Association of CYP3A5 Expression and Vincristine Neurotoxicity in Pediatric Malignancies in Turkish Population.

Vincristine is a widely used chemotherapeutic agent in the treatment of childhood malignancies. Neuropathy is the most common adverse effect. CYP3A4 and CYP3A5 enzymes of cytochrome p450 enzyme system are responsible in vincristine metabolism. Genetic polymorphism may alter the vincristine metabolism and the neurotoxicity rate. In this study, distribution of CYP3A5 alleles among Turkish children with malignancies, relation between CYP3A5 genotype and neurotoxicity rates, as well as severity and duration of neuropathy and total vincristine doses were investigated. Patient group consisted of 115 patients (age, 1 to 17 y) with acute lymphoblastic leukemia and solid tumors, who were treated with vincristine consisting chemotherapy protocols. Control group consisted of 50 children without any neurological symptom or disorders. All patient files were reviewed for presence and severeness of neurotoxicity symptoms. Blood samples were obtained and CYP3A5 genotypes were analyzed. Neurotoxicity occurred in 20.8% of patients. Although it was found to occur more frequently after 4 doses of vincristine, and rates were higher in the low-dose vincristine group suggesting other contributing factors. Although neurotoxicity rate in the CYP3A5*1/*3 genotype was 17.6%, it was 21.6% in the CYP3A5*3/*3 genotype and the difference was not statistically significant (P<0.05). This study suggested that vincristine-related neurotoxicity is dose-independent and genotype is not the only causative factor in the occurrence of neurotoxicity in these patients.

Assessment of brachial artery reactivity, carotid intima-media thickness, and adhesion molecules in pediatric solid tumor patients treated with anthracyclines.

The aim of this study was to determine subclinical atherosclerosis and endothelial functional disturbance with measurement of carotid intima-media thickness (IMT), brachial artery reactivity (BAR), and levels of serum adhesion molecules in children with solid tumors who were treated with anthracyclines and are actually in complete remission. Fifty patients who were in remission and 30 healthy children were included in the study. Mean ages of patient and control groups were 13.5 ± 4.7 years (range: 3-23 years) and 12.00 ± 4.3 years (range: 4-21 years), respectively. The patients were divided into 3 groups according to cumulative doxorubicin dose: Group 1, ≤100 mg/m(2); Group 2, 101-299 mg/m(2); Group 3, ≥300 mg/m(2). The BAR and carotid IMT were measured in order to determine the endothelial function. The serum adhesion molecule levels in our patients and controls were also measured. The BAR of the patients with cumulative anthracycline dose ≥300 mg/m(2) was significantly lower than the patients with cumulative anthracycline dose ≤100 mg/m(2) and healthy controls (P =.005 and P =.003, respectively). Also, there was a negative correlation between brachial artery reactivity and increasing cumulative anthracycline dose (r = -.287, P =.044). We also found significant difference between the mean carotid IMT of the patients and the healthy children (P =.041). No statistically significant difference was detected between the serum levels of sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), sE-selectin of the patients and controls. The use of anthracyclines in pediatric patients with cancer could result in increase of the carotid IMT and endothelial dysfunction.

Recurrent Sertoli-Leydig cell tumor of ovary in 8-year-old girl.

Sertoli-Leydig cell tumors are rare sex cord-stromal neoplasms that account for <0.2% of ovarian tumors. These tumors with a retiform pattern pose difficult diagnostic problems, with the majority of being misinterpreted as serous papillary cystadenocarcinoma and endodermal sinus tumor. We report an 8-year-old female patient presented to our institution with a huge mass and pain in the lower abdomen and recurrence in the 10th months following the first operation. Only four cases of Sertoli-Leydig cell tumors have been reported under age of the eight years in the literature so far. It is difficult to define the stage and the morphology of Sertoli-Leydig cell tumors with retiform pattern in children and chemotherapy or radiotherapy administration is contraversial. However, fertility sparing surgeries should be considered as a first treatment choice on the time of the diagnosis and the recurrence.

Risk factors for cisplatin-induced long-term nephrotoxicity in pediatric cancer survivors.

