Lilian Maria Cristofani

Clinical and Outcome Characteristics of Children With Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry

PURPOSE We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. PATIENTS AND METHODS Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. RESULTS The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushings syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.

Radiation Therapy and High-Dose Tamoxifen in the Treatment of Patients With Diffuse Brainstem Gliomas: Results of a Brazilian Cooperative Study

PURPOSE The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial. PATIENTS AND METHODS TX was administered orally (maintenance dose: 200 mg/m(2) per day) along with conventional local RT and then continued for 52 additional weeks. Survival, tumoral radiologic response, and toxicity were evaluated. Compliance was assessed using pharmacokinetic measurements. RESULTS Of 29 patients, 27 completed RT (median dose, 54 Gy). Of 22 assessable patients, 11 (50%) had an objective radiologic response. The mean TX steady-state serum level was 2.44 micromol/L +/- 1.02 micromol/L. Only three patients completed the entire course of treatment without tumoral progression or significant toxicity. Common side effects included nausea and vomiting. Hepatotoxicity (five patients), neurotoxicity (two patients), venous thrombosis (one patient), bilateral ovarian cysts (two patients), and transient neutropenia (one patient) were also observed. Median survival was 10.3 months. Only four patients remain alive without tumoral progression. The 1-year survival rate (mean +/- SD) was 37.0% +/- 9.5%. CONCLUSION This treatment combination produced no significant change in the overall poor prognosis of these patients. Most tumors responded initially to treatment but recurred as the study progressed. A minority of patients seemed to benefit from the extended use of TX. Generally, treatment was well tolerated, with good patient compliance, but we recommend continuous close monitoring for side effects. Based on our poor results, we recommend that alternative treatments be tested in patients with this type of tumor.

Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

Clinical characteristics of small functioning adrenocortical tumors in children

Twenty of 67 children registered on the International Registry of Childhood Adrenocortical Tumors between May 1988 and December 1994 had small adrenocortical tumors (defined for this study as measuring < or = 200 cm3 and/or weighing < or = 100 g). We reviewed the records of these 20 patients to characterize the clinical and pathologic findings and outcomes of children with small adrenocortical tumors. Median patient age was 2 years (range, 4 months to 5 years). There was only one boy. All had clinical signs of virilization, and seven had signs or symptoms of Cushing syndrome. A median 5.5 months (range, 1-40 months) had elapsed between the first signs of endocrine dysfunction and diagnosis. All tumors were surgically resected. Tumor volume was 3.3-195 cm3 (median, -8.7 cm3), and weight was 3.7-100 g (median, 36 gm Tumor samples were histologically reviewed in 18 cases. Eight were adenomas, and 10 were carcinomas (6 low grade and 4 high grade). Pathology records described tumor with diagnostic features of adrenocortical carcinoma in two patients. One patient received mitotane for 8 months after surgery. Only one patient had recurrent disease, which was detected 6 months after diagnosis and proved rapidly fatal. Another has been lost to follow-up. The remaining 18 patients are alive with no evidence of disease at a median 2.3 years (range, 6 months to 6.1 years) after diagnosis. Our data suggest that children with small adrenocortical tumors have an excellent prognosis with surgery as the sole therapy, regardless of tumor histiotype.

Griscelli Syndrome: Characterization of a New Mutation and Rescue of T-Cytotoxic Activity by Retroviral Transfer of RAB27A Gene

Griscelli syndrome (GS) is caused by mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes, all of which lead to a similar pigmentary dilution. In addition, GS1 patients show primary neurological impairment, whereas GS2 patients present immunodeficiency and periods of lymphocyte proliferation and activation, leading to their infiltration in many organs, such as the nervous system, causing secondary neurological damage. We report the diagnosis of GS2 in a 4-year-old child with haemophagocytic syndrome, immunodeficiency, and secondary neurological disorders. Typical melanosome accumulation was found in skin melanocytes and pigment clumps were observed in hair shafts. Two heterozygous mutant alleles of the RAB27A gene were found, a C-T transition (C352T) that leads to Q118stop and a G-C transversion on the exon 5 splicing donor site (G467+1C). Functional assays showed increased cellular activation and decreased cytotoxic activity of NK and CD8+ T cells, associated with defective lytic granules release. Myosin-Va expression and localization in the patient lymphocytes were also analyzed. Most importantly, we show that cytotoxic activity of the patients CD8+ T lymphocytes can be rescued in vitro by RAB27A gene transfer mediated by a recombinant retroviral vector, a first step towards a potential treatment of the acute phase of GS2 by RAB27A transduced lymphocytes.

