Pekka Riikonen

Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia

Purpose Osteoporosis and pathologic fractures are occasionally found in patients with childhood acute lymphoblastic leukemia (ALL). This study was performed to determine the degree of possible osteopenia in long-term survivors of childhood ALL. Patients and Methods Lumbar spine (L2-L4) and femoral neck bone mineral densities (BMDs) (g/cm2) were measured in 29 survivors (aged 12 to 30 years, median 17) of childhood ALL 2 to 20 (median 8) years after discontinuation of chemotherapy. These results were compared with those from 273 healthy controls and expressed as a percentage of the age- and sex-matched control values (mean ± standard deviation). Results Lumbar and femoral BMDs were significantly reduced in survivors of childhood ALL. Particularly, male gender (lumbar: 91.7 ± 10.4%, p = 0.008; femoral: 91.9 ± 11.3%, p = 0.005) and a history of cranial irradiation (lumbar: 93.0 ± 8.9%, p = 0.005; femoral: 94.4 ± 13.3%, p = 0.03) were associated with low lumbar and femoral BMDs. Conclusions The detected deficit in bone density in survivors of childhood ALL may predispose these patients to osteoporotic fractures later in adulthood. A follow-up of BMD in survivors of childhood ALL should facilitate the identification of patients who would require specific therapeutic interventions to prevent further decrease of their skeletal mass and preserve their BMD.

Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double blind placebo-controlled study in children.

In a double blind study of 58 episodes of fever and profound neutropenia, children with cancer received either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo, combined with identical antimicrobial therapy, i.e. imipenem, on admission. The criteria for discontinuation of therapy were identical. A difference was demonstrated both in the number of hospital days, totaling 252 days in the rhGM-CSF group and 354 in the placebo group, days receiving antibiotics (220 vs. 322), and in the resolution of neutropenia (4.5 days vs. 6.0 days; P < 0.05). The number of episodes requiring antimicrobial therapy for longer than 10 days was 5 of 28 (12%) in the rhGM-CSF group as opposed to 15 of 30 (50%) in the placebo group (P = 0.01). rhGM-CSF was well-tolerated. We conclude that rhGM-CSF was efficacious in accelerating myeloid recovery and reducing the length of hospitalization in febrile neutropenia.

Merkel cell polyomavirus DNA in tumor-free tonsillar tissues and upper respiratory tract samples: Implications for respiratory transmission and latency

Abstract Background Merkel cell polyomavirus (MCPyV) was discovered recently. It is considered a potential causative agent of Merkel cell carcinoma, a life-threatening skin cancer. Objectives To study the prevalence of MCPyV in a large number of clinical samples of various types. Most of the samples were examined also for the other newly found polyomaviruses KI (KIPyV) and WU (WUPyV). Study design Altogether 1390 samples from immunocompetent or immunocompromised patients, including (i) tonsillar tissues and sera from tonsillectomy patients; (ii) nasopharyngeal aspirates (NPAs) and sera from wheezing children and (iii) nasal swabs, sera and stools from febrile leukemic children were studied for MCPyV. The tonsils, nasal swabs and stools were also studied for KIPyV and WUPyV. Results MCPyV DNA was detected in 14 samples altogether; 8 of 229 (3.5%) tonsillar tissues, 3 of 140 (2.1%) NPAs, 2 of 106 (1.9%) nasal swabs and 1 of 840 (0.1%) sera. WUPyV and KIPyV were detected in 5 (2.2%) and 0 tonsils, 1 (0.9%) and 4 (3.8%) nasal swabs and 0 and 2 (2.7%) fecal samples, respectively. The patients carrying in tonsils MCPyV were of significantly higher age (median 42years) than those carrying WUPyV (4years, p <0.001). Conclusions MCPyV DNA occurs in tonsils more frequently in adults than in children. By contrast, WUPyV DNA is found preferentially in children. MCPyV occurs also in nasal swabs and NPAs, in a frequency similar to that of KIPyV and WUPyV. The tonsil may be an initial site of WUPyV infection and a site of MCPyV persistence.

