Strahlentherapie und Onkologie Short Communication Intracerebral Cavernous Hemangioma after Cranial Irradiation in Childhood Incidence and Risk Factors Volker Strenger1, Petra Sovinz1, Herwig Lackner1, Hans Jürgen Dornbusch1, Helga Lingitz2, Hans G. Eder3 Andrea Moser1, Christian Urban1 Background and Purpose: Radiotherapy is an integral part of various therapeutic regimens in pediatric and adult oncology. Endocrine dysfunction, neurologic and psychiatric deficits, secondary malignancies and radiation-induced necrosis are well-known possible late effects of cranial irradiation. However, only sporadic cases of radiation-induced cavernous hemangiomas (RICH) have been reported so far. Patients and Methods: Pediatric patients who underwent cranial radiation therapy for malignant diseases between January 1980 and December 2003 were retrospectively analyzed. After the end of therapy they entered a detailed follow-up program. Results: Of 171 patients, eight (three patients with medulloblastoma, three patients with acute lymphoblastic leukemia, and one patient each with ependymoma and craniopharyngioma) developed intracerebral cavernoma 2.9–18.4 years after irradiation representing a cumulative incidence (according to the Kaplan-Meier method) of 2.24%, 3.86%, 4.95%, and 6.74% within 5, 10, 15, and 20 years following radiation therapy, respectively. In patients treated in the first 10 years of life, RICH occurred with shorter latency and significantly more often (p = 0.044) resulting in an even higher cumulative incidence. Conclusion: These findings and previously published cases show that cavernous hemangiomas may occur after irradiation of the brain several years after the end of therapy irrespective of the radiation dose and type of malignancy. Particularly children < 10 years of age at the time of irradiation are at higher risk. Since patients with RICH frequently do not show symptoms but hemorrhage is a possible severe complication, imaging of the central nervous system should be performed routinely for longer follow-ups, particularly in patients who were treated as young children. Key Words: Cavernous hemangioma · Cavernoma · Children · Radiation-induced late effects Strahlenther Onkol 2008;184:276–80 DOI 10.1007/s00066-008-1817-3 Intrazerebrale kavernöse Hämangiome nach Schädelbestrahlung im Kindesalter. Inzidenz und Risikofaktoren Hintergrund und Ziel: Strahlentherapie ist ein wichtiger Bestandteil bei der onkologischen Behandlung pädiatrischer sowie erwachsener Patienten. Endokrine Dysfunktion, neurologische und psychiatrische Defizite, Sekundärmalignome und strahleninduzierte Nekrosen sind bekannte Spätfolgen nach kranieller Bestrahlung. Das Auftreten strahleninduzierter kavernöser Hämangiome (Kavernome) ist bisher nur vereinzelt beschrieben worden. Patienten und Methodik: Es wurden alle pädiatrischen Patienten, die an der eigenen Abteilung zwischen Januar 1980 und Dezember 2003 aufgrund unterschiedlicher maligner Erkrankungen einer Schädelbestrahlung unterzogen und danach in ein umfassendes Nachsorgeprogramm eingeschleust wurden, retrospektiv analysiert. Ergebnisse: Von 171 Patienten entwickelten acht (drei Patienten mit Medulloblastom, drei Patienten mit akuter lymphatischer Leukämie und je ein Patient mit Ependymom und Kraniopharyngeom) 2,9–18,4 Jahre nach der Strahlentherapie intrazerebrale Kavernome (s. Tabelle 1). Nach der Kaplan-Meier-Methode entspricht dies einer kumulativen Inzidenz von 2,24%, 3,86%, 4,95% bzw. 6,74% innerhalb von 5, 10, 15 bzw. 20 Jahren nach Strahlentherapie (s. Abbildung 1). Bei Patienten, welche in den ersten 10 Lebensjahren behandelt wurden, traten Kavernome mit kürzerer Latenzzeit und häufiger (p = 0,044) auf (s. Abbildung 2). Schlussfolgerung: Diese Ergebnisse und die bisher veröffentlichten Daten zeigen, dass Kavernome – unabhängig von der Art der Grunderkrankung und der Strahlendosis – auch viele Jahre nach kranieller Bestrahlung auftreten können. Kinder < 10 Jahre haben ein höheres Risiko, eine solche Gefäßmalformation zu entwickeln. Da Patienten mit Kavernomen häufig keine Symptome zeigen 1 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria, Department