Effects of Malnutrition on Neutrophil/Mononuclear Cell Apoptotic Functions in Children with Acute Lymphoblastic Leukemia.

BACKGROUND: Recent studies claim that apoptosis may explain immune dysfunction observed in malnutrition. OBJECTIVE: The objective of this study was to determine the effect of malnutrition on apoptotic functions of phagocytic cells in acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Twenty-eight ALL patients (13 with malnutrition) and thirty controls were enrolled. Neutrophil and mononuclear cell apoptosis of ALL patients and the control group were studied on admission before chemotherapy and repeated at a minimum of three months after induction of chemotherapy or when the nutritional status of leukemic children improved. RESULTS: The apoptotic functions of both ALL groups on admission were significantly lower than those of the control group. The apoptotic functions were lower in ALL patients with malnutrition than those in ALL patients without malnutrition, but this was not statistically significant. The repeated apoptotic functions of both ALL groups were increased to similar values with the control group. This increase was found to be statistically significant. CONCLUSIONS: The apoptotic functions in ALL patients were not found to be affected by malnutrition. However, after dietary intervention, increased apoptotic functions in both ALL patient groups deserve mentioning. Dietary intervention should always be recommended as malnutrition or cachexia leads to multiple complications. Enhanced apoptosis might originate also from remission state of cancer.

Biologic tumor behavior in pilocytic astrocytomas.

PURPOSE: The aim is to describe the behavior of pilocytic astrocytoma (PAs) and its effects on patient prognosis by using flow cytometric, immunohistochemical and cytogenetic methods. We also aim to find out whether there is any difference between differently localized tumors by the above mentioned analyses. METHODS: We studied DNA index, expression of p53, p16, pRb, MMAC/PTEN1, VEGF, MIB-1 index and chromosomal anomalies which can be detected by array comparative genomic hybridization (CGH) technique. We analyzed the association of the results of these studies with clinical prognosis and tumor localization. We included 53 patients (18 cerebellar, 20 chiasmatic/hypothalamic and 15 hemispheric). Samples were studied from paraffin embedded tumors. RESULTS: We found that PAs are mostly diploid and ploidy pattern does not affect the prognosis. The expression of p53, p16, pRb, MMAC/PTEN1 and VEGF was not significantly different between different localizations and could not predict the prognosis. Frequently seen copy number aberrations (CNAs) are: amplification in 1p36.33, 2p11.2, 9p11.2, 9q12, 16p11.2, 19q13.12-q13.2, Xp22.2-p21.3, Xp11.3-p11.22, Xq11.1-q12, Xq13.1, Xq21.1-q21.31, Xq22.3, Xq26.3 and homozygous deletion in 2p11.2, 8p23.1, 16p12.3. Among them, 2p11.2 amp, 9p11.2 amp and 1p36.21 hom del were correlated with prognosis. Moreover, we found a significant correlation between 16p11.2 amp and tumor localization. CONCLUSIONS: Differently localized PAs have different properties which make them behave with different biological aggressiveness. PAs demonstrate a significant amount of CNAs that can be detected by a high-resolution study. However, tumor suppressor genes p53, p16, pRb, MMAC/PTEN1 and expression patterns do not play a significant role in PAs.

Clinical features and management of carboplatin-related hypersensitivity reactions in pediatric low-grade glioma.

PURPOSE: The effectiveness of carboplatin and vincristine chemotherapy in the treatment of low-grade glioma (LGG) is well established. However, carboplatin hypersensitivity reactions (CHR) are a major problem leading to premature cessation of therapy. We aimed to investigate the clinical features and the management strategies in CHR, retrospectively. METHOD: Fifty LGG patients treated between October 1997 and January 2008 with carboplatin and vincristine were included in the study. Clinical features, management strategies, influence of demographic factors on CHR, and success rate in terms of continuation with carboplatin therapy were evaluated. RESULTS: CHR were observed in 20 (40%) patients and grade I reactions were the most common. The median number of carboplatin doses administered at the first episode of CHR was nine (range 1-41). Only younger age was found to be correlated with the presence of CHR. Nine patients had carboplatin desensitization protocol; eight patients were given various combinations of premedication while three had no modification. Treatment was terminated in five patients due to CHR. Overall success rate was 75%. CONCLUSIONS: This is the largest single-center study conducted to investigate the frequency and the management strategies in patients with CHR who were treated with the same chemotherapy protocol for LGG. Premedication and desensitization were the preferred modifications in case of CHR. Overall, the success rate for carboplatin continuation is high in comparison to previous studies. Carboplatin can be continued successfully in many cases with CHR if reactions are managed in a timely fashion.

