Reinhold Kerbl

Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years

Abstract Intensive multimodality treatment has led to a remarkable improvement of prognosis in paediatric cancer patients, however, a great number of long-term survivors suffer from considerable tumour- or treatment-related late effects. Between January 1990 and December 1998, 223 consecutive survivors of childhood malignancies entered a prospective follow-up study designed to evaluate the frequency and severity of tumour- and/or therapy-related long-term sequelae. After cessation of therapy and subsequently once a year, all patients underwent a detailed examination programme including physical examination, laboratory tests, abdominal sonography, echocardiography, electrocardiography, electroencephalography, spirometry, audiometry, ophthalmological examination and endocrine stimulation tests. Median follow-up was 5 years (range 0.4 to 9.6 years). A total of 167 patients (75%) had at least one chronic medical problem of whom 80 needed permanent medical support. The organ systems most frequently affected were the nervous system in 39%, the endocrine system in 32%, the ears/eyes in 22%, the kidneys in 17%, and the liver in 12% of the patients. Some late effects (endocrine deficits, hearing loss, tubulopathy) were primarily diagnosed only several years after the end of oncological therapy. Conclusion The results of this study indicate that a considerable number of former paediatric cancer patients suffer from remarkable long-term side-effects. Since life quality is an important parameter of cancer survival, careful follow-up of long-term survivors is mandatory with the aim to reduce or even abrogate possible side-effects at the earliest time.

Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients

Urinary catecholamine metabolites are well‐known to be elevated in patients with neuroblastoma. Some investigators have described different patterns in favorable and unfavorable cases. However, extended studies have not been published.

Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy.

Objective. Chronic hepatitis C is a major long-term problem for children who survive cancer. Interferon (IFN)-α has been shown to be effective in treating patients with chronic hepatitis C; however, the rate of sustained response is low. Combining IFN-α and ribavirin (RBV) has been shown to significantly improve the response in adult patients with chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and safety of a combined virostatic treatment with IFN-α and RBV in a small cohort of children and adolescents with chronic hepatitis C and previous malignancy. Methods. Twelve patients with a history of a hematooncologic disease (median follow-up: 13.5 years; range: 7–14.7 years) and chronic hepatitis C were treated with recombinant IFN-α-2a (6 megaunits/m2 body surface area, 3 times a week, subcutaneously) combined with RBV (15 mg/kg body weight/day, orally) for 12 months. They were tested monthly for blood counts and liver function, and for serum virus concentrations (hepatitis C virus RNA by polymerase chain reaction) every 3 months. Results. At the end of the treatment, hepatitis C virus RNA could not be detected in the serum of 8 of the 12 patients; 2 of these patients relapsed soon after therapy withdrawal, whereas 6 patients maintained in sustained virologic and biochemical remission (follow-up: 12 months). Treatment-induced toxicity was moderate and reversible with influenza-like symptoms and a decrease in blood counts in all 12 patients, alopecia in 5 of the 12, hemolysis in 4 of the 12, and weight loss of >10% in 2 of the 12. Conclusions. As demonstrated in adults with chronic hepatitis C, treatment with IFN-α and RBV also seems to be an effective and safe therapeutic option for children and adolescents with chronic hepatitis C after malignancy.