of Therapeutic Radiology and Oncology, Medical University of Graz, Austria, 3 Department of Neurosurgery, Medical University Graz. 2 Received: September 24, 2007; accepted: February 27, 2008 276 Strahlenther Onkol 2008 · No. 5 © Urban & Vogel Strenger V, et al. Radiation-Induced Cavernous Hemangioma und Blutungen mögliche schwere Komplikationen darstellen, sollte eine regelmäßige Bildgebung des Neurokraniums im Rahmen der Nachsorge auch noch viele Jahre nach Therapieende durchgeführt werden. Schlüsselwörter: Kavernöse Hämangiome · Kavernome · Kinder · Strahleninduzierte Spätschäden Introduction In the past decades, prognosis of childhood cancer has significantly improved due to combination of cytotoxic chemotherapy and radiation therapy [8]. Cranial irradiation is an integral part of treatment for cranial tumors, other solid tumors of the head and for central nervous system (CNS) involvement as well as prevention in acute leukemia. Total-body irradiation (TBI) including irradiation of the cranium is also part of some conditioning regimens before hematopoietic stem cell transplantation (HSCT) [15]. Whereas scattered dose of radiotherapy in pediatric CNS tumors was recently shown not to cause gonadal damage [29], endocrine dysfunction, cognitive deficiency and secondary malignancies like gliomas and meningiomas are well-known radiogenic late effects [21, 26, 35] requiring careful follow-up of long-term survivors [1, 22]. Differentiation between recurrent neoplasm and radiation-induced necrosis frequently poses diagnostic dilemmas [2, 6]. While multicenter analyses of radiation-induced late effects are required [7], only case reports and small series of radiation-induced cavernous hemangioma (cavernoma, RICH) have been reported in the literature so far [1, 2, 4, 5, 10–14, 16, 23, 24, 27, 28, 30, 32–34]. Thus, knowledge about their incidence and risk factors is fragmentary. A recently published review summarizes 76 published patients with a mean age at radiation therapy of 11.7 years. Patients had received a median radiation dose of 60.45 Gy (18– 112 Gy). Cavernomas were diagnosed 0.47–52 years after irradiation (median 8.9 years) of different primary lesions (brain tumors, other solid tumors, acute lymphoblastic leukemia [ALL]) [31]. In another review, younger age (< 10 years) seemed to be a risk factor for developing RICH, whereas higher radiation dose (> 30 Gy) was shown to lead to shorter latency interval to occurrence of RICH [14]. While the natural occurrence of cavernomas is reported to be between 0.02% and 0.53% [14], cumulative incidence of RICH was reported to be 3.4–43% in two articles on children treated for medulloblastoma [9] and different brain tumors [25], respectively. No statistically significant correlations between possible risk factors and development of RICH were found in these articles [9, 25]. This is the first analysis of a large series of children and adolescents who had been treated with irradiation of the brain for different malignant diseases (including hematologic malignancies) evaluating incidence and risk factors for development of RICH as well as the impact of this entity on the follow-up in pediatric hemato-/oncologic patients. Strahlenther Onkol 2008 · No. 5 © Urban & Vogel Patients and Methods Patients with malignant diseases, who underwent cranial radiation therapy in our hospital between January 1980 and December 2003, were analyzed. Treatment was performed according to current treatment protocols, which varied widely due to different underlying diseases and the changes of treatment modalities over the decades. Patients with brain or head-and-neck tumors had a computed tomography (CT) or magnetic resonance imaging (MRI) prior to the start of treatment, as well as most patients with leukemia during the initial phase of therapy. After cessation of therapy all patients underwent a detailed diagnostic follow-up program including clinical and neurologic examination at least once a year [22]. In patients treated for brain or head-and-neck tumors, a CT or – in recent years – MRI was performed once to twice a year. Since the 1990s, patients treated for leukemia underwent