs. The availability of HCPs correlated with country income level, as did pediatric subspecialty access, while availability of support services was unrelated. Twenty-five centers in 11 countries offered PO fellowship training for physicians, whereas 13 PO nurse training centers in 9 countries had the capacity to train 273 nurses annually. The survey respondents indicated that, among their existing workforce, an average of 3·5 physicians and 14 nurses per institution would benefit from additional PO training opportunities.CONCLUSIONS: The participating centers exhibited intra-regional heterogeneity in financial resources, infrastructure, workload, workforce, and medical services. Our findings provide insight into the disparities and regional resources available to POEM, which can be mobilized to rectify specific deficiencies. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/pbc.29858
View details for PubMedID 35713199
PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA REGISTRY
OXFORD UNIV PRESS INC. 2022: 23-24
View details for Web of Science ID 000840122400084
Estimated incidence, prevalence, mortality, and registration of childhood cancer (ages 0-14 years) in the WHO Eastern Mediterranean region: an analysis of GLOBOCAN 2020 data.
The Lancet. Child & adolescent health
2022; 6 (7): 466-473
There is little evidence about childhood cancer burden in the WHO Eastern Mediterranean region (EMR). We aimed to provide an estimate of childhood cancer burden in the EMR, examine the connection between age-standardised mortality rate and level of income (gross domestic product [GDP] per capita), and reflect on the current status of childhood cancer registration in the EMR.Using the GLOBOCAN 2020 data from the Cancer Surveillance Unit of the International Agency for Research on Cancer, we extracted data for childhood cancer (at ages 0-14 years) incidence, prevalence, and mortality for 22 countries in the EMR, the EMR as a whole, and other WHO regions, and categorised by main cancer types. Childhood cancers were classified according to the 10th revision of the International Classification of Diseases. We also searched MEDLINE, Google Scholar, and the grey literature between May 17 and Aug 2, 2021, for English-language articles and reports about the status of childhood cancer registration in the EMR. We further examined the connection between age-standardised mortality rate and GDP per capita for the 22 countries in the EMR.The total estimated number of incident childhood cancer cases in the EMR was 23 847 in 2020, with an age-standardised incidence rate of 10·1 per 100 000 children at risk, ranging from 7·3 per 100 000 children at risk in Pakistan to 13·8 per 100 000 children at risk in Iran. The estimated number of incident cases was 7451 (age-standardised incidence rate 3·10 per 100 000 children at risk) for leukaemia, 3006 (1·30 per 100 000 children at risk) for brain and CNS tumours, 2222 (0·92 per 100 000 children at risk) for non-Hodgkin lymphoma, 1569 (0·67 per 100 000 children at risk) for kidney cancers, and 1420 (0·58 per 100 000 children at risk) for Hodgkin lymphoma. In 2020, the number of total estimated childhood cancer deaths in the EMR was 10 535, with an age-standardised mortality rate of 4·4 (per 100 000 children at risk, ranging from 0·8 per 100 000 children at risk in Qatar to 7·2 per 100 000 children at risk in Somalia. A negative correlation was found between countries' GDP per capita (income level) and mortality rates (r=-0·77, p<0·0001). The scarcity of data and quality of cancer registries in EMR countries prevented further analysis.Given the variable quality and coverage of cancer registries in EMR countries, these findings are likely to be underestimates. Nevertheless, these data, especially the high mortality rates, reflect a need for effective national childhood cancer plans in line with the WHO Global Initiative for Childhood Cancer to improve survival.Friends of Cancer Patients.
View details for DOI 10.1016/S2352-4642(22)00122-5
View details for PubMedID 35605628
Long-term follow-up of children treated with the Repiphysis expandable prosthesis for lower extremity bone sarcoma.
Journal of pediatric orthopedics. Part B
2022; 31 (2): e258-e263
Expandable endoprostheses provide a limb salvage option for skeletally immature patients with bone sarcoma of the lower extremities. Initial reports of the Repiphysis prosthesis were encouraging; however, medium-term follow-up revealed high complication rates. We report on the long-term follow-up of a cohort of patients treated with the Repiphysis prosthesis. Eleven patients were included in the study. Data collected included sex, age at surgery, duration of follow-up, site of disease, histologic diagnosis, number of lengthening sessions, amount lengthened, postoperative complications, endoprosthetic failure, mode of endoprosthetic failure, duration from index surgery to failure and to revision, type of revision surgery and final limb-length discrepancy. The average duration of follow-up from the time of surgery was 180 months (range, 144-215 months). Fifteen Repiphysis implants were used in 11 patients. All implants failed with an average time from surgery to failure of 36 months (range, 3-72 months). Twenty-four complications were observed: one wound dehiscence, two deep infections, 18 mechanical failures, implant collapse with destruction of proximal tibia epiphysis in two and one periprosthetic proximal femur fracture with dislodgement of the stem. Despite being an option for limb salvage, the Repiphysis prosthesis has a high rate of mechanical failure and need for revision, similar to other expandable implants. The authors, therefore, recommend full disclosure of the potential short- and long-term complications and need for revision, as well as alternative treatment options if their use is considered. Level of evidence: IV (Therapeutic).
View details for DOI 10.1097/BPB.0000000000000891
View details for PubMedID 34101677
Vincristine-induced neurotoxicity in pediatric patients with rhabdomyosarcoma: A retrospective analysis of clinical features and outcome
PEDIATRIC HEMATOLOGY AND ONCOLOGY
Vincristine is an essential component of rhabdomyosarcoma treatment. However, it can cause motor neurotoxicity, necessitating dose reductions. We retrospectively reviewed the rates and patterns of vincristine-induced motor neuropathy in children treated for rhabdomyosarcoma, and investigated effects on outcome. Fifteen of 43 patients (35%) developed motor neuropathies necessitating dose reductions, which ranged from 1.7% to 58% of planned cumulative dose. Older age was the only significant clinical risk factor. Almost half (47%) recovered during treatment with subsequent dose escalation. Most patients had complete resolution of symptoms upon follow-up. There was no discernible effect of treatment reduction on survival or relapse rates.
View details for DOI 10.1080/08880018.2022.2047849
View details for Web of Science ID 000766483000001
View details for PubMedID 35262458
Global Neuroblastoma Network: An international multidisciplinary neuroblastoma tumor board for resource-limited countries
PEDIATRIC BLOOD & CANCER
2022; 69 (4): e29568
Tumor boards are part of standard care of patients with complex cancers, but appropriate multidisciplinary expertise and infrastructure are often not available in low- and middle-income countries (LMIC) for pediatric cancers, such as neuroblastoma. Our goal was to review results of a Global Neuroblastoma Network (GNN) tumor board accessible to LMIC.De-identified clinical cases presented via internet conference during a weekly GNN virtual tumor board from 2010 through 2020 were evaluated in a standardized format, including diagnostic imaging, pathology, therapy information, resource limitations, and questions for discussion. Information summarized included the presentations, a survey of the impact on care, and a resource questionnaire.Registered GNN participants included 575 individuals from 77 countries, with a median of 39 participants per session. Total 412 cases were presented from 32 countries, including 351 unique neuroblastoma patients, 52 follow-up cases, and nine non-neuroblastoma diagnoses. Twenty-eight educational sessions were presented. Limited critical resources for diagnostics and staging of cases included MYCN analysis (54.7%), metaiodobenzylguanidine (MIBG) scans (38.7%), and International Neuroblastoma Pathology Classification (49%). Therapies were also limited, with markedly decreased use of radiation and autologous stem cell transplant for high-risk cases, and no availability of anti-GD2 antibody in LMIC. Limited sampling with a post-presentation survey showed that 100% found the GNN helpful, and 70% altered the care plan based on the discussion.This report shows the utility of an international tumor board for LMIC focused on a challenging solid tumor where local expertise may be limited, with international multidisciplinary expert participation and educational sessions.
View details for DOI 10.1002/pbc.29568
View details for Web of Science ID 000747302600001
View details for PubMedID 35084087
- Burden of cancer in adolescents and young adults. The Lancet. Oncology 2021; 23 (1): 2-3
- Cancer care for displaced children in Lebanon. The Lancet. Oncology 2021; 22 (12): 1663-1664
A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia
2021; 18 (05): 431-439
Aim: To evaluate the association between candidate genetic polymorphisms and glucocorticoid-induced osteonecrosis in Arab children treated for acute lymphoblastic leukemia. Methods: A total of 189 children treated for acute lymphoblastic leukemia were genotyped for four SNPs with allele discrimination assays. The incidence and timing of radiologically confirmed symptomatic grade 4 osteonecrosis were classified based on the Ponte di Legno toxicity working group consensus definition. Results: Thirteen children developed grade 4 osteonecrosis (6.8%), of whom 12 received the intermediate/high-risk treatment protocol. GRIN3A variant allele carriers had to stop dexamethasone therapy earlier resulting in significantly shorter duration of dexamethasone treatment (mean [95% CI]: 75.17 [64.28-86.06] vs 85.90 [81.22-90.58] weeks; p = 0.054) and lower cumulative dose (mean [95% CI]: 1118.11 [954.94-1281.29] vs 1341.14 [1264.17-1418.11] mg/m2; p = 0.011). Conclusion: This is the first pharmacogenomics evaluation of the association between GRIN3A variants and glucocorticoid-induced osteonecrosis in Arab children.
View details for DOI 10.2217/pme-2020-0167
View details for Web of Science ID 000685845700001
View details for PubMedID 34406079
Treatment-induced cerebral sinus venous thrombosis in childhood acute lymphoblastic malignancies: New risk factors to consider
PEDIATRIC BLOOD & CANCER
2021; 68 (11): e29210
Cerebral sinus venous thrombosis (CSVT) is one of the many side effects encountered during acute lymphoblastic leukemia (ALL) therapy. Due to the rarity of cases, lack of data, and consensus management, no recommendations exist to target the population at risk.This is a retrospective chart review of 229 consecutive patients diagnosed with ALL with an age range of 1-21 years, treated at the Children's Cancer Center of Lebanon between October 2007 and February 2018.The incidence of CSVT was 10.5%. Using univariate analysis, increased risk of CSVT was observed with male gender, age >10 years, T-cell immunophenotype, intermediate/high-risk disease, maximum triglyceride (TG) level of >615 mg/dl, presence of mediastinal mass, and larger body surface area (BSA). With multivariate analysis, the only statistically significant risk factors were maximum TG level, BSA, presence of mediastinal mass, and risk stratification (intermediate/high risk).Our study was able to unveil TG level of >615 mg/dl, mediastinal mass, and a larger BSA as novel risk factors that have not been previously discussed in the literature.
View details for DOI 10.1002/pbc.29210
View details for Web of Science ID 000679121100001
View details for PubMedID 34327817
Cancer Registration in the Middle East, North Africa, and Turkey: Scope and Challenges
JCO GLOBAL ONCOLOGY
2021; 7: 1101-1109
National cancer control strategies have been identified as essential tools for reducing and managing the growing burden of cancer in low- and middle-income countries. Cancer registration is an instrumental component of any cancer control strategy, providing the data to inform effective cancer policy. In the Middle East, North Africa, and Turkey (MENAT) region, cancer registration varies immensely and faces multifaceted challenges including protracted conflict. This study investigates and maps out the present capacities and outputs of cancer registration in the MENAT region and identifies thematic barriers facing implementation and utilization of cancer registry data.We used a self-administered online survey with open and close-ended questions targeting national and institutional cancer registry managers in the MENAT countries.Registry managers from 19 MENAT countries reported the presence of 97 population-based, 48 hospital-based, and 24 pathology-based registries. Most population-based registries were well- or partially developed. Lack of accurate death records, complete medical records, and communication between stakeholders and deficiencies in trained personnel were critical challenges that were more severe in active conflict zones and neighboring conflict-affected regions. Cancer registration challenges included weak health infrastructure, absence of legislation mandating cancer registration, and disruption of cancer registration because of active conflict and loss of funding. Refugee host countries, such as Lebanon, Turkey, and Jordan, also reported conflict-related challenges including refugee mobility and lack of accurate data on forced migrants.This study provides a much-needed understanding of the current landscape and contextual challenges affecting cancer registration in the MENAT. These data are important for identifying areas on which to focus regional capacity-strengthening initiatives.
