Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.0001) due to a decreased rate of bacteremia (10.9% vs. 24.4%, P < 0.0001). The rate of fungal infections (4.8% vs. 3.6%) and induction death (0.9% vs. 2%) was not significantly different. CONCLUSION: For children with newly diagnosed ALL, uniform antibiotic administration until blood count recovery, including fluoroquinolone prophylaxis for afebrile patients, reduced the incidence of bacteremia during the induction phase. Larger, randomized studies should be performed to confirm these findings.

Impact of baseline clinical and laboratory features on the risk of thrombosis in children with acute lymphoblastic leukemia: A prospective evaluation.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have increased risk of thromboembolism (TE). However, the predictors of ALL-associated TE are as yet uncertain. OBJECTIVE: This exploratory, prospective cohort study evaluated the effects of clinical (age, gender, ALL risk group) and laboratory variables (hematological parameters, ABO blood group, inherited and acquired prothrombotic defects [PDs]) at diagnosis on the development of symptomatic TE (sTE) in children (aged 1 to ≤18) treated on the Dana-Farber Cancer Institute ALL 05-001 study. PROCEDURES: Samples collected prior to the start of ALL therapy were evaluated for genetic and acquired PDs (proteins C and S, antithrombin, procoagulant factors VIII (FVIII:C), IX, XI and von Willebrand factor antigen levels, gene polymorphisms of factor V G1691A, prothrombin gene G20210A and methylene tetrahydrofolate reductase C677T, anticardiolipin antibodies, fasting lipoprotein(a), and homocysteine). RESULTS: Of 131 enrolled patients (mean age [range] 6.4 [1-17] years) 70 were male patients and 20 patients (15%) developed sTE. Acquired or inherited PD had no impact on the risk of sTE. Multivariable analyses identified older age (odds ratio [OR] 1.13; 95% confidence interval [CI]: 1.01, 1.26) and non-O blood group (OR 3.64, 95% CI: 1.06, 12.51) as independent predictors for development of sTE. Patients with circulating blasts had higher odds of developing sTE (OR 6.66; 95% CI: 0.82, 53.85). CONCLUSION: Older age, non-O blood group, and presence of circulating blasts, but not PDs, predicted the risk of sTE during ALL therapy. We recommend evaluation of these novel risk factors in the development of ALL-associated TE. If confirmed, these easily accessible variables at diagnosis can help develop a risk-prediction model for ALL-associated TE.

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity.

Neutropenia and infection are major dose-limiting side effects of chemotherapy. The risk of initial infection and subsequent complications are directly related to the depth and duration of neutropenia. Recent genome-wide association studies identified variants in DARC and CXCL2 genes, and in ORMDL3-GSDMA-CSF3 locus on chromosome 17q21 that influence white blood cell and neutrophil counts in healthy individuals. To investigate whether polymorphisms in these loci in conjunction with chemotherapy may modulate risk of treatment complications, we analyzed 21 SNPs across these genes for an association with chemotherapy-related neutropenia and infection in 286 Caucasian children with acute lymphoblastic leukemia. After correction for multiple testing, DARC polymorphism rs3027012 in 5'-UTR was associated with higher risk of low absolute phagocyte count (APC<500 and <1000 cells per microliter, P=0.001 and P<0.0005, respectively) and hospitalization due to febrile neutropenia (P=0.002). Protective effect was instead seen for DARC rs12075 A to G substitution (P=0.004). The SNP rs3859192 in the GSDMA were associated with hospitalization due to infection (P=0.004); infection was also modulated in the additive manner by the CXCL2 rs16850408 (P=0.002). This study shows for the first time that the variations in DARC, GSDMA and CXCL2 genes may play a role in the onset of chemotherapy complications.

The IVAIRE project--a randomized controlled study of the impact of ventilation on indoor air quality and the respiratory symptoms of asthmatic children in single family homes.