routine CNS imaging as part of a detailed follow-up program [22]. In patients treated before 1990, imaging was performed in case of neurologic symptoms. Follow-up was evaluated until July 2007. Statistical Analysis Patients were grouped according to sex, age, underlying disease, radiation dose, and latency to diagnosis of RICH. Differences between groups were assessed by means of χ2-test. Cumulative incidences were calculated using the Kaplan-Meier method. Statistical analysis was performed by means of SPSS 14.0 for Windows. Results 171 patients (66 females, 105 males, 10.5 months to 38.5 years, median 8.3 years of age) were treated with cranial irradiation between January 1980 and December 2003. Underlying diseases were brain tumors (n = 72), leukemia (n = 83), craniopharyngioma (n = 4), TBI as a part of conditioning regimen prior to HSCT (n = 10), and others (n = 2). Radiation doses ranged from 9 to 85.6 Gy, median 23.2 Gy. Duration of follow-up after irradiation is 3.7–27.6 years, median 14.6 years. In eight patients (4.68%, four females), at least one cavernoma of the brain was diagnosed 2.9–18.4 years after the end of therapy. Patient characteristics, data on irradiation, and description and management of cavernomas are summarized in Table 1. None of the patients had symptoms related to the cavernoma. In patient VIII, hemorrhage had occurred before diag- 277 Tabelle 1. Patientencharakteristik, Bestrahlungsdaten und Beschreibung der Kavernome bzw. deren Management. ALL: akute lymphatische Leukämie; CT: Computertomographie; MRI: Magnetresonanztomographie; PNET: primitiver neuroektodermaler Tumor; RICH: strahleninduziertes kavernöses Hämangiom. 3.5 1984 No 12 8.5 Frontal and parietal lobe 2 30 No Surgery due to hemorrhage prior to diagnosis No further lesions for 6 years a no significant preexisting vascular malformations; b35.2 Gy total dose followed by a boost to posterior fossa with 20 Gy, RICH occurred outside the high-dose-rate irradiation field; cdespite enlargement, surgery was postponed due to unfavorable location of RICH; ddespite enlargement, surgery was postponed due to unfavorable location of RICH Strenger V, et al. Radiation-Induced Cavernous Hemangioma 278 Table 1. Patient characteristics, data on irradiation, and description and management of cavernomas. ALL: acute lymphoblastic leukemia; CT: computed tomography; MRI: magnetic resonance imaging; PNET: primitive neuroectodermal tumor; RICH: radiation-induced cavernous hemangioma. II III IV V VI VII VIII Female C-ALL Male Medulloblastoma (PNET IV) 9.0 2000 MRIa 55b 3.17 Male Anaplastic Ependymoma 4.8 1998 MRIa 55b 3.25 Male Medulloblastoma (PNET IV) 7.4 1997 MRIa 55b 3.92 Female Craniopharyngioma 6.3 1986 CTa 55 10.0 Female C-ALL Male C-ALL 10.9 1985 No 12 18.4 Female Medulloblastoma (PNET IV) 7.6 1996 MRIa 60 2.9 Parietal lobeb Frontal lobeb Frontal lobeb Temporal lobe Parietal lobe Parietal lobe 1 10 1 5 1 15 1 6 2 7 2 12 No Repeated control imaging No Surgery due to enlargement after 2.5 years No further lesions for 4 years No Surgery due to enlargement after 1 year No further lesions for 5 years No Repeated control imaging No No Repeated control Repeated control imaging imagingd Stable in size for 2 years Stable in size for 3 years Sex Diagnosis I Age at irradiation (years) 8.2 Year of irradiation 1986 Imaging prior to irradiation No Total radiation dose (Gy) 18 Diagnosis of cavernoma 14.5 (years after end of irradiation) Localization Frontal and parietal lobe Lesions (n) 3 Size of (biggest) lesion 10 (mm) Symptoms of cavernoma Noc Management of cavernoma Repeated control imaging Enlargement from 3 to 12 mm in 1 year Stable in size for 3 years Stable in size for 5 years Follow-up nosis of RICH. Thus, the lesion was resected. In patients III and IV, the lesions were resected due to progression in size. The tissue specimens showed typical findings of cavernous hemangiomas [18]. In patients II, III, IV and VII, who had been treated according to the HIT ’91 protocol with craniospinal irradiation (35 Gy) followed by a boost to the posterior fossa (up to 55 Gy) [20], the lesions were localized outside the high-dose-rate irradiation