Docetaxel-Based Neoadjuvant Chemotherapy Followed by En Bloc Resection for Esophageal Adenocarcinoma: A 15-Year Retrospective Analysis from a Regional Upper Gastrointestinal Cancer Network.

BACKROUND: Real-world, long-term survival outcomes of neoadjuvant, docetaxel-based therapy for esophageal and junctional adenocarcinoma are lacking. This study describes the long-term survival outcomes of patients with esophageal and junctional adenocarcinoma treated with neoadjuvant docetaxel-based chemotherapy and en bloc transthoracic esophagectomy. METHODS: A retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada, was performed. From January 2007 to December 2021, all patients with locally advanced (cT3 and/or N1) esophageal/Siewert I/II adenocarcinoma treated with neoadjuvant DCFx3 (Docetaxel/Cisplatin/5FU) or FLOTx4 (5FU/Leucovorin/Oxaliplatin/Docetaxel) and transthoracic en bloc esophagectomy were identified. Postoperative, pathological, and survival outcomes were compared. RESULTS: Overall, 236 of 420 patients met the inclusion criteria. Tumor location was esophageal/Siewert I/Siewert II (118/33/85), most were cT3-4 (93.6%) and cN+ (61.0%). DCF and FLOT were used in 127 of 236 (53.8%) and 109 of 236 (46.2%). All neoadjuvant cycles were completed in 87.3% with no difference between the regimens. Operative procedures included Ivor Lewis (81.8%), left thoraco-abdominal esophagectomy (10.6%) and McKeown (7.6%) with an R0 resection in 95.3% and pathological complete response in 9.7% (DCF 12.6%/FLOT 6.4%, p = 0.111). The median lymph node yield was 32 (range 4-79), and 60.6% were ypN+. Median follow-up was longer for the DCF group (74.8 months 95% confidence interval [CI] 4-173 vs. 37.8 months 95% CI 2-119, p <0.001. Overall survival was similar between the groups (FLOT 97.3 months, 78.6-115.8 vs. DCF 92.9, 9.2-106.5, p = 0.420). CONCLUSIONS: Neoadjuvant DCF and FLOT followed by transthoracic en bloc resection are both highly effective regimens for locally advanced esophageal adenocarcinoma with equivalent survival outcomes despite high disease load.

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group.

BACKGROUND: Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. PROCEDURE: Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. RESULTS: Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). CONCLUSIONS: Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data.

Low grade astrocytoma in children under the age of three years: a report from the Canadian pediatric brain tumour consortium.

In children under the age of 3 years, the most common solid tumors are brain tumors. Low grade astrocytomas represent 30-40 % of brain tumours in this age group. This study reviewed the incidence, characteristics, therapy, and outcome of children less than 36 months of age diagnosed with a low grade astrocytoma from 1990 to 2005 in Canada. A data bank was established using data collected from Canadian pediatric oncology centers on children less than age 3 diagnosed with brain tumors between 1990 and 2005. Cases of low grade astrocytoma were extracted from this data bank and their characteristics summarized. From the 579 cases in the data bank, 153 cases of low grade astrocytoma (26 %) were identified. The mean duration of symptoms prior to presentation was 13 weeks, and 53 % of patients underwent a greater than 90 % resection of their tumor, while 30 % underwent 10-90 % resection. Seventy-one percent of patients received no further therapy after surgery and of the 45 who received therapy following surgery, 43 received chemotherapy, and 5 received radiation therapy. Sixty-eight patients had recurrence or progression of their tumor. Eighty-seven percent of patients were alive at the time of the survey with a 2 year survival rate of 95.3 ± 1.8 %, 5 year survival rate of 93.1 ± 2.1 % and 10 year survival rate of 89.1 ± 2.8 %. The 5 year survival rate for Canadian children less than 36 months of age with a low grade astrocytoma was 93.0 ± 2.8 % which is similar to that for older children with this tumor.

Economic evaluation of treatment for acute lymphoblastic leukaemia in childhood.

