Hassan El Solh

Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia.

Background The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance. Materials and methods This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude’s Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase. Results Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 µmol/l (&bgr;=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (&bgr;=−4.905; 95% CI: −9; −0.809 and &bgr;=−5.770; 95% CI: −10.138; −1.403), respectively. Conclusion Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.

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.

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.

Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes

BACKGROUND AND OBJECTIVES Stem cells from umbilical cord blood (CB) have increasingly become a viable alternate source of progenitor cells for hematopoietic cell transplantation (HSCT). Cytomegalovirus (CMV) is thought to contribute significantly to HSCT morbidity and mortality. DESIGN AND SETTING Retrospective case-control study in patients at tertiary care center. PATIENTS AND METHODS We determined the incidence, risk factors and outcomes for CMV infection and disease after unrelated cord blood transplantation (UCBT) in children. RESULTS Between 2003 and 2007, 73 pediatric patients underwent UCBT and 68% of recipients were CMV seropositive. The overall incidence of CMV infection, early and late CMV infection was 58.9% (43/73), 62.8% (27/43), and 37.4% (16/43), respectively. in patients with early CMV infection, 6 of 27 (22%) patients progressed to develop CMV end-organ disease including pneumonitis and retinitis. High levels CMV antigenemia ≥70 infected cells by pp65 antigenemia assay + PMNs, P=.237) were associated with a higher risk of progression to CMV disease. The development of CMV infections was higher in CMV-seropositive recipients (P<.001) and in those who developed graft-versus-host-diseases (GVhD) (P<.001). other risk factors for CMV infection include the use of high-dose corticosteroids (P<.001) and older age of the recipient at the time of transplant (P<.002). Late CMV infection was strongly associated with a previous history of early CMV infection (P<.001). CONCLUSION CMV infection is a significant complication in UCBT recipients in pediatric patients and is associated with an increase in transplant-related morbidity and mortality. Risk factors for CMV infections after UCBT include GvHD, use of corticosteroids, underlying diseases (hematologic malignancies) and older age. Late CMV infection was strongly associated with a previous history of CMV infection.

Effect of Malnutrition at Diagnosis on Clinical Outcomes of Children With Acute Lymphoblastic Leukemia.

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.

Approach to Non-Neutropenic Fever in Pediatric Oncology Patients-A Single Institution Study.

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.

Displaced children with cancer in Lebanon: A sustained response to an unprecedented crisis

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.

Wilms tumor: Successes and challenges in management outside of cooperative clinical trials

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 Childrens 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.

Congenital infantile fibrosarcoma: Association with bleeding diathesis

Patient: Male, 2 month Final Diagnosis: Congenital infantile fibrosarcoma Symptoms: Bleeding Medication: Vincristine • actinomycin • cyclophosphamide Clinical Procedure: Surgical resection Specialty: Pediatric Oncology Objective: Diagnostic/therapeutic accidents Background: 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. Case Reports: 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. Conclusions: CIF needs to be considered in the differential diagnosis of vascular congenital tumors, especially when there is evidence of bleeding, anemia, or thrombocytopenia.

Routine surveillance imaging after end of therapy for pediatric extracranial tumors: A retrospective analysis

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.