Long-Term Prospective Follow-Up Study of Cardiac Function After Cardiotoxic Therapy for Malignancy in Children

PURPOSE To evaluate cardiac function by means of conventional and three-dimensional echocardiography (3DE) and measurement of natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria. PATIENTS AND METHODS Thirty-nine survivors of childhood malignancy were examined in 1994 and 1998. The mean time from the diagnosis was 8.6 (3.9 to 16.8) years and between cardiac evaluations was 4.1 (3.3 to 5.1) years. Patients were divided into two groups according to therapies given (group I (n = 30): no cardiac irradiation, median cumulative anthracycline dose 210 mg/m2; group II (n = 9): irradiation in the cardiac region, median cumulative anthracycline dose 180 mg/m2). RESULTS Fractional shortening (FS) in 1994 was higher than in 1998 (32.5 +/- 4.3 vs. 30.3% +/- 3.3%, P =.009). 33% of patients in group I and 56% in group II in 1994 and 30% of patients in group I and 67% in group II in 1998 had N-terminal of the propeptide-atrial natriuretic peptide (NT-proANP) levels exceeding the 90th percentile of controls. In 1998, both groups (I and II) had lower ejection fraction (EF) measured by 3DE than their matched controls (52.9 +/- 5.2 vs. 58.8% +/- 3.1%, P <.001 and 50.0 +/- 6.6 vs. 60.8% +/- 3.2%, P =.024, respectively). Left atrial maximum volumes/body surface area were smaller in the patients than in controls. B-Type natriuretic peptide values did not differ significantly in either group. CONCLUSION Left ventricular contractility decreases slowly even years after cardiotoxic cancer therapy in children. 3DE and NT-proANP measurements are effective methods to evaluate the cardiac function in these patients.

Acute lymphoblastic leukemia in adolescents and young adults in Finland

Recent reports indicate that adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric rather than adult therapeutic protocols. This Finnish study did not show any major difference between patients treated with pediatric protocols and those treated with adult protocols, but confirmed that adolescents and young adults with acute lymphoblastic leukemia still have a poorer outcome than children below 10 years of age. See related perspective article on page 1124. Background Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland. Design and Methods This population-based study included 225 consecutive patients aged 10–25 years diagnosed with acute lymphoblastic leukemia during 1990–2004. One hundred and twenty-eight patients (10–16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17–25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients. Results For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%.The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white bood cell count ≥ 100×109/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification. Conclusions Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols. Key words: acute lymphoblastic leukemia, adolescents, survival, treatment outcome, young adults.

High Body Mass Index Increases the Risk for Osteonecrosis in Children With Acute Lymphoblastic Leukemia

PURPOSE The aim of the study was to determine the incidence of and clinical risk factors for radiographic osteonecrosis (ON) in children treated for acute lymphoblastic leukemia (ALL) using the Nordic ALL protocols. PATIENTS AND METHODS Ninety-seven consecutive patients with childhood ALL were studied prospectively by magnetic resonance imaging (MRI) of the lower extremities at the end of the treatment. RESULTS Twenty-three (24%) of the 97 patients had ON. Seven of the patients (30%) were symptomatic, and three patients (13%) required surgical interventions. Multiple logistic regression analysis showed that high body mass index (BMI; P = .04), female sex (P = .01), older age at diagnosis (P < .001), and higher cumulative dexamethasone dose (P = .03) were independent risk factors for radiographic ON. The cumulative prednisone dose did not differ significantly between the patients with and without ON. The incidence of radiographic ON decreased significantly, from 36% to 7%, when the duration of dexamethasone exposure during the delayed-intensification phase was shortened from 3 to 4 weeks to 2 weeks with a taper (P = .001). CONCLUSION ON as determined by MRI was found to be a common complication in children and adolescents after treatment with the Nordic ALL protocols. Revision of the ALL protocols by shortening the single exposure to dexamethasone has diminished the risk for ON remarkably. High BMI was identified as a new significant risk factor for ON.

Reduced bone density at completion of chemotherapy for a malignancy

OBJECTIVES Osteoporosis and pathological fractures occur occasionally in children with malignancies. This study was performed to determine the degree of osteopenia in children with a malignancy at completion of chemotherapy. METHODS Lumbar spine (L2–L4) bone mineral density (BMD; g/cm2) and femoral neck BMD were measured by dual energyx ray absorptiometry in 22 children with acute lymphoblastic leukaemia (ALL), and in 26 children with other malignancies. Apparent volumetric density was calculated to minimise the effect of bone size on BMD. Results were compared with those of 113 healthy controls and expressed as age and sex standardised mean Z scores. RESULTS Patients with ALL had significantly reduced lumbar volumetric (−0.77) and femoral areal and volumetric BMDs (−1.02 and −0.98, respectively). In patients with other malignancies, femoral areal and apparent volumetric BMDs were significantly decreased (−0.70 and −0.78, respectively). CONCLUSIONS The results demonstrate that children with a malignancy are at risk of developing osteopenia. A follow up of BMD after the completion of chemotherapy should facilitate the identification of patients who might be left with impaired development of peak bone mass, and who require specific interventions to prevent any further decrease in their skeletal mass and to preserve their BMD.

Impaired Development of Bone Mineral Density During Chemotherapy: A Prospective Analysis of 46 Children Newly Diagnosed with Cancer

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2–L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual‐energy X‐ray absorptiometry in 46 children (age 2.9–16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy‐terminal propeptide (PICP), and type I collagen carboxy‐terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6‐month follow‐up. A significant decrease in lumbar BMDvol (–2.1%, p < 0.05), and in femoral BMDareal (–9.9%, p = 0.0001) and BMDvol (–8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow‐up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.

Imipenem compared with ceftazidime plus vancomycin as initial therapy for fever in neutropenic children with cancer.

&NA; Two antibiotic regimens were assessed, imipenem as monotherapy and ceftazidime plus vancomycin as combination therapy, for initial empiric therapy in febrile neutropenic children with cancer. In a prospective randomized trial of 89 evaluable consecutive episodes, 45 were treated with imipenem and 44 with ceftazidimevancomycin. In 87% of the episodes the neutropenia was severe. Of the 89 episodes 20% were bacteremias, 10% were clinically defined focal infections and 70% were considered fevers of unknown origin. The initial treatment was successful in 82% of the imipenem group and 59% of the ceftazidime plus vancomycin group. Both regimens were well‐tolerated. There was no mortality, probably owing to the prompt admission and institution of antimicrobial therapy. All of the patients were treated until neutrophil recovery; no recurrent infections were seen. In conclusion imipenem monotherapy was welltolerated and effective as initial therapy for fever in neutropenia in children.

Respiratory viral infections in children with leukemia.

Background: Respiratory viruses occur frequently in the community and are a common cause of fever in children. Data on respiratory viral infections in children with cancer are limited. Methods: A long-term, prospective, multicenter study was carried out in Finland searching for respiratory viruses in febrile children with leukemia. For this purpose, 138 febrile episodes in 51 children with leukemia were analyzed. Twelve types of respiratory viruses were searched for by viral culture, antigen detection, and polymerase chain reaction tests. Results: Evidence of a respiratory viral infection was found in 61 of 138 febrile episodes (44%), accounting for an incidence of 0.8 (range, 0–2.4) per person year at risk during the treatment of leukemia. The most common viruses detected were rhinovirus (22%), respiratory syncytial virus (11%), human bocavirus (5%), and influenza A virus (4%). Dual viral infections were detected in 12 cases (9%). Half of the children had respiratory symptoms with cough being the most common symptom. Two children developed pneumonia. The mean duration of fever was 2.6 (SD 1.7) days in children with respiratory viral infection and 2.1 (SD 1.3) days in children without evidence of viral infection (P = 0.44). Conclusions: Respiratory viruses are found commonly during febrile episodes in children with leukemia. The detection of viruses permits the use of available antiviral agents, may explain a poor response to antimicrobial agents, and minimizes the proportion of febrile episodes without possible etiologic agents in children with leukemia.