Diffusion weighted imaging in predicting progression free survival in patients with squamous cell carcinomas of the head and neck treated with induction chemotherapy.

RATIONALE AND OBJECTIVES: The aim of this study was to assess the role of diffusion-weighted imaging in predicting progression-free survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with induction chemotherapy. MATERIALS AND METHODS: Eighteen patients with HNSCC underwent diffusion-weighted imaging studies prior to treatment and within 3 weeks after completion of induction chemotherapy. Median apparent diffusion coefficient (ADC) values were computed from the largest cervical metastatic lymph node. Percentage changes in ADC values from pretreatment to posttreatment time points were compared between alive and dead patients using the Mann-Whitney U test. P values < .05 were considered statistically significant. RESULTS: A 22% increase in ADC was observed after induction chemotherapy in alive patients (n = 15), while patients who died from HNSCC (n = 3) demonstrated a 33% decrease in ADC. The difference in percentage change in ADC between alive and dead patients was significant (P = .039). CONCLUSIONS: ADC may be a useful marker in predicting progression-free survival in patients with HNSCC undergoing induction chemotherapy.

Defining and ranking effects of individual agents based on survival times of cancer patients treated with combination chemotherapies.

An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression-free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination's overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents.

Which therapy works better in choroid plexus carcinomas?

Choroid plexus carcinomas (CPCs) are rare tumors with dismal outcome. While it has been established that surgery, radiotherapy, and chemotherapy improve survival, the best chemotherapy drugs for treating this disease still need to be identified. Since CPC is too rare to permit a prospective clinical trial, we performed a meta-analysis to evaluate the effects of individual drugs in patients with CPCs. We expanded a pre-existing database and included all cases of choroid plexus tumors, identified in PubMed through the end of 2007, for a total of 906 patients. At first, we restricted the analysis to patients with histologically confirmed CPC (n = 361) and with residual tumor after surgery (n = 130/361 patients), and we compared response and survival between patients who received a particular drug and those who did not. Response to chemotherapy was documented in 43 patients. Of the drugs used in these patients, etoposide was associated with the highest response rate (17/36). Next survival was compared among all CPC. Kaplan-Meier curves and log-rank tests suggested a statistically significant treatment benefit for cyclophosphamide, etoposide, and carboplatin, while the effect of vincristine was found to be marginally significant (P = 0.07, log rank). Of these, only etoposide's effect could be confirmed in a limited Cox multiple regression analysis. In conclusion, etoposide should be included in future standard treatment protocols. However the survival rates are still unsatisfactory, and additional novel drugs should be studied in prospective multicenter studies.

Invasive respiratory aspergillosis is a treatable disease with early diagnosis and aggressive therapy.

This study aimed to document outcome of invasive respiratory aspergillosis (IRA) in pediatric malignancy patients. Patients with febrile neutropenia episodes followed between January 2003 and May 2007 were enrolled. Antifungal therapy was added to those who were still febrile on the 5th day of febrile neutropenia treatment. Patients were screened with computerized tomographies. IRA was identified in 22 of 98 patients. There were 13 males and the mean age was 97 months. Proven infection was established in 3, probable in 7, and possible in 12 patients. Liposomal amphotericin B was administered to all patients and was successful in 10 patients. Modifications with caspofungin or voriconazole were done in liposomal amphotericin B failures. The median duration of antifungal therapy was 5.5 months. The median follow-up time was 29 months. There was no evidence of IRA in 12 patients after completion of cancer chemotherapy. Six patients died due to underlying disease, whereas IRA was either in remission or stable disease. Four patients were lost due to IRA. The remission rate for IRA was 82%. Survival at 37 months was 55% (95% confidence interval 25-47 months). The amount of time that absolute neutrophil count after initiation of treatment for IRA remained at zero was found to be an independent prognostic factor on survival (P = .01). These results suggest that early diagnosis and aggressive treatment may increase the successful outcome of IRA.