View details for DOI 10.1200/GO.21.00065
View details for Web of Science ID 000757079500004
View details for PubMedID 34236931
View details for PubMedCentralID PMC8457856
Pediatric oncology infrastructure and workforce training needs: A report from the Pediatric Oncology East and Mediterranean (POEM) Group
PEDIATRIC BLOOD & CANCER
2021; 68 (9): e29190
Inadequate numbers of trained health care providers (HCPs) contribute to poor pediatric oncology (PO) outcomes, particularly in low- and lower middle-income countries (L/LMICs). An understanding of the characteristics of the workforce challenges is vital for addressing these problems.The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of North Africa, Middle East, Central Asia, and Indian subcontinent on infrastructure and workforce capacity, service availability, and training opportunities for HCPs. Participating centers were categorized by the World Bank income levels for their countries and correlated with services, workload and staffing characteristics, and training needs.Fifty of 82 member centers (61%) from 21 countries responded to the survey. Two hundred ninety-nine pediatric oncologists and 1176 nurses treated 12 496 new PO patients/year, with a 1451-bed utilization. The majority (71%) of new cases occurred in L/LMICs. The availability of HCPs correlated with country income level, as did pediatric subspecialty access, while availability of support services was unrelated. Twenty-five centers in 11 countries offered PO fellowship training for physicians, whereas 13 PO nurse training centers in nine countries had the capacity to train 273 nurses annually. The survey respondents indicated that, among their existing workforce, an average of 3.5 physicians and 14 nurses per institution would benefit from additional PO training opportunities.The participating centers exhibited intraregional heterogeneity in financial resources, infrastructure, workload, workforce, and medical services. Our findings provide insight into the disparities and regional resources available to POEM, which can be mobilized to rectify specific deficiencies.
View details for DOI 10.1002/pbc.29190
View details for Web of Science ID 000668592200001
View details for PubMedID 34197011
Extraskeletal Ewing sarcoma: Diagnosis, management and prognosis
2021; 21 (5): 354
Extraskeletal Ewing sarcoma (EES) is a relatively uncommon primary tumor of the soft tissues, which accounts for 20-30% of all reported cases of ES. Being uncommon, all members of the ES family tumors are treated following the same general protocol of sarcoma tumors. The present review summarizes the diagnosis, management and prognosis of EES, focusing on the differences between the subtypes of ESS. The clinical features and imaging of EES are also discussed. Magnetic resonance imaging is the modality of choice for diagnostic imaging and local staging, while core-needle biopsy with pathological testing is used to obtain a definitive diagnosis. Although several oncology groups endorse that ES family of tumors should be treated with similar algorithm and protocols, some studies have demonstrated that surgery and radiotherapy may be used as a form of local control. However, further studies are required to conclude the optimum treatment option for EES.
View details for DOI 10.3892/ol.2021.12615
View details for Web of Science ID 000630051400001
View details for PubMedID 33747211
View details for PubMedCentralID PMC7967932
Childhood cancer care in the Middle East, North Africa, and West/Central Asia: A snapshot across five countries from the POEM network
2021; 71: 101727
The Pediatric Oncology East and Mediterranean (POEM) network, through this report, provides a snapshot view of an expected child's treatment journey in five countries in the region.Pediatric oncologists from cancer centers in Egypt, Lebanon, Iraq, Jordan, and Pakistan provided input on referral pathways, barriers to care, and patient outcomes, based on personal experience and published data. Outcome data were extracted from institutional registries. A literature review of articles and meeting abstracts was conducted, and results summarized.Countries across the Middle Eastern, North African, and West Asian region face common difficulties relating to the provision of pediatric oncology care. National registries are largely lacking, with unavailability of outcome data. Economic barriers are a common theme, leading to delays in patient diagnosis, and interruptions and abandonment of therapy. Insufficient infrastructure and human resources, high rates of toxic deaths, and lack of common national protocols are common. The establishment of successful fundraising organizations linked to specific cancer hospitals showcase several success stories, enhancing services, improving patient access, and leading to outcomes comparable to those in developed countries. All identified published literature is institution-based and from only one or a few hospitals. Therefore, outcomes at a national level likely differ due to disparate cancer care capabilities.Well-designed national registries are essential for identifying gaps, and clear referral networks are needed to address delays to diagnosis and therapy. National and transversal programs to improve infrastructure, facilitate knowledge transfer, and promote advocacy, are needed to accelerate progress in the region.
View details for DOI 10.1016/j.canep.2020.101727
View details for Web of Science ID 000632627700002
View details for PubMedID 32499117
PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2020: 297–98
View details for Web of Science ID 000606080100101
RE-IRRADIATION OF DIPG: DATA FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2020: 301–2
View details for Web of Science ID 000606080100117
Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity
FRONTIERS IN ONCOLOGY
2020; 10: 1784
Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Advanced Proteomics-bioinformatics analysis of the protein cargo of exosomes isolated from C2C12 myoblasts transduced with P3F fusion gene revealed 52 deregulated proteins compared to control cells, with 26 enriched and 26 depleted proteins. Using both PANTHER gene classification and Ingenuity Pathway Analysis (IPA) software, we found that the main biological processes in which the 52 deregulated proteins are involved, include "catalytic activity," "binding," "metabolic process," and "cellular process." The pathways engaging the 26 enriched proteins include the "14-3-3 mediated signaling," "cell cycle," and "ERK5, VEGF, IGF1,and p70S6K signaling." Furthermore, the main nodes in which deregulated exosome proteins and miRNAs intersected revealed pathways conferring protection from stress and promoting plasticity. Based on the bioinformatics analysis and the altered exosome proteome profile, we performed biochemical functional analysis to study the diverse properties of these exosomes where angiogenesis, stemness, and anti-oxidative stress properties were validated using different platforms. P3F-modulated exosomes activated ERK, 4-EBP1, and MMP-2 in recipient cells, and enhanced angiogenesis and stemness. In addition, P3F led to lower cellular reactive oxygen species levels and enhanced resistance against oxidative stress; and treatment of stromal cells with P3F-modulated exosomes also conferred protection against exogenous oxidative stress. Our findings highlight the role of P3F fusion protein in modulating exosome cargo to confer a protective effect on recipient cells against oxidative stress and to promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of RMS.
View details for DOI 10.3389/fonc.2020.01784
View details for Web of Science ID 000577473400001
View details for PubMedID 33117671
View details for PubMedCentralID PMC7560303
Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2020; 42 (6): E428-E433
The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.
View details for DOI 10.1097/MPH.0000000000001785
View details for Web of Science ID 000562759500016
View details for PubMedID 32205785
Impact of the coronavirus disease 2019 (COVID-19) pandemic on pediatric oncology care in the Middle East, North Africa, and West Asia Region: A report from the Pediatric Oncology East and Mediterranean (POEM) Group
2020; 126 (18): 4235-4245
Childhood cancer is a highly curable disease when timely diagnosis and appropriate therapy are provided. A negative impact of the coronavirus disease 2019 (COVID-19) pandemic on access to care for children with cancer is likely but has not been evaluated.A 34-item survey focusing on barriers to pediatric oncology management during the COVID-19 pandemic was distributed to heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Responses were collected on April 11 through 22, 2020. Corresponding rates of proven COVID-19 cases and deaths were retrieved from the World Health Organization database.In total, 34 centers from 19 countries participated. Almost all centers applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use. Essential treatments, including chemotherapy, surgery, and radiation therapy, were delayed in 29% to 44% of centers, and 24% of centers restricted acceptance of new patients. Clinical care delivery was reported as negatively affected in 28% of centers. Greater than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in <30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey.Mechanisms to approach childhood cancer treatment delivery during crises need to be re-evaluated, because treatment interruptions and delays are expected to affect patient outcomes in this otherwise largely curable disease.
View details for DOI 10.1002/cncr.33075
View details for Web of Science ID 000546720200001
View details for PubMedID 32648950
View details for PubMedCentralID PMC7404449
Circulating Tumor Cell Detection Technologies and Clinical Utility: Challenges and Opportunities
2020; 12 (7)
The potential clinical utility of circulating tumor cells (CTCs) in the diagnosis and management of cancer has drawn a lot of attention in the past 10 years. CTCs disseminate from tumors into the bloodstream and are believed to carry vital information about tumor onset, progression, and metastasis. In addition, CTCs reflect different biological aspects of the primary tumor they originate from, mainly in their genetic and protein expression. Moreover, emerging evidence indicates that CTC liquid biopsies can be extended beyond prognostication to pharmacodynamic and predictive biomarkers in cancer patient management. A key challenge in harnessing the clinical potential and utility of CTCs is enumerating and isolating these rare heterogeneous cells from a blood sample while allowing downstream CTC analysis. That being said, there have been serious doubts regarding the potential value of CTCs as clinical biomarkers for cancer due to the low number of promising outcomes in the published results. This review aims to present an overview of the current preclinical CTC detection technologies and the advantages and limitations of each sensing platform, while surveying and analyzing the published evidence of the clinical utility of CTCs.
View details for DOI 10.3390/cancers12071930
View details for Web of Science ID 000554796100001
View details for PubMedID 32708837
View details for PubMedCentralID PMC7409125
Global Retinoblastoma Presentation and Analysis by National Income Level
2020; 6 (5): 685–95
View details for Web of Science ID 000536236800012
The value of diffusion weighted imaging and apparent diffusion coefficient in primary Osteogenic and Ewing sarcomas for the monitoring of response to treatment: Initial experience
EUROPEAN JOURNAL OF RADIOLOGY
2020; 124: 108855
To assess the value of using Apparent Diffusion Coefficient (ADC) mapping in Diffusion Weighted Imaging (DWI) when monitoring treatment response in pediatric Osteogenic and Ewing sarcomas and to correlate with level of necrosis on post-surgical excision pathology.This retrospective study includes 7 Osteosarcoma and 8 Ewing sarcoma patients. Pre-treatment and post-treatment focal MRIs were evaluated for ADC values, tumor volumes and variability of both measurements. We also compared the measurement between Ewing and Osteosarcoma groups, as well as between good (=/>90 % necrosis post-excision) and poor (<90 % necrosis post-excision) responders.All measurements except Maximum ADC (p = 0.20) showed a statistically significant difference when comparing them before and after treatment. When we segregated our population according to pathologic complete response, there was no difference in ADC measurements, volumetric measurements or either variability between good (8 Patients) and poor responders (7 Patients). When comparing the before-after changes in our measurement between the Ewing sarcoma and Osteosarcoma cases, there was no significant difference in the change between pre and post treatment (Δ) Mean or Maximum ADC, or in Δtumor-volume when measured on STIR or SPIR T1 post-contrast sequences. Only the ΔMinimum-ADC showed a statistically significant difference (p < 0.02) in this group.ADC can potentially reflect cellular changes associated with chemotherapy use, reflecting a response to treatment. However, quantitative use of those parameters to dictate a change in management, treatment regimen or chemotherapy dose in order to target a good response (>/ = 90 % necrosis post-excision) needs further investigation.
View details for DOI 10.1016/j.ejrad.2020.108855
View details for Web of Science ID 000512890500039
View details for PubMedID 32018075
Global Retinoblastoma Presentation and Analysis by National Income Level.
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n=3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n=2638 [62.8%]), followed by strabismus (n=429 [10.2%]) and proptosis (n=309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
View details for DOI 10.1001/jamaoncol.2019.6716
View details for PubMedID 32105305
Signaling pathways in Rhabdomyosarcoma invasion and metastasis
CANCER AND METASTASIS REVIEWS
2020; 39 (1): 287-301
Rhabdomyosarcoma (RMS) is an aggressive childhood mesenchymal tumor with two major molecular and histopathologic subtypes: fusion-positive (FP)RMS, characterized by the PAX3-FOXO1 fusion protein and largely of alveolar histology, and fusion-negative (FN)RMS, the majority of which exhibit embryonal tumor histology. Metastatic disease continues to be associated with poor overall survival despite intensive treatment strategies. Studies on RMS biology have provided some insight into autocrine as well as paracrine signaling pathways that contribute to invasion and metastatic propensity. Such pathways include those driven by the PAX3-FOXO1 fusion oncoprotein in FPRMS and signaling pathways such as IGF/RAS/MEK/ERK, PI3K/AKT/mTOR, cMET, FGFR4, and PDGFR in both FP and FNRMS. In addition, specific cytoskeletal proteins, G protein coupled receptors, Hedgehog, Notch, Wnt, Hippo, and p53 pathways play a role, as do specific microRNA. Paracrine factors, including secreted proteins and RMS-derived exosomes that carry cargo of protein and miRNA, have also recently emerged as potentially important players in RMS biology. This review summarizes the known factors contributing to RMS invasion and metastasis and their implications on identifying targets for treatment and a better understanding of metastatic RMS.