field. A CT scan or an MRI of the brain before radiation therapy to exclude a preexisting vascular malformation was available in five of eight patients. In children irradiated in the first 10 years of life, cavernomas occurred significantly more often than in older children (p = 0.047; 7/91 vs. 1/80), and latency to development was more often < 15 years after radiation therapy than in older children (p = 0.005). Sex, underlying disease (brain tumor vs. other solid tumors vs. leukemia vs. TBI) or radiation dose did not show a significant influence on the development of RICH. According to our data, cumulative incidence of developing cavernoma was 2.24%, 3.86%, 4.95%, and 6.74% within 5, 10, 15, and 20 years following radiation therapy, respectively (Figure 1). In children irradiated within the first 10 years of life, cumulative incidence increased to 4.42%, 7.04%, and 8.49% within 5, 10, and 15 years following radiation therapy, respectively (Figure 2). Discussion In eight out of 171 patients who were treated with cranial irradiation for different malignant diseases, a cavernoma was detected 2.9–18.4 years after therapy. Time of occurrence and time of detection might differ considerably in some cases, since imaging of the brain was performed after different intervals depending on underlying diseases, time of treatment, time after the end of therapy and symptoms. In addition, sensitivity of diagnostic methods for detection of hemangiomas has improved extensively during the study period. In the literature, single cases and small cohorts of RICH were reported. Strahlenther Onkol 2008 · No. 5 © Urban & Vogel Strenger V, et al. Radiation-Induced Cavernous Hemangioma 0.10 Proportion of patients with RICH Proportion of patients with RICH 0.10 0.08 0.06 0.04 0.02 0.00 0.08 0.06 0.04 0.02 0.00 0 5 10 15 20 25 30 Years after radiation therapy 0 5 10 15 20 25 Years after radiation therapy 30 Figure 1. Cumulative incidence of radiation-induced cavernous hemangioma (RICH) analyzed by means of the Kaplan-Meier method. Analysis of all included patients. Figure 2. Cumulative incidence of radiation-induced cavernous hemangioma (RICH) analyzed by means of the Kaplan-Meier method. Analysis of patients treated at an age < 10 years. Abbildung 1. Kumulative Inzidenz strahleninduzierter kavernöser Hämangiome (nach der Kaplan-Meier-Methode). Analyse aller untersuchten Patienten. Abbildung 2. Kumulative Inzidenz strahleninduzierter kavernöser Hämangiome (nach der Kaplan-Meier-Methode). Analyse der Patienten, die im Alter < 10 Jahren behandelt wurden. They occurred after radiation therapy of primitive neuroectodermal tumor (PNET) [9, 25], adenoma of the pituitary gland [1, 9], papilloma of the choroid plexus [10], astrocytoma [9, 24], germinoma [9, 28], ALL with CNS involvement [16, 23, 24], and of a cerebral metastasis of bronchial carcinoma [33]. Underlying diseases in our patients were ALL, craniopharyngioma, ependymoma, and medulloblastoma. Independent of the underlying disease and irrespective of whether chemotherapy has been performed or not [3, 9, 25] irradiation of the brain may induce development of these vascular lesions. Two recently published articles analyzed the incidence of RICH after irradiation for medulloblastoma [25] and different brain tumors [9], respectively. Similar to our data, Burn et al. reported a cumulative incidence of 3.4%, while Lew et al. calculated an incidence of 43% within 10 years after irradiation. The higher incidence might be explained by the loose definition of RICH (“magnetic susceptibility consistent with cavernoma”) possibly leading to an overdiagnosis of cavernoma. While Burn et al. and Lew et al. did not find statistically significant correlations between different parameters and occurrence of RICH [9, 25], Heckl et al. proposed an age < 10 years at the time of irradiation to be a risk factor [14], which is confirmed by our data. In addition, it was proposed that patients with radiation doses > 30 Gy show a shorter latency interval to occurrence of RICH [14]. This is not reflected by our data. However, we observed shorter latency intervals in younger patients. Interestingly, in