Carlos Rodriguez-Galindo

Inactivation of the p53 pathway in retinoblastoma.

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.

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.

Comparing Adult and Pediatric Rhabdomyosarcoma in the Surveillance, Epidemiology and End Results Program, 1973 to 2005: An Analysis of 2,600 Patients

PURPOSE To compare clinical features and outcomes of adults and children reported to have rhabdomyosarcoma. PATIENTS AND METHODS We analyzed data from 1,071 adults (age > 19 years) and 1,529 children (age < or = 19 years) reported in the public-access Surveillance, Epidemiology and End Results database as having rhabdomyosarcoma, diagnosed from 1973 to 2005. Survival estimates were determined using survival time with the end point being death from any cause. RESULTS Adults with rhabdomyosarcoma had significantly worse outcome than children (5-year overall survival rates, 27% +/- 1.4% and 61% +/- 1.4%, respectively; P < .0001). Tumors in adults were more likely to be at an unfavorable site (65% v 55%; P < .0001) and to have histologies that are unusual during childhood, particularly the pleomorphic subtype (19%) and not otherwise specified (43%). Regional and distant spread was not more frequent in adults. Adults had significantly worse outcome than children with similar tumors. The most significant difference was in localized disease; 5-year survival estimates were 82% +/- 2.0% for children and 47% +/- 2.9% for adults (P < .0001). Multivariate analysis showed that age, histologic subtype, primary site location, stage, and local control with surgery and/or radiation were significant predictors of survival. However, alveolar subtype and unfavorable primary site lost significance when analysis was restricted to adults. CONCLUSION Adults reported to have rhabdomyosarcoma had worse survival than children with similar tumors. Predictors of poor outcome in children were valid in adults except for alveolar histology and unfavorable tumor site.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical Work-Up, and Treatment for Patients Till the Age of 18 Years

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work‐up, and treatment and long‐term follow‐up of LCH patients are presented. Pediatr Blood Cancer 2013;60:175–184.

Treatment of Intraocular Retinoblastoma With Vincristine and Carboplatin

PURPOSE To evaluate the efficacy of chemoreduction using vincristine and carboplatin in preventing or delaying external-beam radiotherapy (EBRT) or enucleation in patients with intraocular retinoblastoma. PATIENTS AND METHODS Twenty-five patients (43 eyes) with newly diagnosed intraocular retinoblastoma received primary treatment with eight courses of vincristine and carboplatin. Focal treatments were delayed until documentation of disease progression. Outcome measures for each eye were length of time to disease progression, avoidance or delay of EBRT, and globe survival. Event-free survival was defined as the length of time to EBRT or enucleation. RESULTS Disease in all eyes responded to chemotherapy and progressed in only two patients before completion of the eight courses of therapy. Disease in all but four eyes progressed and required focal treatments. Event-free survival estimates at 2 years were 59.2% +/- 12.0% for Reese-Ellsworth group I, II, and III eyes and 26.3% +/- 9.2% for group IV and V eyes. Nineteen eyes (44.2%) required EBRT and 13 eyes (30.2%) were enucleated. The ocular salvage rate was 83.3% for Reese-Ellsworth group I to III eyes and 52.6% for group IV and V eyes. For those patients receiving EBRT, the median time from enrollment to EBRT was 9.5 months (median age at EBRT, 21 months). CONCLUSION In combination with appropriate early intensive focal treatments, chemoreduction with vincristine and carboplatin, without etoposide, may be an alternative treatment for patients with early-stage intraocular retinoblastoma, although additional studies are needed. Patients with advanced intraocular disease require more aggressive treatments.

Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies.

Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups.

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. Objective: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. Methods: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. Results: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). Conclusions: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

The Genomic Landscape of Pediatric Ewing Sarcoma

UNLABELLED Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease. SIGNIFICANCE We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.

Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma.

Retinoblastoma is the most common intraocular malignant childhood tumor in need of prospective clinical trials to address important unanswered questions about biology, treatment, and prognostic factors. Currently, there is controversy about the definitions for choroidal invasion and an inconsistency in the handling of eyes with retinoblastoma. The International Retinoblastoma Staging Working Group (IRSWG) composed of 58 participants from 24 countries on 4 continents had a series of Internet meetings to discuss the staging and tissue handling guidelines to reach consensus for adequate processing, establishing definitions of histopathologic risk factors, and reporting of enucleated eyes with retinoblastoma to serve as the basis for clinical trials and studies to validate the proposed criteria. The meetings were facilitated by the International Outreach Program of the St. Jude Childrens Research Hospital through Cure4Kids. The retinoblastoma guidelines from the Childrens Oncology Group, the French Society for Pediatric Cancers, the Association of Directors of Anatomic and Surgical Pathology, and some published data were the basis for this consensus document. Discussions of the feasibility, practicality, and efficacy of the guidelines and criteria resulted in this report. The consensus definitions reached included definition of massive choroidal invasion stated as a maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue. Focal choroidal invasion is defined as a tumor focus of less than 3 mm and not reaching the sclera. Optic nerve invasion is classified as prelaminar, laminar, retrolaminar, or tumor at surgical margin, and the measurement of the depth of invasion should also be recorded. These guidelines also address handling of the enucleated eye with retinoblastoma in an efficient, practical, and feasible manner for a meaningful diagnosis. The consensus criteria reached by the IRSWG should be validated through prospective clinical trials and studies.