View details for DOI 10.1007/s10555-020-09860-3
View details for Web of Science ID 000515593100004
View details for PubMedID 31989508
The PAX3-FOXO1 oncogene alters exosome miRNA content and leads to paracrine effects mediated by exosomal miR-486
2019; 9: 14242
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The alveolar subtype (ARMS) is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 that drives oncogenic cellular properties. Exosomes are small, secreted vesicles that affect paracrine signaling. We show that PAX3-FOXO1 transcript alters exosome content of C2C12 myoblasts, leading to pro-tumorigenic paracrine effects in recipient cells. Microarray analysis revealed alteration in miRNA content of exosomes, affecting cellular networks involved in cell metabolism, growth signaling, and cellular invasion. Overexpression and knockdown studies showed that miR-486-5p is an effector of PAX3-FOXO1, and mediates its paracrine effects in exosomes, including promoting recipient cell migration, invasion, and colony formation. Analysis of human RMS cells showed miR-486-5p is enriched in both cells and exosomes, and to a higher extent in ARMS subtypes. Analysis of human serum samples showed that miR-486-5p is enriched in exosomes of patients with RMS, and follow-up after chemotherapy showed decrease to control values. Our findings identify a novel role of both PAX3-FOXO1 and its downstream effector miR-486-5p in exosome-mediated oncogenic paracrine effects of RMS, and suggest its possible use as a biomarker.
View details for DOI 10.1038/s41598-019-50592-4
View details for Web of Science ID 000488482200024
View details for PubMedID 31578374
View details for PubMedCentralID PMC6775163
Proteomic Profiling of Rhabdomyosarcoma-Derived Exosomes Yield Insights into Their Functional Role in Paracrine Signaling
JOURNAL OF PROTEOME RESEARCH
2019; 18 (10): 3567-3579
Exosomes are important intercellular communication vehicles, secreted into body fluids by multiple cell types, including tumor cells. They have been demonstrated to contribute to the metastatic progression of tumor cells through paracrine signaling. Tumor exosomes contain intact and functional proteins, mRNA and miRNA that may alter the cellular environment to favor tumor growth. We evaluated the protein cargo of exosomes derived from the childhood tumor rhabdomyosarcoma (RMS) and the molecular pathways they are implicated in to decipher their role in the progression of this aggressive disease. We conducted a mass spectrometry analysis of exosome content isolated from five RMS cell lines: three of embryonal RMS (ERMS) and two of alveolar RMS (ARMS) histology and verified results by multiple reaction monitoring and western blot analyses. Results revealed 161 common proteins in ERMS-derived exosomes and 122 common proteins in ARMS-derived exosomes, of which 81 proteins were common to both subtypes. Using both PANTHER gene classification and Pathway Studio software, we assessed the perturbed biological processes and altered pathways in which the exosomal proteins are involved. The 81 commonly expressed proteins included those involved in "cell-signaling," "cell-movement," and "cancer." Pathways engaging the identified proteins revealed 37 common pathways including "integrin signaling pathway," "inflammation mediated by chemokine and cytokine signaling pathway," and "angiogenesis." Finally, a comparison of exosomal proteins of RMS cells with publicly available datasets from other cancer cells revealed that 36 proteins are specific and endogenous to the RMS-exosomes. Taken together, our results reveal that RMS-derived exosomes carry a protein cargo that contributes to conserved cellular signaling networks across multiple cell lines, and we also identify RMS exosome-specific proteins that should be further evaluated as possible novel biomarkers for this tumor.
View details for DOI 10.1021/acs.jproteome.9b00157
View details for Web of Science ID 000489200400003
View details for PubMedID 31448612
Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome
PEDIATRIC BLOOD & CANCER
2019; 66 (11): e27959
Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age-adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.
View details for DOI 10.1002/pbc.27959
View details for Web of Science ID 000481784600001
View details for PubMedID 31423715
Illness cognition and health anxiety in parents of children with cancer
JOURNAL OF PSYCHOSOCIAL ONCOLOGY
2019; 37 (6): 713-728
Purpose: Health anxiety is a clinical entity characterized by a pathological fear of illness. Illness cognition refers to persistent positive or negative thoughts an individual has towards illness. Evidence has shown that patients with chronic conditions who possess negative illness cognitions experience greater social, emotional, and physical difficulties than patients with positive illness cognitions. This study aims to measure the prevalence of health anxiety in a population of parents of children with cancer, and investigate the association between positive and negative illness cognitions and health anxiety. Methods: We interviewed 105 parents of children with cancer and administered Arabic versions of the Illness Cognition Questionnaire - Parent Version and the Short Health Anxiety Inventory. Results: The mean parental age was 37.7 years with the majority of participants being mothers (78.1%) and married (94.3%) and with 35.2% having completed university education. The average age of the child with cancer was 8.4 years, with the largest proportion of children suffering from leukemia. The prevalence of health anxiety among parents of children with cancer was 21%. The following two dimensions of illness cognition were significantly associated with health anxiety: Helplessness (B = 0.222, p = 0.021) and lower Acceptance (B = -0.242, p = 0.008). Other variables associated with health anxiety were perceived inadequate income (B = -0.238, p = 0.021) and personal illness or illness of a family member/close friend (B = 0.251, p = 0.013). Conclusions: Parents of children with cancer may experience health anxiety. Predictors of health anxiety include feelings of helplessness, lower acceptance, inadequate income, and extended family illnesses.
View details for DOI 10.1080/07347332.2019.1600629
View details for Web of Science ID 000476399300001
View details for PubMedID 31286846
Identifying barriers to treatment of childhood rhabdomyosarcoma in resource-limited settings: A literature review
PEDIATRIC BLOOD & CANCER
2019; 66 (7): e27708
We performed a literature review to examine barriers for rhabdomyosarcoma treatment in low-resource settings, and identified 29 articles from 14 middle-income countries, with none from low-income countries. Notable findings included inconsistent use of local control modalities, lack of diagnostics in some settings, and high rate of abandonment specifically in low middle-income countries. Reported limitations included lack of surgical expertise and/or radiation therapy, advanced stage of disease, and absence of health insurance. Although very poor outcomes were prevalent in several settings, good outcomes were achievable in others when multidisciplinary therapy and financial coverage of medical care were made available.
View details for DOI 10.1002/pbc.27708
View details for Web of Science ID 000468629000018
View details for PubMedID 30907501
Clinical Prognostic Factors and Outcome in Pediatric Osteosarcoma: Effect of Delay in Local Control and Degree of Necrosis in a Multidisciplinary Setting in Lebanon
JOURNAL OF GLOBAL ONCOLOGY
2019; 5: 1-8
Outcomes in pediatric osteosarcoma have dramatically improved over the past few decades, with overall survival rates of 70% and 30% for patients with localized and metastatic disease, respectively.We retrospectively reviewed clinical characteristics and outcomes of 38 patients treated between 2001 and 2012 at a single institution in Lebanon. All patients received a uniform three-drug chemotherapy regimen consisting of cisplatin, doxorubicin, and methotrexate. Ifosfamide and etoposide were added to the adjuvant treatment regimen in case of metastatic disease and/or poor degree of tumor necrosis (< 90%).After a median follow-up of 61 months (range, 8 to 142 months), patients with localized disease had 5-year overall and event-free survival rates of approximately 81% and 68%, respectively, whereas for metastatic disease, they were approximately 42%. The most common primary site was the long bones around the knee (n = 34; 89.5%). Six patients (15.8%) had metastatic disease to lungs, and three (7.9%) had synchronous multifocal bone disease with lung metastases. Adverse prognostic factors included nonlower extremity sites, metastasis, poor degree of necrosis, and delay of more than 4 weeks in local control. In bivariable analysis, only degree of necrosis was a prognostic predictor for survival and disease recurrence.Treatment of pediatric osteosarcoma in a multidisciplinary cancer center in Lebanon resulted in survival similar to that in developed countries. Delay in local control was associated with worse outcome. The only statistically significant inferior outcome predictor was poor degree of necrosis at the time of local control.
View details for DOI 10.1200/JGO.17.00241
View details for Web of Science ID 000468142600001
View details for PubMedID 30946633
View details for PubMedCentralID PMC6528739
Spirituality among parents of children with cancer in a Middle Eastern country
EUROPEAN JOURNAL OF ONCOLOGY NURSING
2019; 39: 21-27
Family caregivers of children with cancer face emotional, psychological, and spiritual challenges coping with their child's illness. For ensuring comprehensive multidisciplinary pediatric care, there is a need to understand and define what spirituality means for them in relation to their child's illness. The purpose of this study is to understand the meaning of spirituality for parents of cancer patients in Lebanon.This qualitative study followed the Heideggerian interpretive phenomenological method. Through purposeful sampling, 11 parents (mother or father) of children with cancer receiving treatment at a tertiary care center in Beirut, Lebanon were interviewed. Data were analyzed following the hermeneutical process as described by Diekelmann and Ironside (1998).A constitutive pattern and overarching theme, "spirituality is a two-level relationship. It is a relation with God and with people. It is the act of receiving and giving back" and five major themes emerged from the data. These were "Being there for me; " "Connectedness with other parents is a blessing and a torment; " "The power of knowing; " "Communication with Unknown" and "Spirituality is not religiosity".Lebanese parents of children with cancer defined the elements of their own spirituality. Relational aspects dominated and communication was an important factor.This is the first study in the Middle East to address the meaning of spirituality in this population, and would pave the way for a customized palliative care program and integrative approach to patient care.
View details for DOI 10.1016/j.ejon.2018.12.009
View details for Web of Science ID 000462419500003
View details for PubMedID 30850134
The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma
CANCER BIOLOGY & THERAPY
2019; 20 (3): 272-283
Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21Cip1 and p27Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post-translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21Cip1 and p27Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects . Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS.
View details for DOI 10.1080/15384047.2018.1529093
View details for Web of Science ID 000457544200006
View details for PubMedID 30307360
View details for PubMedCentralID PMC6370390
Infantile myofibromatosis: review of imaging findings and emphasis on correlation between MRI and histopathological findings
2019; 54: 40-47
Infantile myofibromatosis (IM) is the most common fibrous tumor of infancy. MRI is considered the gold standard in IM evaluation. Very little has been published about IM with histopathology correlation in the pediatric age.Describe imaging findings in IM and correlate MRI findings with histopathology.Imaging findings of 17 patients with IM were retrospectively analyzed including CT, US and MRI. Signal characteristics on T1-, T2-weighted and STIR imaging, extent of T2-hyperintensity, degree & pattern of enhancement, diffusion restriction, location & margins, & involvement of adjacent structures were tabulated. Histopathology findings included cellularity, collagenization, myxoid changes, atypia, mitosis & microscopic invasion. Established grading scores were utilized.Relative to normal skeletal muscle, on T1-weighted imaging, 9 lesions had similar signal while the remaining had a mixture of iso & hypo intensity; whereas on T2-weighted and STIR imaging, all 12 lesions demonstrated a mixture of iso, hypo & hyperintensity. T2-hyperintensity was grade 2 in one, grade 3 in 8 & grade 4 in 3 lesions. Intensity of enhancement was grade 2 in one, grade 3 in 8 & grade 4 in 3 lesions. Enhancement was predominantly peripheral in all 12 lesions. Extent of T2-hyperintensity & degree of enhancement corresponded to variable grades on histopathology. CT and US showed nonspecific findings.On MRI, IM has a mixture of signal intensity with predominant hyperintense signal on T2W images. However various signal & enhancement features correlated poorly with specific histopathologic grades.
View details for DOI 10.1016/j.clinimag.2018.11.003
View details for Web of Science ID 000462805000010
View details for PubMedID 30529421
Genetic polymorphisms in candidate genes are not associated with increased vincristine-related peripheral neuropathy in Arab children treated for acute childhood leukemia: a single institution study
PHARMACOGENETICS AND GENOMICS
2018; 28 (8): 189-195
The aim of this study was to evaluate the potential association between candidate genetic polymorphisms and vincristine-related peripheral neuropathy in Arab children with acute lymphoblastic leukemia (ALL).This is a retrospective evaluation of 133 Arab children treated for ALL at the Children's Cancer Center of Lebanon. Incidence and severity of, as well as the timing (in weeks) at which grade 2 or higher peripheral neuropathy occurred were recorded. Genotyping for ABCB1 (rs1045642), ABCB1 (rs1128503), ABCC2 (rs717620), CEP72 (rs924607), ETAA1 (rs17032980), and MTNR1B (rs12786200) was performed.A total of 26 (19.5%) individuals developed peripheral neuropathy, three of which occurred during the induction phase. No statistically significant associations were revealed for any of the polymorphisms with either incidence of vincristine-related toxicity, toxicity severity, or time to the first episode of grade 2 or higher vincristine-related peripheral neuropathy.This study presents the first pharmacogenetic analysis of vincristine-related peripheral neuropathy in children with ALL in an Arab country. We have shown that genetic polymorphisms in candidate genes are not associated with peripheral neuropathy secondary to chronic therapy with high-dose vincristine (2 mg/m) during the continuation phase. Concerning CEP72, our results are in line with the findings from the St Jude cohort of children treated for ALL with higher vincristine doses during chronic treatment. Larger high-throughput genetic analyses may be warranted to evaluate variants in other candidate genes such as CYP3A5 and reveal new nonpreviously reported alleles that may be peculiar to this region of the world.