Berlin-Frankfurt-Munster (BFM) and Dana-Farber Cancer Institute (DFCI) consortia's treatment strategies for acute lymphoblastic leukaemia (ALL) in children are widely used. We compared the health effects and monetary costs of hospital treatments for these two strategies. Parents of children treated at seven centres in Canada, Italy and the USA completed health-related quality of life (HRQL) assessments during four active treatment phases and at 2 years after treatment. Mean HRQL scores were used to calculate quality-adjusted life years (QALYs) for a period of 5 years following diagnosis. Total costs of treatment were determined from variables in administrative databases in a universally accessible and publicly funded healthcare system. Valid HRQL assessments (n = 1200) were collected for 307 BFM and 317 DFCI patients, with costs measured for 66 BFM and 28 DFCI patients. QALYs per patient were <1.0% greater for BFM than DFCI. Median HRQL scores revealed no difference in QALYs. The difference in mean total costs for BFM (US$88 480) and DFCI (US$93 026) was not significant (P = 0.600). This study provides no evidence of superiority for one treatment strategy over the other. Current BFM or DFCI strategies should represent conventional management for the next economic evaluation of treatments for ALL in childhood.

ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia.

Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P ≤ .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P = .005; ASNS tandem-repeat and related haplotype, P ≤ .01) were subsequently analyzed in the replication cohort. The E coli-dependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P = .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P ≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P ≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli-induced asparagine depletion may explain our observed results.

Effectiveness of pamidronate as treatment of symptomatic osteonecrosis occurring in children treated for acute lymphoblastic leukemia.

BACKGROUND: Osteonecrosis (ON) is a severe complication of acute lymphoblastic leukemia (ALL) treatments. Recent studies suggest that bisphosphonates might reduce pain and loss of motor function in patients with ON. We assessed the effects of pamidronate compared to standard care in patients with symptomatic ON (sON) and studied whether steroids might be continued after diagnosis of ON in some patients. METHODS: We evaluated 17 patients with sON as complication of primary ALL treatment between 2000 and 2008. Fourteen patients were treated with pamidronate. Mobility and pain control were monitored in all patients. Affected joints were classified by magnetic resonance imaging (MRI) at ON diagnosis and after 6-72 months. RESULTS: Out of 220 patients with ALL, 17 (7.7%) patients developed sON. The median age at ALL diagnosis was 11 years (range: 2.7-16.6 years) and sON occurred a median of 13.4 months (range: 2.5-34 months) after ALL diagnosis. Affected joints were hip, knee and ankle. MRI scans showed 7 severe, 4 moderate, and 6 mild ON lesions. Fourteen patients showed improvement in pain (77% of patients) and motor function (59% of patients), even though corticoids were reintroduced in 4 patients. MRI demonstrated improvement, stability or worsening in 6, 3, and 5 cases, respectively. CONCLUSIONS: Pamidronate seems to be effective in the management of pain and motor function recovery in sON. Further studies are needed to provide evidence as to whether bisphosphonates can be recommended for the treatment or the prevention of ON in childhood ALL patients.

Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors.

OBJECTIVE: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population. STUDY DESIGN: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated. RESULTS: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the -786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems. CONCLUSION: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.

Predictive factors of internalized and externalized behavioral problems in children treated for acute lymphoblastic leukemia.

BACKGROUND: Pediatric cancer survivors are at increased risk of various neurological and psychological problems. The prevalence of behavioral problems was assessed in a longitudinal study in pediatric patients with an acute lymphoblastic leukemia (ALL). Multilevel modeling was used to identify associated predictive factors. PROCEDURE: ALL patients and their parents (n = 138) took part to this study. Patients were treated according to the Dana-Farber Cancer Institute (DFCI) consortium protocols 91-01 or 95-01. Mothers filled out questionnaires providing a measure of behavioral problems for their child at diagnosis and during the subsequent 4 years, and of their perceived familial stress at diagnosis and post-induction. RESULTS: Prevalence of internalized behavioral problems at diagnosis was increased [42% above 1 standard deviation (SD); P < 0.001], but it normalized over time. Internalized problems resolved more slowly in the presence of medical variables associated with increased stress related to the disease (hospitalization duration, P < 0.001; relapse risk at diagnosis, P < 0.001). Externalized behavioral problems were within the expected normal range, but more sustained over time with the 95-01 than with the 91-01 treatment protocols (P < 0.05), likely due to the type of corticosteroid (CS) used (dexamethasone vs. prednisone). CONCLUSIONS: Assessment of both internalized and externalized problems is required in this population. The impact of pharmacological variables on externalized behavioral problems is likely related to CS use.

Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia.

Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.

Spinal cord tumors in children under the age of 3 years: a retrospective Canadian review.

BACKGROUND: Tumors of the spinal cord are exceedingly rare in infancy and only a paucity of literature exists describing the spectrum of this disease and its management. The objectives of our study were to describe the demographic characteristics of spinal cord tumors (SCT) in children less than 3 years of age at diagnosis and to review their treatment and outcome. METHODS: A national retrospective chart review was conducted on patients under the age of 3 years diagnosed with a primary tumor of the central nervous system (CNS) between 1990 and 2005 across Canada. Inclusion criteria were: age ≤ 3 years, histologic confirmation of the diagnosis, and residency in Canada. A centralized database was created and information regarding SCT was extracted. RESULTS: Twenty-five of five hundred seventy-nine patients (4.3%) in the data bank had a SCT. The majority of tumors were low-grade astrocytomas (14/25). Leptomeningeal dissemination based on neuroradiologic imaging and/or cerebrospinal fluid cytology was present in five (20%) patients. The majority of patients underwent an incomplete surgical resection (52%). Most patients (64%) did not receive postoperative radiotherapy or chemotherapy. Seventy-two percent (18/25) developed recurrent/progression of disease. Overall 2- and 5-year survival for low- and high-grade malignancies was 93 ± 6.4% and 37.5 ± 17.1% respectively. Significant predictors of survival included mean duration of symptoms prior to initial diagnosis and recurrence/progression of disease. CONCLUSIONS: Relapse/progression of disease in infant SCT is frequent. Prolonged survival of low-grade tumors is possible with further therapy; however, the prognosis of high-grade malignancies remains poor.

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.

BACKGROUND: Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS: Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS: 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99). INTERPRETATION: Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. FUNDING: US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

Patterns of enrollment of infants with central nervous system tumours on cooperative group studies: a report from the Canadian Pediatric Brain Tumour Consortium.

In children under the age of 3, the most common solid tumours are brain tumors. Treatment for many of these patients includes surgery, chemotherapy and rarely radiation therapy. Many clinical trials have been performed in an attempt to establish the best treatment for these patients. Patients enrolled on clinical trials contribute to the establishment of the best therapy. We performed a national survey of all children less than the age of three with brain tumours and examined the contribution these patients made to clinical trials. A data bank was established using data collected from Canadian pediatric oncology centers on children less than age 3 diagnosed with brain tumours between 1990 and 2005. Data were collected on the use of adjunctive treatment after surgery, treatment on a protocol, reasons patients were not registered on a protocol, and reasons for discontinuation of therapy. From the 579 cases in the data bank, 302 (52%) patients were treated with further therapy after surgery. The use of further therapy after surgery was significantly higher in patients with cerebellar and brain stem tumors, patients who were over 1 year of age, patients with ependymal and embryonal tumors, and patients with high grade malignant tumors. Only 62 (21%) patients were enrolled on a protocol for therapy. No factor was significant for being enrolled on a protocol. Reasons for not being registered on a protocol were mainly that there was no open COG/POG/CCG study or the study was not open at the institution. The therapy was stopped because of completion of the protocol in 50% and because of disease progression in 34%. In Canada, about half of children under the age of 36 months with brain tumors are undergoing therapy following surgery for their malignancy but only a small fraction of them are enrolled on a clinical trial. There needs to be improved availability of clinical trials for these patients so that novel therapies can be evaluated and survival improved.

von Willebrand factor and thrombin activation in children with newly diagnosed acute lymphoblastic leukemia: an impact of peripheral blasts.

