Andrea Moser

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.

Intracerebral cavernous hemangioma after cranial irradiation in childhood. Incidence and risk factors.

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.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 diagund Blutungen mögliche schwere Komplikationen darstellen, sollte eine regelmäßige Bildgebung des Neurokraniums im Rahmen der Nachsorge auch noch viele Jahre nach Therapieende durchgeführt werden.

Intracerebral Cavernous Hemangioma after Cranial Irradiation in Childhood

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.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 diagund Blutungen mögliche schwere Komplikationen darstellen, sollte eine regelmäßige Bildgebung des Neurokraniums im Rahmen der Nachsorge auch noch viele Jahre nach Therapieende durchgeführt werden.

Multimodal treatment of children with unresectable or recurrent desmoid tumors: an 11-year longitudinal observational study.

The primary goal of treatment for desmoid tumors is complete surgical resection to achieve negative margins. In adults with unresectable or recurrent lesions, treatment options include noncytotoxic and cytotoxic drugs, but little is known about nonsurgical treatment in children. Between 1992 and 2003 six children (four girls, two boys) with a median age of 2.5 years (range 11 months to 9 years) received multimodal adjuvant therapy for unresectable or recurrent desmoid tumors. Primary treatment consisted of noncytotoxic treatment with tamoxifen (1 mg/kg orally, twice daily) and diclofenac (2 mg/kg rectally, twice daily), whereas two children with life-threatening tumor progression in addition received treatment intensification with weekly vinblastine (6 mg/m2 intravenously) and methotrexate (30 mg/m2 intravenously). Of the four children with unresectable tumors, two achieved remarkable tumor shrinkage and two had stable disease, whereas two patients were disease-free for 3.7 and 2.6 years after nonradical resection. Median observation time was 3.1 years (range 1–11 years). Treatment was generally well tolerated; only one patient developed pubertal acceleration after a duration of tamoxifen treatment of 9.3 years. Because of the potential life-threatening situation, the management of children with unresectable or recurrent desmoid tumors requires a multidisciplinary approach. Nonaggressive therapy with tamoxifen and diclofenac may be the first treatment choice in these patients, but in patients with progressive disease, cytotoxic chemotherapy is indicated. Weekly administration of vinblastine and methotrexate seems to be safe and effective in these children.

Hemophagocytic lymphohistiocytosis as severe adverse event of antineoplastic treatment in children

Hemophagocytic lymphohistiocytosis is a rare but lifethreatening complication of antineoplastic therapy in children. Early diagnosis is of fundamental importance. Hemophagocytic lymphohistiocytosis (HLH) during childhood cancer treatment is a rare adverse event posing major diagnostic and therapeutic challenges. Between 1995 and 2006, 6 children developed HLH while on conventional chemotherapy (n=4) or after allogeneic stem cell transplantation (n=2). Treatment of HLH included dexamethasone and etoposide, 2 children additionally received infliximab or daclizumab. Three children survived, whereas 3 children died 2, 5, and 47 days after diagnosis of HLH. HLH is a severe adverse event of childhood cancer therapy. Early diagnosis and immediate initiation of adequate treatment are mandatory to overcome this severe condition.

Aseptic osteonecrosis in children and adolescents treated for hemato-oncologic diseases: a 13-year longitudinal observational study.

Aseptic osteonecrosis (AON) is a serious long-term complication of childhood cancer therapy. A retrospective study was undertaken to describe treatment and long-term follow-up of patients with AON. Between 1990 and 2003, 630 consecutive children with various malignancies were treated at the University Childrens Hospital in Graz, Austria. In nine of these patients presenting with skeletal symptoms, MRI revealed AON. All nine had hematologic malignancies. The median age at diagnosis of malignancy was 15.8 years (range 13.7-18.6 years), and the median interval between diagnosis of malignancy and onset of osteonecrosis-related symptoms was 16 months (range 6-53 months). All patients had received previous corticosteroid therapy. Treatment of AON included restriction of weight-bearing, physiotherapy, and analgesics. Three patients were treated with hyperbaric oxygen therapy combined with the prostacyclin analog iloprost, and one patient also received pamidronate, a second-generation bisphosphonate. This conservative treatment resulted in alleviation of symptoms in all patients. One patient had to undergo bilateral hip replacement and two had to undergo arthrotomy with sequestrotomy due to subsequent deterioration of symptoms. Close monitoring for skeletal symptoms is mandatory during follow-up of patients with hematologic malignancies. Previous corticosteroid treatment and age older than 10 years seem to be major risk factors. Early detection of AON leading to prompt intervention may prevent more severe morbidity.

Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation

Cutaneous mastocytosis (CM) in children is a usually benign skin disorder caused by mast cell proliferation. Progressive disease leading to systemic involvement and fatal outcomes has been described. C-kit receptor mutations have been identified as causative for CM, some of which potentially respond to imatinib treatment as described for patients with systemic mastocytosis. We report successful therapy of progressive CM with imatinib in a 23-month-old boy. KIT gene analysis revealed not only a somatic deletion of codon 419 in exon 8 (c.1255_1257delGAC) which responds to imatinib therapy, but also a novel germ line p. Ser840Asn substitution encoded by exon 18 in the c-kit kinase domain. Family history suggests this exchange does not affect receptor function or cause disease. Imatinib therapy was well tolerated, stopped symptoms and disease progression, and appeared to shorten the course of the disease. Imatinib could possibly represent a novel therapeutic option in patients with progressive CM.

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.

Residual or recurrent cerebellar low-grade glioma in children after tumor resection: is re-treatment needed? A single center experience from 1983 to 2003.

Purpose:The aim of this study was to report on children with cerebellar low-grade glioma (LGG), who were found to have progressive or nonprogresssive residual tumors or tumor recurrence after tumor resection. Patients and Methods: Medical records and magnetic resonance imaging (MRI) studies of children (<16 years) with cerebellar LGG were retrospectively analyzed. Results: Of 289 patients with CNS tumors referred between 1983 and 2003, 28 (9.7%) (15 male, 13 female; median age at diagnosis: 71 months) had cerebellar LGG (pilocytic astrocytoma grade I: n = 21; fibrillary astrocytoma grade II: n = 5; mixed hamartoma/pilocytic astrocytoma: n = 1; radiographic diagnosis: n = 1). Total resection was initially performed in 16 patients (57.1%), near total resection in 4 (14.3%), and partial resection in 6 patients (21.4%). One patient underwent biopsy. At a median follow-up of 112 months, 25 patients (89.3%) were alive, 18 of them being in complete remission. Three patients died, 2 due to symptoms related to brain stem compression/infiltration and 1 patient due to postoperative cerebral edema. Presently 5 patients have nonprogressive residual tumors and 2 patients developed nonprogressive recurrences 10 years and 20 months after initial total resection, respectively. None of them required second surgery and none received additional nonsurgical therapies. Only 1 additional patient had to undergo second surgery due to disease progression. Conclusions: A ‘wait and see’ strategy is justified in patients with nonprogressive recurrent or residual cerebellar LGG after primary tumor resection. However, long-term follow-up with repeated MRI is mandatory in these patients to detect disease progression. Second surgery is indicated only in patients with unequivocal disease progression, as documented by MRI.

Successful unrelated cord blood transplantation in a 7-year-old boy with Evans syndrome refractory to immunosuppression and double autologous stem cell transplantation

Abstract:  Evans syndrome is an autoimmunopathy characterized by thrombocytopenia and autoimmune hemolytic anemia with poor response to immunosuppression. A 2‐yr‐old boy with Evans syndrome showed only short‐lasting responses to immunosuppressive treatment including double autologous peripheral stem cell transplantation (SCT). Intracranial bleeding required emergency splenectomy and external ventricular drainage. Unrelated umbilical cord blood was given following conditioning with busulfan, thiotepa, etoposide and antithymocyte globulin. One year after SCT the patient shows stable blood counts without immunosuppression. This is the first child reported with Evans syndrome successfully treated by means of unrelated cord blood transplantation.