View details for DOI 10.1097/FPC.0000000000000345
View details for Web of Science ID 000446528500001
View details for PubMedID 30119132
Genomics of adult and pediatric solid tumors.
American journal of cancer research
2018; 8 (8): 1356-1386
Different types of cancers exhibit disparate spectra of genomic alterations (germline and/or somatic). These alterations can include single nucleotide variants (SNVs), copy number alterations (CNAs) or structural changes (e.g. gene fusions and chromosomal rearrangements). Identification of those genomic alterations has provided the opportune element to derive new strategies for molecular-based precision medicine of adult and pediatric cancers including risk assessment, non-invasive detection, molecular diagnosis and personalized therapy. Moreover, it is now becoming clear that the spectra of genomic-based alterations and mechanisms in pediatric malignancies are different from those predominantly occurring in adult cancer. Adult cancers on average exhibit substantially higher mutational burdens compared with the vast majority of childhood tumors. Accumulating evidence also suggests that the type of genomic alterations frequently encountered in adult cancers is different from those observed in pediatric malignancies. In this review, we discuss the state of knowledge on adult and pediatric cancer genomes (or "mutatomes"), specifically focusing on solid tumors. We present an overview of mutational signatures and processes in cancer as well as comprehensively compare and contrast the diverse spectra of genomic alterations (somatic and familial) among major adult and pediatric solid tumors. The review also discusses the role of genomics in molecular-based precision medicine of adult and pediatric solid malignancies as well as comprehending resistance mechanisms to various targeted therapies. In addition, we present a perspective that discusses upon emerging concepts in cancer genomics including intratumoral heterogeneity, the precancer (premalignant) genome as well as the interface between the host immune response and tumor genome - immunogenomics - as they relate to adult and pediatric tumors.
View details for PubMedID 30210910
View details for PubMedCentralID PMC6129500
CHARACTERISTICS OF PATIENTS >= 10 YEARS OF AGE WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2018: 63
View details for Web of Science ID 000438339000164
CD4-positive lymphoepithelial-like carcinoma: Report of unusual case.
Avicenna journal of medicine
2018; 8 (2): 58-62
We are reporting an unusual case of lymphoepithelial-like carcinoma (LELC) in an 8-year-old female patient where the tumor cells showed unusual CD4 expression. The lesion was found in the left submandibular neck region, in the vicinity of the submandibular gland. The salivary gland was not infiltrated by the tumor, and the tumor exhibited a classic LELC with single and clusters of tumor cells surrounded by many hematolymphoid cells. The tumor cells revealed strong positivity for Epstein-Bar virus as confirmed by the EBER: Epstein-Barr Virus in situ hybridization (EBER-ISH) method of staining. Interestingly, the tumor cells expressed membranous immunostaining for the T-helper lymphocyte antibody (CD4) in addition to pan-cytokeratin. A brief discussion about this unusual finding is offered. The patient was treated as a case of Epstein-Bar virus-associated nasopharyngeal carcinoma with excellent response.
View details for DOI 10.4103/ajm.AJM_135_17
View details for PubMedID 29682480
View details for PubMedCentralID PMC5898185
Displaced Children With Cancer in Lebanon: A Sustained Response to an Unprecedented Crisis
2018; 124 (7): 1464-1472
The unrest in Syria has resulted in an escalating refugee crisis. The postwar lack of health care infrastructure in Iraq has also resulted in Iraqis seeking health care in neighboring countries. Pediatric cancer is largely curable, although its treatment is expensive and complex. Strategies to implement pediatric cancer care with curative intent in these vulnerable populations are lacking.To assess the feasibility of a collaborative approach for the provision of care to displaced children with cancer, this study reviewed the experience of the authors over the past 6 years in Lebanon, the country with the highest number of refugees per capita in the world.The American University of Beirut Medical Center and the Children's Cancer Center of Lebanon Foundation, in partnership with St. Jude Children's Research Hospital and the American Lebanese Syrian Associated Charities, established 3 successive funding programs to treat displaced children with cancer along with a continuous assessment of resource utilization. Between 2011 and 2017, 575 non-Lebanese children suspected to have cancer were evaluated. Of those, 311 received direct medical support, with 107 receiving full-treatment coverage and 204 receiving limited-workup/specialty services; the remaining 264 patients received medical consultations.In addition to providing lifesaving humanitarian support, the coordination of care delivery, including the establishment of guidelines for prioritization, can help direct future efforts. Many patients continue to be in dire need of support, and this should be addressed via collaboration among governmental, nongovernmental, and health care organizations. Cancer 2018;124:1464-72. © 2018 American Cancer Society.
View details for DOI 10.1002/cncr.31273
View details for Web of Science ID 000428314500020
View details for PubMedID 29489012
Interplay between p53 and Ink4c in spermatogenesis and fertility
2018; 17 (5): 643-651
The tumor suppressor p53, and the cyclin-dependent kinase inhibitor Ink4c, have been both implicated in spermatogenesis control. Both p53-/- and Ink4c-/- single knockout male mice are fertile, despite testicular hypertrophy, Leydig cell differentiation defect, and increased sperm count in Ink4c-/- males. To investigate their collaborative roles, we studied p53-/- Ink4c-/- dual knockout animals, and found that male p53-/- Ink4c-/- mice have profoundly reduced fertility. Dual knockout male mice show a marked decrease in sperm count, abnormal sperm morphology and motility, prolongation of spermatozoa proliferation and delay of meiosis entry, and accumulation of DNA damage. Genetic studies showed that the effects of p53 loss on fertility are independent of its downstream effector Cdkn1a. Absence of p53 also partially reverses the hyperplasia seen upon Ink4c loss, and normalizes the Leydig cell differentiation defect. These results implicate p53 in mitigating both the delayed entry into meiosis and the secondary apoptotic response that occur in the absence of Ink4c. We conclude that the cell cycle genes p53 and Ink4c collaborate in sperm cell development and differentiation, and may be important candidates to investigate in human male infertility conditions.
View details for DOI 10.1080/15384101.2017.1421874
View details for Web of Science ID 000430934900014
View details for PubMedID 29334315
View details for PubMedCentralID PMC5969541
Routine surveillance imaging after end of therapy for pediatric extracranial tumors: A retrospective analysis
PEDIATRIC BLOOD & CANCER
2018; 65 (1)
Frequent surveillance imaging is routine practice for pediatric patients after cancer therapy. This retrospective study evaluated the follow-up of 301 children with extracranial tumors diagnosed between 2002 and 2012, at a tertiary pediatric cancer center in Beirut, Lebanon. Recurrence occurred in 15% of patients, at a median of 12 months after end of primary therapy. Outcome was not different comparing patients with recurrence detected via imaging surveillance versus clinically. False positive findings in 55 patients led to further interventions. These results raise important questions regarding benefit of current surveillance practices as standard care, especially in countries with limited resources.
View details for DOI 10.1002/pbc.26723
View details for Web of Science ID 000416119400016
View details for PubMedID 28727257
Pediatric cancer pathology review from a single institution: Neuropathology expert opinion is essential for accurate diagnosis of pediatric brain tumors
PEDIATRIC BLOOD & CANCER
2018; 65 (1)
Second pathology review has been reported to improve accuracy in oncologic diagnoses, including pediatric malignancies. We assessed the impact of second review on the diagnosis of pediatric malignancies at a tertiary care referral center in Beirut, Lebanon.Pathology reports of patients treated at the Children's Cancer Institute in Lebanon were retrospectively reviewed for the period 2008-2016 and compared with same samples' diagnoses at St. Jude Children's Research Hospital. Diagnostic disagreements were divided into major, minor, and none based on their effect on diagnosis and/or patient management.Second review was requested for 171 cases, accounting for 19% of all cases during that period. Second opinion was mostly requested for brain tumors (62% of all brain tumor cases) and neuroblastoma for NMYC testing (65% of all neuroblastoma), while hematologic malignancies had the fewest referrals (3% of all hematologic cases). Major disagreements in second review occurred in 20 cases (12% of total), and minor disagreements in 21 cases (12% of total). The largest proportion of major disagreements (71%) occurred in pediatric brain tumors, and novel molecular tests contributed to the diagnosis in 55% of these cases.The availability of a specialized pediatric neuropathologist and a basic panel of relevant molecular testing are essential for appropriate diagnosis of pediatric brain tumors. Centers that do not have the available infrastructure in place can benefit greatly from second review referrals for this challenging subset of tumors.
View details for DOI 10.1002/pbc.26709
View details for Web of Science ID 000416119400005
View details for PubMedID 28675683
Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management
PEDIATRIC BLOOD & CANCER
2017; 64 (12)
Cerebral sinus venous thrombosis (CSVT) is a rare but serious complication of childhood acute lymphoblastic leukemia (ALL) therapy. No available consensus exists regarding its risk factors and appropriate management due to the rarity of cases.Out of 209 ALL patients aged 1-21 years treated at the Children's Cancer Center of Lebanon between May 2002 and May 2015, 13 developed CSVT during therapy. Patient characteristics, clinical management, and outcomes were studied.The incidence of CSVT was 6.2% (95% confidence interval [CI]: 3.4-10.4). Using univariate analysis, increased risk of CSVT was observed with age >10 years (odds ratio [OR]: 3.56, 95% CI: 1.13-11.2), T-cell immunophenotype (OR: 4.14, 95% CI: 1.16-14.7), and intermediate/high risk disease (OR: 3.4, 95% CI: 1.03-11.7). The only statistically significant risk factor by multivariate analysis was the treatment as per the intermediate-/high-risk protocol (HR: 15.6, 95% CI: 1.43-171.3). Most cases (77%) occurred in the postinduction phases of treatment while receiving a combination of asparaginase and dexamethasone rather than prednisone. Treatment with low molecular weight heparin (LMWH) for a minimum of 3 months and until significant radiological improvement is observed resulted in 100% survival rate. All but one patient had complete neurological recovery.CSVT is an important complication of childhood ALL therapy. Postinduction combined asparaginase and dexamethasone intensive treatment for intermediate-/high-risk patients was the most important risk factor. Treatment with LMWH for a minimum of 3 months, and until asparginase therapy is over, with major radiological improvement seems to be effective and feasible.
View details for DOI 10.1002/pbc.26694
View details for Web of Science ID 000413372700054
View details for PubMedID 28660695
Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia
CURRENT RESEARCH IN TRANSLATIONAL MEDICINE
2017; 65 (3): 115-119
Different conditioning regimens have been evaluated in matched-related donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acquired severe aplastic anemia (SAA) with varying results. In this manuscript, we report our experience with fludarabine (120mg/m2), very low dose cyclophosphamide (1200mg/m2) and antithymocyte globulin (7.5mg/kg). Low dose total body irradiation (2Gy) was added to the conditioning regimen for patients older than 15 years. Nineteen patients (median age 23years) underwent transplant between 2008 and 2015. The majority (89%) were younger than 40 years. Stem cell source was BM (n=11) or PBSC (n=8). GvHD prophylaxis consisted of cyclosporine and either a short course of methotrexate (n=9) or mycophenolate mofetil (n=10). Eighteen (94.7%) patients achieved sustained engraftment. The median times to neutrophil and platelet engraftments were 19 (range: 14-34) and 17.1 (range: 12-25) days, respectively. The day-30 cumulative incidence of neutrophil and platelet engraftment was 89.4% and 94.7%, respectively. No secondary graft rejection was observed. The 1-year cumulative incidence of aGvHD (grade II-IV) and cGvHD was 11.7% and 0%, respectively. The 2-year GvHD-free survival rate was 78.6% (95% CI: 52.5-91.4%). Fludarabine-based reduced intensity regimen for MRD allo-HSCT in SAA compares favorably to other available regimens. This regimen deserves further investigations with larger cohort of patients.
View details for DOI 10.1016/j.retram.2017.09.001
View details for Web of Science ID 000416784500003
View details for PubMedID 28988743
- Predictors of benzodiazepine use among parents of children with cancer: a cross-sectional study from Lebanon PSYCHO-ONCOLOGY 2017; 26 (8): 1225-1228
Multisite external validation of a risk prediction model for the diagnosis of blood stream infections in febrile pediatric oncology patients without severe neutropenia.
Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness.A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables.From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI.The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017. © 2017 American Cancer Society.
View details for DOI 10.1002/cncr.30792
View details for PubMedID 28542918
Collaborative Pediatric Bone Tumor Program to Improve Access to Specialized Care: An Initiative by the Lebanese Children's Oncology Group
JOURNAL OF GLOBAL ONCOLOGY
2017; 3 (1): 23-30
Children with malignant bone tumors have average 5-year survival rates of 60% to 70% with current multimodality therapy. Local control modalities aimed at preserving function greatly influence the quality of life of long-term survivors. In developing countries, the limited availability of multidisciplinary care and limited expertise in specialized surgery and pediatric radiation therapy, as well as financial cost, all form barriers to achieving optimal outcomes in this population.We describe the establishment of a collaborative pediatric bone tumor program among a group of pediatric oncologists in Lebanon and Syria. This program provides access to specialized local control at a tertiary children's cancer center to pediatric patients with newly diagnosed bone tumors at participating sites. Central review of pathology, staging, and treatment planning is performed in a multidisciplinary tumor board setting. Patients receive chemotherapy at their respective centers on a unified treatment plan. Surgery and/or radiation therapy are performed centrally by specialized staff at the children's cancer center. Cost barriers were resolved through a program development initiative led by St Jude Children's Research Hospital. Once program feasibility was achieved, the Children's Cancer Center of Lebanon Foundation, via fundraising efforts, provided continuation of program-directed funding.Findings over a 3-year period showed the feasibility of this project, with timely local control and protocol adherence at eight collaborating centers. We report success in providing standard-of-care multidisciplinary therapy to this patient population with complex needs and financially challenging surgical procedures.This initiative can serve as a model, noting that facilitating access to specialized multidisciplinary care, resolution of financial barriers, and close administrative coordination all greatly contributed to the success of the program.
View details for DOI 10.1200/JGO.2016.003103
View details for Web of Science ID 000461065100004
View details for PubMedID 28717738
View details for PubMedCentralID PMC5493233
NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon
PEDIATRIC BLOOD & CANCER
2017; 64 (1): 146-150
Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases.The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per μl.One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00-66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort.This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect.
View details for DOI 10.1002/pbc.26189
View details for Web of Science ID 000389051100024
View details for PubMedID 27577869
Mandibular melanotic neuroectodermal tumor of infancy: a role for neoadjuvant chemotherapy
EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY
2016; 273 (12): 4629-4635
Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a rare, locally aggressive neoplasm with a predilection for the head and neck area, most commonly occurring in the maxilla. The vast majority of treatment modalities for all cases of MNTI to date have involved surgical intervention only, with just 9.6 % involving some sort of chemotherapy, radiotherapy, or a combination of the prior mentioned modalities. There is very limited information available regarding the use of neoadjuvant chemotherapy, due to its rare nature. In this report, a 4 month old girl presented to our clinic with a chief complaint of a large oral mass of about 2.5 months in duration. Intraoral examination showed an oral mass arising from the lingual aspect of inferior alveolar ridge with extensive mandibular invasion. The patient received three cycles of vincristine, Adriamycin, and cyclophosphamide as neodajuvant therapy. Upon completion, the tumor had decreased significantly in size. The patient was then scheduled for surgery and underwent surgical resection of the tumor. We were able to obtain adequate shrinkage of the tumor to allow better resectability, easier surgical access and a more minimally invasive approach with no lip split and a smaller neck incision. In conclusion, we have reported an extremely rare case of MNTI of the mandible that was successfully treated with neoadjuvant chemotherapy and surgical resection. This approach was advantageous to minimize the chance of recurrence and improve resectability in particularly large tumors, while maximizing functional outcomes and minimizing deformity.
View details for DOI 10.1007/s00405-016-4066-6
View details for Web of Science ID 000387700400072
View details for PubMedID 27107579
Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts
2016; 6: 37088
Rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue tumor, which exists in oncoprotein PAX-FOXO1 fusion positive and fusion negative subtypes, with the fusion-positive RMS being characterized by a more aggressive clinical behavior. Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and have been implicated in metastatic progression through paracrine signaling. We characterized exosomes secreted by a panel of 5 RMS cell lines. Expression array analysis showed that, for both fusion-positive and fusion-negative cells, exosome miRNA clustered well together and to a higher extent than cellular miRNA. While enriched miRNA in exosomes of fusion-negative RMS cells were distinct from those of fusion-positive RMS cells, the most significant predicted disease and functions in both groups were related to processes relevant to cancer and tissue remodelling. Functionally, we found that RMS-derived exosomes exerted a positive effect on cellular proliferation of recipient RMS cells and fibroblasts, induced cellular migration and invasion of fibroblasts, and promoted angiogenesis. These findings show that RMS-derived exosomes enhance invasive properties of recipient cells, and that exosome content of fusion-positive RMS is different than that of fusion-negative RMS, possibly contributing to the different metastatic propensity of the two subtypes.
View details for DOI 10.1038/srep37088
View details for Web of Science ID 000388151900001
View details for PubMedID 27853183
View details for PubMedCentralID PMC5112573
The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma
INTERNATIONAL JOURNAL OF CANCER
2016; 138 (6): 1528-1537
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.
View details for DOI 10.1002/ijc.29886
View details for Web of Science ID 000370080900023
View details for PubMedID 26453552
Wilms tumor: Successes and challenges in management outside of cooperative clinical trials.
Hematology/oncology and stem cell therapy
2016; 9 (1): 20-5
OBJECTIVE/BACKGROUND: Management of Wilms tumor (WT) in children depends on a multidisciplinary approach to treatment, and outcomes have significantly improved as reported by cooperative group clinical trials. Here, we review the clinical outcomes of patients with WT and identify challenges and barriers encountered in multidisciplinary management outside of cooperative clinical trials.METHODS: We retrospectively reviewed the clinical records of 35 children with WT treated between April 2002 and June 2013 at the Children's Cancer Institute in Lebanon.RESULTS: Upfront resection was performed in 23 cases. Biopsies were performed for Stage V tumors (n=4), those with unresectable tumors or inferior vena caval thrombus (n=5), and patients who had partial surgery performed elsewhere prior to presentation (n=2). One patient died due to toxicity prior to surgery. The tumor was Stage I in eight patients, Stage II in five patients, Stages III and IV in nine patients each, and bilateral (Stage V) in four patients. Adherence to The National Wilms Tumor Study-5 recommendations was adequate. At the time of analysis, 30 patients were free of disease and four patients had relapse-all having metastatic disease initially.CONCLUSION: The National Wilms Tumor Study-5 therapy resulted in favorable outcomes in children with nonmetastatic Wilms tumor in the setting of a multidisciplinary approach to therapy and resolution of financial barriers to medical care. Upstaging due to prior intervention and lung radiation therapy to all those with computed tomography-detected lung nodules may both have resulted in overtreatment of a subset of patients. Finally, the relatively high incidence of bilateral tumors suggests the need for further genetic and molecular studies in this patient population.
View details for DOI 10.1016/j.hemonc.2015.12.006
View details for PubMedID 26802622
Effect of Malnutrition at Diagnosis on Clinical Outcomes of Children With Acute Lymphoblastic Leukemia
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2016; 38 (2): 107-110
Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Although studies have shown that malnutrition can negatively affect treatment outcome, results are controversial. This retrospective study aims at determining the prevalence of malnutrition and its association with treatment outcome among children with ALL treated at the Children's Cancer Institute in Lebanon. A total of 103 patients diagnosed with ALL between April 2002 and May 2010 were enrolled. Anthropometric data were collected from medical records upon diagnosis, at 3 and 6 months, and at the end of treatment. Body mass index was calculated for children 2 years of age and older, whereas weight-for-height ratio was used for patients below 2 years. Patients were considered underweight, stunted, or wasted if their Z-scores were <-2 SD. The prevalence of malnourished children was 25.2% at diagnosis and remained almost the same at the end of treatment. The odds of having a poor outcome (death and relapse) was higher among malnourished children and more so among stunted children with an odds ratios=2.15; 95% confidence interval, 0.5-8.3 and odds ratio=2.63; 95% confidence interval, 0.6-11.5, respectively. Although there was a trend showing worse outcomes in malnourished children with ALL at diagnosis when compared with well-nourished children larger studies using additional tools like arm anthropometry need to be conducted to prove the association.
View details for DOI 10.1097/MPH.0000000000000428
View details for Web of Science ID 000372852600004
View details for PubMedID 26479995
p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells
MOLECULAR AND CELLULAR BIOLOGY
2016; 36 (3): 438-451
The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.
View details for DOI 10.1128/MCB.00747-15
View details for Web of Science ID 000368337900005
View details for PubMedID 26598601
View details for PubMedCentralID PMC4719431
Approach to Non-Neutropenic Fever in Pediatric Oncology Patients-A Single Institution Study
PEDIATRIC BLOOD & CANCER
2015; 62 (12): 2167-2171
Pediatric oncology patients with fever, even when not neutropenic, are known to be at an increased risk of bloodstream infections. However, there are no standard guidelines for management of fever in non-neutropenic patients, resulting in variability in practice across institutions.We retrospectively analyzed the clinical characteristics, management, and outcome of all febrile non-neutropenic episodes in pediatric oncology patients at a single institution over the two-year period 2011-2012, to identify predictors of bloodstream infections. We assessed the efficacy of a uniform approach to outpatient management of a defined subset of patients at low risk of invasive infections.A total of 254 episodes in 83 patients were identified. All patients had implanted central venous catheters (port). Sixty-two episodes (24%) were triaged as high-risk and admitted for inpatient management; five (8%) had positive blood cultures. The remaining 192 episodes were triaged as low risk and managed with once daily outpatient intravenous ceftriaxone; three (1.6%) were associated with bacteremia, and 10% required eventual inpatient management. Of all the factors analyzed, only signs of sepsis (lethargy, chills, hypotension) were associated with positive bloodstream infection.Treatment of a defined subset of patients with outpatient intravenous ceftriaxone was safe and effective. Signs of sepsis were the only factor significantly associated with bloodstream infection. This study provides a baseline for future prospective studies assessing the safety of withholding antibiotics in this subset of patients.
View details for DOI 10.1002/pbc.25660
View details for Web of Science ID 000365412600019
View details for PubMedID 26175012
CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence-Implications for Therapeutic Intervention
MOLECULAR CANCER RESEARCH
2015; 13 (1): 29-40
Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence.These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors.
View details for DOI 10.1158/1541-7786.MCR-14-0163
View details for Web of Science ID 000347937400004
View details for PubMedID 25149358
Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma.
Ocular oncology and pathology
2014; 1 (2): 77-82
To report the outcome of pediatric patients with retinoblastoma refractory to traditional local therapy who were treated with indocyanine green (ICG)-enhanced thermotherapy.This is a retrospective review of a case series of 3 patients with bilateral retinoblastoma who were treated with ICG-enhanced thermotherapy after showing no response to conventional chemothermotherapy or transpupillary thermotherapy (TTT) alone noted on two consecutive examinations under anesthesia.The 3 patients had had one eye enucleated previously due to advanced disease, and the remaining eye was diagnosed with a large tumor, which showed either a marginal or no response to systemic chemotherapy and TTT. Addition of ICG enhancement during the subsequent TTT session shrunk the tumor to a measurable size that could then be followed by TTT alone as a means of treatment. One patient had tumor recurrence, at which time additional TTT without ICG was successfully applied after the tumor size had decreased; ICG enhancement was then added whenever TTT alone provided no response.ICG enhancement with TTT led to a measurable tumor regression in lesions that had previously not been responsive to traditional chemothermotherapy or isolated TTT.These tumors had shown a minimal to no response to previous TTT treatment. However, adding ICG resulted in a measurable regression even though the same TTT treatment parameters were applied.
View details for DOI 10.1159/000368558
View details for PubMedID 27231688
View details for PubMedCentralID PMC4873706
- Cytomegalovirus retinitis in children and young adults with acute lymphoblastic leukemia in Lebanon LEUKEMIA & LYMPHOMA 2014; 55 (8): 1918-1921
Caregivers' Perception of Drug Administration Safety for Pediatric Oncology Patients
JOURNAL OF PEDIATRIC ONCOLOGY NURSING
2014; 31 (2): 95-103
Medication errors (MEs) are reported to be between 1.5% and 90% depending on many factors, such as type of the institution where data were collected and the method to identify the errors. More significantly, the risk for errors with potential for harm is 3 times higher for children, especially those receiving chemotherapy. Few studies have been published on averting such errors with children and none on how caregivers perceive their role in preventing such errors. The purpose of this study was to evaluate pediatric oncology patient's caregivers' perception of drug administration safety and their willingness to be involved in averting such errors. A cross-sectional design was used to study a nonrandomized sample of 100 caregivers of pediatric oncology patients. Ninety-six of the caregivers surveyed were well informed about the medications their children receive and were ready to participate in error prevention strategies. However, an underestimation of potential errors uncovered a high level of "trust" for the staff. Caregivers echoed their apprehension for being responsible for potential errors. Caregivers are a valuable resource to intercept medication errors. However, caregivers may be hesitant to actively communicate their fears with health professionals. Interventions that aim at encouraging caregivers to engage in the safety of their children are recommended.