BACKGROUND: The pathogenesis and the impact of therapy on thrombin activation in children with acute lymphoblastic leukemia (ALL) are unknown. Steroids may contribute to ALL-associated thrombosis. We explored the hemostatic effects of methylprednisolone monotherapy (MpMT) (32 mg/m2/day IV x 3 days) in children with newly diagnosed ALL. METHODS: Children (>1 to < or = 18 years of age) enrolled on DFCI ALL05-01 protocol (n = 30; mean age 6.3 years), without prior steroid therapy, were eligible for study. Overnight fasting pre- and post-MpMT samples were analyzed for coagulation factors [FVIII:C, von Willebrand factor antigen (vWF:Ag) and fibrinogen] and parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-dimer]. RESULTS: At diagnosis F1.2 (1.5 nmol/L), TAT (10.9 microg/L), and D-dimers (2,766 ng/ml) levels were increased indicating endogenous thrombin activation. Patients with peripheral blasts (n = 17) had higher levels of vWF:Ag (1.89 vs. 1.14 P = 0.001), TAT (15.39 vs. 5.02 P = 0.038), and D-dimer (3,640 vs. 1,623 P = 0.019) compared to those without peripheral blasts. Following MpMT the blast count decreased significantly from 24% to 3.5% (P < 0.001) with reduction in level of vWF:Ag (1.5, P < 0.01), TAT (8.9, P = 0.42), and D-dimer (P = 0.018) despite 30% increase in FVIII:C levels (P = 0.005). However, patients without peripheral blasts had no significant change in vWF:Ag levels (1.14 vs. 1.25; P = 0.142) and had an increase in thrombin generation parameters. CONCLUSIONS: We postulate that peripheral blasts through endothelial activation stimulate vWF:Ag production/secretion causing coagulation activation. Methylprednisolone therapy reduces the blast count and indirectly suppresses the coagulation activation. Future studies are required to confirm these findings.

Medulloblastoma in children under the age of three years: a retrospective Canadian review.

Children under the age of 3 with medulloblastoma have an inferior survival to older children with this disease. This study reviewed the incidence, characteristics, therapy, and outcome of children less than 36 months of age diagnosed with medulloblastoma from 1990 to 2005 in Canada. Ninety-six cases were identified with a median age at diagnosis of 19.5 months. Forty-seven percent of patients had a complete resection, 25% a 90-95% near complete resection, 20% an incomplete (10-90%) resection, and 3% biopsy only. Therapy consisted of chemotherapy (90%), high dose chemotherapy with stem cell rescue (13%), and radiation therapy (21%). The median survival time was 45 +/- 13.82 months. There was no significant difference in survival when comparing patients with <90% resection versus >90% resection, nor when comparing the presence of metastases versus their absence. There was a significant increase in survival time in patients who received radiation therapy compared to those who were not treated with this modality, as well as for those who were over 18 months at diagnosis compared to those under 18 months.

Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study.

Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

Deep cutaneous fungal infections in immunocompromised children.

BACKGROUND: Life-threatening infections from ubiquitous fungi are becoming more prevalent in adults and children because of the increased use of immunosuppressive agents and broad-spectrum anti-infective drugs. Extremely low birth weight premature neonates and patients with a disrupted epidermal barrier are also at increased risk. Lethality is high, particularly with delayed diagnosis. As cutaneous lesions are often the first manifestation of such infections, early recognition of suspicious lesions is crucial to decrease associated morbidity and mortality. The clinical features of deep cutaneous fungal infection (DCFI) in immunocompromised children deserve special attention. OBJECTIVES: This study aimed to characterize our pediatric patients with DCFI, the causative fungi, and the associated risk factors. METHODS: A medical record review was conducted of pediatric patients with DCFI treated at out institution using data retrieved from the hospital's pathology and microbiology database (1980-2008). RESULTS: In all, 26 patients with DCFI were identified (9 girls and 17 boys) ranging in age from 1 day to 18 years (mean age: 8 years), the majority of whom had a hematologic disorder. All patients were immunocompromised, 90% were receiving broad-spectrum antibiotics, and 50% had severe neutropenia (absolute neutrophilic count < or = 500 x 10(6)/L). Necrotic ulcers (42%) and papules (34%) represented the most frequent lesion morphology. Fungal species were identified by culture in 20 (87%) of 23 patients tested and were observed histopathologically in 20 of 23 patients tested. Aspergillus was identified in 12 (44%) patients and Candida in 9 (33%). The other species included Fusarium (one), Exserohilum rostratum (one), Alternaria (one), Zygomycetes (two), and Blatomycetes (one). All but two patients received systemic antifungal therapy; wide surgical excision was performed in 13. Infection resolved in 20 (77%), whereas 6 (23%) died of disseminated infection. LIMITATIONS: This study was limited by the small number of cases and the retrospective nature of the collected data. DISCUSSION: DCFI should rank high in the differential diagnosis of any suspicious skin lesions in immunocompromised children. Early biopsies should be performed for histopathology and microbiological analysis, as lethality is high if appropriate treatment is delayed.

Delphinidin, a dietary anthocyanidin, inhibits platelet-derived growth factor ligand/receptor (PDGF/PDGFR) signaling.

Most cancers are dependent on the growth of tumor blood vessels and inhibition of tumor angiogenesis may thus provide an efficient strategy to retard or block tumor growth. Recently, tumor vascular targeting has expanded to include not only endothelial cells (ECs) but also smooth muscle cells (SMCs), which contribute to a mature and functional vasculature. We have reported previously that delphinidin, a major biologically active constituent of berries, inhibits the vascular endothelial growth factor-induced phosphorylation of vascular endothelial growth factor receptor-2 and blocks angiogenesis in vitro and in vivo. In the present study, we show that delphinidin also inhibits activation of the platelet-derived growth factor (PDGF)-BB receptor-beta [platelet-derived growth factor receptor-beta (PDGFR-beta)] in SMC and that this inhibition may contribute to its antitumor effect. The inhibitory effect of delphinidin on PDGFR-beta was very rapid and led to the inhibition of PDGF-BB-induced activation of extracellular signal-regulated kinase (ERK)-1/2 signaling and of the chemotactic motility of SMC, as well as the differentiation and stabilization of EC and SMC into capillary-like tubular structures in a three-dimensional coculture system. Using an anthocyan-rich extract of berries, we show that berry extracts were able to suppress the synergistic induction of vessel formation by basic fibroblast growth factor-2 and PDGF-BB in the mouse Matrigel plug assay. Oral administration of the berry extract also significantly retarded tumor growth in a lung carcinoma xenograft model. Taken together, these results provide new insight into the molecular mechanisms underlying the antiangiogenic activity of delphinidin that will be helpful for the development of dietary-based chemopreventive strategies.

Fatal disseminated Trichosporon asahii infection in a child with acute lymphoblastic leukemia.

Few cases of Trichosporon species infection have been reported in children. The present report describes a case of fatal disseminated Trichosporon asahii infection in a child treated for relapsed leukemia. Voriconazole has previously shown promising activity in vitro, and has been used successfully in the treatment of T asahii infections. The patient died five days after voriconazole treatment was started, and the autopsy revealed widespread systemic dissemination to all organs.

The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia.

BACKGROUND: Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage. METHODS: To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (>0.01 ng per milliliter)--the primary end point--or extremely elevated (>0.025 ng per milliliter). RESULTS: Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P<0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P<0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test). CONCLUSIONS: Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.

Inhibition of HuR and MMP-9 expression in macrophage-differentiated HL-60 myeloid leukemia cells by green tea polyphenol EGCg.

Matrix metalloproteinase (MMP)-9 expression is linked with myeloid cell differentiation, as well as inflammation and angiogenesis processes related to cancer progression. MMP-9 secretion and macrophage-like HL-60 myeloid leukemia cells differentiation were triggered by the tumor-promoting agent PMA. The chemopreventive effects of green tea catechins epigallocatechin-gallate, catechin-gallate, and epicatechin-gallate, but not those catechins that lack a 3'-galloyl group, inhibited in a time- and dose-dependent manner MMP-9 secretion. The gene and protein expression of MMP-9 and of the mRNA stabilizing factor HuR were also inhibited, while that of the 67 kDa laminin receptor remained unaffected. Specific catechins may help optimize current chemotherapeutic treatment protocols for leukemia.