UNLABELLED: A randomized controlled trial was carried out to measure the impact of an intervention on ventilation, indoor air contaminants, and asthma symptoms of children. Eighty-three asthmatic children living in low-ventilated homes were followed over 2 years. Several environmental parameters were measured during the summer, fall, and winter. The children were randomized after Year 1 (43 Intervention; 40 Control). The intervention included the installation of either a Heat Recovery Ventilator (HRV) or Energy Recovery Ventilator (ERV). During the fall and winter seasons, there was a significant increase in the mean ventilation rate in the homes of the intervention group. A statistically significant reduction in mean formaldehyde, airborne mold spores, toluene, styrene, limonene, and α-pinene concentrations was observed in the intervention group. There was no significant group difference in change in the number of days with symptoms per 14 days. However, there was a significant decrease in the proportion of children who experienced any wheezing (≥1 episode) and those with ≥4 episodes in the 12-month period in the intervention group. This study indicates that improved ventilation reduces air contaminants and may prevent wheezing. Due to lack of power, a bigger study is needed. PRACTICAL IMPLICATIONS: Positive findings from this study include the fact that, upon recruitment, most of the single family homes with asthmatic children were already equipped with a mechanical ventilation system and had relatively good indoor air quality. However, the 8-h indoor guideline for formaldehyde (50 µg/m3) was frequently exceeded and the ventilation rates were low in most of the homes, even those with a ventilation system. Both ERVs and HRVs were equally effective at increasing air exchange rates above 0.30 ACH and at preventing formaldehyde concentrations from exceeding the 50 µg/m3 guideline during the fall and winter seasons. Furthermore, the ERVs were effective at preventing excessively low relative humidities in the homes. Based on observed difference of risk, intervention to increase ventilation in five sample homes and children would prevent 1 home to exceed the indoor air long-term formaldehyde guideline and prevent 1 asthmatic child experiencing at least one episode of wheezing over a year.

Determinants of masked hypertension in hypertensive patients treated in a primary care setting.

BACKGROUND: Recent data suggest that masked hypertension (MH) carries a cardiovascular risk similar to that of uncontrolled hypertension. AIMS: The objective of this study was to determine the prevalence and determinants of MH in patients treated for hypertension in a Canadian primary care setting. METHODS: Office blood pressure (OBP) was measured at baseline and after 3 months of valsartan-based therapy in 5636 hypertensive patients who had recorded their home blood pressure monitoring (HBPM) for seven consecutive days at month 3 using an Omron HEM-711 apparatus. MH was defined in nondiabetic patients as an OBP <140/90 mmHg and an HBPM ≥135/85 mmHg, and in those with diabetes as an OBP <130/80 mmHg and an HBPM ≥125/75 mmHg. RESULTS: Of the 5636 patients, 1025 had diabetes. OBP was controlled at 3 months in 268 (26.1%) of them, but 167 (62.3%) had MH. OBP was controlled in 2728 (59.1%) of the 4611 patients without diabetes, and 935 (34.3%) of them had MH. Overall, 1102 patients had MH, representing 36.8% of patients with controlled OBP and 19.6% of the entire hypertensive study population. Stepwise multiple logistic regression analysis in nondiabetic patients with controlled OBP at 3 months revealed that older age, male sex, higher body mass index and higher office systolic blood pressure were determinants of MH. CONCLUSION: Our results indicate that one of five hypertensive patients and more than one of three with controlled OBP will have MH. MH is associated with other cardiovascular risk factors, such as diabetes, and in nondiabetics, with male sex, older age and obesity.

A community-based clinical trial of Intra-Venous zOledRonic acid once Yearly in comparison to oral bisphosphonates in postmenopausal women with osteoporosis: the IVORY trial Methodological considerations.

BACKGROUND: Zoledronic acid is an intravenous once yearly bisphosphonate that has been shown to be effective and safe in improving BMD (bone mineral density) and reducing fracture risk in controlled clinical trials. IVORY is a Canadian post marketing study aiming at assessing real-life effectiveness, health care resource utilization, safety and compliance to treatment with zoledronic acid in comparison to orally administered bisphosphonates (OBP). METHODS: IVORY is a prospective two cohort observational study of patients treated with zoledronic acid or OBP. Eligible patients are postmenopausal females, >45 years old with osteoporosis for whom initiation of treatment with OBP or zoledronic acid is indicated. Subjects will be followed for four years. Outcomes are the change in lumbar spine, femoral neck and total hip BMD and the incidence of fractures. The study cohort will consist of 920 patients treated with zoledronic acid and 460 treated with OBP. Additional comparisons will be based on external standardization to the population of Quebec patients treated with OBP. DISCUSSION: Post Marketing Observational Studies (PMOS) are essential for the assessment of real-life effectiveness and population based benefit-risk ratios. The effect of access to care, compliance, adherence to guidelines, patient comorbidity and concomitant medication use could only be assessed with observational studies. IVORY will provide information about true life effectiveness, benefit-risk ratios, cost-effectiveness and barriers to the process-outcome optimization. The results will have implications for decision makers and health care stakeholders regarding the management of osteoporosis in Canada.

Biological aspects of neuroblastomas identified by mass screening in Quebec.

BACKGROUND: Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. PROCEDURE: Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. RESULTS: Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. CONCLUSIONS: The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.

