Petra Sovinz

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.

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.

Unrelated peripheral blood stem cell transplantation with ‘megadoses’ of purified CD34 + cells in three children with refractory severe aplastic anemia

Three children with refractory severe aplastic anemia were transfused with high numbers of unrelated matched (n = 2) or C-locus haploidentical mismatched (n = 1) CD34-selected peripheral blood stem cells in the absence of an HLA-identical family donor. Two leukaphereses of the donors yielded a median number of 10.1 × 1010nucleated cells (range 9.7–15.4) with a median number of 9.89 × 108CD34+ cells (range 7.46–26.1) and a median percentage of CD34+cells of 0.98% (range 0.77–1.7). After positive selection by magnetic cell sorting the patients received a median of 14.3 × 106 CD34+ cells/kg (range 11.7–24.3) and of 1.3 × 104 CD3+ cells/kg (range 0.57–5.8). Median time to ANC ⩾0.5 × 109/l was 7 days (range 7–12) and to platelets ⩾20 × 109/l 13 days (range 13–27). Chimerism analysis of peripheral blood after transplantation revealed permanent 100% donor hematopoiesis in all patients. The patient with the C-locus haploidentical mismatch presented with acute GVHD (grade III–IV) of the skin, liver and lower gastrointestinal tract (onset day +40) and died despite intensive immunosuppressive treatment on day +238. The two survivors developed lymphopoietic recovery of B and T lymphocytes within 3 months after transplantation. To our knowledge this experience represents the first report of transplantation with unrelated CD34+ enriched peripheral blood stem cell in children with refractory severe aplastic anemia. Bone Marrow Transplantation (2000) 25, 513–517.

Fusarium verticillioides Abscess of the Nasal Septum in an Immunosuppressed Child: Case Report and Identification of the Morphologically Atypical Fungal Strain

ABSTRACT Morphologically atypical Fusarium verticillioides causing a nasal abscess in a severely immunosuppressed child was successfully treated with repeated surgical intervention and liposomal amphotericin B, despite amphotericin B resistance in vitro. Definitive identification was achieved by sequencing the translation elongation factor α gene after ribosomal sequencing proved inadequate.

Survival and late effects in children with stage 4 neuroblastoma.

Treatment of metastatic neuroblastoma (NB) demands aggressive oncological therapy, which may cause long‐term sequelae in survivors. The aim of this retrospective single center study is to give an overview of survival in children with stage 4 NB and to describe the spectrum of late effects seen in survivors.

Procalcitonin—a marker of invasive fungal infection?

Procalcitonin (PCT) has been described as a marker of bacterial sepsis. However, little is known of its diagnostic value in fungal infections. We calculated the sensitivity of PCT for detection of invasive fungal infections (IFI) by analyzing 55 episodes of proven or probable IFI (three in our series, 52 reported in the recent literature). In the early phase of IFI, PCT was elevated in fewer than half of invasive candidiasis episodes and in only one patient (5.3%) with invasive aspergillosis. Due to low sensitivity and specificity, PCT adds little to the diagnosis of IFI.

Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma.

Summary: The use of the recombinant human granulocyte colony-stimulating factor filgrastim to shorten the duration of severe neutropenia after cytotoxic chemotherapy has become an integral part of supportive care. However, due to its short serum half-life, filgrastim must be injected daily. Pegfilgrastim, a new long-lasting form of filgrastim administrated once per cycle, has been shown in adults to be as effective in reducing the duration of severe neutropenia as daily filgrastim. The aim of this study was to evaluate the effects of pegfilgrastim in pediatric patients. Five children with Ewing sarcoma were alternately treated with a single 100 μg/kg pegfilgrastim dose or daily doses of 10 μg/kg Filgrastim after a total number of 58 chemotherapy cycles. Pegfilgrastim was well tolerated. The duration of severe neutropenia and the incidence of febrile neutropenia after pegfilgrastim and filgrastim were comparable. By using pegfilgrastim, the number of subcutaneous injections could be reduced to one single injection per cycle.