Laparoscopic nephrectomy for Wilms’ tumor

The role of minimally invasive surgery for the treatment of pediatric urological tumors has been limited to biopsies and resection for small neuroblastomas and benign tumors. The purpose of this study is to present the experience of a Brazilian group pioneering laparoscopic nephrectomy for Wilms’ tumor. A total of 15 children with unilateral non-metastatic Wilms’ tumor were preoperatively treated with vincristine and actinomycin D, and afterwards were submitted to laparoscopic nephrectomy and lymph node sampling. A Veress needle umbilical punction was performed and a four-trocar transperitoneal approach was used. The tumor was extracted inside a plastic bag and without morcellation through a Pfannenstiel incision. In all 15 patients the tumor was completely removed, as well as lymph node samples and no ruptures occurred. A fibrous capsule involved the tumor, making the dissection easy to perform. Intraoperative bleeding was minimal. The postoperative course was free of complications and all the patients were discharged early. No recurrences or long-term complications have been detected in 7–61 months or more of follow-up. We conclude that laparoscopic nephrectomy for Wilms’ tumor is a feasible and safe procedure in a selected group of children after chemotherapy. It reproduces all the steps of the open surgical approach required to treat this tumor, with the advantages of a short hospital stay and cosmetically more acceptable incisions.

Discrimination of acute lymphoblastic leukemia from systemic-onset juvenile idiopathic arthritis at disease onset

OBJECTIVE: To assess clinical and laboratory features that differentiate acute lymphoblastic leukemia from systemic juvenile idiopathic arthritis at disease onset. METHODS: Fifty-seven leukemia patients with musculoskeletal involvement, without blasts on peripheral blood and without glucocorticoid therapy at disease onset and 102 systemic juvenile idiopathic arthritis patients (International League of Associations for Rheumatology criteria) were retrospectively evaluated. The following features were examined: fever, rheumatoid rash, arthritis, limb pain, hepatomegaly, splenomegaly, pericarditis, myocarditis, pleuritis, weight loss, bleeding, anemia, leukopenia, neutropenia, thrombocytopenia, erythrocyte sedimentation rate, and lactic dehydrogenase levels. RESULTS: The median age at disease onset was significantly higher in leukemia patients than in those with systemic-onset juvenile idiopathic arthritis (5.8 vs. 3.8 years). In addition, the frequencies of limb pain, hepatomegaly, weight loss and hemorrhagic manifestations were significantly higher in leukemia patients than in systemic-onset juvenile idiopathic arthritis patients (70% vs. 1%, 54% vs. 32%, 30% vs. 8%, and 9% vs. 0%, respectively). Likewise, the frequencies of anemia, leukopenia, neutropenia, thrombocytopenia and high lactic dehydrogenase levels were statistically higher in leukemia patients than in patients with systemic-onset juvenile idiopathic arthritis (88% vs. 57%, 39% vs. 1%, 60% vs. 1%, 77% vs. 1%, and 56% vs. 14%, respectively). Remarkably, multivariate analysis revealed that limb pain (OR = 553; 95% CI = 46.48-6580.42) and thrombocytopenia (OR = 754.13; 95% CI = 64.57-8806.72) were significant independent variables that differentiated leukemia from systemic-onset juvenile idiopathic arthritis. The R2 of the Nagelkerke test was 0.91, and the Kaplan-Meier survival curves were similar for acute lymphoblastic leukemia patients with and without limb pain. CONCLUSION: Our study emphasizes the importance of investigating leukemia in patients presenting with musculoskeletal manifestations and, in particular, limb pain associated with thrombocytopenia.