View details for DOI 10.1177/1043454213517749
View details for Web of Science ID 000332388600004
View details for PubMedID 24569227
Outcome of Ewing sarcoma in a multidisciplinary setting in Lebanon.
Pediatric blood & cancer
2014; 61 (8): 1472-5
Treatment of Ewing sarcoma (ES) necessitates coordinated multi-disciplinary care. We analyzed outcome for 39 patients treated at a single institution in Lebanon, a developing country with available multidisciplinary treatment modalities, where financial barriers to care are overcome by a fundraising system. Median follow-up was 58 months. Five-year overall and event-free survival were 76% and 58%, respectively, for localized disease, and 40% and 38%, respectively, for metastatic disease. We conclude that, in a country with emerging economy, by following international protocols and ensuring availability of needed resources, outcome of patients with ES is similar to that in developed countries.
View details for DOI 10.1002/pbc.24926
View details for PubMedID 24395458
- Premalignancy and Cellular Senescence TUMOR DORMANCY, QUIESCENCE, AND SENESCENCE, VOL 2: AGING, CANCER, AND NONCANCER PATHOLOGIES 2014: 195-206
A Case of Pitt-Hopkins Syndrome With Absence of Hyperventilation
JOURNAL OF CHILD NEUROLOGY
2013; 28 (12): 1698-1701
Pitt-Hopkins syndrome is characterized by mental retardation, hyperventilation, and dysmorphic features due to TCF4 mutations. We report a case of Pitt-Hopkins syndrome in a 2½-year-old boy presenting with psychomotor retardation, recurrent respiratory tract infections, and dysmorphic features with absence of hyperventilation or other breathing abnormalities. Comparative genomic hybridization and quantitative real-time polymerase chain reaction were used to confirm TCF4 haploinsufficiency. Pitt-Hopkins syndrome is a rare debilitating disease that should be in the differential diagnosis of other neurodevelopmental disorders characterized by mental retardation and hypotonicity despite the absence of hyperapnea and seizures. Quantitative real-time polymerase chain reaction is another method to identify TCF4 and to confirm Pitt-Hopkins syndrome diagnosis.
View details for DOI 10.1177/0883073812468054
View details for Web of Science ID 000326859900024
View details for PubMedID 23248353
Cyclophosphamide and Topotecan as First-line Salvage Therapy in Patients With Relapsed Ewing Sarcoma at a Single Institution
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2013; 35 (5): 356-360
The combination of cyclophosphamide and topotecan (cyclo/topo) has shown objective responses in relapsed Ewing sarcoma, but the response duration is not well documented. We reviewed characteristics and outcome of 14 patients with Ewing sarcoma, treated uniformly at a single institution and offered cyclo/topo at first relapse. Six patients (43%) had relapse at distant sites. All patients received first-line salvage therapy with cyclophosphamide 250 mg/m and topotecan 0.75 mg/m, daily for 5 days repeated every 21 days. The median number of cycles was 4 (range 1 to 10). All toxicities were manageable, the most common being transient cytopenias. There were also 4 episodes of febrile neutropenia, and 3 episodes of gross hematuria. Response was assessable in 13 patients and showed progressive disease in 6 (46%), stable disease in 4 (31%), and partial response in 3 (23%). Nine patients had local control, consisting of radical surgery in 2, radiation in 3, and a combination in 4 patients. Response, when it occurred, was maintained for a median of 8 months (range, 4 to 28 mo). Four patients (29%) are alive at 3, 7, 9, and 110 months after relapse; 1 is receiving cyclo/topo, 1 is on third-line therapy, and 2 are in second and fourth remission. The low toxicity of this combination, and the lack of sustained responses, warrant its investigation in combination with targeted or novel therapeutic agents in relapsed disease.
View details for DOI 10.1097/MPH.0b013e318270a343
View details for Web of Science ID 000323224000015
View details for PubMedID 23042020
Complete heart block in a patient with acute lymphoblastic leukaemia: teicoplanin as a possible cause and review of literature
JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS
2013; 38 (2): 156-158
Teicoplanin is a glycopeptide antibiotic used against documented or presumed methicillin-resistant infections. We report a 31-month-old boy with acute lymphocytic leukaemia who developed permanent complete atrioventricular block (CAVB) necessitating pacemaker insertion after receiving teicoplanin for Staphylococcus epidermidis bacteremia.Clinical assessment of the child revealed febrile neutropenia. After thorough assessment and work-up, the patient was started on teicoplanin intravenously after which he had sudden onset of bradycardia. Electrocardiography showed CAVB that eventually required permanent pacemaker insertion. Twenty-nine months from the incident, the patient is doing well.We report on a case of teicoplanin-associated CAVB in a child with acute lymphoblastic leukaemia (ALL). This is one of only two similar cases reported in the literature. Teicoplanin remains the most probable cause. The use of teicoplanin should be approached cautiously in the setting of immunosuppression. Whether VZV contributed and teicoplanin triggered remains speculative. Physicians should be aware of this possible complication.
View details for DOI 10.1111/jcpt.12002
View details for Web of Science ID 000318164700014
View details for PubMedID 23278346
Calcaneal osteosarcoma: a rare cause of heel pain in the paediatric population.
BMJ case reports
Osteosarcoma is the most common primary non-haemopoietic malignant bone tumour in children and adolescents. However, it rarely occurs in the calcaneus with only a few case reports in the literature. We report a case of a 14-year-old boy with calcaneal osteosarcoma, who presented with heel pain followed by swelling. The pain was initially thought to be related to a benign process and treated with analgesics, delaying the diagnosis. We discuss the clinical presentation, the differential diagnosis, multi-imaging and pathological findings of a calcaneal osteosarcoma, its clinical outcome and the importance of early diagnosis to improve outcome.
View details for DOI 10.1136/bcr-2012-008497
View details for PubMedID 23386499
Congenital infantile fibrosarcoma: Association with bleeding diathesis
AMERICAN JOURNAL OF CASE REPORTS
2013; 14: 481-485
Male, 2 monthCongenital infantile fibrosarcoma Symptoms: Bleeding Medication: Vincristine • actinomycin • cyclophosphamide Clinical Procedure: Surgical resection Specialty: Pediatric Oncology.Diagnostic/therapeutic accidents.Congenital infantile fibrosarcoma (CIF) is a soft-tissue tumor occurring during the first 2 years of life, most commonly in the extremities. CIF is frequently initially misdiagnosed as a vascular tumor, but its association with bleeding and coagulopathy has not been well characterized.We describe 2 infants with CIF presenting with bleeding and coagulopathy, requiring urgent intervention. Both patients did well; one underwent partial resection followed by chemotherapy, and the other received 2 cycles of chemotherapy followed by gross total resection. We also provide a review of all reported cases of coagulopathy in the setting of CIF in the English literature, uncovering an association that seems to be more prevalent in patients diagnosed in the neonatal period, with associated anemia and thrombocytopenia, and a significant mortality rate.CIF needs to be considered in the differential diagnosis of vascular congenital tumors, especially when there is evidence of bleeding, anemia, or thrombocytopenia.
View details for DOI 10.12659/AJCR.889489
View details for Web of Science ID 000421173500121
View details for PubMedID 24265847
View details for PubMedCentralID PMC3835170
Correlation of non-mass-like abnormal MR signal intensity with pathological findings surrounding pediatric osteosarcoma and Ewing's sarcoma
2012; 41 (11): 1453-1461
The aim of this work was to determine the role of MRI in interpreting abnormal signals within bones and soft tissues adjacent to tumor bulk of osteosarcoma and Ewing's sarcoma in a pediatric population by correlating MR findings with histopathology.Thirty patients met the inclusion criteria, which included (1) osteosarcoma or Ewing's sarcoma, (2) MR studies no more than 2 months prior to surgery, (3) presence of abnormal MR signal surrounding the tumor bulk, (4) pathological material from resected tumor. The patients received standard neoadjuvant chemotherapy. Using grid maps on gross pathology specimens, the abnormal MR areas around the tumor were matched with the corresponding grid sections. Histopathology slides of these sections were then analyzed to determine the nature of the regions of interest. The MR/pathological correlation was evaluated using Mann-Whitney U test and Fisher's exact test.Twenty-seven patients had osteosarcoma and three patients had Ewing's sarcoma. Of the studied areas, 17.4% were positive for tumor (viable or necrotic). There was no statistically significant correlation between areas positive for tumor and age, gender, signal extent and intensity on MRI, or tissue type. There was, however, a statistically significant correlation between presence of tumor and the appearance of abnormal soft tissue signals. A feathery appearance correlated with tumor-negative areas whereas a bulky appearance correlated with tumor-positive regions.MR imaging is helpful in identifying the nature of abnormal signal areas surrounding bone sarcomas that are more likely to be tumor-free, particularly when the signal in the soft tissues surrounding the tumor is feathery and edema-like in appearance.
View details for DOI 10.1007/s00256-012-1383-8
View details for Web of Science ID 000308952600014
View details for PubMedID 22406919
Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon
AMERICAN JOURNAL OF HEMATOLOGY
2012; 87 (7): 678-683
With modern risk-adapted therapy, over 80% of children with acute lymphoblastic leukemia (ALL) in high-income countries (HICs) are cured. In countries with limited resources, however, therapy results for pediatric ALL are still not encouraging. We describe our experience in treating children with ALL using a risk-adapted protocol at a tertiary referral center in Lebanon. From May 2002 to August 2009, 111 consecutive patients 1-21 years of age with newly diagnosed ALL received the CCCL ALL protocol which was based on the St. Jude Children's Research Hospital Total XV Study. The median age at diagnosis was 5 years 5 months. The male to female ratio was 1.5. Forty-six patients received the intermediate-/high-risk arm and 65 received the low-risk arm. Only one patient (0.9%) died during induction therapy. Relapse occurred in 8 (7.2%) patients. Eight (7.2%) patients died, 4 of whom were in remission. The median follow-up of the patients was 38 months. The 5-year overall survival and event-free survival were and 88.5% (95% CI: 77.1-94.4) and 78.7% (95% CI: 69.8-88.4), respectively. Our results are comparable to those in HICs in spite of the limited resources and the relatively low socioeconomic status of the Lebanese population. Children treated on this protocol experienced significant toxicity necessitating expert supportive care, but benefited from improved cure rates and prolonged survival.
View details for DOI 10.1002/ajh.23222
View details for Web of Science ID 000305209700007
View details for PubMedID 22565284
Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma
PEDIATRIC BLOOD & CANCER
2012; 58 (6): 877-884
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation.We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts.ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation.Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.
View details for DOI 10.1002/pbc.23246
View details for Web of Science ID 000301656300010
View details for PubMedID 21755593
Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor
2012; 11: 28
Cellular senescence represents a tumor suppressive response to a variety of aberrant and oncogenic insults. We have previously described a transgenic mouse model of Cyclin D1-driven senescence in pineal cells that opposes tumor progression. We now attempted to define the molecular mechanisms leading to p53 activation in this model, and to identify effectors of Cyclin D1-induced senescence.Senescence evolved over a period of weeks, with initial hyperproliferation followed by cell cycle arrest due to ROS production leading to activation of a DNA damage response and the p53 pathway. Interestingly, cell cycle exit was associated with repression of the Cyclin-dependent kinase Cdk2. This was followed days later by formation of heterochromatin foci correlating with RB protein hypophosphorylation. In the absence of the Cdk4-inhibitor p18Ink4c, cell cycle exit was delayed but most cells eventually showed a senescent phenotype. However, tumors later arose from this premalignant, largely senescent lesion. We found that the p53 pathway was intact in tumors arising in a p18Ink4c-/- background, indicating that the two genes represent distinct tumor suppressor pathways. Upon tumor progression, both p18Ink4c-/- and p53-/- tumors showed increased Cdk2 expression. Inhibition of Cdk2 in cultured pre-tumorigenic and tumor cells of both backgrounds resulted in decreased proliferation and evidence of senescence.Our findings indicate that the p53 and the RB pathways play temporally distinct roles in senescence induction in Cyclin D1-expressing cells, and that Cdk2 inhibition plays a role in tumor suppression, and may be a useful therapeutic target.
