First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors.

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.

Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Old drugs still work! Oral etoposide in a relapsed medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children. Approximately 30% of children with medulloblastoma will progress or relapse despite being treated. New therapies have been proposed in recent years, including high-dose chemotherapy, immunotherapy, and targeted therapy. However, the best treatment for these patients remains unclear, and in this situation prognosis is poor. Oral etoposide has been used as a single agent or in combination for treating relapsed brain tumors since the 1990s. We report an 8-year-old patient with recurrent metastatic medulloblastoma who had an excellent response after treatment with oral etoposide, maintaining a great quality of life. As clinicians, we must always try to include our patients in clinical trials; however, when this is not possible, we should not forget that "old drugs" such as oral etoposide may work in some patients, with a good response of the tumor, and what is most important, providing the patient with a good quality of life.

El síndrome del teratoma en crecimiento / Growing teratoma síndrome

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Dicentric translocation (9;12) in acute lymphoblastic leukemia: a chromosomal abnormality with an excellent prognosis?

PURPOSE: Recurrent chromosomal abnormalities present in the leukemic cells of pediatric patients with acute lymphoblastic leukemia (ALL) often allow us to classify patients according to their prognosis, in order to establish further treatment. The dicentric translocation (9;12) consists of the rearrangement of the short arms of chromosomes 9 and 12 generating a dicentric chromosome (9;12). Patients with this alteration present a very good response to treatment and an excellent prognosis. METHODS: We present the case of an adolescent with ALL in which the dicentric translocation (9;12) was observed in the karyotype of the blasts at diagnosis. RESULTS AND CONCLUSION: Given the excellent results of our patient and most of the series published to date, an international study is necessary to determine the true prognostic significance of this molecular alteration.

Situación de la preservación de fertilidad en pacientes con cáncer en nuestro medio: grado de conocimiento, información e implicación de los profesionales / Current situation on fertility preservation in cancer patients in Spain: Level of knowledge, information, and professional involvement

Introducción: Los riesgos de infertilidad en cáncer infantil, en función de la radioterapia, quimioterapia y/o cirugía son bien conocidos. La implicación de los profesionales y los avances en los métodos de preservación son cada vez mayores. Sin embargo, muchos pacientes no reciben información ni realizan ningún método de preservación. Material: Se realiza una encuesta nacional de 22 preguntas a especialistas en hematología y/o oncología infantil para valorar sus conocimientos, la posibilidad de realizar preservación en sus centros y la práctica habitual. Resultados: Respondieron 50 miembros de la Sociedad Española de Hematología y Oncología Pediátrica, que representan 24 de 43 centros. Están representados el 82% de los centros que tratan un mayor número de pacientes. El 78% de los encuestados refiere conocer los efectos sobre la fertilidad de los tratamientos. El 76% admite no conocer ninguna guía sobre fertilidad en niños y adolescentes. En cuanto al momento para informar al paciente y/o su familia solo un 14% opina que debe hacerse en la entrevista del diagnóstico del cáncer. En su práctica clínica el 12% de los encuestados nunca deriva pacientes a las unidades de reproducción humana. Otro 12% solo lo hace si los afectados demuestran interés. El 38% deriva solo a pacientes púberes. El 34% remite a aquellos que vayan a recibir tratamiento altamente gonadotóxico. Conclusiones: Un gran porcentaje de especialistas manifiestan su falta de conocimientos y el valor de guías clínicas al respecto. Existen claras diferencias en preservación entre pacientes púberes y prepúberes. La frecuencia de preservación es baja (AU)