Administration of live attenuated varicella vaccine to children with cancer before starting chemotherapy

From July 1985 to February 1987, of 46 consecutive children with cancer (26 male, 20 female; median age, 4 years) with no prior history of chickenpox, the initial 30 patients were randomized either to receive or not to receive live attenuated varicella vaccine (LAVV) before chemotherapy was started and the remaining 16 patients were all immunized without randomization. Before immunization, Varicella zoster (VZ) antibodies were detected by immunofluorescence and ELISA in 11 (34%) of 32 vaccinated children and two (14%) of 14 controls, indicating previous infection. A booster effect was evident in 70% of them and no side effects were noted. Ten (28%) of 32 vaccinees were excluded from the analysis because of early death due to cancer (1-4 weeks). Seroconversion was demonstrated in ten (77%) of 13 vaccinees, with high antibody titres. Only three of them lost their antibodies 2 years after immunization, as disclosed by serological follow-up. Eight out of 13 vaccinees had household contacts with VZ and none became infected. Zoster immunoglobulin (ZIG) was never given. Among controls, seven out of 14 were exposed to VZ and four (57%) became infected. Mild side effects were observed in four (12.5%) out of 32 vaccinees (three with papulovesicular rash, 6-30 lesions, and one with a 3-day intermittent fever). Local reactions, zoster and spreading of vaccinal virus did not occur. LAVV proved to be safe and effective when administered before starting chemotherapy to children with cancer and no history of varicella.

Evaluación de la calidad de vida en niños y adolescentes portadores de enfermedades crónicas y/o incapacitadoras: un estudio brasileño

Objetivo Evaluar la calidad de vida de ninos y adolescentes portadores de leucemia linfocitica aguda (LLA) y artritis reumatoide juvenil (ARJ). Material y metodos Se aplico la Children’s Global Assessment Scale (CGAS), la Vineland Adaptative Behavior Scale (VABS) y el Autoquestionnaire Qualite de Vie Enfant Image (AUQEI) en 28 portadores de LLA, 28 portadores de ARJ y 28 escolares sanos pareados, de 4 a 13 anos incompletos y diagnostico entre 1 y 5 anos. Resultados Hubo discreta diferencia entre los grupos LLA y ARJ respecto a la edad. No hubo diferencias significativas en relacion al tiempo de tratamiento, ni a la puntuacion de la CGAS. Hubo diferencia significativa en la puntuacion total de la VABS, asi como del dominio comunicacional de la VABS. La diferencia ente los grupos ARJ y Sanos en relacion a la puntuacion de la VABS, dominio de actividades de vida cotidiana, no fue significativa. No hubo diferencia significativa entre los grupos respecto a la puntuacion del dominio socializacion de la VABS ni del AUQEI. Conclusion En nuestro estudio, es nitido el peor desempeno de los ninos cronicamente enfermos en lo que se refiere al desarrollo de comportamientos adaptables. No obstante, refieren una calidad de vida compatible con los controles sanos. Urge que se desarrollen metodos de evaluacion habilitados en captar la percepcion de la enfermedad y del tratamiento proveniente del propio paciente pediatrico.

Retinoblastoma: a three-year-study at a Brazilian medical school hospital

OBJECTIVE: To present the characteristics and treatment outcomes of patients with retinoblastoma. METHODS: A retrospective case series was conducted to review the records of all new patients diagnosed with retinoblastoma between 2003 and 2005. Eyes with early disease, or advanced disease with potential vision were treated with chemotherapy (carboplatin and etoposide) in conjunction with early local therapy (laser or cryo). Radiotherapy was used in cases where the disease did not respond to the above protocols or in recurrent cases. Eyes in the late stage of disease with no potential vision in the initial examination or eyes and where conservative treatment had failed were enucleated. RESULTS: In total, we reviewed 28 new cases of retinoblastoma, 15 of which were unilateral and 13 of which were bilateral (46%). These data correspond to a mean of 9.3 new cases per year (0.77 case/month). The mean age at diagnosis was 33.8 months for unilateral cases, and 19.15 months for bilateral cases (p=0.015). Leucocoria was the major presenting symptom (75%). All but one patient with unilateral disease had the affected eye enucleated due to advanced disease (mean follow-up: 39.91 months). Among the 13 bilateral cases, 13 eyes (50%) were enucleated, 11 eyes (42.4%) were saved with chemotherapy in conjunction with local therapy and 2 eyes (7.6%) were saved using external beam radiotherapy (mean follow-up: 41.91 months). In unilateral and bilateral disease, pathology data revealed choroid involvement in 50% and 30%, respectively, and optic nerve invasion in 92% and 50%, respectively. CONCLUSION: In this population, retinoblastoma was diagnosed too late and most eyes were consequently enucleated. In cases with bilateral disease, half of the eyes were preserved.