Functional and oncological outcomes of patients with proximal humerus osteosarcoma managed by limb salvage.

BACKGROUND: Osteosarcoma is the most common primary bone malignancy in skeletally immature patients. The proximal humerus is the third most common site of osteosarcoma. The literature shows a paucity of published data concerning the outcome of proximal humerus osteosarcoma managed by limb salvage. The purpose of this study was to answer the following questions: (1) do patients with proximal humerus osteosarcoma managed by limb salvage and neoadjuvant chemotherapy show good functional and oncological outcomes, and (2) are there any prognostic factors that are associated with better oncological and functional outcomes? MATERIALS AND METHODS: The study was a retrospective case series study assessing the overall outcome of 34 patients with proximal humerus osteosarcoma. Eighteen patients were males (53%) while 16 were females. Biological reconstruction was done in 15 patients (44%), while nonbiological reconstruction was done in 19 patients. Resections were mainly intraarticular (82%). Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) score, while oncological outcome was assessed based on local recurrence and development of chest metastasis. Comparisons between quantitative variables were done using the nonparametric Mann-Whitney test. To compare categorical data, the chi-square (χ2) test was performed. The exact test was used instead when the expected frequency was less than 5. Correlations between quantitative variables were examined using the Spearman correlation coefficient. RESULTS: The mean MSTS score was 25.5 (range 23-29). A younger age was statistically correlated with a poorer MSTS score (P = 0.0016). Six patients out of 34 (17.6%) had local recurrence and four of them (67%) were treated by forequarter amputation. 41% of patients developed chest metastasis, and the majority of them were treated by chemotherapy (71%). In comparison with patients with osteosarcoma at other sites who were also managed in our institution, proximal humerus osteosarcoma patients showed higher incidence rates of local recurrence and chest metastasis along with lower 5-year patient and limb survivorships compared to distal femur, proximal tibia and proximal femur osteosarcoma patients. CONCLUSION: Treatment of osteosarcoma of the proximal humerus by limb salvage and chemotherapy yields a good functional outcome. The method of reconstruction does not impact the resultant function. The 5-year survivorship of these patients is 65%. Younger patients have a better oncological outcome and an inferior functional outcome. LEVEL OF EVIDENCE: Level IV therapeutic study.

Functional and Oncological Outcome of Patients with Distal Femoral Osteosarcoma Managed by Limb Salvage Using Modular Endoprosthesis.

BACKGROUND: The aim of the study was to assess the functional and oncological outcomes of patients with distal femoral osteosarcoma managed by limb salvage using modular endoprosthesis as well as to assess related complications. PATIENTS AND METHODS: A total of 82 patients were included in our study. Functional outcome was assessed using MSTS score and knee range of motion. Oncological outcome was assessed regarding local recurrence, chest metastasis, and patient survivorship. Complications were classified according to Henderson et al. RESULTS: The mean MSTS score was 26.21 (87.4%) (range 8-30 points) with 70.7% of patients having more than 90° of flexion. The incidence of local recurrence was 3.7% (3 patients), while the incidence of chest metastasis was 14.6% (12 patients). Aseptic loosening (type 2 failure) was the commonest complication (19.5%), followed by infection (15.9%). The 5- and 10-year survivorships of the limb were 98.8%, while the 5- and 10-year survivorships of the prosthesis were 67.7% and 52.4%, respectively. CONCLUSION: This study showed that patients with osteosarcoma distal femur who are treated by chemotherapy and limb salvage have an excellent long-term prognosis in terms of patient as well as limb survivorship. The use of modular endoprosthesis in these patients offer an acceptable function, with two-thirds of the patients retaining their prosthesis after 5 years and more than half retaining them after 10 years.