Toxicity profile of interferon alfa-2b in children: A prospective evaluation.

The toxicity of interferon (IFN) alfa-2b therapy was prospectively evaluated in 53 children treated from 1991 to 1996 in 2 successive studies of IFN alfa therapy for severe hemangiomas at Sainte-Justine Hospital. Toxicity was generally mild and transient, with grade 1 toxicity occurring in 100% of patients, grade 2 toxicity in 89%, grade 3 toxicity in 58%, and grade 4 toxicity in 17%. Ten of 43 patients available for evaluation had an abnormal neurologic examination. Severe neurotoxicity in the form of spastic diplegia occurred in one patient. In conclusion, IFN alfa therapy is generally well tolerated in children. However, it may rarely be associated with severe toxicity and must be used with caution.

Amplifications of DNA primase 1 (PRIM1) in human osteosarcoma.

We studied the involvement of PRIM1 in osteosarcoma by differential display, Northern and Southern hybridization, as well as fluorescence in situ hybridization (FISH) on interphase nuclei. In total, 22 pediatric oncology specimens were tested. PRIM1 was found to be amplified in 41% of the samples. PRIM1 is coamplified with the core 12q13 amplicon genes CDK4, SAS, and OS9, and was physically mapped very close to them. PRIM1 is therefore a new candidate for the role of a major target gene of 12q13 amplifications in human cancers. Genes Chromosomes Cancer 26:62-69, 1999.

Safety, tolerability, antiemetic efficacy, and pharmacokinetics of oral dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.

PURPOSE: The safety, antiemetic efficacy, and pharmacokinetics of single oral doses of dolasetron, a new highly selective 5-HT3 receptor antagonist, were evaluated in children with cancer undergoing treatment with moderately to highly emetogenic chemotherapy. PATIENTS AND METHODS: A total of 32 children, ages 3 to 18 years, were enrolled in a nonrandomized, multicenter, open-label, dose-escalation study. Three oral dose levels (0.6, 1.2, or 1.8 mg/kg) were studied. Safety, efficacy, and pharmacokinetic parameters were assessed over 24 hours at each dosage level. RESULTS: The most effective dose was 1.8 mg/kg; 60% of the patients achieved a complete or major response (< or =2 emetic episodes in 24 hours). A complete response was achieved in 3 of 9 patients (33%) who received 0.6 mg/kg, 4 of 13 (31%) patients who received 1.2 mg/kg, and 5 of 10 (50%) patients who received 1.8 mg/kg of dolasetron. Overall, dolasetron was well tolerated. Adverse events were mild and similar to those reported in adults. Peak plasma concentrations (Cmax) of dolasetron's active reduced metabolite, MDL 74,156, were dose proportional and occurred, on the average, within 1 hour of oral administration. The half-life (t1/2) in plasma was approximately 6 hours for all dose levels, and the mean clearance (CLapp) was unrelated to dose. CONCLUSIONS: Oral dolasetron is safe and effective in reducing chemotherapy-induced nausea and vomiting, particularly at the 1.8-mg/kg dose level. These results support further evaluation of oral dolasetron in larger randomized clinical trials in the pediatric cancer population.

Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.

BACKGROUND: Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy. PROCEDURE: An open-label dose-escalation study was conducted to assess the appropriate intravenous dose of dolasetron for pediatric patients undergoing chemotherapy. Patients received dolasetron in single intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters were evaluated at each dose level and efficacy was evaluated over the first 24 hr following the administration of dolasetron. RESULTS: A complete response was achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg, 67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma concentrations (Cmax) were observed between 0. 33 and 0.75 hr following dolasetron infusion. Cmax and area under plasma concentration-time (AUC) increased with larger doses of dolasetron, while terminal disposition half-life (t1/2) and apparent clearance (Clapp) were not significantly changed with respect to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious events occurred. Conclusions. This study suggests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy-induced emesis in pediatric patients.

Survival rates among Canadian children and teenagers with cancer diagnosed between 1985 and 1988.

