Alessandro Jenkner

Improved Survival of Children With Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry

PURPOSE To describe treatment, clinical course, and survival of a cohort of Italian patients with neuroblastoma. PATIENTS AND METHODS The study includes data from 2,216 children (age 0 to 14 years) diagnosed between 1979 and 2005. Overall survival (OS) was analyzed by clinical and biologic features at presentation and periods of diagnosis: 1979 to 1984, 1985 to 1991, 1992 to 1998, and 1999 to 2005. The relative risk of second malignant neoplasm (SMN) was assessed by the standardized incidence ratio (SIR), with the Italian population selected as referent. RESULTS Yearly patient accrual increased over time from 58 to 102. Patients age 0 to 17 months represented 45.6% of the total population, and their incidence increased over time from 36.5% to 48.5%. The incidence of stage 1 patients increased over time from 5.8% to 23.2%. A total of 898 patients (40.5%) developed disease progression or relapse, 19 patients developed SMN, and two patients developed myelodysplasia. The cumulative risk of SMN at 20 years was 7.1%, for an SIR of 8.4 (95% CI, 5.1 to 13.2). A total of 858 patients (39%) died (779 of disease, 71 of toxicity, six of SMN, and two of tumor-unrelated surgical complications). Ten-year OS was 55.3% (95% CI, 53.0% to 57.6%) and increased over time from 34.9% to 65.0%; it was significantly better for females and patients age 0 to 17 months at diagnosis, with extra-abdominal primary, and stage 1 and 2 disease. OS improved significantly over time in stage 1 and 3 patients. In patients with stage 4 disease, the improvement occurred between the first and second time cohorts (6.7% v 23.5%), but not afterward. CONCLUSION The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/ cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front‐line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second‐line treatment for children with relapsed neuroblastoma, particularly after high‐dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty‐one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty‐one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow‐up is needed to confirm a survival advantage. Second‐line treatment was effective in obtaining remissions, some of them long lasting. Third‐line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

Spindle cell (Kaposiform) hemangioendothelioma with Kasabach‐Merritt syndrome in an infant: Successful treatment with α‐2A interferon

A two-month-old infant developed a vascular tumor of the right flank which upon biopsy proved to be a spindle cell hemangioendothelioma. The increased capillary bed characterizing the neoplasm caused a severe thrombocytopenia together with a consumption coagulopathy (Kasabach-Merritt syndrome). The patient, who was dependent on platelet transfusions, improved quickly after interferon alpha-2a was given at the dosage of 3,000,000 U/m2, with resolution of the Kasabach-Merritt syndrome after three weeks and a 75% decrease of the tumor volume within three months of treatment.

Temozolomide in resistant or relapsed pediatric solid tumors

We report the off‐label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day × 5 days or 180 mg/m2/day × 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT).

Antibiotic lock with vancomycin and urokinase can successfully treat colonized central venous catheters in pediatric cancer patients.

We used an antibiotic lock technique with vancomycin in combination with urokinase in 10 consecutive eligible children with Gram-positive catheter-related bacteremia persisting after appropriate intravenous antibiotics. Treatment was successful in sterilizing all colonized central venous catheters, avoiding device removal and delay of further chemotherapy. The antibiotic lock technique may represent a safe and effective therapeutic option in patients with selected, uncomplicated catheter-related bacteremias resistant to systemic antimicrobial therapy, particularly when maintaining a venous access is mandatory.

Treatment of high‐risk relapsed Wilms tumor with dose‐intensive chemotherapy, marrow‐ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology

We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high‐risk features.

Local Lymph Node Involvement in Pediatric Renal Cell Carcinoma: A Report From the Italian TREP Project

One of the most important adverse prognostic factors for adult renal cell carcinoma (RCC) is the retroperitoneal lymph node involvement. The aim of this article is to study the prognostic significance of local lymph node involvement in pediatric RCC and the role of retroperitoneal lymph node dissection (RLND) at diagnosis.

Nephroblastoma: Multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells

The development of chemoresistance in a variety of cancers seems related to overexpression of the P-glycoprotein (P-gp) drug pump. Nephroblastoma, the most common malignant renal tumor of childhood, usually is responsive to treatment, and prognosis is favorable in most cases. However, the disease in a subset of patients is refractory to treatment, and the disease follows an aggressive course. To study P-gp expression in this tumor and its correlation with outcome, tumor samples from 93 patients were examined by immunohistochemical analysis. P-gp expression was determined separately in both tumor cells and intratumoral capillary endothelium. The likelihood ratio test, the Kaplan-Meier method, and the log-rank test were used to evaluate its association with clinical course, grade, stage, and administration of preoperative chemotherapy. The results for the majority of nephroblastomas were variably positive; in 43 (46%) of them, newly formed capillary endothelial cells also stained positive. While no association of P-gp expression in tumor cells with clinical course, stage, and grade could be demonstrated, positivity in endothelial cells correlated significantly with unfavorable outcome, suggesting that chemoresistance depended on an active blood-tumor barrier. Previous chemotherapy induced P-gp overexpression in tumor cells.

Tyrosinemia Type 1: Metastatic Hepatoblastoma With a Favorable Outcome

The clinical course of tyrosinemia type 1 is characterized by acute liver failure in infancy or chronic liver dysfunction and renal Fanconi syndrome in late-presenting cases. Dietary treatment may improve liver function but does not prevent the development of hepatocellular carcinoma (HCC) in late childhood. A new treatment strategy that uses 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which prevents the production of toxic/carcinogenic metabolites, has dramatically changed the outcome of the disease by reducing the occurrence of liver cancer, especially in patients who start this treatment before the age of 2 years. We report here the case of a patient with a diagnosis of tyrosinemia type 1 at 5 months of age who was treated with NTBC and dietary restriction and in whom a liver neoplasm with lung metastases, histologically determined to be HCC, was found at the age of 15 months. A conservative approach that consisted of chemotherapy and partial hepatectomy resulted in a 12-year disease-free period. The excellent postchemotherapy course, in sharp contrast to the expected course of HCC, led to histologic reevaluation with reclassification of the neoplasm as hepatoblastoma. A diagnosis of hepatoblastoma would no longer be a mandate for a liver transplant for patients with tyrosinemia type 1 undergoing NTBC treatment. We encourage clinicians to perform more accurate evaluation of liver histology, because a neoplastic mass in a child with tyrosinemia type 1 is not the same as HCC.

Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: Pharmacological rationale and clinical response†

Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case‐series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed.