Rita Alaggio

Pediatric Malignant Peripheral Nerve Sheath Tumor: The Italian and German Soft Tissue Sarcoma Cooperative Group

PURPOSE To assess the value of chemotherapy and radiotherapy in children with malignant peripheral nerve sheath tumors (MPNSTs) and to identify risk factors associated with outcome. PATIENTS AND METHODS A total of 167 untreated eligible patients enrolled onto the Italian and German studies between 1975 and 1998 entered this analysis. Seventeen percent of patients had neurofibromatosis type 1 (NF1). Chemotherapy was administered to 74% of patients; radiotherapy was administered to 38% of patients. RESULTS With a median follow-up of 7 years, 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 37%, respectively. The 5-year OS and PFS by Intergroup Rhabdomyosarcoma Study (IRS) groupings were as follows: group I, 82% and 61%; group II, 62% and 37%; group III, 32% and 27%; group IV, 26% and 21%, respectively. Univariate analysis identified IRS groups, size, invasiveness, primary site, age, and presence of NF1 as prognostic factors; multivariate analysis identified absence of NF1, tumor invasiveness T1, IRS groups I to II and extremity of primary site as independent favorable factors for OS. A trend was observed toward a benefit from radiotherapy after initial gross resection. The overall response rate to primary chemotherapy, including minor responses, in group III patients was 45%. CONCLUSION MPNST is an aggressive tumor for which complete surgical resection is the mainstay of successful treatment. Postoperative radiotherapy may have a role in improving local control in patients with minimal residual tumor. The reported responses to primary chemotherapy suggest that it may be effective in patients with tumor considered unresectable at diagnosis.

Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age.

Liposarcomas typically occur in middle aged to older adults. Altogether, approximately 50 bona fide liposarcomas have been reported in children and adolescents, most of which have represented myxoid liposarcomas, with a good prognosis. We undertook a retrospective study of 82 liposarcomas occurring in patients below 22 years of age. Clinicopathologic and follow-up information was obtained. Fluorescence in situ hybridization for FUS, EWSR1, CHOP (DDIT3), and MDM2 was performed in 30 cases. The tumors occurred in 28 males and 54 females (5 to 22 y of age) and involved many locations. Fifty-six cases were typical myxoid liposarcomas, including 2 with round cell areas. The tumors were grade 1 (56 cases) and grade 3 (2 cases). Thirty-seven of 38 patients with follow-up are alive without disease and 1 is alive with disease (median 59 mo follow-up duration, range: 8 to 108 mo). Six cases showed myxoid liposarcoma with spindled growth (“spindle cell myxoid liposarcoma”); these arose in 5 females and 1 male (median age 14 y) and involved the thigh in 40% of cases. All were grade 1. Follow-up (4 of 6 patients) showed local recurrences in 2 cases and metastases in 1 case. Twelve tumors consisted of conventional myxoid liposarcoma and pleomorphic liposarcoma (“pleomorphic myxoid liposarcoma”); these arose in 4 males and 8 females (10 to 22 y of age) and often involved the mediastinum. Tumor grades were 2 (4 cases) and 3 (8 cases). Follow-up (10 patients) showed 7 dead of disease, 1 alive with disease, and 2 disease free. Four atypical lipomatous tumors were seen including 2 with low-grade dedifferentiation. Two local recurrences were seen; all patients are disease free. Two conventional pleomorphic liposarcomas were seen; 1 patient with follow-up is disease free. FUS-CHOP and EWSR1-CHOP rearrangements were identified by fluorescence in situ hybridization in 15/23 and 2/23 conventional myxoid liposarcomas, respectively, and in no other tumors. Amplification for MDM2 was absent in all cases. We conclude that conventional myxoid liposarcoma is by far the most common subtype of liposarcoma in young patients, with an excellent prognosis. Two apparently novel subtypes of liposarcoma, termed pleomorphic myxoid liposarcoma and spindle cell myxoid liposarcoma comprise considerable percentages of liposarcomas in this age group and should be distinguished from conventional myxoid liposarcoma and conventional pleomorphic liposarcoma. Pleomorphic myxoid liposarcoma and spindle cell myxoid liposarcoma most likely represent high-grade and low-grade variants of myxoid liposarcoma, respectively. Additional study of such cases will be necessary for definitive classification.

Aggressive fibromatosis in children and adolescents: the Italian experience.

Aggressive fibromatosis (AF) is a rare tumor of intermediate malignancy that has a strong potential for local invasiveness and recurrence. To date, there are no general recommendations for the clinical management of pediatric AF.

Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1

Patients affected by neurofibromatosis type 1 (NF1) are at higher risk of developing soft‐tissue sarcomas (STS) than the general population. The clinical findings and outcome in 43 children and adolescents with NF1 treated for STS in the Italian protocols between 1988 and 2004 are reported.