Malignancy-associated hemophagocytic lymphohistiocytosis in pediatric cases: a multicenter study from Turkey.

This study evaluates the clinical and laboratory data of children with secondary hemophagocytic lymphohistiocytosis (sHLH) related to malignancy. Charts of patients who met the diagnostic criteria for sHLH associated with malignancy between January 2000-2006 at six different hospitals in Turkey were reviewed retrospectively. The diagnosis of HLH had been established by bone marrow aspiration in 27 patients, cerebrospinal fluid and bone marrow aspiration in one patient and lung-liver biopsy in another. Twenty-nine children were diagnosed as having sHLH related to malignancy. Twenty cases (18 ALL and 2 AML) with acute leukemia (10 girls/10 boys, median age: 8 years [3-14 years]) were found to have sHLH. Five patients with acute leukemia had HLH at the time of diagnosis (Group 1a), and 15 patients with acute leukemia were diagnosed as having sHLH during therapy (Group 1b), namely reactive sHLH associated with the chemotherapy. Nine patients, including two cases each of rhabdomyosarcoma, neuroblastoma, Hodgkin disease, and non-Hodgkin lymphoma (NHL) and one case with Langerhans cell histiocytosis, were diagnosed as having concomitant hemophagocytosis at the initial evaluation of the tumor (Group 2). Fever, anemia, and hypertriglyceridemia were present in all sHLH cases of all three groups. Hepatomegaly was detected in 60.0%, 73.3%, and 88.8% of the three groups, respectively. Splenomegaly was more frequent in patients of Groups 1a (60.0%) and 2 (88.8%) than in those of Group 1b, the reactive ones (13.3%). Hypofibrinogenemia was detected in all patients of Group 1a and Group 2. Low level of fibrinogen was present in 91.6% of patients in Group 1b. All patients in Group 1b (100%) had neutropenia and thrombocytopenia. Neutropenia was found at rates of 60.0% and 55.5% in Group 1a and Group 2, respectively. Thrombocytopenia was detected in 80.0% of patients in Group 1a and 77.7% in Group 2. The overall mortality rate was 34.4% (10 cases) in our series of 29 children with sHLH; 50% of deaths were directly attributable to HLH. Pediatric malignancy-associated HLH patients have been commonly described as case presentations or in a review of the literature. We believe that our cohort, compiling 29 children regarding the association between malignancy and HLH, will be useful for pediatricians who are interested in this still mysterious topic.

Cushing's syndrome due to a non-adrenal ectopic adrenocorticotropin-secreting Ewing's sarcoma in a child.

Ectopic ACTH syndrome (EAS) is extremely rare in the pediatric age group. Sarcomatous tumors causing EAS are even rarer. We report a 9 year-old girl presenting with Cushing's syndrome caused by ectopic ACTH production by a Ewing's sarcoma. This case illustrates that rapid appearance of Cushingoid symptoms, absence of growth retardation and the presence of hypokalemia are suggestive clues for ectopic ACTH production as the source of Cushing's syndrome.

Prognostic factors and outcomes for osteosarcoma: an international collaboration.

