Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031.

We previously reported preliminary findings that post induction imatinib mesylate (340 mg/m(2)/day), in combination with intensive chemotherapy, resulted in outcomes similar to blood and marrow transplant (BMT) for pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We now report 5-year outcomes of imatinib plus intensive chemotherapy in 91 children (1-21 years) with and without allogeneic BMT (N=91). We explore the impacts of additional chromosomal abnormalities and minimal residual disease (MRD) by flow cytometry on outcomes. The 5-year disease-free survival was similar for Cohort 5 patients, treated with chemotherapy plus imatinib (70%±12%, n=28), sibling donor BMT patients (65%±11%, n=21) and unrelated donor BMT patients (59±15%; P=0.60, n=13). Patients with additional cytogenetic abnormalities had worse outcomes (P=0.05). End induction (pre-imatinib) MRD was not prognostic for Cohort 5 or allogeneic BMT patients, although limited by small numbers. The re-induction rate following relapse was similar to other higher-risk ALL groups. Longer-term follow-up confirms our initial observation of substantially good outcomes for children and adolescents with Ph+ ALL treated with imatinib plus intensive chemotherapy with no advantage for allogeneic BMT.

[Sensorineural hearing loss in cerebral palsy patients]. / Hipoacusia neurosensorial en pacientes con parálisis cerebral.

INTRODUCTION: Cerebral palsy (CP) is the most common chronic motor disorder in children and frequently associates sensorial pathology. The objective of our study was to establish the prevalence and characteristics of sensorineural hearing loss in children with CP. METHODS: We performed a retrospective study of patients born between the years 1975 and 2004, diagnosed of CP in the "Marqués de Valdecilla" University Hospital. Clinical data were collected including the presence of sensorineural hearing loss, age at diagnosis, treatment and associated pathology. RESULTS: Sixty four patients had confirmed CP. Audiological testing had been performed in thirty patients (47%) of them 18 (60%) had sensorineural hearing loss (12 bilateral and 6 unilateral). In thirteen cases hearing loss was associated with mental retardation. The age at diagnosis ranged from 3 months to 7 years (mean 23.2 months). Eight patients were treated with hearing aids and one with a cochlear implant. CONCLUSIONS: Sensorineural hearing loss is frequent in CP patients. Management of this problem is difficult in this setting because of the motor disorder and the associated pathology. Early audiological assessment is very important to improve the language outcome in these children.

Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene.

Albers-Schönberg disease, or autosomal dominant osteopetrosis, type II (ADO II), is the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption. Following the assignment of the gene causing ADO II to chromosome 16p13.3, we now report seven different mutations in the gene encoding the ClCN7 chloride channel in all 12 ADO II families analysed. Additionally, a patient with the severe, autosomal recessive, infantile form of osteopetrosis (ARO) was identified as being homozygous for a ClCN7 mutation. From genotype-phenotype correlations, it seems that ADO II reflects a dominant negative effect, whereas loss-of-function mutations in ClCN7 do not cause abnormalities in heterozygous individuals. Because some ARO patients have mutations in both copies of the ClCN7 gene, ADO II is allelic with a subset of ARO cases.

Successful treatment of metastatic retinoblastoma.

BACKGROUND: In the past, patients with metastatic retinoblastoma have had a poor prognosis when treated with conventional modalities. In the current study, the authors evaluated the use of combined intensive conventional chemotherapy, high dose chemotherapy with autologous stem cell rescue (ASCR), and radiation therapy. METHODS: Four patients with metastatic retinoblastoma were treated. All had orbital and bone marrow metastases. In addition, three patients had bone metastases and two patients had liver metastases. None had central nervous system disease. Patients received intensive conventional chemotherapy that included vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Stem cells were harvested after bone marrow disease was no longer detectable. High dose chemotherapy with carboplatin (500 mg/m(2)/day x 3 days or area under the curve = 7 via the Calvert formula) and thiotepa (300 mg/m(2)/day x 3 days) with (n = 3 patients) or without (n = 1 patient) etoposide (250 mg/m(2)/day x 3 days) was administered with ASCR. Sites that originally harbored bulky disease were irradiated after recovery from the high dose chemotherapy. RESULTS: The therapy was associated with substantial acute hematopoietic and mucosal toxicities. At last follow-up, all four patients had survived event free from 46-80 months after the diagnosis of metastatic disease. CONCLUSIONS: The treatment strategy described in the current study is effective for patients with metastatic retinoblastoma that does not involve the central nervous system. However, a multicenter trial should be considered to evaluate it in a larger group of patients.

[Evaluation of the vaccination campaign in Cantabria 2 years of epidemiological evolution]. / Evaluación de la campaña de vacunación en Cantabria dos años de evolución epidemiológica.

The results of the meningococcal vaccination campaign carried out in Cantabria in February-March 1997 are presented. In the short term, the campaign reduced the rate of incidence in the risk group from 21.33/100,000 in the previous 12 months, to zero in the 12 months following the campaign. In the medium term (2 and a half years later), the rate of incidence was maintained 80% lower in the risk group and 77.3% lower in the population overall. The vaccinal efficacy in the third year following the campaign remained above 91% for all age groups, although some biases commented upon in the study have meant that this efficacy has been underestimated. Also, the vaccinal efficacy is much higher than the percentages of seroprotection measured by the rate of bactericidal antibodies, particularly in the younger age groups. The clinical cases in vaccinated individuals experienced a benign clinical course.

Desmoplastic small round cell tumor with primary ovarian involvement: case report and review.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, malignant neoplasm that has recently been characterized. It has not been associated with a primary visceral organ. In women, cases are even more rare and often have some ovarian involvement. CASE: An 11-year-old girl presented with abdominal pain, nausea, and vomiting. A CT scan revealed a large heterogeneous pelvic mass with cystic components and an 8-cm midabdominal mass. During exploratory laparotomy, the patient was found to have a pelvic mass measuring 12. 9 cm replacing normal ovarian tissue. The midabdominal mass was also removed. Pathology, cytology, and immunohistochemistry confirmed a desmoplastic small round cell tumor. Even with aggressive surgical and medical intervention, the patient died 11 months after initial diagnosis. CONCLUSION: We present a rare small cell tumor that is associated with ovarian involvement. The prognosis in these patients is extremely poor and very few survivals have been reported.

Spontaneous remission of congenital acute nonlymphoblastic leukemia with normal karyotype in twins.

BACKGROUND: Congenital acute nonlymphoblastic leukemia (cANLL) is an extremely rare event and represents only 0.5-1% of the leukemias in the first year of life. It is usually more common among patients with chromosomal abnormalities. Transient myeloproliferative disease (TMD) is an hyperleukocytosis entity that occurs almost exclusively in Down syndrome patients and remits spontaneously. Spontaneous remission of congenital leukemia has been reported and related to the presence of an extra chromosome 21. PROCEDURE: A pair of non-Down syndrome newborn twins presented with a clinical picture of skin rash and hyperleukocytosis. Twin B had full-blown cANLL with bone marrow, peripheral blood, skin, CSF, and placental invasion. Twin A presented transient peripheral blood and skin involvement by the same type of blast cells. No cytotoxic therapy was given. With 2 years follow-up, they continue to do well. RESULTS: Histologic and immunophenotypical analysis of placentas, cord blood, skin, CSF, bone marrows, and peripheral blood revealed a consistent picture of intrautero cANLL in twin B, with transplacental invasion of twin A. Normal and blast cells were found to be karyotypically normal. Spontaneous remission occurred. CONCLUSIONS: cANLL with karyotypically normal blasts can develop a self-limited clinical course, which has resemblances to TMD.

Expression of HER2/erbB-2 correlates with survival in osteosarcoma.