Introduction: The estimated risks of infertility in childhood cancer due to radiation, chemotherapy and surgery are well known. The involvement of professionals and advances in the different methods of preservation are increasing. However, many patients do not receive information or perform any method of preservation. Material: Questionnaires to paediatric onco-haematology institutions throughout Spain. The questionnaire consisted of 22 questions assessing their usual practices and knowledge about fertility preservation. Results: Fifty members of the Spanish Society of Paediatric Haematology and Oncology, representing 24 of 43 centres, responded. These represented 82% of centres that treated higher numbers of patients. The effect of treatment on fertility was known by 78% of those who responded, with 76% admitting not knowing any guideline on fertility in children or adolescents. As for the ideal time and place to inform the patient and/or family, only 14% thought it should be done in the same cancer diagnosis interview. In clinical practice, 12% of those surveyed never referred patients to Human Reproduction Units, another 12% only did so if the patients showed interest, and 38% only refer patients in puberty. Just over one-third (34%) of those referrals were going to receive highly gonadotoxic treatment. Conclusions: There are clear differences between pre-puberty and puberty patients. The frequency with which some method of fertility preservation is performed in patients is low. All respondents believe that the existence of national guidelines on the matter would be of interest (AU)

[Current situation on fertility preservation in cancer patients in Spain: Level of knowledge, information, and professional involvement]. / Situación de la preservación de fertilidad en pacientes con cáncer en nuestro medio: grado de conocimiento, información e implicación de los profesionales.

INTRODUCTION: The estimated risks of infertility in childhood cancer due to radiation, chemotherapy and surgery are well known. The involvement of professionals and advances in the different methods of preservation are increasing. However, many patients do not receive information or perform any method of preservation. MATERIAL: Questionnaires to paediatric onco-haematology institutions throughout Spain. The questionnaire consisted of 22 questions assessing their usual practices and knowledge about fertility preservation. RESULTS: Fifty members of the Spanish Society of Paediatric Haematology and Oncology, representing 24 of 43 centres, responded. These represented 82% of centres that treated higher numbers of patients. The effect of treatment on fertility was known by 78% of those who responded, with 76% admitting not knowing any guideline on fertility in children or adolescents. As for the ideal time and place to inform the patient and/or family, only 14% thought it should be done in the same cancer diagnosis interview. In clinical practice, 12% of those surveyed never referred patients to Human Reproduction Units, another 12% only did so if the patients showed interest, and 38% only refer patients in puberty. Just over one-third (34%) of those referrals were going to receive highly gonadotoxic treatment. CONCLUSIONS: There are clear differences between pre-puberty and puberty patients. The frequency with which some method of fertility preservation is performed in patients is low. All respondents believe that the existence of national guidelines on the matter would be of interest.

Very late isolated CNS relapse of acute myeloid leukemia.

Isolated central nervous system (CNS) relapse in acute myeloid leukemia (AML) rarely occurs later than 2 years after remission. We present a child diagnosed with AML (FAB M5) without CNS involvement at diagnosis who was treated with chemotherapy and consolidated with autologous hematopoietic stem cell transplantation. He was in complete remission for >6 years until he had an isolated CNS relapse. He was treated with only intrathecal chemotherapy and achieved a second complete remission, but relapsed in the bone marrow 5 months after the CNS relapse. Treatment of late isolated CNS relapse of AML is discussed.

Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study.

We retrospectively analyzed outcomes in 67 children with acute leukemia who received hematopoietic stem cell transplantation from alternative allogeneic donors: 29 received a haploidentical family donor and 38, an unrelated cord blood donor. All transplantations were performed from 1996 through 2010 in our center. Neutrophil and platelet engraftment were significantly delayed after cord blood transplantation. The median times to neutrophil and platelet recovery were 13 d (7-34) and 11 d (5-70) after haploidentical transplant and 20 d (9-125) and 56 d (12-200) after cord blood (P < 0.001). All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group.Transplant-related mortality rates was lower with haplo donors (25 ± 9%) than with cord blood donors (47 ± 9%) (P < 0.05). Acute graft-versus-host disease (GVHD) more than grade II was also lower in haploidentical transplants (19 ± 7%) than in cord blood transplants (44 ± 10%) (P < 0.03). Relapse and chronic GVHD incidence were not significantly different in the two groups. Leukemia-free survival was higher after haploidentical transplants (44 ± 10%) than after cord blood transplants (33 ± 7%) (P < 0.03). Main differences were observed in patients diagnosed with acute lymphoblastic leukemia: haplo, 41 ± 13%; cord blood, 26 ± 9% (P < 0.03) and in advanced phase of disease: haplo, 37 ± 14%; cord blood, 21 ± 8% (P < 0.05). In conclusion, haploidentical transplants are a good and promising alternative option for patients with childhood leukemia who lack an human leukocyte antigen-matched donor (sibling or unrelated donor).