BACKGROUND: The aim of this study was to compare the nephrotoxicity risk of cisplatin (CPL) and ifosfamide (IFO) combination treatment (CT) with that of CPL alone and to evaluate the prevalence of CPL-induced long-term nephrotoxicity in pediatric cancer survivors (CS). METHODS: A total of 33 patients with pediatric solid tumors who have been cured of their disease were included in the study. They were divided into two groups based on the type of chemotherapeutics, either CPL (n = 21) or CT (n = 12), given during cancer treatment and were evaluated for glomerular and tubular function using the Skinner grading system. RESULTS: Nephrotoxicity was found in 15 CS (45.4%): seven (21.3%) of those had moderate, six (18.2%) had mild, and two (6.1%) had severe nephrotoxicity. Neither the rates of overall nephrotoxicity, glomerular toxicity and tubular toxicity, nor the mean overall, glomerular and tubular toxicity scores differed significantly among the CPL and CT groups (P > 0.05 for all parameters). Cumulative IFO dose and age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity (P = 0.025 and P = 0.036 for development of nephrotoxicity; P = 0.004 and P = 0.050 for severity of nephrotoxicity, respectively). CONCLUSIONS: Although CPL-induced long-term nephrotoxicity was found in half of the pediatric CS of solid tumors, clinically significant nephrotoxicity was detected only in a minority of them. Both higher cumulative IFO dose and younger age at treatment were found to be independent risk factors for both development and severity of CPL-induced nephrotoxicity.

Breastfeeding and Childhood Cancer: Is Breastfeeding Preventative to Childhood Cancer?

Breastfeeding is well-known to have a protective effect against infection in infants. It has been suggested that breast milk may play a role in the prevention of certain childhood cancer. We investigated this issue in a case-control study comprising 300 patients with childhood cancer. There was 73 patients (24.3%) with leukemia, 82 patients (27.3%) with lymphoma, and 146 patients (48.4%) with solid tumors (brain tumors, neuroblastoma, soft tissue sarcomas, germ cell tumors, renal tumor, bone tumor, retinoblastoma, hepatoblastoma, and others) and 316 controls matched for age and sex. Breastfeeding duration of the control group was found to be significantly longer than the patient group (X(2) = 57.774; P < .001). In conclusion, breastfeeding was found to be inversely associated with pediatric cancer in our study.

Successful multimodal treatment for aggressive metastatic and recurrent fibrolamellar hepatocellular carcinoma in a child.

Fibrolamellar variant of hepatocellular carcinoma (FLHCC) does not have a favorable prognosis than conventional HCC, and there is no difference regarding the response to chemotherapy and the degree of surgical resectability. FLHCC commonly recurs after complete surgical resection, and there is a high rate of lymph node metastases. Herein, we report a 12-year-old girl with metastatic FLHCC with multiple recurrences aggressively treated with surgery, chemotherapy, and antiangiogenic agents. She is in complete remission after 4 years and 2 months after the diagnosis of metastatic FLHCC. The standard treatment of FLHCC is excision of the primary tumor and its metastases. Chemotherapy for FLHCC is controversial, and it has been suggested that cytoreductive chemotherapy was ineffective and adjuvant chemotherapy did not improve survival. Our patient with multiple recurrences was successfully treated with surgery, first-line chemotherapy with cisplatin and doxorubicin, second-line chemotherapy with 5-fluorouracil/interferon-α combination, and adjuvant antiangiogenic agents like cyclophosphamide and thalidomide. As FLHCC patients have no underlying liver disease, they can tolerate higher doses of chemotherapy compared with conventional HCC patients. We support the use of repeated aggressive surgery with adjuvant chemotherapy and antiangiogenic therapy, which provided complete remission in our patient with metastatic and recurrent FLHCC.

Resveratrol and adipose-derived mesenchymal stem cells are effective in the prevention and treatment of doxorubicin cardiotoxicity in rats.