P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer.

Background Our aim was to ascertain whether or not the response to preoperative chemoradiotherapy for rectal cancer is associated with p27kip1 and p53 protein expression.Methods: Thirty-eight patients (27 male, 11 female) with a mean age of 59 years (age range 33–87) and stage II-III rectal cancer received preoperative chemoradiotherapy (45–50.4 Gy; 5-FU 350 mg/m2/day and leucovorin 10 mg/m2/day). Thirty-one underwent low anterior resection; seven underwent abdominoperineal excision. Endoscopic tumor biopsies, performed before adjuvant therapy, were evaluated for: histologic type, tumor differentiation, mitotic index, and p27kip1 and p53 protein expression which were immunohistochemically determined. p53 expression was graded as: a) absent or present in ≤10% of tumor cells; b) present in 11–25%; c) present in 26–75%; and d) present in >75% of tumor cells. p27kip1 expression was assessed using both light microscopy (percent of stained cells x10 HPF) and cytometry with an image analysis workstation. Tumor response, ascertained with histology, was classified using a scale from 0 (no response) to 6 (complete pathologic response).Results: The mitotic index for the endoscopic biopsies was low in 14 cases, moderate in 17 cases, and high in 7 cases. p53 protein expression was found in 21 (a), 3 (b), 3 (c), and 11 (d) cases. The mean percentage of cells expressing the p27kip1 protein was 34 (range 0–77.14%). A close correlation was found between cytometric and light microscopy findings for p27kip1 (r2 = 0.92, P = .0001). Tumor differentiation was good in 5 cases, poor in 2 cases, and moderate in the remaining 31 cases. While the response to adjuvant therapy was good/complete in 25 (65.78%) cases, it was absent/poor in 13 (34.21%) cases. Univariate analysis associated type of adjuvant therapy (chemoradiotherapy, P = .0428) and p27kip1 protein lower expression (P = .0148) with a poor response to adjuvant treatment. Stepwise linear regression found overexpression of p53 and p27kip1 and young age to be independent variables that were linked to a good response to adjuvant therapy.Conclusions:Lack of p27kip1 and p53 protein expression in rectal cancer is associated with a poor response to preoperative adjuvant therapy.

Massive response of severe infantile hepatic hemangioma to propanolol.

To the Editor: Infantile hepatic hemangioma is a rare and potentially lethal infantile tumor that exhibits rapid postnatal growth followed by slow involution. Most lesions are clinically silent and self-limiting, whereas others become symptomatic, manifesting as cardiac failure secondary to high volume shunting, hypothyroidism secondary to overproduction of type III iodothyronine deiodinase from the endothelial tissue, fulminant hepatic failure, and abdominal compartment syndrome. A subtype classification in focal, multifocal, and diffuse lesions was recently proposed [1]. Treatment is reserved to severe and complicated hemangiomas, and includes corticosteroids, vincristine, cyclophosphamide, and a-interferon. Here, we describe the case of a female infant with a biopsy-proven diffuse hepatic hemangioma. The child was referred to our center at the age of 2 months because of abrupt abdominal enlargement with a liver occupying the entire abdomen, associated to some subcutaneous nodules, and millimetric skin hemangiomas. Abdominal ultrasound and MRI revealed a near-total replacement of the hepatic parenchyma with multiple centripetally enhancing lesions. Hepatic and skin biopsy were then performed, with a diagnosis of infantile hepatic hemangioma (Fig. 1) and of infantile capillary skin hemangioma. Thyroid function tests showed an elevated TSH (33.8 mU/L, n.v. 0.62–8.05), a mildly increased fT4 (17.5 ng/ml, n.v. 8–18), and a normal fT3 (3.6 ng/L, n.v. 1.8–4.6). She was started on thyroid hormone replacement with levothyroxine (1 mcg/kg/day) and on high-dose steroid therapy (4 mg/kg/day). At 4 months of age abdominal circumference rapidly increased from 55 to 59 cm and TSH level increased to 39.9 mU/L. Abdominal ultrasound confirmed a marked enlargement of the hepatic lesions. Treatment with vincristine (1.5 mg/m weekly) was then started, without any significant improvement after 45 days of therapy and after a 5-day course of cyclophosphamide. Based on the recent article of Léauté-Labrèze et al. [2] about the use of propanolol in severe infantile cutaneous hemangiomas [3], we started a treatment with propanolol at a dose of 1 mg/kg/day. During 48 h of hospitalization, only transient and asymptomatic bradicardia was noted, without hypotension and hypoglycemia. After 1 week, a dramatic improvement was observed despite the fact that steroid therapy was simultaneously and gradually stopped. Abdominal circumference reduced to 50 cm, ultrasound showed marked reduction of hepatic lesions, and TSH level normalized (8 mU/L). After 1 month, the hepatic hemangioma continued to progressively improve with only propanolol (2 mg/kg/day) treatment. Potential explanations for the therapeutic effect of propanolol include vasoconstriction, decreased expression of vascular endothelial growth factor and/or basic fibroblast growth factor [4], and the triggering of apoptosis of capillary endothelial cells [5]. Although these are preliminary data, we believe that propanolol should be considered as a therapeutic option in the treatment of infantile hepatic hemangioma.

Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement

Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.

Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis

Abstract:  Objective: Data on the use of combination of liposomal amphotericin B and caspofungin followed by voriconazole, as maintenance or further rescue treatment, in 10 patients with invasive mycosis are reported. Material and methods: The diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkins lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6; and possible, 1) refractory to first‐line antifungal treatment (liposomal amphotericin B in all patients except one who received fluconazole). Results: Rescue therapy with a combination of caspofungin and liposomal amphotericin B was well tolerated, hypokalemia, and thrombophlebitis being the most common side‐effects. Combination therapy was administered for a median of 17 d, range 6–40. Among the nine patients with proven or probable mycosis, one was not evaluated because of early death caused by massive hemoptysis whilst in the remaining eight patients, the response was classified as complete, stable and failure in four, three, and one patients, respectively. Complete response was also observed in patient with possible mycosis. Eight of nine patients received voriconazole for a median of 75 d, range 42–194. Voriconazole was well tolerated although some drug interactions were observed during treatment with methotrexate and digoxin. After a median follow‐up of 125 d, nine of 10 patients are alive. Overall, a favorable response to antifungal treatment (including the case of possible mycosis) was obtained in eight of 10 patients. Conclusion: These data suggest that medical antifungal treatment may be intensified in severely ill patients without significantly compromising patient safety. The combination of synergistic antifungal drugs as well as their sequential use warrants further investigation by a larger randomized controlled study.

The real-time polymerase chain reaction-guided modulation of immunosuppression enables the pre-emptive management of Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation.

To assess a real‐time polymerase chain reaction‐based modulation of immunosuppression in patients with an increasing Epstein–Barr virus (EBV) viral load, we studied 79 paediatric allogeneic stem cell transplantations (allo‐SCT) performed between January 1998 and December 2003. EBV reactivation was observed in 42 of 79 patients (53%) after a median time of 45 d from allo‐SCT: 37 (88%) and five (12%) patients had received the graft from an unrelated and a related donor respectively (P = 0·001). Twenty‐eight patients (67%) had a viral load ≥300 genomic copies ×105 peripheral blood mononuclear cells (PBMC) and antithymocyte globulin was the only factor significantly associated with EBV reactivation (P = 0·001, RR 7·1). Among these 28 patients, immunosuppression was suspended and reduced in 17 and 11 patients respectively. Overall, post‐transplant lymphoproliferative disease was diagnosed in one of 79 patients (1%). The pre‐emptive modulation of immunosuppression in patients with EBV reactivation and a viral load ≥300 genomic copies ×105 PBMC did not negatively influence transplant‐related mortality, overall survival or event‐free survival. In conclusion, EBV reactivation is frequent even in ‘low risk’ patients and the pre‐emptive modulation of immunosuppression enables it to be managed safely, with no significant flare in graft‐versus‐host disease status.

Voriconazole for invasive aspergillosis in oncohematological patients: a single-center pediatric experience

Voriconazole is a new triazole active orally and parenterally that recently proved effective in the treatment of invasive aspergillosis and in empirical antifungal therapy for persistently febrile neutropenic patients. Limited data are available for pediatric patients. We report our experience with voriconazole in seven children with invasive aspergillosis, i.e., four girls and three boys with a median age of 5 (range 2–13) years affected by acute lymphoblastic leukemia (3), acute myeloid leukemia (2), refractory anemia with excess of blasts (1), and severe aplastic anemia (1). First-line therapy in all patients was liposomal amphotericin B (AmBisome) administered at a dosage of 3–5 mg/kg day. Voriconazole was administered for a median 8 (range 2–15) weeks. Response was complete and partial in two patients, respectively, stable in one, and there was no response (failure) in two. The voriconazole treatment was well tolerated. Four patients died—two of progressive aspergillosis. Three patients are alive and well 6, 5, and 4 months after the diagnosis of aspergillosis. Voriconazole appears to be an effective salvage treatment for invasive aspergillosis in pediatric patients, with good responses in patients who recover from neutropenia or are not relapsing.