Long-term follow-up of children treated with the Repiphysis expandable prosthesis for lower extremity bone sarcoma.

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).

A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

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.

Lay abstract This study aimed at uncovering variants in the genetic material of Arab children, that might predispose them to develop a specific treatment-related adverse effect, during their therapy for acute lymphoblastic leukemia (a type of blood cancer). We looked at specific changes in the DNA of our patient cohort that might predispose them to develop treatment-induced osteonecrosis. Osteonecrosis is by definition a loss of blood flow to the bone tissue in one's body, causing the bone to die. Osteonecrosis may be caused by long-term exposure to steroid-based medication, among which dexamethasone. Dexamethasone a main component of the combination of chemotherapeutic agents used to treat acute lymphoblastic leukemia. Our findings suggested that children who had one of the variants detected in a specific location of DNA, the GRIN3A gene, were more likely to develop osteonecrosis earlier and had to stop dexamethasone earlier during therapy.

Treatment-induced cerebral sinus venous thrombosis in childhood acute lymphoblastic malignancies: New risk factors to consider.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Implementation of Pharmacogenetics to Individualize Treatment Regimens for Children with Acute Lymphoblastic Leukemia.

Despite major advances in the management and high cure rates of childhood acute lymphoblastic leukemia (ALL), patients still suffer from many drug-induced toxicities, sometimes necessitating dose reduction, or halting of cytotoxic drugs with a secondary risk of disease relapse. In addition, investigators have noted significant inter-individual variability in drug toxicities and disease outcomes, hence the role of pharmacogenetics (PGx) in elucidating genetic polymorphisms in candidate genes for the optimization of disease management. In this review, we present the PGx data in association with main toxicities seen in children treated for ALL in addition to efficacy, with a focus on the most plausible germline PGx variants. We then follow with a summary of the highest evidence drug-gene annotations with suggestions to move forward in implementing preemptive PGx for the individualization of treatment regimens for children with ALL.

Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon.

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.

Clinical Prognostic Factors and Outcome in Pediatric Osteosarcoma: Effect of Delay in Local Control and Degree of Necrosis in a Multidisciplinary Setting in Lebanon.

PURPOSE: 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. PATIENTS AND METHODS: 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%). RESULTS: 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. CONCLUSION: 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.

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.

OBJECTIVE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cerebral sinus venous thrombosis during childhood acute lymphoblastic leukemia therapy: Risk factors and management.

BACKGROUND: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

BACKGROUND: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.

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 (ß=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 (ß=-4.905; 95% CI: -9; -0.809 and ß=-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.

Thrombosis in children with acute lymphoblastic leukemia treated at a tertiary care center in Lebanon: revisiting the role of predictive models.

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.

Severe hypoglycemic seizures in a child receiving 6-mercaptopurine.

A 4-year-old boy with acute lymphoblastic leukemia who was receiving 6-mercaptopurine during the maintenance chemotherapy experienced prolonged generalized tonic nocturnal seizures because of severe hypoglycemia after his evening dose by a 12-hour period of fasting. Investigations ruled out all causes of these seizures other than the 6-mercaptopurine-induced severe hypoglycemia.

Seven-year experience of using Repiphysis expandable prosthesis in children with bone tumors.

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.

Essential thrombocythemia with myelofibrosis transformed into acute myeloid leukemia with der(1;15)(q10;q10): case report and literature review.

Translocations involving chromosomes 1 and 15 are uncommon in hematologic malignancies. So far, only 42 cases have been reported with t(1;15) as a reciprocal or complex chromosomal abnormalities. We herein report the first case in the literature, to our knowledge, of a 44-year-old female with essential thrombocythemia and severe myelofibrosis who developed acute myeloid leukemia (AML-M4) with der(1;15)(q10;q10) after 13 years of treatment. In addition, we reviewed the literature for all up-to-date published cases with t(1;15).

Severe cerebral vaso-occlusive disease in macrophage activation syndrome.

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.

Morvan syndrome following B-cell lymphoma.

Morvan syndrome is a rare autoimmune disease named after the French physician Augustin Marie Morvan. It is characterized by multiple, irregular contractions of the long muscles, weakness, pruritus, hyperhidrosis, insomnia, and delirium. Here, we describe a 17-year-old young man, previously diagnosed with B-cell lymphoma, who presented with multiple asynchronous fasciculations of the long muscles of his lower extremities accompanied by numbness. The patient responded initially to pulse corticosteroids with diminution of the fasciculations. He achieved complete remission following 7 consecutive, monthly intravenous immunoglobulin injections. The present case is described in the context of the available literature.

Use of recombinant activated factor VII for intractable bleeding in patients without hemophilia: A developing country tertiary care center's experience.

Although the use of recombinant activated factor VII (rFVIIa) to control intractable bleeding in nonhemophiliac patients is expanding, several issues pertinent to its potential thrombotic complications and effect on patient mortality are still of concern. We herein describe our experience at a developing country tertiary care center over a period of 4 years. A total of 49 patients were identified of whom 28.6% belong to the pediatric age group. The most common bleeding settings were intracerebral hemorrhage, abdominal aortic surgery, general surgery, and disseminated intravascular coagulopathy. All patients achieved cessation or significant reduction in bleeding. Only 1 patient had a documented postuse thrombotic complication. Of the whole group, 12 patients (24.4%) eventually died with only 1 death having a possible association to rFVIIa use. There was a statistically significant reduction in the need for blood product transfusion after the use of rFVIIa. The use of rFVIIa was in accordance with the hospital's algorithm (identifying salvageable patients, preconditioning, blood product replacement, and dosing) in 30 (61.2%) patients. We conclude that rFVIIa should continue to be considered in nonhemophiliac patients failing to respond to conventional measures of bleeding control. However, this off-label use should be coupled with strict adherence to the treatment algorithms, which remains essential in developing countries with limited health care resources.

Pulmonary hypertension in children and young adults with sickle cell disease: evidence for familial clustering.

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: PHTN was common, associated with increased hemolysis but not G6PD deficiency, and clustered in families. Moreover, PHTN developed despite hydroxyurea therapy in five patients.

Familial infantile pyknocytosis in association with pulmonary hypertension.

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.

Primary malignant peripheral nerve sheath tumor of the lung in a young child without neurofibromatosis type 1.

Malignant peripheral nerve sheath tumors (MPNST) are uncommon in children and almost half of the cases occur in patients with neurofibromatosis 1 (NF1). We report a child with a primary MPNST of the lung without NF1. MPNST of the lung has similar clinical and radiologic characteristics as pleuropulmonary blastoma. We suggest to include MPNST of the lung in the differential diagnosis of intrapulmonary masses in children.