Neuroblastoma in Europe: differences in the pattern of disease in the UK

BACKGROUND Neuroblastoma is a major contributor to childhood cancer mortality, but its prognosis varies with age and stage of disease, and some tumours regress spontaneously. Urinary screening programmes or clinical examination may detect the disease before symptoms appear, but the benefit of early diagnosis is uncertain. We examined the incidence, pattern, and presentation of neuroblastoma in four European countries. METHOD Population-based incidence rates were derived for France, Austria, Germany, and the UK. Age, sex, and stage distribution were analysed by Mantel-Haenszel techniques and Poisson regression. The proportion of incidental diagnoses (cases without symptoms found at routine health checks or during investigation of other disorders) and mortality rates were also compared. FINDINGS Between 1987 and 1991, 1672 cases of neuroblastoma were diagnosed in children under 15 years old (France, 624; Austria, 69; Germany, 493; UK, 486). Age-standardised annual incidence was significantly lower in the UK (10.1/million) than in France (12.5) and Germany (11.4). In the UK a deficit of low-stage disease in infants was accompanied by an excess of stage IV in older children. The UK had significantly fewer incidental diagnoses (8%) than Austria (27%) and Germany (34%). UK mortality rates were significantly higher than German or French rates. INTERPRETATION In the UK, neuroblastoma diagnosis is delayed, possibly because of a less rigorous system of health checks for children. Although some overdiagnosis occurs in mainland Europe, our data suggest that in the UK some low-stage cases, undetected in infancy, may later present as advanced disease. This finding has implications for screening programmes and organisation of routine surveillance of infant health in the UK.

Intratumoural heterogeneity of 1p deletions and MYCN amplification in neuroblastomas.

BACKGROUND At least three genetic hallmarks identify aggressive tumour behaviour in neuroblastomas; amplification of the oncogene MYCN; deletion (loss of heterozygosity [LOH]) at the short arm of chromosome 1 (del1p36), seen in approximately 28% of the cases; and di-tetraploidy. The MYCN oncogene is amplified in approximately 23% of all neuroblastomas and becomes important for the stratification of therapy in localised and 4s tumours. Up to now, it has been believed that the genetic constellation of neuroblastic tumours is stable and does not alter during tumour evolution or during tumour progression. PROCEDURE Using fluorescence in situ hybridisation techniques (FISH) to investigate different tumour areas on touch preparations and histological sections, we show that genetic heterogeneity can be detected in neuroblastomas, especially in tumours detected by urinary mass screening. CONCLUSION The identification of such cell clones is important, because the MYCN amplification and/or the deletion at 1p36 appear to be responsible for aggressive local growth and development of metastases.

Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: results of a prospective, randomized single-center trial.

Purpose To investigate the efficacy and side effects of two different intravenous immunoglobulin (IVIG) dose regimens for the initial treatment of childhood acute immune thrombocytopenic purpura (ITP). Methods Thirty-four consecutive patients with a clinical diagnosis of acute ITP and a platelet count below 20 × 109/L were randomized to receive either 1 g/kg body weight (n = 17; group A) or 0.3 g/kg body weight (n = 17; group B) IVIG per day for 2 consecutive days (total dose 2 g/kg and 0.6 g/kg). Results Fifteen of the 17 patients (88.2%) in group A and 13 of the 17 patients (76.5%) in group B achieved a platelet count of more than 20 × 109/L within 72 hours. The increase in platelet counts on day 2 and 3 was more pronounced in the high-dose group. Two patients in the high-dose group and four in the low-dose group were non-responders. Chronic disease occurred in three patients receiving 2 g/kg IVIG and in five patients receiving 0.6 g/kg IVIG. Side effects of IVIG administration were more common in the high-dose group. Conclusions The present study showed that platelet counts increased more rapidly after high-dose IVIG administration within the first 72 hours, although a platelet count of more than 20 × 109/L can be achieved also with low-dose IVIG in most children with acute ITP. For patients with very low platelet counts, doses higher than 0.6 g/kg seem, therefore, to be more effective.

Congenital central hypoventilation syndrome (Ondine's curse syndrome) in two siblings: Delayed diagnosis and successful noninvasive treatment

Congenital central hypoventilation syndrome (CCHS, Ondines curse syndrome) is a rare respiratory disorder; less than 100 cases have been reported. Familiality of the disease has been discussed, but only few familial cases have been reported so far. In this report we describe the occurrence of CCHS in two male siblings. Diagnosis was established only at the age of 4 years in the first case, although the patient had disease related symptoms since early infancy. The second patient was one of dizygotic twins, he was diagnosed with CCHS at the age of 8 months. Up to that age only moderate desaturations had been observed. The other twin was unaffected by the disease. Both patients were successfully treated by nocturnal positive-pressure ventilation via a specially adapted face mask. They show satisfactory physical and neurologic development.