PURPOSE: To describe the survival rates among Canadian children and teenagers with cancer diagnosed between 1985 and 1988 using population-based data, specifically for the more common forms of childhood cancer, and to assess the effect of age at diagnosis and sex as prognostic factors for selected childhood cancers. DESIGN: Retrospective survival study based on incident cases of cancer identified by the National Cancer Incidence Reporting System and follow-up ascertained by computer record linkage to the Canadian Mortality Database. SUBJECTS: A total of 4409 patients with cancer first diagnosed at 19 years of age or younger between 1985 and 1988, and followed up to Dec. 31, 1991. MAIN OUTCOME MEASURES: Survival rates calculated at 1, 3 and 5 years according to the actuarial life table and the proportional hazards models. RESULTS: The 5-year survival rate for all cancers combined was 71%. Females with acute lymphoblastic leukemia and astrocytoma had markedly higher survival rates than their male counterparts (p < 0.05). Age at diagnosis was a significant predictor of survival among children with acute lymphoblastic leukemia or acute nonlymphoblastic leukemia (p < 0.01), infants having a substantially poorer prognosis than older children. Conversely, the survival rate among infants with neuroblastoma was higher than that among older children, 87% surviving for 5 years after diagnosis. CONCLUSIONS: The survival rate among Canadian children and teenagers with cancer is favourable in relation to the rate among adults with cancer. Nonetheless, the 5-year survival rates for several childhood cancers remain poor (i.e., less than 65%). The survival rates among Canadian children with cancer are similar to those among children with cancer in other developed countries.

Pathology review of screening negative neuroblastomas: a report from the Quebec Neuroblastoma Screening Project.

BACKGROUND: The Quebec Neuroblastoma Screening (QNS) Project completed a 5-year program for measuring urinary vanillylmandelic acid (VMA)/homovanillic acid (HVA) levels at age 3 weeks and/or 6 months in 89% of 476,603 Quebec-born infants from 1989-1994; 45 screening positive preclinical cases (S-positive cases) and 20 congenital/neonatal (C/N) cases were identified. As of April 1997, an additional 59 cases in the same birth cohort were diagnosed clinically; these neuroblastomas developed after screening verified normal VMA/HVA levels (S-negative cases). METHODS: Pathology specimens from 45 of 59 S-negative cases were reviewed centrally and classified according to the Shimada system. Results were compared with clinical data and also with S-positive and C/N cases. RESULTS: Of 45 S-negative cases, 27 tumors had favorable histology (FH) and 18 had unfavorable histology (UH). Approximately 52% of FH tumors were diagnosed before age 1 year, whereas UH tumors were nearly exclusively (94%) diagnosed after age 1 year (P < 0.01). Approximately 89% of FH tumors were Stage I, II, or IV-S, whereas 72% UH tumors were Stage III or IV (P < 0.001). All children with FH tumors were alive at last follow-up (range of follow-up period: 9-79 months; median, 35 months), whereas 8 children with UH tumors died of disease even after limited follow-up (range of follow-up period: 0-60 months; median, 20 months). By contrast, S-positive and C/N cases were predominantly (97%) FH tumors, often (76%) Stage I, II, or IV-S, with excellent clinical outcome (survival rate of 98%). CONCLUSIONS: The majority of the UH neuroblastomas that developed in the birth cohort of the QNS Project were included in the group of S-negative cases and could not be detected by the screening at age 3 weeks and/or 6 months.

Psychometric properties of the Health Utilities Index Mark 2 system in paediatric oncology patients.

This study examined the reliability and validity of the Health Utilities Index (HUI) Mark 2 system, a health-related quality of life (QoL) instrument, in children with cancer. The sample consisted of 61 mothers of paediatric oncology patients, aged 4.1-17.3 years, who were either on treatment (n = 20) or off treatment (n = 41). The test-retest reliability was very good for the HUI Mark 2 system global score and all of its dimensions except pain. The HUI Mark 2 dimensions of emotion, pain and self-care as well as its overall score showed moderate convergent validity with other measures. In addition, the HUI Mark 2 system demonstrated good discriminant validity. However, the content validity of the HUI Mark 2 system when considered as a multiattribute descriptive health profile is questionable because it falls to assess domains such as neuropsychological and psychosocial functioning. Overall, the results indicate that the HUI Mark 2 system is reliable and valid as a measure of health-related QoL for paediatric oncology patients.

Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children.

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC0-24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, Cmax, AUC0-24, and the half-life, respectively, were (mean +/- standard deviation) 571+/-416 ng/ml, 6,930+/-5,830 ng.h/ml, and 47+/-55 h in the children aged 6 months to 2 years; 534+/-431 ng/ml, 7,330+/-5,420 ng.h/ml, and 30.6+/-25.3 h in the children aged 2 to 5 years; and 631+/-358 ng/ml, 8,770+/-5,050 ng.h/ml, and 28.3+/-9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-beta-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.

Excess of congenital abnormalities in French-Canadian children with neuroblastoma: a case series study from Montréal.