Characterization of CRLF2 Expression in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with several underlying genetic ab-normalities. Several studies have tried to elucidate the prognostic significance of cytokine receptor-like factor 2 (CRLF2) overexpression in pediatric B-cell precursor (BCP)-ALL; however, it is still controversial. METHODS: CRLF2 expression was assessed by flow cytometry in 87 newly diagnosed BCP-ALL pediatric patients, and 80 age and gender-matched control group. Janus Kinase2 (JAK2) (R683) mutation analysis was also performed in those identified to have CRLF2 overexpression with adequate DNA samples by direct sequencing. RESULTS: CRLF2 overexpression was identified in 26/87 (29.9%) of our patients with cutoff set at mean fluorescence intensity (MFI = 3.8) using the Receiver Operating Characteristic (ROC) curve. There were no significant differences in the clinical and laboratory features between patients with high and low-CRLF2 expression, apart from thrombocytopenia which showed statistically significant association with the low-expression group (p = 0.041). Sequence analysis of samples with high CRLF2 expression (n = 23) revealed that 2/23 (8.7%) cases harbored the mutation JAK2 (R683). CRLF2 levels did not have a significant impact on either overall survival (OS) or disease free survival (DFS) (p = 0.601; p = 0.212, respectively). CONCLUSIONS: CRLF2 overexpression was not an adverse parameter in pediatric BCP-ALL patients. However, patients with CRLF2 overexpression may harbor the JAK2 mutation presenting a group that can benefit from targeted therapy by kinase inhibitors. The usage of CRLF2 expression to monitor minimal residual disease of BCP-ALL would be an area of interest for further evaluation.

The role of ß-catenin and paired-like homeobox 2B (PHOX2B) expression in neuroblastoma patients; predictive and prognostic value.

BACKGROUND: The expression of ß-catenin and paired-like homeobox 2B (PHOX2B) expression were assessed in Neuroblastoma (NB) patients as a diagnostic, prognostic and/or predictive markers. METHODS: Bone marrow (BM) samples of 52 NB patients were assessed for the expression of ß-catenin by immunohistochemistry (IHC), and PHOX2B by real time PCR (RT-PCR), compared to 12 healthy normal controls (NC). The data were correlated to the clinic-pathological features of the patients, response to treatment and disease relapse. RESULTS: ß-catenin was expressed in 40 (76.92%) patients (P < .001). While PHOX2B was expressed in 32/52 (61.5%) patients, with a fold change of 0.29 (0.01-40.0, P = .096). ß-catenin expression associated significantly with advanced tumor stage, high risk, positive results by MIBG and bone scan (P = .002, P < .001, P = .006, P = .013; respectively). Also it associated significantly with synaptophysin expression in the BM biopsy (P < .001), with a significant concordance (K = 0.519, P < .001). The expression of ß-catenin associated significantly with PHOX2B gene expression [28/32 (87.5%), P = .04], and its fold change (P = .027), with a significant measure of agreement (K = 0.297, P = .022). The fold change of PHOX2B gene expression associated significantly with the high risk of the patients (P = .04). Poor response to treatment associated significantly with the expression of neuron specific enolase (NSE), ß-catenin and PHOX2B in NB patients (P = .021, P = .019 and P = .040; respectively). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of synaptophysin for the diagnosis of BM metastasis in NB patients were (69%, 65.2%, 71.4%, 62.5%; respectively, P = .024). While with ß-catenin (93.1%, 43.5%, 67.5%, 83.3%; respectively, P = .003), and PHOX2B expression (65.5%, 34.5%, 59.4%, 50%; respectively, P = .574). CONCLUSION: ß-Catenin could be used as a sensitive and reliable marker for detection of BM metastasis and also a good predictor for resistance to treatment in NB patients. While, PHOX2B gene expression in BM aspirate could be a marker for high risk patients and poor response to treatment.

Early impact of treatment modifications adopted for acute lymphoblastic leukemia during SARS-CoV-2 pandemic; a single center experience and lessons for LMICs.

Treatment modifications adopted during pandemic aimed at reducing infection, myelosuppression, and optimizing hospital resources. This study evaluated outcomes for pediatric patients with ALL who had treatment modifications during pandemic compared to historical cohorts at the National Cancer Institute, Cairo University, Egypt. Bi-directional cohort study included 378 patients. Treatment modifications included omission of specific drugs or adjusting chemotherapy schedules to 6-mercaptopurine/methotrexate. Median follow-up were 45.1 and 43.2 months, for cohorts (A) and (B), respectively. The three-year overall survival were 84.9% and 87.5% (p = .48) and three-year relapse free survival were 82.8% and 86.5% (p = .11) for cohorts (A) and (B), respectively. Infection-related mortality was 11% and 4.4% for cohorts (A) and (B), respectively (p = .03). Treatment modifications adopted during the pandemic did not adversely affect the outcome of patients with ALL and notably reduced infection-related deaths. Longer follow-up is warranted to validate these findings.

Outcome and prognostic factors of pediatric patients with Hodgkin lymphoma: a single-center experience.

BACKGROUND: Hodgkin lymphoma (HL) is a highly curable malignant tumor. Risk-adapted treatment for children with HL aims to maximize survival while minimizing toxicity. The purpose of this study is to evaluate the outcome and prognostic characteristics of Egyptian pediatric HL patients treated at the National Cancer Institute (NCI), Cairo University. METHODS: All newly diagnosed cases of classic HL treated between January 2016 and December 2018 were included in this study. RESULTS: The median age at initial presentation was 8 years in 69 eligible individuals, with a male-to-female ratio of 4.7:1. Eighteen percent of patients had an elevated erythrocyte sedimentation rate (ESR) of more than 50, 42% had more than three lymph node (LN) group involvements, 18.8% had bulky disease, 52.2% were at an advanced stage, and 34% had B symptoms. Age > 15 years, B symptoms, > 3 LN group involvement, extra-nodal disease, and advanced stages significantly affected the overall survival rate (OS) (P-values = 0.03, 0.033, 0.008, 0.017, and 0.032). There was no statistically significant difference between patients who got combined modality therapy (CMT) and those who received chemotherapy alone (3-year OS and event-free survival (EFS) were 95.5% and 87.6% vs. 89.9% and 83.3%, P-values of 0.70 and 0.90). Patients with an interim-negative positron emission tomography-computed tomography (PET-CT) had a 3-year OS of 94.7%, compared to 74.1% in patients with an interim-positive PET-CT (P = 0.06), suggesting that rapid early response (RER) is a significant prognostic factor. There was no statistically significant survival difference between patients with a negative interim PET-CT who got CMT and those who received chemotherapy alone (3-year OS and EFS: 100% and 88.2% vs. 95% and 90%; P = 0.35 and 0.70, respectively). Three-year OS was 93.3% and 100%, and EFS was 74.3% and 100% (P = 0.495 and 0.196%) for those who got 15 Gy versus those who received 20 Gy or more, respectively. At the end of the study, the OS and EFS at 3 years for the whole group were 91.9% and 83.6%. CONCLUSION: Treatment with risk- and response-adaptive treatment should be the standard of care for treating pediatric patients with HL.

Impact of Rapid Molecular Diagnostic Technique on Time to Optimal Antimicrobial Therapy and Hospital Outcomes in Pediatric Cancer Patients with Sepsis.

BACKGROUND: sepsis is a leading cause of morbidity and mortality in pediatric cancer patients. We sought to assess the impact of using rapid molecular diagnostic techniques on time to pathogen identification, early administration of targeted antimicrobial treatment, and hospital outcomes. PATIENTS AND METHODS: This prospective study was conducted at the Egyptian National Cancer Institute (1/2018-1/2019) on pediatric cancer patients with suspected sepsis. The cohort was divided into two groups. In one group, blood samples were sent for rapid molecular detection [multiplex-Polymerase Chain Reaction (PCR)] and blood cultures (PCR-group). While only blood cultures were collected for the second group (BC-group). RESULTS: In the entire cohort (n=120), the most common bacteria identified on blood cultures was Escherichia Coli (n=33,27.5%) followed by Klebsiella (n=31,25.8%). Multidrug-resistant bacteria were identified in 63 patients (52.5%). The median turnaround time to initial results was 5 hours in PCR-group (n=60), and 120 hours in BC-group (n=60)(P<0.001). For PCR-group, agreement in pathogen identification between the rapid molecular detection kit (PCR) and blood cultures was noted in 56 patients (93.3%). While the remaining four patients had no bacterial growth on blood cultures. The empirical antibiotic treatment for the PCR-group was modified based on the result of the PCR test. Antibiotic shift, based on blood culture sensitivity results, was done in 29 patients (48%) in PCR-group, compared to 45 patients (75%) in BC-group (P=0.003). Median sepsis episode duration [8-days vs. 10-days,P=0.361), and hospital mortality (42% vs. 50%, P=0.360) were slightly lower in PCR-group. However, this did not reach statistical significance. CONCLUSION: There was a substantial agreement in pathogen identification between the rapid molecular detection method (PCR) and blood culture results. PCR had a much shorter turnaround time, which allows for earlier start of optimal antimicrobial treatment, and might potentially improve hospital outcomes, which in turn will reduce associated health care costs.

Neural Control and Online Learning for Speed Adaptation of Unmanned Aerial Vehicles.

Unmanned aerial vehicles (UAVs) are involved in critical tasks such as inspection and exploration. Thus, they have to perform several intelligent functions. Various control approaches have been proposed to implement these functions. Most classical UAV control approaches, such as model predictive control, require a dynamic model to determine the optimal control parameters. Other control approaches use machine learning techniques that require multiple learning trials to obtain the proper control parameters. All these approaches are computationally expensive. Our goal is to develop an efficient control system for UAVs that does not require a dynamic model and allows them to learn control parameters online with only a few trials and inexpensive computations. To achieve this, we developed a neural control method with fast online learning. Neural control is based on a three-neuron network, whereas the online learning algorithm is derived from a neural correlation-based learning principle with predictive and reflexive sensory information. This neural control technique is used here for the speed adaptation of the UAV. The control technique relies on a simple input signal from a compact optical distance measurement sensor that can be converted into predictive and reflexive sensory information for the learning algorithm. Such speed adaptation is a fundamental function that can be used as part of other complex control functions, such as obstacle avoidance. The proposed technique was implemented on a real UAV system. Consequently, the UAV can quickly learn within 3-4 trials to proactively adapt its flying speed to brake at a safe distance from the obstacle or target in the horizontal and vertical planes. This speed adaptation is also robust against wind perturbation. We also demonstrated a combination of speed adaptation and obstacle avoidance for UAV navigations, which is an important intelligent function toward inspection and exploration.

Role of matrix metalloproteinase MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) in the clinical progression of pediatric acute lymphoblastic leukemia.

BACKGROUND: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed. METHODS: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- cancer stem cells (CSCs) were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. RESULTS: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, p < 0.001], and CSCs CD34+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), p < 0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, area under curve (AUC) of MMP-2 were (80.3%, 53.3% and 0.568, p = 0.404), and of MMP-9 were (53.9%, 40% and 0.660, p = 0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, p < 0.001), and that of CD34+CD38- CSCs were (78.9%, 73.3% and 0.855, p < 0.001). Increased TIMP-1 expression associated with the high-risk disease (p < 0.001). CD34+CD38- CSCs and MMP-2 overexpression associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (p < 0.05). TIMP-1 overexpression is associated with shorter DFS and OS rates (p = 0.009 and p = 0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, p = 0.046], and CD34+CD38- CSCs [OR: 6.873, p = 0.005] could be potential independent diagnostic factors for pediatric ALL. CONCLUSION: TIMP-1 and CD34+CD38- CSCs could be possible useful diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

Expression of microRNA-181a and microRNA-196b in Egyptian Pediatric acute Lymphoblastic Leukemia.