Anthracyclines can cause severe cardiac toxicity leading to heart failure. The aim of this study was to determine the effects of cardioprotective polyphenolic compound resveratrol (RES) and adipose-derived mesenchymal stem cells (ADMSCs) on cardiac tissue of rats treated with doxorubicin (DOX). Forty-two female and three male Wistar-Albino rats were included in the study. The study groups and the control groups were as follows: Group I: DOX; Group II: DOX + RES; Group III: DOX + ADMSCs; Group IV: DOX + RES + ADMSCs; Group V: Sham operation; and Group VI: normal saline. ADMSCs obtained from male rats were defined with stem cell markers [CD11b/c(-), CD45(-), CD90(+), CD44(+), and CD49(+)]. DOX 12 mg/kg intraperitoneally (i.p.) was injected as a single dose in female rats. Resveratrol 100 mg/kg was injected three times i.p. in Groups II and IV. ADMSCs 2 × 10(6) cells/kg/dose were labeled with bromodeoxyuridine (BrdU) and injected i.p. for a total of three times in Groups III and IV. When the study was terminated after 4 weeks, the beating hearts were connected to a Langendorff setup and records were obtained for 30 minutes. Histopathological, immunhistochemical, and immunofluorescent examination with H&E, Troponin I, and BrdU stains were also performed. Also, ADMSCs were demonstrated in the myocardium of transplanted rats. Left ventricle functions and myocardial histology demonstrated significant impairment in DOX only group compared to groups with ADMSCs (P < .05). We suggest that RES and ADMSCs were successful in the prevention and treatment of the doxorubicin cardiomyopathy in rats. The hypothetical mechanisms of regeneration are multiple, including cell differentiation and autocrine/paracrine effects of ADMSCs.

High-risk ALK negative anaplastic large-cell lymphoma presenting with hypereosinophilic syndrome in a 2.5-year-old child.

The hypereosinophilic syndromes (HES) are characterized by prolonged nonreactive peripheral blood hypereosinophilia with tissue damage. The lymphocytic HES variant can precede malignant clonal T-cell disease in adults but it is extremely rare to be the presenting feature of lymphomas in children. Here we present a 2.5-year-old boy with HES and mediastinal T-cell anaplastic lymphoma kinase (ALK) negative systemic anaplastic large-cell lymphoma. Mature and immature eosinophils without blasts were shown on bone marrow aspiration while biopsy revealed malignant infiltration. The patient responded well to initial corticosteroid therapy, but high-risk features make a challenge of finding the cure in this extremely rare case.

Institutional experience of paediatric high-grade central nervous system tumours: an analysis of 74 patients and review of the literature.

AIM OF THE STUDY: Although the survival for children with certain central nervous system (CNS) tumour types has improved through current surgical and adjuvant treatment modalities, the prognosis of many high-grade tumours remains poor despite aggressive treatment. The aim of this study is to analyse patients with high-grade brain tumours in our institution to determine the histopathology, clinical characteristics, treatment modalities, and survival. MATERIAL AND METHODS: A total of 74 patients with a diagnosis of high-grade brain tumour were analysed. There were a total of 31 patients with embryonal tumours, 27 patients with high-grade glial tumours, 12 patients with brain stem gliomas and 4 patients with other high-grade brain tumours. RESULTS: There were 48 (65%) boys and 26 (35%) girls (ratio: 1.85) with a median age of 99.7 months (range = 2-204 months). The median follow-up period was 19 months (range = 1-204 months). Tumour recurrence was observed in 38 patients (51.4%). The overall survival rate and event-free survival rate of our patients were 27% and 19.5%, respectively. CONCLUSIONS: Pediatric high-grade CNS tumours have a very aggressive behaviour and a significant number of children eventually succumb to disease despite multimodal treatment. There is a need of more effective therapeutic approaches for these tumours with poor prognosis. The future improvement in childhood high-grade brain tumour management depends on a better understanding of the molecular genetics and biology of brain tumours.

Clinical significance of serum vascular endothelial growth factor, endostatin, and leptin levels in children with lymphoma.

