Kaposiform hemangioendothelioma further broadens the phenotype of PIK3CA-related overgrowth spectrum.

Kaposiform hemangioendothelioma (KHE) is a rare locally aggressive mixed vascular tumor, with typical onset in early childhood and characterized by progressive angio- and lymphangiogenesis. Its etiopathogenesis and molecular bases are still unclear. Here, we report the first case of congenital KHE harboring a PIK3CA mosaic pathogenic variant (c.323G > A, p.Arg108His) in a boy with very subtle PIK3CA-related overgrowth spectrum (PROS) features. This finding provides insights into the pathophysiology of KHE, offering targeted therapeutic options by inhibition of the PI3K/Akt/mTOR pathway. We propose the inclusion of this mixed lymphatic and vascular anomaly within the PROS.

Anthracycline-induced cardiotoxicity in patients with paediatric bone sarcoma and soft tissue sarcoma.

OBJECTIVES: Anthracycline cardiotoxicity is an important side-effect in long-term childhood cancer survivors. We evaluated the incidence of and factors associated with anthracycline cardiotoxicity in a population of patients diagnosed with bone or soft tissue sarcoma. Materials and methods We retrospectively enrolled patients diagnosed with bone or soft tissue sarcoma, from 1995 to 2011, treated with anthracycline chemotherapy at our Centre and with a follow-up echocardiography carried out ⩾3 years from cardiotoxic therapy completion. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0. RESULTS: A total of 82 patients were eligible. The median age at treatment was 11.9 years (1.44-18). We evaluated the median cumulative anthracycline dose, age at treatment, sex, thoracic radiotherapy, hematopoietic stem cell transplantation, and high-dose cyclophosphamide treatment as possible risk factors for cardiotoxicity. The median cumulative anthracycline dose was 390.75 mg/m2 (80-580). Of the 82 patients, 12 (14.6%) developed cardiotoxicity with grade ⩾2 ejection fraction decline: four patients were asymptomatic and did not receive any treatment; six patients were treated with pharmacological heart failure therapy; one patient with severe cardiomyopathy underwent heart transplantation and did not need any further treatment; and one patient died while waiting for heart transplantation. The median time at cardiac toxicity, from the end of anthracycline frontline chemotherapy, was 4.2 years (0.05-9.6). Cumulative anthracycline dose ⩾300 mg/m2 (p 0.04) was the only risk factor for cardiotoxicity on statistical analyses. CONCLUSIONS: In our population, the cumulative incidence of cardiotoxicity is comparable to rates in the literature. This underlines the need for primary prevention and lifelong cardiac toxicity surveillance programmes in long-term childhood cancer survivors.

FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients.

Despite the success in treating the majority of children with newly diagnosed acute leukemia, children with relapsed or refractory disease are an exceptionally difficult group of patients to cure. We assessed the combination of fludarabine with cytarabine and granulocyte colony-stimulating factor (FLAG) and nonpegylated liposomal doxorubicin (Myocet) in children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) refractory to first-line therapy or who had relapsed after risk-tailored chemotherapy. We treated 35 patients with FLAG-Myocet. The median age at treatment was 9 years and 7 months (range, 1 to 18 y). The 94% of ALL patients (16/17) and the 61% AML patients (11/18) achieved complete remission after FLAG-Myocet. A partial response was observed in the 17% of AML patients (3/18). Twenty-eight of 35 (80%) patients received hematopoetic stem cell transplantation in remission induced by FLAG-Myocet regimen. The ALL and AML overall survival at 3 years after FLAG-Myocet is 33% and 38%, respectively. The probability of ALL and AML event-free survival at 3 years after FLAG-Myocet is 33% and 40%, respectively. The probability of ALL and AML disease-free survival at 3 years after hematopoietic stem cell transplantation is 19% and 58%, respectively. Nonhematological toxicity was remarkably low, while almost all patients showed severe hematological toxicity. FLAG-Myocet is an efficient and a well-tolerated regimen that allows nearly all patients to undergo hematopoetic stem cell transplantation. FLAG-Myocet proved to be safe in terms of acute cardiac toxicity although particular care must be taken to reduce infectious complications due to severe myelosuppression. The promising results shown in our study need to be confirmed by larger and possibly randomized trials.

Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation.