Wait and see strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening.

Neuroblastomas in infants may regress or mature spontaneously. Consequently, some authors have applied a “wait and see” strategy for tumors found by urinary mass screening. Recently, improved technique and increasing frequency of ultrasound examinations have led to an increase of neuroblastoma cases in pre‐ and post‐natal period. We describe five cases, four diagnosed by routine ultrasound examination and one detected by urinary mass screening, who were monitored with a “wait and see” strategy in order to spare surgery. Median age at diagnosis was 4 months (range 2–10 months). All tumors were adrenal neuroblastomas. All patients met the following criteria: localized tumors, tumor size less than 5 cm in diameter, absence of invasive growth, vanillylmandelic acid (VMA) and homovanillic acid (HVA) less than 50 µg/mg creatinine, and informed consent of parents. Monitoring was performed by monthly ultrasound examinations and urine catecholamine analysis. Median follow‐up is 14 months (5–28 months). Three tumors showed spontaneous regression, one is still under observation. In one patient the tumor increased in size and was resected after 14 months of observation displaying favorable histology, but chromosome 1p imbalance. Previous reports describe the adoption of a “wait and see” strategy in selected cases of localized neuroblastoma detected by mass screening. Our study confirms that this strategy may be similarly applied in incidentally or clinically detected cases. However, possible benefit has to be carefully balanced against possible risks.

Elevated Expression of Galanin Receptors in Childhood Neuroblastic Tumors

The neuropeptide galanin (GAL) has been shown to be present in certain brain tumors. In order to learn more about GAL and its receptors in human tumors of the peripheral nervous system, we investigated the expression of the GAL peptide and the GAL receptors in tumor tissue from childhood neuroblastic tumors. GAL peptide concentrations up to 674 ± 166 fmol/mg of tissue were detected by radioimmunoassay, but no significant correlation with standard tumor markers or the prognosis of the 14 patients investigated was observed. Ligand binding experiments showed different levels of GAL binding in all 28 primary neuroblastomas and 7 ganglioneuromas investigated. All three human GAL receptor subtypes cloned to date could be detected, with the GALR1 receptor subtype being expressed most prominently. GAL binding did not significantly correlate with genetic markers such as unfavorable DNA ploidy, amplification of the oncogene MYCN and allelic loss of chromosome 1p. However, low galanin binding was significantly correlated with survival (p = 0.021) in this limited analysis of neuroblastic tumor samples. These results raise the possibility that the expression of GAL binding sites may play a role in neuroblastic tumor biology and behavior.

Outcome and Long-Term Side Effects after Synchronous Radiochemotherapy for Childhood Brain Stem Gliomas

Between 1993 and 1999, 11 children with histologically confirmed diffuse and exophytic brain stem glioma (BSG) were treated with intensive induction chemotherapy and simultaneous external beam irradiation. Chemotherapy was performed according to the German/Austrian Pediatric Brain Tumor Study HIT ’91 and included two cycles of ifosfamide (days 1–3), etoposide (days 4–6), methotrexate (days 15 and 22), cisplatin (days 29–31) and cytarabine (days 29–31), separated by a 3-week interval. Maintenance chemotherapy with carmustine, carboplatin and vincristine (8 cycles over a 1-year period) was given in those patients who responded clinically or radiographically to induction chemotherapy. Six of 11 patients showed an objective reduction in tumor size on magnetic resonance imaging and 4 of 11 are alive in good general condition >22, >22, >90 and >92 months, respectively, after diagnosis without radiographic evidence of tumor progression (1 complete remission, 2 partial remissions, 1 stable disease), but suffer from moderate to severe long-term side effects. Three patients died due to disease progression after having achieved a partial remission which lasted 5, 6 and 18 months, respectively, whereas only short-term stabilization was observed in 4 patients who died within 1 year after diagnosis. Acute hematologic toxicity was severe but manageable. This intensive combined modality treatment was toxic but yielded objective responses in more than 50% and long-term survivors in one third of childhood BSG patients.