BACKGROUND: A number of clinical studies conducted in adults have demonstrated the prognostic significance of angiogenic factors in malignancies, however, only a limited number of studies have been conducted in children. The aim of this study was to determine serum vascular endothelial growth factor (VEGF), endostatin, and leptin levels in children with lymphoma and to investigate whether these factors provide prognostic information. PROCEDURE: Serum samples from 36 children with lymphoma (non-Hodgkin lymphoma (NHL) N = 21, Hodgkin lymphoma (HL) N = 15) were collected at diagnosis and during remission. Serum samples were also collected from 18 healthy children as the control group. Serum VEGF and endostatin levels were quantified by using enzyme-linked immunosorbent assay (ELISA) and serum leptin by immunoradiometric assay. RESULTS: The serum VEGF levels were found elevated in patients compared to controls (P = 0.033), while endostatin and leptin levels were lower in patients than in controls (endostatin, 43.9 ± 5.8 ng/ml vs. 123.6 ± 13.5 ng/ml, P < 0.001; leptin, 5 ± 1.5 ng/ml vs. 6.7 ± 1.2 ng/ml, P = 0.013). VEGF levels declined (pre, 151.6 ± 55.9 pg/ml vs. post, 16.2 ± 7.9 pg/ml, P = 0.041), while endostatin and leptin levels increased in patients who achieved remission (33 of 36 patients) when compared to pre-treatment levels (endostatin pre, 43.1 ± 5.9 ng/ml vs. post, 65.9 ± 6.8 ng/ml, P = 0.047; leptin, pre, 5.3 ± 1.6 ng/ml vs. post, 9.8 ± 2.7 ng/ml, P = 0.012). Serum VEGF, endostatin, and leptin levels were not predictive of survival. CONCLUSION: Serial measurement of serum VEGF, endostatin, and leptin levels could potentially be used to predict response to treatment or progressive disease in children with lymphoma.

Early diagnosis of anthracycline toxicity in asymptomatic long-term survivors: dobutamine stress echocardiography and tissue Doppler velocities in normal and abnormal myocardial wall motion.

AIMS: Asymptomatic long-term cancer survivors treated with anthracycline were investigated for late anthracycline cardiotoxicity using dobutamine stress echocardiography (DSE) and tissue Doppler (TD) velocities. METHODS AND RESULTS: The study comprised 20 asymptomatic patient and 18 healthy children as the control group. Twenty patients were divided into two groups according to the myocardial wall motion during DSE: Group 1 (normal myocardial wall motion; six girls and five boys) and Group 2 (abnormal myocardial wall motion: nine boys). Intravenous dobutamine infusion was started at a dose of 5 µg/kg/min (D5) and gradually increased to 10 (D10), 15 (D15) and 20 µg/kg/min (D20). Echocardiographic assessment was performed at rest and after each dose of dobutamine infusion. Abnormal myocardial wall motion was observed at rest in 3 patients and during DSE in six patients. There were no significant differences between the patients and control groups at rest except the end systolic wall stress and mitral deceleration time measured by conventional methods; however, both patients group showed significant differences of systolic and diastolic functions at D20. In patients groups, systolic and diastolic functions of interventricular septum (IVS) and systolic function of left ventricle (LV) and right ventricle (RV) TD velocities showed significant changes compared with control group at rest. Significant differences of diastolic functions of IVS and RV were noted during dobutamine infusion in abnormal myocardial wall motion compared with other groups. CONCLUSION: LV, RV and IVS TD velocities systolic function at rest and during DSE can provide valuable information for early detection of subclinical cardiac toxicity. TD velocities of diastolic functions during DSE are a valuable parameter for assessment of subclinical cardiac toxicity in patient with abnormal wall motion.

Tissue and flow myocardial performance index measurements taken during dobutamine stress echocardiography for early diagnosis of late anthracycline cardiotoxicity.