BACKGROUND: Differential expression of miRNA provides important insights into pathogenesis of cancer including leukemia. Deregulation of microRNA may contribute to hematopoietic malignancies. In this study, we aimed to evaluate the role of miR-181a and miR-196b in acute lymphoblastic leukemia (ALL) and correlate their expression with clinical and laboratory data. METHODS: The study was performed on bone marrow samples of 70 consecutive newly diagnosed pediatric (ALL) patients, of which 56 were evaluated for both miR-181a and miR-196b (all 70 for miR-181a) by real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). In addition, bone marrow from seven age and sex matched healthy controls derived from donors of bone marrow transplantation were assessed. RESULTS: miR-181a expression was significantly up-regulated in ALL patients compared with healthy controls (p <0.001). However, miR-196b expression was significantly down-regulated in patients compared with healthy controls (p=0.038). CONCLUSION: Our results suggest that miR-181a has an oncogenic, while miR-196b has a tumor suppressive role in pediatric ALL patients. A finding which demonstrate the potential role of these microRNAs in pathogenesis of pediatric ALL. Also, estimation of their expression level may provide a tool for confirmation of a diagnosis of childhood ALL and could be a possible predictor of early relapse.
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Expression of Micro-RNA 128 and Let-7b in Pediatric Acute Lymphoblastic Leukemia Cases

Background: MicroRNAs (miRNAs) play important roles in the pathogenesis of leukemia and their altered expression is associated with many types of solid and hematological malignancies. Methods: The study was performed on 70 consecutive newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients, of which 56 were evaluated for both bone marrow miR-128 and let-7b (all 70 for let-7b) by real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). In addition, seven age and sex matched healthy controls were assessed. Results: miR-128 expression was significantly higher in ALL patients compared with healthy controls (p<0.001). However, the expression levels of let-7b showed no statistical significant difference between the groups. No significant links were noted with clinical details, laboratory data and response to treatment. Conclusion: The results suggest that determination of miR-128 expression level may provide a tool for confirmation of a diagnosis of childhood ALL, follow up for response of treatment and a possible predictor of early relapse. Any role of let-7b in pediatric ALL needs to be further assessed.

Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia.

Methotrexate inhibits the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase (MTHFR). MTHFR has a common functional polymorphism C677T. The present study aimed to investigate the prevalence of MTHFR polymorphisms in Egyptian children with ALL and the relation to MTX-related toxicity, relapse, and MTX pharmacokinetic parameters. Forty patients with ALL were included in the study. They were treated according to ALL-NCI total XIII protocol. MTX-related toxicity and MTX pharmacokinetic parameters were assessed during therapy. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay, and MTX pharmacokinetic parameters were assessed by HPLC. The MTHFR C677T polymeric allele frequencies were 55, 35, and 10% for CC, CT, and TT genotypes, respectively, among the studied patients with ALL. MTX therapy was significantly associated with toxicity signs in TT genotype: elevated transaminases (P < 0.0001), elevated serum alpha 1-microglobulin protein (P < 0.0001), anemia (P < 0.0001), neutropenia (P < 0.0001), thrombocytopenia (P < 0.0001), and elevated CSF-ß-glucuronidase activity (P < 0.0001). Patients with TT genotype showed significant increase in MTX t(½) and AUC (P < 0.0001), while MTX elimination rate and total body clearance were significantly decreased (P < 0.0001 and P < 0.05, respectively) compared with CC genotype. The TT genotype was significantly associated with relapse in 2 years in 50% compared with 28.57% in CT and 13.64% in CC alleles. The overall 2-year survival was significantly lower in TT genotype (50%) compared with CC genotype (90.91%; P = 0.01). MTHFR TT genotype is significantly associated with increased toxicity during methotrexate therapy as well as increased relapse rate in pediatric patients with ALL. In future, MTX dose adjustment in ALL treatment protocols should be considered based on patient's genotype.

Insulin-like growth factor system in Egyptian children with acute lymphoblastic leukemia.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been reported to play an important role in tumor proliferation. This study aimed to investigate the validity of measuring IGFs and specific IGFBPs in the serum of Egyptian children with acute lymphoblastic leukemia (ALL) as additional markers in diagnosis and follow-up of the disease. IGF-I, IGF-II, IGFBP-2, and IGFBP-3 were determined in the sera of 33 ALL patients at time of diagnosis and after an intensification phase of chemotherapy (IPC) that lasts about 6 months as well as in 15 healthy children as a control group using enzyme-linked immunosorbent assay (ELISA) technique. At time of diagnosis, serum IGF-I, IGF-II, and IGFBP-3 were significantly lower than those in the control group. After IPC, serum IGF-I and IGF-II returned to their normal levels, while serum IGFBP-3 was still decreased. On the other hand, serum IGFBP-2 was significantly higher than those in the control group at diagnosis, but returned to normal value after IPC. In conclusion, the changes in IGF system could be useful to support diagnosis and follow-up of children with ALL.

Role of 131-I MIBG Therapy in the Treatment of Advanced Neuroblastoma.

INTRODUCTION: Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most extracranial malignant solid tumor of childhood. Many therapeutic strategies has evolved over the last 20 years, based upon work by international cooperative groups and smaller cohort studies. Novel therapies to improve initial disease response and treatment of minimal residual disease are required to improve survival for these children with highrisk neuroblastoma. Radio-labeled MIBG therapy has been tried in the treatment of advanced stage 3&4 neuroblastoma in an attempt to improve patients' outcome. The use of radio-labeled MIBG to treat neuroblastoma has arisen from the high sensitivity and specificity of in-vivo MIBG imaging for detection of primary and metastatic tumors. AIM OF WORK: To determine the impact of MIBG therapy on neuroblastoma patients' outcome and its impact on their quality of life. PATIENTS AND METHODS: Thirty pediatric patients with stage 4 pathologically proven neuroblastoma are included in this study. Eighteen of the study patients (60%) were males and 12 (40%) were females. All the patients had partially responsive tumor to first-line therapy +/- surgey. 131-I MIBG doses ranged from 100 to 150mCi with number of courses ranged from 1-7 according to response and toxicity. RESULTS: Two patients achieved complete remission (CR) and were still disease-free after 64 &69 months. Nine patients showed partial remission (PR) to 131-I MIBG, all the nine patients were alive at 16-57 months (mean 30.6 months) among whom seven were alive with stable disease and two patients were alive with progressive disease (PD) at the end of study. Eighteen patients remained stable after 131-I MIBG therapy, among them six were alive with PD and four were alive with stable disease at the end of study, while the remaining eight patients died. The last patient developed PD and died within 15 months. The 5 years event free survival (EFS) was 48.2% and the overall survival (OS) was 69%. CONCLUSIONS: We concluded that 131-I MIBG therapy has favorable therapeutic effect for advanced neuroblastoma patients. Controlled clinical trials should be considered to evaluate the true potential of 131-I MIBG therapy. KEY WORDS: MIBG therapy - Advanced neuroblastoma.

ZAP-70 as a possible prognostic factor in childhood acute lymphoblastic leukemia.

BACKGROUND: Zeta-chain-associated protein (ZAP- 70) is a 70kD adaptor protein that acts quickly after T cell activation to propagate signal. The role of ZAP-70 in Tcell function is well established, and in the previous years, this molecule was considered to be T-cell specific. More recent data have documented a role of ZAP-70 in B cells. Interest in ZAP-70 has grown since it has been shown, through gene expression profiling, that it is expressed in a subset of cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). PURPOSE: The aim of this study was to investigate the expression of ZAP-70 in leukemic blasts of 50 newly diagnosed patients of B-lineage acute lymphoblastic leukemia (ALL), and to assess the correlation between ZAP-70 expression and various prognostic factors and outcome. PATIENTS AND METHODS: This study included 50 pediatric patients with newly diagnosed B-lineage ALL. They were 28 males (56% ) and 22 females (44% ) presented to the Pediatric Oncology Department, National Cancer Institute, Cairo University, during the period from 2005 to 2007. The age range was 2 to 17 years with a mean of 8.58+/-5.8 years and median 8 years. All patients were subjected at presentation to a full clinical history and physical examination. Patients diagnosed with ALL were enrolled on St. Jude Total XV protocol: standard risk and low risk according to results of primary investigation. Immunophenotyping was done using monoclonal antibodies which were analyzed on Coulter XL (Panel included CD1, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD19, CD22, Cytoplasmic m, anti k, anti l, CD13, CD33, anti classII MHC and TdT). Cases were considered ZAP-70 positive when exhibiting a ZAP/GAPDH (Glyceraldehyde- 3-phosphate dehydrogenase) ratio >or= 0.13. RESULTS: The study revealed expression of ZAP-70 in 5/50 cases (10% ). There was no statistically significant relation between ZAP-70 expression and the following: age, Total Leukocytic Count, hepatomegaly and splenomegaly. There was a correlation however between ZAP-70- expression and sex. Four patients died of disease progression: one patient with positive ZAP-70 expression and 3 patients with negative ZAP-70 expression. Fifteen patients (30% ) relapsed after achieving complete remission (CR) and 3 patients (6% ) did not achieve CR. Four patients of those who relapsed had positive ZAP-70 expression. The 2.5 years DFS was 73.1% for negative ZAP-70 cases while it was 20% in positive ZAP-70 cases. There was a statistically significant difference between 2.5-year DFS and ZAP-70 expression (p=0.048). The Overall Survival at 2.5-years for negative ZAP-70 cases was 93.3% while it was 80% for positive ZAP-70 cases with p-value =0.27. CONCLUSIONS: Our results show that in B-Lineage ALL, ZAP-70 expression correlates with a worse DFS and an increased relapse rate. Furthermore, these results raise the need of prospective trials to evaluate the possibility of designing new compounds targeting this protein.

Detection of anti-asparaginase antibodies during therapy with E.coli asparaginase in children with newly diagnosed acute lymphoblastic leukemia and lymphoma.

BACKGROUND: Asparaginase is an effective antileukemic agent which is included in most front-line protocols for pediatric acute lymphoblastic leukemia (ALL) worldwide. Since asparaginase is a bacterial protein, it may induce formation of antibodies. The reported frequency of anti-asparaginase antibodies is highly variable: antibodies have been reported in as many as 79% of adults and as many as 70% of children after intravenous or intramuscular administration of E.coli asparaginase. PURPOSE: The aim of this study was to determine if the presence of antibodies during induction and continuation phases in newly diagnosed children with ALL and lymphoblastic lymphoma during therapy with E.coli asparaginase, had any correlation with various factors such as: age, gender, hypersensitivity reactions, response to therapy and Event Free Survival (EFS). PATIENTS AND METHODS: Between the period from March 2005 to May 2007, sixty-four children who attended the Menia outpatient pediatric oncology clinic, or were admitted to the inpatient department of the Menia oncology center, were enrolled in the study. Forty children had newly diagnosed ALL and 24 had lymphoblastic lymphoma. Patients were 48 males (75%) and 16 females (25%) with a male:female ratio 3:1. Their ages ranged from 3.5 to 17 years with mean age of 9.6 years. All patients received asparaginase therapy according to the St. Jude Total XIII protocol, in a dose of 10,000 IU/m(2)/dose, intramuscularly for 6-9 doses during the induction phase and another 6-9 doses during continuation phase according to disease status. RESULTS: Forty one patients achieved complete remission, 9 had partial remission, and 14 were lost to followup at different intervals of treatment. Antiasparaginase antibodies were detected in 36 patients (56%) out of 64 patients, and 37 patients (60%) out of 62 patients who were treated with asparaginase at day 8 and day 27 of induction phase respectively. Moreover, 33 patients (61%) out of 54 patients, and 41 patients (83%) out of 50 patients had positive antiasparaginase antibodies at week 10 and week 21 of continuation phase respectively. The 2-year EFS of the whole group was 50%. There was no statistically significant relation between positivity of antiasparaginase antibodies and the following: age, gender, hypersensitivity reaction, response to therapy and EFS. CONCLUSIONS: The presence of antiasparaginase antibodies was unrelated to age, gender, hypersensitivity reaction, response to therapy and event free survival of newly diagnosed children with acute lymphoblastic leukemia and lymphoblastic lymphoma.