View details for DOI 10.1186/1476-4598-11-28
View details for Web of Science ID 000311440600001
View details for PubMedID 22548705
View details for PubMedCentralID PMC3497584
Rhabdomyosarcoma Treatment and Outcome at a Multidisciplinary Pediatric Cancer Center in Lebanon
PEDIATRIC HEMATOLOGY AND ONCOLOGY
2012; 29 (4): 322-334
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Outcome of patients treated on standard protocols, in a multidisciplinary cancer center setting outside of clinical trials, is not well reported. We reviewed characteristics and outcome of 23 pediatric patients treated at a single, multidisciplinary cancer center in Lebanon, between April 2002 and December 2010. Median follow-up was 41 months. The most commonly affected primary site was the head and neck (48%, n = 11). Nineteen tumors (82.6%) were of embryonal histology. Tumor size was ≥5 cm in eight (34.8%) patients. Sixteen patients (69.6%) had localized disease, and one (4.4%) had metastatic disease. Fifteen (65.2%) had Group III tumors. All patients received chemotherapy, for a duration ranging 21-51 weeks. Upfront surgical resection was performed in 10 patients (43.5%). Eighteen patients (78.3%) received radiation therapy. The 5-year overall and disease-free survival rates were 83% and 64%, respectively. Relapse correlated with absence of surgery. Treatment of childhood RMS in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. There was a higher incidence of local relapse, but those were salvageable with further therapy and surgical local control.
View details for DOI 10.3109/08880018.2012.676721
View details for Web of Science ID 000303832800004
View details for PubMedID 22568795
Senescence and pre-malignancy: How do tumors progress?
SEMINARS IN CANCER BIOLOGY
2011; 21 (6): 385-391
Cellular senescence is a tumor suppressor response that has been observed both in vitro and in vivo, and features of senescence have been documented in various human premalignant lesions, including melanoma, colon and lung adenoma, prostatic intraepithelial neoplasia, and others. The fact that a subset of these lesions eventually progress to malignant invasive tumors suggests that premalignant cells can either bypass or escape the senescent response. Much work has been done to understand the mechanisms underlying such progression, but it remains unclear whether tumors progress by evasion of senescence induction, or by disruption of senescence maintenance, or whether both mechanisms can occur in human cancer development. This review presents the current evidence for mechanisms of senescence evasion and reversion, and discusses what has been learnt about this process using in vitro and in vivo experimental systems. As we learn more about the key signaling effectors of senescence, the hope is that appropriate targets will be identified for preservation and/or re-induction of senescence in human tumors. Such knowledge may also find application in better estimation of risks of cancer progression in individual premalignant lesions, which will lead to more accurate allocation of appropriate treatment options for such patients.
View details for DOI 10.1016/j.semcancer.2011.09.013
View details for Web of Science ID 000298571300007
View details for PubMedID 21982725
Thrombosis in Children with Acute Lymphoblastic Leukemia Treated at a Tertiary Care Center in Lebanon: Revisiting the Role of Predictive Models
PEDIATRIC HEMATOLOGY AND ONCOLOGY
2011; 28 (8): 676-681
The incidence of symptomatic venous thromboembolism (VTE) in children receiving therapy for acute lymphoblastic leukemia (ALL) varies widely and is protocol dependent. The authors herein report the incidence and potential risk factors for VTE in children with ALL while being treated on a uniform protocol at a single tertiary care center in Lebanon. The authors also examine necessary modifications in a recently published model before it could predict VTE in their patients.
View details for DOI 10.3109/08880018.2011.578705
View details for Web of Science ID 000296154800007
View details for PubMedID 21787123
Bereaved Parental Evaluation of the Quality of a Palliative Care Program in Lebanon
PEDIATRIC BLOOD & CANCER
2011; 57 (2): 310-316
Palliative care (PC) is important in Pediatric Oncology as more than 20% of children with cancer still die despite modern treatment. As a significant number of children reside in countries with limited resources; more research in PC is needed there. This study aimed at evaluating the quality of care provided to children with cancer at the Children's Cancer Center of Lebanon (CCCL) during their last month of life as perceived by the bereaved parents.Between 2002 and 2007, 76 children with cancer treated at CCCL succumbed to their disease. Twenty-nine of the bereaved parents were interviewed at home about the symptoms and suffering experienced by their children during the last month of life, communication with the healthcare team, quality of care delivered, and recommendations for improving care.Fatigue, anorexia, and pain were the most prevalent symptoms and edema was the most distressing. The overall communication with the healthcare team and the overall quality of care delivered was rated as "very good" to "excellent" by 86.2% and 93.1% of the participants, respectively. Parents suggested improving the organization of care, the communication, and the availability of human and material resources.This study is the first conducted in Lebanon to evaluate the quality of pediatric palliative care (PPC). The parents' experiences in our country were similar to those described in other countries, religions, and cultures. Significant strengths and weaknesses in the management of the dying children, from the parents' perspective, were uncovered and recommendations for improving practice were made.
View details for DOI 10.1002/pbc.23082
View details for Web of Science ID 000292301400024
View details for PubMedID 21394892
MYOGENESIS AND RHABDOMYOSARCOMA: THE JEKYLL AND HYDE OF SKELETAL MUSCLE
CANCER AND DEVELOPMENT
2011; 94: 197-234
Rhabdomyosarcoma, a neoplasm composed of skeletal myoblast-like cells, represents the most common soft tissue sarcoma in children. The application of intensive chemotherapeutics and refined surgical and radiation therapy approaches have improved survival for children with localized disease over the past 3 decades; however, these approaches have not improved the dismal outcome for children with metastatic and recurrent rhabdomyosarcoma. Elegant studies have defined the molecular mechanisms driving skeletal muscle lineage commitment and differentiation, and the machinery that couples differentiation with irreversible cell proliferation arrest. Further, detailed molecular analyses indicate that rhabdomyosarcoma cells have lost the capacity to fully differentiate when challenged to do so in experimental models. We review the intersection of normal skeletal muscle developmental biology and the molecular genetic defects in rhabdomyosarcoma with the underlying premise that understanding how the differentiation process has gone awry will lead to new treatment strategies aimed at promoting myogenic differentiation and concomitant cell cycle arrest.
View details for DOI 10.1016/13978-0-12-380916-2.00007-3
View details for Web of Science ID 000287717300007
View details for PubMedID 21295688
- L-ASPARAGINASE-INDUCED PANCREATITIS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA: Is Allopurinol Protective? PEDIATRIC HEMATOLOGY AND ONCOLOGY 2010; 27 (6): 496-501
Seven-Year Experience of Using Repiphysis (R) Expandable Prosthesis in Children With Bone Tumors
PEDIATRIC BLOOD & CANCER
2010; 55 (3): 457-463
Results of the use of the non-invasive expandable endoprosthetic device Repiphysis in limb salvage surgery for skeletally immature children with bone cancer have been promising.In this report, we analyze the outcomes and complications associated with using 17 Repiphysis prosthesis from January 2002 to March 2009 in 17 skeletally immature children with bone sarcoma around the knee.The average follow-up was 61.7 months. All patients who underwent active expansion experienced successful lengthening with a total of 38 lengthening sessions and an average of 8.6 mm gained per session. The Musculoskeletal Tumor Society functional scores averaged 90% at the most recent follow-up. The average survival time of the device from implementation to revision or last follow-up was 2 years and 8 months. There were 12 complications in 12 patients, including 6 mechanical problems, 2 tibial fractures and 3 infections. For the 17 insertions, 7 revision operations were performed, 3 of which were done using a new Repiphysis device.Despite the high rate of complications, the goal of achieving equal leg length at skeletal maturity with fewer surgeries per patient has been relatively achieved with the use of this device.
View details for DOI 10.1002/pbc.22598
View details for Web of Science ID 000280438600012
View details for PubMedID 20658617
Zinc and biotin deficiencies after pancreaticoduodenectomy
ACTA GASTRO-ENTEROLOGICA BELGICA
2010; 73 (2): 283-286
We report zinc and biotin deficiencies after pancreaticoduodenectomy in a 16 year old female presenting clinically with marked alopecia, total body hair loss, dry skin with scales, and maculopathy with significant vision loss. These micronutrient deficiencies likely occurred due to resection of the duodenum and proximal jejunum, sites of primary absorption of several micronutrients and their protein carriers, including zinc and biotin. Early diagnosis is essential to prevent irreversible sequelae. Adequate supplementation of zinc and biotin as well as dietary advice is needed for clinical improvement.
View details for Web of Science ID 000280316400015
View details for PubMedID 20690572
Severe Cerebral Vaso-Occlusive Disease in Macrophage Activation Syndrome
2010; 42 (4): 283-286
A 14-year-old girl was diagnosed with macrophage activation syndrome, based on clinical presentation, laboratory tests, and bone marrow aspirate findings. She developed severe central nervous system involvement in the form of seizure disorder and severe diffuse occlusive cerebral vasculopathy, with extensive collateral circulation consistent with moyamoya disease. To our knowledge, this description is the first of these findings in association with macrophage activation syndrome.
View details for DOI 10.1016/j.pediatrneurol.2009.11.007
View details for Web of Science ID 000276340400010
View details for PubMedID 20304334
Pulmonary Hypertension in Children and Young Adults With Sickle Cell Disease: Evidence for Familial Clustering
PEDIATRIC BLOOD & CANCER
2010; 54 (3): 398-402
Pulmonary hypertension (PHTN) is increasingly recognized as a serious complication of sickle cell disease (SCD). Our objective was to determine the prevalence of PHTN and identify factors associated with PHTN among children and young adults with SCD in Lebanon.From June 2004 to June 2008, 90 patients were studied. Correlation of TRV with LDH, mean corpuscular volume (MCV), fetal hemoglobin (HbF), hydroxyurea use, and G6PD deficiency was performed. Transthoracic Doppler echocardiography was performed during steady-state at each patient's initial visit and yearly thereafter. PHT was defined as a tricuspid regurgitant jet velocity (TRV) > or =2.5 m/sec.Twenty-seven patients (31.8%) were found to have PHTN. They had significantly higher LDH levels (P = 0.008) and MCV (P = 0.024). There was a higher percentage of patients on hydroxyurea in the group with PHTN (78% vs. 50%, P = 0.015). Furthermore, five children, mean age 9.8 years (range, 6-13 years), with initially normal TRV developed PHTN while on hydroxyurea for at least 3 years, at a mean dose of 19.2 mg/kg/day (range, 14-24). PHTN clustered in families and was found in all members with SCD in 7 of the 21 families studied; they contributed 16 of the 27 patients with PHTN. None of the 21 patients with PHTN were G6PD deficient compared to 4 of 36 without PHTN.PHTN was common, associated with increased hemolysis but not G6PD deficiency, and clustered in families. Moreover, PHTN developed despite hydroxyurea therapy in five patients.
View details for DOI 10.1002/pbc.22306
View details for Web of Science ID 000274421400013
View details for PubMedID 19827138
Cellular Senescence: Many Roads, One Final Destination
2010; 10: 727-741
Cellular senescence is a tumor-suppressor mechanism that has been shown to occur in response to multiple signals, including oncogenic stress, DNA damage, oxidative stress, telomere shortening, and other tumor-promoting insults. Over the past decade, much has been uncovered regarding the phenotype of this tumor-suppressor response and the underlying pathways necessary for its establishment. However, we have also learned that the intricate details of signaling pathways underlying senescence as a tumor-suppressor response are very much context dependent. In addition, cross-talk among pathways, and negative and positive feedback loops, all complicate our understanding of this process. This short review attempts to summarize what is known to date regarding senescence in tumor suppression, both in vitro and in vivo. Further insights into pathways necessary for senescence will hopefully identify appropriate targets for interventions to not only induce senescence as a treatment of cancerous lesions, but also to maintain this state in premalignant lesions in an effort to prevent progression to cancer.
View details for DOI 10.1100/tsw.2010.68
View details for Web of Science ID 000276795500009
View details for PubMedID 20419281
View details for PubMedCentralID PMC5763822
Wernicke's Encephalopathy during Total Parenteral Nutrition in a Child with Acute Lymphoblastic Leukemia and Acute Pancreatitis
2009; 40 (5): 249-251
We herein describe a 16-year-old child with acute lymphoblastic leukemia and acute pancreatitis who developed Wernicke's encephalopathy secondary to prolonged total parenteral nutrition (TPN) that lacked vitamin B1 supplementation. The patient showed a direct and complete response to thiamine therapy. Diagnostic challenges are discussed and recommendations for prophylactic vitamin B1 supplementation in children with leukemia who are placed on TPN are made.