PURPOSE: In osteosarcoma, prognostic factors at diagnosis other than clinical stage have not been clearly identified. The aim of this study was to determine whether human epidermal growth factor receptor 2 (HER2)/erbB-2, p-glycoprotein, or p53 expression correlated with histologic response to preoperative chemotherapy or event-free survival. PATIENTS AND METHODS: We performed a retrospective immunohistochemical study on material obtained from patients treated on the Memorial Sloan-Kettering Cancer Center T12 protocol between 1986 and 1993. Paraffin-embedded tissue was identified from 53 patients (73% of patients enrolled onto protocol) and stained for HER2/erbB-2, p53, and p-glycoprotein expression using standard monoclonal antibodies and methods. RESULTS: At the time of initial biopsy, 20 (42.6%) of 47 samples demonstrated high levels of HER2/erbB-2 expression. Higher frequencies of expression were observed in samples from patients with metastatic disease at presentation and at the time of relapse. Expression of HER2/erbB-2 correlated with a significantly worse histologic response (P =.03). In patients presenting with nonmetastatic disease, expression of HER2/erbB-2 at the time of initial biopsy was associated with a significantly decreased event-free survival (47% v 79% at 5 years, P =.05). p53 and p-glycoprotein expression did not correlate with histologic response or patient event-free survival. CONCLUSION: The correlation of HER2/erbB-2 expression with histologic response to preoperative chemotherapy and event-free survival in this study suggests that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator. The correlation also suggests that clinical trials of antibodies that target this receptor, such as recombinant humanized anti-HER2 monoclonal antibody (Herceptin; Genentech, San Francisco, CA), should be considered for the treatment of osteosarcoma.

Septicemia and septic shock in pediatric patients: 140 consecutive cases on a pediatric hematology-oncology service.

PURPOSE: This report describes the incidence of septic shock in pediatric hematology-oncology patients with positive blood cultures and investigates parameters of potential use in early diagnosis of gram-negative (GN) bacteremia and septic shock. PATIENTS: In a 12-month period, 140 consecutive episodes of septicemia (135 bacterial and 5 fungal) were seen in 100 patients. The absolute neutrophil count (ANC) was > 500/microl in 89 episodes (65%). RESULTS: Septic shock developed in patients with positive blood cultures with an overall incidence of approximately 19%. Of the 12 bacteremic patients who required transfer to the intensive care unit, 83% had a GN isolate recovered. The incidence of septic shock was not significantly lower in the group of patients with ANC > 500/microl. Low serum bicarbonate correlated with GN infection in patients with bacteremia. CONCLUSIONS: GN organisms were the major cause of septic shock in a group of pediatric hematology-oncology patients with positive blood cultures although they were recovered less frequently than gram-positive organisms. In our study, non-neutropenic patients with indwelling catheters were at approximately the same risk for GN shock as neutropenic patients. Monitoring blood carbon dioxide content may be useful in the early diagnosis of GN infection.

Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma, in children and young adults.

PURPOSE: To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma), while testing the feasibility of intensive use in adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV). PATIENTS AND METHODS: This report concerns previously untreated patients with newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100 cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140 mg/kg per course for patients < 10 years old), plus 72-hour infusions of doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are used. Courses start after neutrophil counts reach 500/microL and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radiotherapy follows completion of all chemotherapy. RESULTS: Among the first 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patients and partial responses (PRs) in two patients. For 24 patients with locoregional disease, the 2-year event-free survival rate was 77%; adverse events were two locoregional relapses, one distant relapse, and one secondary leukemia. All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are not assessable in terms of long-term efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone marrow transplantation), or septic death (autopsy showed no residual pPNET). All six patients with widespread metastases had major responses, including eradication of extensive bone marrow involvement, but distant relapses ensued. Myelosuppression was severe, but most patients received the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic toxicities were mucositis and peripheral neuropathy. CONCLUSION: Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in young adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge.

Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia.

We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced continuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.

[Free fluoride content in Spanish infant formulas]. / Contenido de flúor libre en leches infantiles españolas.

A study on the content of free fluoride in 39 milk formulae available in Spain. The selective ion electrode method has been selected. All formulae but one supply F amounts inadequate for cavities prophylaxis. Additional F should before be routinely administered per os in the form of sodium fluoride.