Risk adapted combined modality treatment in children with Hodgkin's disease: NCI, Cairo.

OBJECTIVE: The objective of this study is to maximize the chance of cure while minimizing surgery, radiotherapy and chemotherapy as much as possible to avoid late effects and toxicity of combined modality treatment in children with Hodgkin's disease. PATIENTS AND METHODS: One hundred twenty-one (121) children under the age of 18 years with a histopathologic diagnosis of Hodgkin's disease were enrolled into this study. Patients were stratified according to stage into 3 risk groups: low (Stages: I, II A), intermediate (Stages: II B, III A) and high risk group (Stages: III B, IV). Oral Etoposide was used in this study instead of procarbazine in the management of boys with HD to reduce the gonadotoxic effects of procarbazine. Two cycles of OPPA for females and E-OPA for males were effective induction treatment for children with all stages of HD and stage-tailored chemotherapy (2, 4, 6 cycles of OPPA, E-OPA/ COPP) was sufficient to eradicate occult microfoci. Involved field radiotherapy was given in doses of 30, 25, 20 Gy, depending on the extent of initial chemotherapy and risk status. Staging laparotomy was performed in 30 patients out of the 121 patients, 24 of them underwent splenectomy. Patients who received whole neck radiotherapy were submitted to thyroid U/S and thyroid hormonal profile. Only 3 adolescent patients did semen analysis. RESULTS: The overall and disease-free survival rates at 6 years were 95.3% and 86.1% (95% CI), respectively (entire group), 96.1% , 92.3% (95% CI) for low risk, 96.1% , 80.7% (95% CI) for intermediate risk and 93.3% , 80% (95% CI) for high risk patients. During the followup period all patients had normal thyroid functions. CONCLUSIONS: In children with HD, only low dose involved field radiotherapy with reduced doses is needed,if a risk-dependent chemotherapy is given. In this series the strategy of selective laparotomy and restrictive splenectomy is very useful in the context of combined modality treatment, in which laparotomy was omitted if both abdominal U/S and CT were negative.

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia; experience at the National Cancer Institute, Cairo University, Egypt.

PURPOSE: To identify chromosomal pattern among the major immunophenotypic subgroups in Egyptian children with ALL, and its correlation with clinical presentation and disease free survival. PATIENTS AND METHODS: Cytogenetic and immunophenotypic analysis were done for all patients. Patients received ALL-PNCI-III/98 chemotherapy protocol used at NCI, Cairo University. RESULTS: The frequency of pseudodiploidy and normal karyotype in the whole group was 42.9% and 33.3% respectively. The frequency of pseudodiploidy was 36.8% in CALLA positive early pre B, 30.7% in pre B cases, 71.4% in T cell cases and 100% in mature B cell cases. At 12 months, DFS was 50% for pseudodiploid group having pre B phenotype, compared to 16.6% for pseudodiploid group with CALLA positive early pre B ALL. Sixteen percent of the studied cases showed T cell phenotype, 71.4% of them showed pseudodiploid karyotype, all of them had high risk features. Hyperdiploidy was found in 31.5% of CALLA positive early pre B cases and was associated with favorable prognostic features and DFS of 66.6% at 12 months. Hyperdiploidy of >50 chromosome represented 62.5% of hyperdipoid cases, 80% of them were CALLA positive early pre B ALL carrying good risk features. Fifty percent of normal karyotypic patients showed pre B phenotype, while 42.8% showed CALLA positive early pre B ALL. Their age, TLC, DFS, were almost comparable. CONCLUSION: CALLA early pre B phenotype has a positive impact on chromosomal pattern having best outcome among patients with hyperdiploidy. The Pseudodiploid karyotype carries a better outcome with pre B phenotype.