The purpose of this study was to define the role of tissue and flow myocardial performance index (MPI) measured during dobutamine stress and tissue Doppler echocardiography in the early diagnosis of late cardiotoxicity among patients with childhood cancer treated with anthracycline. The study included 20 patients (14 male and 6 female; mean age 18.4 +/- 3.2 years) as the study group and 18 healthy volunteers (14 female and 4 male, mean age: 19.2 +/- 4.0) as the control group. The mean cumulative dose of anthracycline treatment was 282.1 +/- 125.9 mg/m2, and the mean time period after the last dose of anthracycline was 10.2 +/- 4.0 years. Echocardiography was performed during rest and at infusions of 5, 10, 15, and 20 micro/kg/min dobutamine. Although only isovolumetric relaxation and contraction times of the patient group were prolonged at rest, dobutamine infusion showed significant differences in % left ventricle (LV) posterior wall thickening, LV end-systolic wall stress, LV diastolic and systolic diameter, mitral acceleration, and deceleration time in the patient group compared with the control group. Tissue and flow MPI of the LV, tissue MPI of the right ventricle (RV), and interventricular septum of the patient group were higher than the control group throughout the test. LV tissue MPI increased much more than LV flow MPI when stress was increased. In conclusion, LV tissue MPI value during stress is more valuable than LV flow MPI in the early diagnosis of late cardiotoxicity. RV function can be assessed by tissue Doppler MPI.

Treatment of Wilms tumor: a report from the Turkish Pediatric Oncology Group (TPOG).

AIM: To standardize diagnosis and treatment of childhood Wilms tumor (WT) in Turkey. METHODS AND PATIENTS: Between 1998 and 2006, WT patients were registered from 19 centers. Patients <16 years with unilateral WT whose treatment started in first postoperative 3 weeks were included. Treatments were stage I favorable (FH) and unfavorable histology (UH) patients, VCR + Act-D; stage IIA FH, VCR + Act-D; stage IIB FH, VCR + Act-D + radiotherapy (RT); stage III-IV FH, VCR + Act-D + adriamycin (ADR) + RT; stages II-IV UH tumors, VCR + Act-D + ADR + etoposide + RT. RESULTS: 165/254 registered cases were eligible (bilateral, 5.9%) [median age 3.0 years; M/F: 0.99; 50/165 cases < or =2 years]. 9.7% cases had UH tumors. Disease stages were stage I 23.6%; IIA 36.4%; IIB 5.5%; III 22.4%; IV 12.1%. Cases >2 years had significantly more advanced disease. 1/11 cases with recurrent disease died; 2/165 had progressive disease, 2/165 had secondary cancers, and all 4 died. In all cases 4-year OS and EFS were 92.8 and 86.5%, respectively. Both OS and EFS were significantly worse in stage IV. CONCLUSIONS: Despite problems in patient management and follow-up, treatment results were encouraging in this first national experience with a multicentric study in pediatric oncology. Revisions and modifications are planned to further improve results and minimize short- and long-term side effects.

Late relapsing Wilms tumor with rhabdomyomatous differentiation.

The authors report a patient with abdominally relapsed Wilms tumor with rhabdomyomatous differentiation leading to renal failure and death 9 years after the initial diagnosis. The patient was treated with intensive chemotherapy because of inoperable tumor but no response was obtained. The prognosis of children with Wilms tumor relapsed in abdomen and in previously irradiated fields is poor and intensive chemotherapy protocols for differentiated tumors after chemotherapy will increase the risk of complications without obvious benefit.

Primitive neuroectodermal tumor of the kidney in a child.

Primary renal primitive neuroectodermal tumor (PNET) is an extraordinarily rare neoplasm in childhood. It generally occurs in young adults and only a few pediatric cases have been reported. PNET in the kidney acts aggressively and the record shows poor therapeutic response. The authors present the case of a 16-year-old girl who was diagnosed with renal PNET and treated with high-dosage chemotherapy and peripheral blood stem cell transplantation (PBSCT).

Localized abdominal Castleman disease masquerading as malabsorption syndrome.

Castleman disease is a rare lymphoproliferative disorder of unclear etiology. It usually presents as localized enlarged lymph nodes in children. Surgical excision is curative in localized form. Clinical findings of malabsorption are rarely reported in the literature. Herein, we describe a 14-year-old girl who presented with anemia, failure to thrive, osteoporosis, zinc, and vitamin deficiency. She was diagnosed as localized mesenteric mixed type of Castleman disease. Her clinical findings improved after surgical excision of the mass.