We aimed to evaluate the prognostic significance of traditional clinical predictors in osteosarcoma through an international collaboration of 10 teams of investigators (2680 patients) who participated. In multivariate models the mortality risk increased with older age, presence of metastatic disease at diagnosis, development of local recurrence when the patient was first seen, use of amputation instead of limb salvage/wide resection, employment of unusual treatments, use of chemotherapeutic regimens other than anthracycline and platinum and use of methotrexate. It was also influenced by the site of the tumour. The risk of metastasis increased when metastatic disease was present at the time the patient was first seen and also increased with use of amputation or unusual treatment combinations or chemotherapy regimens not including anthracycline and platinum. Local recurrence risk was higher in older patients, in those who had local recurrence when first seen and when no anthracycline and platinum were used in chemotherapy. Results were similar when limited to patients seen after 1990 and treated with surgery plus combination chemotherapy. This large-scale international collaboration identifies strong predictors of major clinical outcomes in osteosarcoma.

Acute megakaryoblastic leukemia mimicking small round cell tumor with novel t(1;5)(q21;p13).

Acute megakaryoblastic leukemia is a relatively rare form of acute leukemia that has heterogeneous blast morphology and karyotypic abnormalities. An 8-month-old boy with a retroperitoneal mass was diagnosed as having acute megakaryoblastic leukemia that initially presented as small round cell tumor of childhood. Bone marrow aspiration showed syncytial groups of atypical medium sized cells with scant cytoplasm and fine nuclear chromatin. Retroperitoneal mass biopsy showed several lymph nodes with cohesive clusters of neoplastic cells that demonstrated expression of Factor VIII. Flow cytometric analysis of the second bone marrow aspiration showed CD 61 positivity. Karyotypic analysis of bone marrow cells showed a novel translocation, (1;5)(q21;p13).

Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients.

Even though past studies have suggested efficacy of nitrosourea drugs in patients with high-grade glioma and temozolomide has recently been shown significantly to be beneficial, no conclusive comparisons between these agents have been published. We performed a survival gain analysis of 364 studies describing 24,193 patients with high-grade glioma treated in 504 cohorts, and compared the effects of drugs. The most frequent diagnoses were glioblastoma multiforme (GBM) (72%) and anaplastic astrocytoma (22%). The mean overall survival (mOS) was 14.1 months. The outcome was influenced by several of the known prognostic factors including the histological grade, if the tumors were newly diagnosed or recurrent, the completeness of resection, patients' age, and gender. This information allowed the calculation of a predicted mOS for each cohort based on their prognostic factors independent of treatment. Survival gain to characterize the influence of treatment was subsequently defined and validated as the difference between the observed and the predicted mOS. In 62 CCNU-treated cohorts and 15 ACNU-treated cohorts the survival gain was 5.3 months and 8.9 months (P < 0.0005), respectively. No detectable survival gain for patients treated with various BCNU-containing regimens was found. Conclusion CCNU- and ACNU-containing regimens were superior to BCNU containing regiments.

False positivity of FDG-PET/CT in a child with Hodgkin disease.

Role of Positron Emission Tomography (PET) with F-18-2-fluoro-2-deoxy-D-glucose (FDG) in staging of Hodgkin disease is well established despite several controversies. We report a Stage III Hodgkin lymphoma patient with false positive FDG-PET/CT results. Seven-year-old male with Hodgkin lymphoma was in remission at end of chemotherapy. At third and fourth month of postchemotherapy follow-up, increased Gallium uptake and positive FDG-PET/CT in right lower quadrant of abdomen was observed. Open biopsy revealed lymphoid hyperplasia. He has been followed for 21 months without any evidence of disease. Despite its documented benefit, we believe that results of FDG-PET/CT should be interpreted with great caution in order to avoid unnecessary interventions.

Use of recombinant factor VIIa in a preterm infant with coagulopathy and subdural hematoma.

Activated recombinant factor VIIa was administered to a preterm infant with bleeding diasthesis and a huge subdural hematoma that could not be controlled by the blood products. The coagulation tests were normalized the following day. Recombinant factor VIIa can be a choice in selected cases with intractable bleedings unesponsive to conventional replacement therapy.

A double-blind, crossover, randomized dose-comparison trial of granisetron for the prevention of acute and delayed nausea and emesis in children receiving moderately emetogenic carboplatin-based chemotherapy.

BACKGROUND: Granisetron is a safe and effective prophylaxis for nausea and vomiting associated with moderate to highly emetogenic chemotherapy. Few trials have been conducted to determine the optimal effective dose of granisetron in children with cancer. The objective of this report was to compare two doses of granisetron in patients with optic pathway tumors receiving moderately emetogenic doses of carboplatin. PATIENTS AND METHODS: In this double-blind, crossover, randomized study, antiemetic efficacy and tolerability of two dose levels (10 and 40 microg/kg) of granisetron in the prevention of acute and delayed nausea/emesis were compared in children and young adults. A total of 18 patients (13 boys) aged 1-23 years (median 7.7 years) treated with a moderately emetogenic dose of carboplatin were randomly assigned to receive either 10 or 40 microg/kg of slow granisetron intravenous (i.v.) infusions at alternating cycles of chemotherapy in a blinded fashion until the end of the study period or until their chemotherapy regimen ended. In this way, the patients acted as their own controls. RESULTS: Patients in the granisetron 10 and 40 microg/kg groups received 104 and 121 cycles of chemotherapy, respectively. There was no significant difference in antiemetic efficacy in terms of nausea and emesis between the dose groups in the first 5 days of chemotherapy. The treatment was well tolerated. CONCLUSION: We conclude that granisetron 10 and 40 microg/kg have comparable efficacy in controlling carboplatin-induced acute and delayed nausea/emesis and is well tolerated in children and young adults.

Cardiac echinococcosis with intra-atrial localization.

Echinococcosis is a frequently encountered parasitic disease in the Mediterranean region, including Turkey. Cardiac disease is seen in 0.5-2% of patients. Usually the cysts are located within the pericardium or intramyocardially; intracavitary localization of the cyst is rarely seen. We herein report a patient who initially presented with hemoptysis and was echocardiographically diagnosed to have an intra-atrial hydatid cyst. Although patients with cardiac hydatid cysts may present with cardiac symptoms, symptoms typically involve other organ systems, following dissemination of the organism. Therefore, echocardiographic screening of patients who are diagnosed with echinococcosis, even if they have no cardiac symptoms, may ensure early diagnosis and prevent development of lethal complications, such as cyst rupture or embolization.

High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity.

BACKGROUND: Sixteen pediatric osteosarcoma patients, previously treated with conventional chemotherapy (including ifosfamide (IFX), 9 g/m(2)) were retreated with high-dose ifosfamide (HD-IFX, 14 g/m(2) per course), following relapse or development of a new bone tumor. The objective was to obtain responses and an improved event-free survival (EFS). PROCEDURE: HD-IFX was administered as described by Patel SR: J Clin Oncol 1997;15:2378. Efficacy of treatment was assessed initially after two to four courses. The interval between the courses was 3 to 4 weeks. Provided a response was obtained after two to four courses, treatment was continued for an additional eight courses unless progressive disease or an untoward event, for example, renal failure occurred. Tumor sites were: lung, (10) bone (9), and bone and soft-tissue (1). RESULTS: Response after two to four courses was 62.5%: CR 6 and PR 4. A total of 84 courses were administered to the 16 patients: (range 2-10, median 5.5 per patient). Median interval between courses was 28.5 days (range 15-90). Five patients were disease free at 15+ to 63+ months after induction and maintenance therapy. Fever and neutropenia occurred in 12 courses. Nephrotoxicity was a major toxic event and was characterized by creatinine levels at or above three times the upper limit of normal. It was unpredictable and occurred in four patients: two were reversible. The other two patients developed full-blown renal failure; one was treated with renal dialysis, but both eventually succumbed to osteosarcoma. Our past experience also indicated that two patients treated with IFX (9 g/m(2)/course) developed renal failure: one recovered and the other required a renal transplant. CONCLUSIONS: HD-IFX is effective in patients who have failed conventional chemotherapy including IFX (9 g/m(2)). Improved disease-free survival was achieved in 30% of patients. However, renal failure constitutes an important life-threatening complication and its development is unpredictable.