patients with inhomogeneous radiation doses, cavernoma did not occur in regions with the highest doses. The pathophysiological mechanism for the development of RICH remains unclear. It has been speculated that radiation might induce growth of preexisting occult cavernoma [24]. However, in most reported cases and in five of our patients, MRI or CT scans before treatment were available and did not show signs of preexisting vascular malformations. However, very small lesions cannot be ruled out in standard imaging. Some authors speculated that radiation might induce the production of structural proteins like fibronectin and angiogenetic factors like vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-(TGF-)α, which are considered to be causative for the development of spontaneous cavernous malformation [17, 19, 36, 37]. Analysis of these angiogenetic factors was not done in our patients. Histological findings were reported indicating radiation-induced venous restriction with consecutive increase of venous pressure leading to cavernous malformation [27]. Since cavernomas can lead to acute hemorrhage with consecutive neurologic defects [31], it is important to detect RICH before they become symptomatic. We observed lesions which remained stable for several years as well as lesions which enlarged within a few months. In the latter case, a surgical resection should be considered to eliminate the risk of hemorrhage. Since most patients did not show any cavernoma-related symptoms and cavernoma may occur after decades with a con- Strahlenther Onkol 2008 · No. 5 © Urban & Vogel 279 Strenger V, et al. Radiation-Induced Cavernous Hemangioma siderably high incidence, imaging should be included in the routine long-term follow-up. This particularly concerns children treated with irradiation before 10 years of age being at higher risk for development of RICH. References 1. Alexander MJ, DeSalles AA, Tomiyasu U. Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report. J Neurosurg 1998;88:111–5. 2. Amirjamshidi A, Abbassioun K. Radiation-induced tumors of the central nervous system occurring in childhood and adolescence. Four unusual lesions in three patients and a review of the literature. Childs Nerv Syst 2000; 16:390–7. 3. Baumgartner JE, Ater JL, Ha CS, et al. Pathologically proven cavernous angiomas of the brain following radiation therapy for pediatric brain tumors. Pediatr Neurosurg 2003;39:201–7. 4. Bejjani GK, Caputy AJ, Kurtzke RN, et al. Remote hemorrhage of a pontine cavernous angioma fifty-two years after cerebral irradiation. Acta Neurochir (Wien) 1997;139:583–4. 5. Bentele KHTM, Thobaben M, Hornung D, et al. Supratentorial cavernous malformation subsequent to radical resection of an infratentorial medulloblastoma and craniospinal irradiation: was it induced by irradiation therapy? Neuropediatrics 2000;31:A26. 6. Beuthien-Baumann B, Hahn G, Winkler C, et al. Differentiation between recurrent tumor and radiation necrosis in a child with anaplastic ependymoma after chemotherapy and radiation therapy. Strahlenther Onkol 2003; 179:819–22. 7. Bolling T, Schuck A, Rube C, et al. [Therapy-associated late effects after irradiation of malignant diseases in childhood and adolescence. Feasibility analyses of a prospective multicenter register study]. Strahlenther Onkol 2006;182:443–9. 8. Brenner H. Up-to-date survival curves of children with cancer by period analysis. Br J Cancer 2003;88:1693–7. 9. Burn S, Gunny R, Phipps K, et al. Incidence of cavernoma development in children after radiotherapy for brain tumors. J Neurosurg 2007;106:Suppl: 379–83. 10. Chang SD, Vanefsky MA, Havton LA, et al. Bilateral cavernous malformations resulting from cranial irradiation of a choroid plexus papilloma. Neurol Res 1998;20:529–32. 11. Ciricillo SF, Cogen PH, Edwards MS. Pediatric cryptic vascular malformations: presentation, diagnosis and treatment. Pediatr Neurosurg 1994; 20:137–47. 12. Duhem R, Vinchon M, Leblond P, et al. Cavernous malformations after cerebral irradiation during childhood: report of nine cases. Childs Nerv Syst 2005;21:922–5. 13. Findlay JM, Akabutu J, Johnson ES, et al. Radiation-induced meningioma. J Neurosurg 1994;80:594–5. 