Pseudomonas aeruginosa is one leading gram-negative organism associated with nosocomial infections. Bacteremia is life-threatening in the immunocompromised host. Increasing frequency of multi-drug-resistant (MDRPA) strains is concerning. We started a retrospective survey in the pediatric hematology oncology Italian network. Between 2000 and 2008, 127 patients with Pseudomonas aeruginosa bacteremia were reported from 12 centers; 31.4% of isolates were MDRPA. Death within 30 days of a positive blood culture occurred in 19.6% (25/127) of total patients; in patients with MDRPA infection it occurred in 35.8% (14/39). In the multivariate analysis, only MDRPA had significant association with infection-related death. This is the largest series of Pseudomonas aeruginosa bacteremia cases from pediatric hematology oncology centers. Monitoring local bacterial isolates epidemiology is mandatory and will allow empiric antibiotic therapy to be tailored to reduce fatalities.

Survival after second and subsequent recurrences in osteosarcoma: a retrospective multicenter analysis.

PURPOSE: Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse. METHODS: This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013. RESULTS: Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR. CONCLUSIONS: This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.

Survival after Second and Subsequent Recurrences in Osteosarcoma: A Retrospective Multicenter Analysis.

Purpose Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse. Methods This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013. Results Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR. Conclusions This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.

Endocrine late effects after total body irradiation in patients who received hematopoietic cell transplantation during childhood: a retrospective study from a single institution.

PURPOSE: To evaluate the effects of total body irradiation (TBI) on the endocrine system in adults treated with hematopoietic cell transplantation (HCT) during childhood. METHODS: We studied 40 patients who underwent HCT between 1988 and 2004, mainly for childhood cancer. In 23 patients, the conditioning regimen consisted of high-dose chemotherapy and TBI (TBI+). In the other 17 patients, who did not receive TBI (TBI-), HCT was performed after high-dose chemotherapy alone. RESULTS: Overall, 34% of patients in the TBI+ group showed growth hormone deficiency, compared with none of the patients in the TBI- group (P < 0.05). Leydig cell failure was found in 23% of patients in the TBI+ group and in 0% of the patients in the TBI- group. Elevated FSH levels, suggesting spermatogenesis damage, were found in all the patients receiving TBI and in 36% of the patients in the TBI- group (P < 0.001). Also, primary hypothyroidism was more common in TBI+ (34%) than in TBI- (5.8%) patients (P < 0.05). CONCLUSIONS: Our data indicate that endocrine late effects after HCT are more frequent in patients who received TBI, an observation that should be considered, even if the choice of the conditioning regimen is determined by the underlying condition in most cases.

Prospective bone ultrasound patterns during childhood acute lymphoblastic leukemia treatment.

OBJECTIVE: Bone impairment is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors but less is known about bone dynamics during ALL therapy. We longitudinally assessed by Quantitative Ultrasound (QUS) skeletal modifications during this treatment. MATERIALS AND METHODS: Forty-four newly diagnosed ALL children underwent bone measurement by QUS parameters BTT (Bone Transmission Time) and AD-SoS (Amplitude-Dependent Speed of Sound), mainly reliant on bone density and cortical thickness, respectively. Measurements were performed at diagnosis, and 6, 12, and 24 months thereafter. The occurrence of skeletal complications such as fractures, vertebral collapse, osteonecrosis, and osteopenia was related to measurement outcome. RESULTS: A rapid deterioration of bone properties measured by BTT and AD-SoS was evident in the first semester of therapy (p<0.001). Subsequently, the next measurements were characterized by progressive uncoupling of the two QUS parameters (p<0.001). These were both significantly reduced at the end of therapy (p<0.001). Twelve subjects with in-treatment skeletal complications displayed an almost two-fold decrease of both parameters (p<0.001). BTT decreasing more than 1 Standard Deviation (SD) over 6 months of therapy was able to predict skeletal complication occurrence (p<0.001). CONCLUSION: This report represents the largest longitudinal cohort systematically submitted to bone condition assessment from the beginning to the end of therapy for childhood ALL. Bone deterioration occurs early and persists throughout therapy, consistent with bone properties uncoupling. This pattern possibly reflects an initial impairment of both mineral density and cortical thickness with a subsequent recovery of this latter. QUS permits an early detection of bone deterioration and related skeletal complications in childhood ALL.