High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study.

We analyzed the outcome in 22 children with refractory or relapsed non-Hodgkin lymphoma who underwent autologous peripheral blood progenitor cell transplantation between 1994 and 2009. The conditioning regimen used in all patients consisted of busulfan and cyclophosphamide. Median age was 6 years (range 2 to 16 y). The most common histologic subtype was Burkitt lymphoma. Ten patients were in complete remission and 12 in partial remission at the time of transplant. The median dose of CD34+ cells that was infused was 4.6 × 10/kg (range 2.1 to 58.7 × 10/kg). All the patients were engrafted, with a median time for neutrophils and platelets recovery of 11 (range, 8 to 15 d) and 14 (range, 9 to 60 d) days, respectively. Nonhematologic treatment-related toxicity included severe mucositis in 3 patients and hepatic sinusoidal obstruction syndrome in 1 patient. There were no transplant-related mortalities. With a median follow-up of 60 months (range, 4 to 180 d) the disease-free survival was 90 ± 6.5% for the whole group. This retrospective study shows a high long-term survival using busulfan/cyclophosphamide as conditioning regimen in children with refractory or relapsed non-Hodgkin lymphoma.

High-dose busulfan and melphalan as conditioning regimen for autologous peripheral blood progenitor cell transplantation in high-risk neuroblastoma patients.

The aim of this retrospective study was to analyze the outcome and identify risk factors associated with progression-free survival (PFS) in 36 children with high-risk neuroblastoma who underwent autologous peripheral blood progenitor cell (PBPC) transplantation between 1994 and 2010. The conditioning regimen used in all cases consisted of high-dose of busulfan and melphalan. Median age at transplantation was 3 years (range: 0.7-14 years). The median times to neutrophil and platelet engraftment were 11 days (range: 9.16 days) and 13 days (range: 9.33), respectively. Twenty-one patients developed nonhematologic toxicity: 15 patients had mucositis, 4 patients developed an engraftment syndrome, and there were 2 cases of liver toxicity. No toxic deaths were observed. There were 15 patients who relapsed. The median time to relapse was 6 months after the transplant (range: 3-13 months). With a median follow-up of 55 months (range: 4-180 months), the PFS was 57% ± 8.5% for the whole group. In multivariate analysis, age below 3 years (P < .005), complete remission (CR) pretransplantation (P < .07) and 1p germline status (P < .01) were variables associated with better outcomes. Patients who were or achieved early CR following transplantation (3 months posttransplantation) had a probability of PFS of 91% ± 6% as compared to patients who did not (PFS 9% ± 8%) (P < .0001). This retrospective study shows that high dose of busulfan and melphalan as conditioning regimen in children with high-risk neuroblastoma is associated with very low morbidity and no mortality in the authors' hands. Younger patients with no 1p deletions and in first CR at transplantation had the better outcome.

A persistent epidural mass in a child with B-lineage ALL.

Epidural spinal cord compression as the initial presentation of acute lymphoblastic leukemia (ALL) is a rare and serious complication. Extramedullary disease is rarely reported in patients with ALL. The most common sites are bone, followed by soft tissue, skin and lymph nodes. We describe a child with common B-lineage ALL who presented with a mass in the spinal epidural space. She was initially treated with intrathecal chemotherapy and intravenous dexamethasone with total resolution of her clinical symptoms but a persistent epidural mass. An open biopsy of the residual epidural mass was performed 7 months after diagnosis. The histological examination did not reveal any tumor infiltration, only fibrosis. We conclude that a persistent epidural mass in patients with ALL may not indicate resistant disease and may require over a year for resolution, even when response to therapy is adequate.

Hernia diafragmática de Morgagni- Larrey: una rara causa de derrame pericárdico / Morgagni-Larrey hernia: a rare cause of pericardial effusion

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