View details for DOI 10.1055/s-0030-1248244
View details for Web of Science ID 000275698300010
View details for PubMedID 20221964
Renal venous thrombosis in a newborn with prothrombotic risk factors
BLOOD COAGULATION & FIBRINOLYSIS
2009; 20 (6): 458-460
Renal venous thrombosis (RVT) is a rare but a well recognized entity in children and neonates. The clinical signs of neonatal RVT include hypertension, enlarged kidney(s), hematuria, renal insufficiency, proteinuria, thrombocytopenia, or all. Persisting impairment of kidney function and hypertension are serious and common complications in patients with RVT. Risk factors for the development of RVT include maternal diabetes mellitus, pathologic states associated with thrombosis (e.g., shock, dehydration, perinatal asphyxia, polycythemia), and sepsis. Inherited prothrombotic abnormalities have been described in some reports of RVT. We report the case of a male newborn with left RVT and associated homozygosity for both factor V Leiden (G1691A) and methylenetetrahydrofolate reductase C677T mutations in addition to elevated serum lipoprotein (a). The patient was treated with heparin. We believe our case to be the first reported case in the English medical literature of such an association between neonatal RVT and homozygosity for both factor V Leiden and methylenetetrahydrofolate reductase. This case and other studies clearly demonstrate that neonatal RVT should be evaluated for thrombophilia conditions.
View details for DOI 10.1097/MBC.0b013e32832ca3d8
View details for Web of Science ID 000269330200013
View details for PubMedID 19542880
Comparing Children and Adults With Synovial Sarcoma in the Surveillance, Epidemiology, and End Results Program, 1983 to 2005 An Analysis of 1268 Patients
2009; 115 (15): 3537-3547
Synovial sarcoma (SS) is a typical soft tissue sarcoma subtype crosswise between the pediatric and the adult age groups. Less satisfactory overall outcome has been recorded in adult series.This study compares clinical features and outcomes of SS across the different age groups, by analyzing 1268 cases, 213 children/adolescents (
View details for DOI 10.1002/cncr.24424
View details for Web of Science ID 000268060500022
View details for PubMedID 19514087
Expression of the Arf tumor suppressor gene is controlled by Tgf beta 2 during development
2009; 136 (12): 2081-2089
The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by ;abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous (PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor beta2 (Tgfbeta2) might control Arf expression, as we show that mice lacking Tgfbeta2 have primary vitreous hyperplasia similar to Arf(-/-) mice. Consistent with a potential linear pathway, Tgfbeta2 induces Arf transcription and p19(Arf) expression in cultured mouse embryo fibroblasts (MEFs); and Tgfbeta2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by beta-galactosidase activity in Arf(lacZ/+) mice, we show that Tgfbeta2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgfbeta receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1beta. In summary, Tgfbeta2 and p19(Arf) act in a linear pathway during embryonic development. We present the first evidence that p19(Arf) expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.
View details for DOI 10.1242/dev.033548
View details for Web of Science ID 000266296400012
View details for PubMedID 19465598
View details for PubMedCentralID PMC2685726
- First-Line Therapy of Generalized Infantile Myofibromatosis With Low-Dose Vinblastine and Methotrexate PEDIATRIC BLOOD & CANCER 2009; 52 (2): 308
p18(Ink4c) and p53 Act as Tumor Suppressors in Cyclin D1-Driven Primitive Neuroectodermal Tumor
2009; 69 (2): 440-448
The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to approximately 4 months. Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.
View details for DOI 10.1158/0008-5472.CAN-08-1892
View details for Web of Science ID 000262582900011
View details for PubMedID 19147556
View details for PubMedCentralID PMC2629408
Familial infantile pyknocytosis in association with pulmonary hypertension
PEDIATRIC BLOOD & CANCER
2008; 51 (2): 290-292
Infantile pyknocytosis is a rare condition characterized by transient neonatal hemolytic anemia associated with increased pyknocyte count on blood smear. We describe three siblings with infantile pyknocytosis, born to consanguineous parents. The first and third siblings had neonatal hemolytic anemia that resolved spontaneously at 6 months. The second sibling presented at 11 days with severe hemolytic anemia along with pulmonary hypertension. He died at 39 days from sepsis. The findings support a possible autosomal recessive inheritance. We hypothesize that pulmonary hypertension may be secondary to or aggravated by neonatal hemolysis.
View details for DOI 10.1002/pbc.21583
View details for Web of Science ID 000256871800027
View details for PubMedID 18421717
Epidemiology and management options for colorectal cancer in children.
2008; 10 (3): 177-92
Colorectal carcinoma (CRC), although primarily a disease of adulthood, accounts for 2% of malignancies in adolescents and has been reported in children as young as 9 months of age. Our knowledge of CRC in pediatrics is based on a handful of case series and case reports. Apart from one small clinical trial, there has been a lack of prospective clinical studies in this age group. Based on these published reports, most CRC in children is sporadic, but it can also arise in the setting of predisposing conditions, such as gastrointestinal polyposis syndromes, nonpolyposis familial cancer syndromes, and inflammatory bowel disease. Despite some similarities to adult disease, CRC in childhood may be intrinsically different biologically, because it differs from adult-onset CRC in several respects. Childhood CRC tends to be diagnosed at an advanced stage, is largely of mucinous histology, and (probably because of these features) tends to have a poorer outcome. As a result of its rarity in children and the lack of prospective pediatric studies, recommendations for therapy are primarily extrapolated from adult clinical trials. A review of pediatric case series in the English literature emphasizes the prognostic significance of stage of disease, as well as extent of surgical resection. As in adults, early detection is critical in an effort to capture the disease at less advanced stages. Complete surgical resection with aggressive lymph node dissection is essential for cure, and neoadjuvant chemotherapy may be used in an effort to render unresectable lesions resectable. Active agents in adults with CRC include fluorouracil, folinic acid (leucovorin), oxaliplatin, and irinotecan. Furthermore, newer targeted therapeutic agents, such as bevacizumab and cetuximab, have added additional efficacy to the standard chemotherapy backbone. Collaborative multi-institutional pediatric clinical trials are needed to evaluate the prognosis, optimal treatment response, and the basic biology of childhood onset CRC.
View details for DOI 10.2165/00148581-200810030-00006
View details for PubMedID 18454570
Desmoplastic small round cell tumor in childhood: The St. Jude Children's Research Hospital experience
PEDIATRIC BLOOD & CANCER
2007; 49 (3): 274-279
Desmoplastic small round cell tumor (DSRCT) is a rare, primarily intra-abdominal tumor that has a poor outcome with current therapies.We retrospectively reviewed patient characteristics, presenting symptoms, tumor pathology, treatment, and outcome of 11 pediatric patients with DSRCT at our institution.The cohort included 1 female and 10 male patients. Median age at diagnosis was 14 years (range 5-21 years). In eight (73%) patients, the primary tumor was abdominal or pelvic, and in one patient each, it was submental, mediastinal, and paratesticular. Nine (82%) patients had metastatic disease. All tumors showed polyphenotypic differentiation by immunohistochemistry. The EWS-WT1 transcript was detected in six of seven tumors tested. One tumor showed rhabdomyoblastic differentiation after therapy. All patients received chemotherapy; eight underwent surgical resection, seven received primary site radiation, and four received myeloablative chemotherapy with stem-cell support. Three (27%) patients are alive 23 months, 8 years, and 10 years from diagnosis. Two died of treatment-related toxicity, six died of disease. None of the patients in whom surgery and initial chemotherapy failed to induce complete remission survived.DSRCT is an aggressive malignancy that does not respond well to contemporary treatments, and patients who do not enter complete remission after initial chemotherapy and surgery appear to have a particularly dismal outcome. Patients with localized extra-abdominal disease have a better prognosis, most likely due to increased feasibility of resection. Better understanding of molecular and genetic mechanisms of tumorigenesis and treatment-related changes may contribute to development of more effective therapy for DSRCT.
View details for DOI 10.1002/pbc.20893
View details for Web of Science ID 000248536800010
View details for PubMedID 16685737
Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells
MOLECULAR CANCER THERAPEUTICS
2006; 5 (5): 1299-1308
Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D-dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C12 myoblasts arrested in G(1) phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G(1) cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G(1) arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma.
View details for DOI 10.1158/1535-7163.MCT-05-0383
View details for Web of Science ID 000238073800024
View details for PubMedID 16731763
Osteosarcoma of the pelvis in children and young adults: The St. Jude children's research hospital experience
WILEY-BLACKWELL. 2005: 1468-1474
Pelvic osteosarcomas are difficult to resect. The authors reviewed their institution's experience with patients who had such tumors to characterize the patients' clinical findings and to assess the impact of surgical resection on outcome.A review was conducted of the records from patients with pelvic osteosarcoma who were treated at the authors' institution between January, 1970 and March, 2004.Among 442 patients with osteosarcoma, 19 patients (4%) had high-grade tumors arising in the pelvic bones, including the ilium in 15 patients, the pubis in 2 patients, and the sacrum in 2 patients. The median patient age at diagnosis was 16.8 years. Four tumors were secondary to radiation therapy. Five patients had metastases in the lung (n = 4 patients) or bone (n = 1 patient) at diagnosis. Ten tumors were chondroblastic. The median greatest tumor dimension for the 13 tumors with known size was 10 cm. Ten patients had unresectable pelvic tumors, and 9 patients underwent hemipelvectomy (2 internal and 7 external); complete resection with negative margins was achieved in 5 patients. Four patients survived, including one patient who survived with disease. Of the three patients who survived disease-free, one patient underwent complete resection, one patient underwent incomplete resection (nonviable tumor at the soft tissue margin) with a good response to chemotherapy, and one patient with a sacral tumor underwent radiotherapy only for local control. Of the 9 patients who underwent resection, 7 experienced disease recurrence (n = 5 patients) or progression (n = 2 patients) at distant sites and died. All patients with metastatic disease at diagnosis died.Pelvic osteosarcomas often were large and unresectable. A high propensity for metastasis contributed to the poor outcome of patients with pelvic osteosarcoma. New therapeutic approaches are needed.
View details for DOI 10.1002/cncr.20959
View details for Web of Science ID 000227770400021
View details for PubMedID 15739209
Efficacy of intravenous immunoglobulin in Landau-Kleffner syndrome
2002; 26 (4): 298-300
We administered 2 gm/kg of intravenous gamma globulin (IVIG) to each of five consecutive patients with Landau-Kleffner syndrome, over 4 days. We compared the 1-month baseline to that following IVIG using a severity score assessing speech, comprehension, behavior, seizures, and electroencephalography. There was a significant drop in this score after IVIG (P = 0.025). Two patients had a dramatic response to IVIG, with complete resolution of symptoms. This finding suggests that IVIG has at least some efficacy for the therapy of Landau-Kleffner syndrome.
View details for DOI 10.1016/S0887-8994(01)00402-7
View details for Web of Science ID 000175513900007
View details for PubMedID 11992758
Successful use of intravenous immunoglobulin as initial monotherapy in Landau-Kleffner syndrome
2000; 41 (7): 880-886
There is a need for new and more effective therapies for Landau-Kleffner syndrome. In this article we present the first case in which a patient with Landau-Kleffner syndrome was given intravenous immunoglobulin (IVIG) as his first and only therapy and responded to it.This previously healthy, left-handed boy presented at 31 months of age with a 3-month history of auditory agnosia, behavioral abnormalities, and progressive, eventually complete loss of speech. Electroencephalography (EEG) showed frequent and, in sleep, continuous right central and temporal spike slow wave discharges. Metabolic workup, magnetic resonance imaging, and auditory evoked potentials were normal. Cerebrospinal fluid IgG index was high (18%). The patient was treated with IVIG, as his initial and only therapy, receiving 500 mg/kg/day over four consecutive days.On the third day of IVIG, the patient started using single words, and on the fourth, two-word sentences. Two weeks later his speech and behavior returned to normal. At the end of 4 days of IVIG therapy, EEG was within normal limits. Two months later, however, he had a severe relapse clinically and by EEG. He promptly responded to another course of IVIG. A subsequent cerebrospinal fluid IgG index showed normalization (6%). Three months later he had essentially normal speech and behavior.Repeated, immediate, and remarkable clinical and EEG responses of this patient suggest that IVIG was helpful as first-line therapy in the treatment of Landau-Kleffner syndrome. It also supports the hypothesis that immunological mechanisms contributed to his symptoms.
View details for DOI 10.1111/j.1528-1157.2000.tb00257.x
View details for Web of Science ID 000087947400015
View details for PubMedID 10897161