Immunohistochemical expression of angiogenic cytokines in childhood Hodgkin lymphoma.

This immunohistochemical study was carried out to evaluate the role of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), their inhibitor (tissue inhibitor of metalloproteinase-1, TIMP-1), and microvessel density (MVD) in the clinicopathologic behavior of childhood Hodgkin's lymphoma (HL). Paraffin-embedded histologic sections from 15 children with HL were immunohistochemically stained with MMP-2, MMP-9, TIMP-1, VEGF, and CD31 antibodies to investigate the correlation between the expression of these markers and the clinicopathologic characteristics of HL. Expression of MMP-2 and VEGF in Hodgkin and Reed-Sternberg cells (HRS) was more frequent in nodular sclerosis than in other subtypes (p=0.07 and 0.08, respectively). None of the study parameters in HRS cell were associated with age, sex, disease stage, extranodal disease, and the occurrence of bulky tumor. There was a trend toward advanced stage in negative TIMP-1 staining in HRS cells (p=0.06). In reactive lymphocytes, MMP-2 expression was correlated with MVD (r=0.68, p=0.005), and MMP-9 expression was correlated with B symptoms (p=0.003). Also, low TIMP-1 expression in reactive lymphocytes was frequently found in patients with advanced stage (p=0.048). There was a positive correlation with the ratio of MMP-2 expression in reactive lymphocytes and MVD (r=0.68, p=0.005). Expression of MMP-9 in reactive lymphocytes was correlated with MVD without statistical significance (r=0.487, p=0.06). Our results suggest that, as in many solid tumors, angiogenesis and angiogenic factors may play an important role in childhood HL. Larger series of patients are needed to determine the prognostic value of angiogenesis in childhood HL.

Role of gelatinases (MMP-2 and MMP-9), TIMP-1, vascular endothelial growth factor (VEGF), and microvessel density on the clinicopathological behavior of childhood non-Hodgkin lymphoma.

The present study was carried out to clarify the role of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), and microvessel density (MVD) in the clinicopathologic behavior of childhood B-cell non-Hodgkin lymphoma (NHL). Paraffin-embedded biopsy specimens from 25 children with NHL were studied by immunohistochemically and the correlate the expression of these markers to clinicopathologic characteristics. Positive MMP-9 staining was associated with an increased prevalence of B-symptoms (p = .046). High microvessel density (MVD) showed a tendency toward an adverse outcome and it was correlated with clinical stage (p = .023). The event-free survival of high MVD patients was less than for those with low MVD, but the difference was not statistically significant (64.1% vs. 85.71% respectively, p = 0.15). The overall survival of high MVD patients was less than for those low with MVD and the difference was statistically significant (55.53% vs. 100% respectively, p = .039). Neither gelatinases nor VEGF correlated with age, sex, disease stage, the occurrence of bulky disease, or extranodal disease. The results showed that angiogenesis and angiogenic factors might have a role in development and clinical behavior of childhood NHL. Larger series of patients are needed to determine the prognostic value of angiogenesis in childhood non-Hodgkin lymphoma.

Management of plexiform neurofibroma with interferon alpha.

Plexiform neurofibroma is a relatively common but potentially devastating manifestation of neurofibromatosis type 1 (NF 1). A substantial number of plexiform neurofibroma causes morbidity. Various treatment modalities are considered to decrease pain. In this paper a case with plexiform neurofibroma causing severe pain and in whom alpha-interferon was used is presented.

Nodular regenerative hyperplasia and focal nodular hyperplasia of the liver mimicking hepatic metastasis in children with solid tumors and a review of literature.

Nodular regenerative hyperplasia (NRH) and focal nodular hyperplasia (FNH) of the liver rarely occur in children after completion of tumor therapy. These lesions mimic hepatic metastasis and they must be distinguished from metastatic lesions. The authors present 2 children, one with NRH and one with FNH, after undergoing antineoplastic therapy for non-hepatic childhood solid tumors and discuss their patients in the context of the literature.