Neuroblastoma is one of the most common cancers of childhood. Some studies have shown an excess of congenital abnormalities in children who have been diagnosed with neuroblastoma. In this study we examined the medical records of all children with neuroblastoma seen at St. Justine Children's Hospital between the years 1977 and 1993. A total of 141 children (131 of French-Canadian ancestry) were included in this study. Twelve children (8.5%) had 21 defined congenital abnormalities (1,490 per 10,000 children). This compared with a rate of 444.3 children with abnormalities per 10,000 live births (4.44%) for all congenital abnormalities in the British Columbia Health Surveillance Registry, 1979-1988 (relative risk = 1.91, P = 0.03). Six of the 12 children had cardiovascular malformations. These and previous results suggest that there may be a common developmental origin to neuroblastoma and to some congenital malformations. Genes that control development may be worthy of further study in these children.

Microsatellite instability in childhood T cell acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer encountered in children. Little is known about the molecular pathology of childhood T cell ALL. Oncogenesis is a multistep process that involves alterations in proto-oncogenes and tumor suppressor genes. Recently, a mutator phenotype detectable by microsatellite instabilities was shown to be associated with predisposition to cancer. This new mechanism for human carcinogenesis is caused by defects in the DNA replication/repair system. To study the involvement of some of these mutational events in the development of T cell ALL, we have initiated a systematic search for losses of heterozygosity (LOH) and microsatellite instabilities in children affected with this disease. These patients were allelotyped by PCR using 56 microsatellite markers located near known or putative tumor suppressor genes. The microsatellite patterns were altered in more than 80% of the patients. LOH were detected in chromosomes 6p, 12p and 9p. Two third of the patients were deleted for chromosome 9p21, suggesting the involvement of a tumor suppressor gene, probably the p16 gene. The only patient refractory to chemotherapy was shown to be associated with a mutator phenotype. This is the first documented case of a childhood neoplasia associated with genomic instabilities. Our results suggest that defects in DNA replication/repair components are involved in the development of a subset of childhood T cell ALL.

Cardiovascular responses to dynamic submaximal exercise in children previously treated with anthracycline.

This study assessed the long-term (5-year) outcome of pediatric low-dose anthracycline therapy on the circulatory response to moderate exercise. Thirteen patients (13 +/- 4 years old) and 15 age-matched control subjects completed a maximal cycle ergometer protocol as well as two 5-minute cycling tests at 33% and 66% maximal oxygen uptake (V(O2)max) for determination of cardiac index (carbon dioxide rebreathing). V(O2)max was lower in patients than in control subjects (1.3 +/- 0.5 L/min vs 2.3 +/- 0.6 L/min) (p< 0.05). Smaller relative increases in cardiac index for similar increases in relative exercise intensities were found in patients (33% V(O2)max, 73% vs 116%; 66% V(O2)max, 115% vs 192%), as a result of smaller increases in stroke index from rest (33% V(O2)max, 33% vs 54%; 66% V(O2)max, 33% vs 69%; p< 0.05). Similarly, despite normal resting systolic function, patients exhibited a lower stroke index and higher heart rate for any given value of oxygen uptake (milliliters per minute per square meter). Children who had survived cancer exhibited stroke index impairment during exercise similar in intensity to that of recreational activities or play, attesting to a limited inotropic reserve.

Correlation of MYCN amplification, Trk-A and CD44 expression with clinical stage in 250 patients with neuroblastoma.

In contrast to MYCN amplification, expression of either trk-A or CD44 in neuroblastoma is a favourable prognostic factor and were therefore investigated in tumours from 250 patients. One hundred and eleven localised/4s (Group 1) and 139 stage 4 (Group 2) tumours were analysed. MYCN copy number was obtained by Southern blotting or PCR amplification and was detected in 28 stage 4 tumours. Trk-A and CD44 expression was detected by immunoperoxidase staining using murine monoclonal antibodies 5C3 and L178, respectively. Expression was scored as positive (homogeneous), mixed (heterogeneous) or non-reactive (negative). Trk-A expression was found in 95% of Group 1 tumours and 49% of Group 2 tumours. CD44 expression was found in 100% of Group 1 tumours, the majority of which had a strong homogeneous expression. Lack of CD44 expression occurred in 25% of tumours, all stage 4 neuroblastoma. Of the 28 MYCN amplified tumours, 27/28 (96%) were trk-A negative, and 13/28 (46%) CD44 negative. We conclude that (1) a significant percentage of stage 4 neuroblastoma express either or both trk-A and CD44, (2) the absence of CD44 expression is highly restricted to stage 4 neuroblastoma and is associated with the lack of trk-A expression, (3) trk-A negativity among CD44-positive tumours is associated with stage 4 neuroblastoma and (4) the absence of trk-A expression is highly correlated with MYCN amplification.