14. Heckl S, Aschoff A, Kunze S. Radiation-induced cavernous hemangiomas of the brain: a late effect predominantly in children. Cancer 2002;94:3285–91. 15. Heinzelmann F, Ottinger H, Muller CH, et al. Total-body irradiation – role and indications. Results from the German Registry for Stem Cell Transplantation (DRST). Strahlenther Onkol 2006;182:222–30. 16. Humpl T, Bruhl K, Bohl J, et al. Cerebral haemorrhage in long-term survivors of childhood acute lymphoblastic leukaemia. Eur J Pediatr 1997; 156:367–70. 17. Jung KH, Chu K, Jeong SW, et al. Cerebral cavernous malformations with dynamic and progressive course: correlation study with vascular endothelial growth factor. Arch Neurol 2003;60:1613–8. 18. Kalimo H, Kaste M, Haltia M. Vascular diseases. In: Graham DI, Lantos PL, eds. Greenfield’s neuropathology. London: Arnold, 1997:315–96. 19. Kilic T, Pamir MN, Kullu S, et al. Expression of structural proteins and angiogenic factors in cerebrovascular anomalies. Neurosurgery 2000;46:1179–91, discussion 91–2. 280 20. Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT ’91. Int J Radiat Oncol Biol Phys 2000;46:269–79. 21. Kortmann RD, Timmermann B, Taylor RE, et al. Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II: Treatment-related late toxicity. Strahlenther Onkol 2003;179:585–97. 22. Lackner H, Benesch M, Schagerl S, et al. Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years. Eur J Pediatr 2000;159:750–8. 23. Laitt RD, Chambers EJ, Goddard PR, et al. Magnetic resonance imaging and magnetic resonance angiography in long term survivors of acute lymphoblastic leukemia treated with cranial irradiation. Cancer 1995;76:1846–52. 24. Larson JJ, Ball WS, Bove KE, et al. Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children. J Neurosurg 1998;88:51–6. 25. Lew SM, Morgan JN, Psaty E, et al. Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma. J Neurosurg 2006;104:Suppl:103–7. 26. Mack E. Radiation-induced tumors. In: Berger MS, Wilson CB, eds. The gliomas. Philadelphia: Saunders, 1999:724–35. 27. Maeder P, Gudinchet F, Meuli R, et al. Development of a cavernous malformation of the brain. AJNR Am J Neuroradiol 1998;19:1141–3. 28. Maraire JN, Abdulrauf SI, Berger S, et al. De novo development of a cavernous malformation of the spinal cord following spinal axis radiation. Case report. J Neurosurg 1999;90:Suppl:234–8. 29. Mazonakis M, Zacharopoulou F, Kachris S, et al. Scattered dose to gonads and associated risks from radiotherapy for common pediatric malignancies. A phantom study. Strahlenther Onkol 2007;183:332–7. 30. Miyamoto T, Irie F, Ukita T. [Multiple cavernous angiomas accompanied with a convexity meningioma: a case report.] No Shinkei Geka 1994;22:1053–6. 31. Nimjee SM, Powers CJ, Bulsara KR. Review of the literature on de novo formation of cavernous malformations of the central nervous system after radiation therapy. Neurosurg Focus 2006;21:e4. 32. Novelli PM, Reigel DH, Langham Gleason P, et al. Multiple cavernous angiomas after high-dose whole-brain radiation therapy. Pediatr Neurosurg 1997; 26:322–5. 33. Olivero WC, Deshmukh P, Gujrati M. Radiation-induced cavernous angioma mimicking metastatic disease. Br J Neurosurg 2000;14:575–8. 34. Pozzati E, Giangaspero F, Marliani F, et al. Occult cerebrovascular malformations after irradiation. Neurosurgery 1996;39:677–82, discussion 82–4. 35. Trott KR, Kamprad F. Estimation of cancer risks from radiotherapy of benign diseases. Strahlenther Onkol 2006;182:431–6. 36. Tsao MN, Li YQ, Lu G, et al. Upregulation of vascular endothelial growth factor is associated with radiation-induced blood-spinal cord barrier breakdown. J Neuropathol Exp Neurol 1999;58:1051–60. 37. Wu WZ, Sun HC, Shen YF, et al. Interferon alpha 2a down-regulates VEGF expression through PI3 kinase and MAP kinase signaling pathways. J Cancer Res Clin Oncol 2005;131:169–78. Address for Correspondence Volker Strenger, MD Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical University of Graz Auenbruggerplatz 30 8036 Graz Austria Phone (+43/316) 385-3485, Fax -3450 e-mail: volker.strenger@meduni-graz.at Strahlenther Onkol 2008 · No. 5 © Urban & Vogel