Timing of spermatogonial stem cell transplantation affects the spermatogenic recovery outcome in mice.

Spermatogonial stem cell transplantation (SSCT) is a strategy that has demonstrated to be feasible to restore spermatogenesis in animal models when it is performed shortly after the gonadotoxic onset to destroy their endogenous germ cells. However, in the case of boys subjected to fertility preservation, future transplantations will be performed with a delay of many years. In order to study how timing of SSCT affects donor-derived spermatogenic recovery in mice, we compared the percentage of spermatogenic tubule cross-sections within testes of 59 C57BL/6NCrl mice distributed in 6 groups: group 1, untreated mice controls (n = 9); group 2, mice that received a single dose of busulfan 40 mg/kg (n = 10); group 3, mice that received two additional doses of busulfan 10 mg/kg every 5 weeks (n = 10); group 4 (SSCT-A), mice subjected to a standard SSCT performed 5 weeks after a single injection of busulfan 40 mg/kg (n = 10); group 5 (SSCT-B), mice subjected to a delayed SSCT performed 15 weeks after a single injection of busulfan 40 mg/kg (n = 10); and group 6 (SSCT-C), mice subjected to a delayed SSCT with two additional doses of busulfan 10 mg/kg every 5 weeks (n = 10). Spermatogenic recovery in standard SSCT-A and SSCT-C groups ranged between 22.29 and 22.65%, compared with a lower recovery rate of 11.54% showed in the SSCT-B group. However, donor contribution resulted higher in standard SSCT-A, representing a 69.71% of cross-sections, compared with the rest of conditions ranging from 34.69 to 35.42%. Overall, we concluded that a delay in the SSCT from the gonadotoxic onset decreases the efficiency of donor-derived spermatogenic recovery in mice.

Histologic Analysis of Testes from Prepubertal Patients Treated with Chemotherapy Associates Impaired Germ Cell Counts with Cumulative Doses of Cyclophosphamide, Ifosfamide, Cytarabine, and Asparaginase.

Cryopreservation of immature testicular tissue is an experimental strategy for the preservation of fertility in prepubertal boys that will be subjected to a gonadotoxic onset, as is the case of oncologic patients. Therefore, the objective of this study was to assess the impact of chemotherapeutic treatments on the testicular histologic phenotype in prepubertal patients. A total of 56 testicular tissue samples from pediatric patients between 0 and 16 years old (28 with at least one previous chemotherapeutic onset and 28 untreated controls) were histologically analyzed and age-matched compared. At least two 5-µm sections from testis per patient separated by a distance of 100 µm were immunostained for the germ cell marker VASA, the spermatogonial markers UTF1, PLZF, UCHL1, and SALL4, the marker for proliferative cells KI67, and the Sertoli cell marker SOX9. The percentage of tubule cross-sections positive for each marker and the number of positive cells per tubule cross-section were determined and association with the cumulative dose received of each chemotherapeutic drug was statistically assessed. Results indicated that alkylating agents, cyclophosphamide and ifosfamide, but also the antimetabolite cytarabine and asparaginase were associated with a decreased percentage of positive tubules and a lower number of positive cells per tubule for the analyzed markers. Our results provide new evidences of the potential of chemotherapeutic agents previously considered to have low gonadotoxic effects such as cytarabine and asparaginase to trigger a severe testicular phenotype, hampering the potential success of future fertility restoration in experimental programs of fertility preservation in prepubertal boys.

Fertility preservation in boys: recent developments and new insights †.

BACKGROUND: Infertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility. OBJECTIVE AND RATIONALE: With this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss. SEARCH METHODS: Based on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity. OUTCOMES: Since the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation. LIMITATIONS REASONS FOR CAUTION: The review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention. WIDER IMPLICATIONS: The revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss. STUDY FUNDING/COMPETING INTERESTS: The work was funded by ESHRE. None of the authors has a conflict of interest.

La Unidad de Oncología Pediátrica del Hospital La Fe en 2013 / The Pediatric Oncology Unit of the Hospital la Fe in 2013

Tras un breve recorrido histórico y tras señalar la misión, visión y valores de la Unidad de Oncología Pediátrica, se describe la estructura de la unidad, recursos estructurales y humanos y su actividad asistencial, docente y de investigación. En referencia a la labor asistencial cabe destacar su atención universal en régimen ambulatorio (consulta externa y hospitalización a domicilio), de hospitalización y de urgencia, incluyendo todos los tratamientos disponibles en Oncología Pediátrica en todas las fases de la enfermedad (desde el diagnóstico hasta la terminal en su caso o en la prevención o rehabilitación de efectos adversos a largo plazo. Su labor en docencia e investigación es también destacable (AU)

After a short history and to point out objectives and care level of Pediatric Oncology Unit, we describe structural and human resources of the Unit and its clinical, investigational and teaching activity. Concerning clinical, activity, we would like to highline the global dedication in outpatient and impatient regimen including home care assistance. We also remark out disposition to offer all types of treatments with known efficacy in children with cancer, including every phase of the disease and late effects (AU)

Evaluation of chimerism by quantitative PCR analysis of DNA polymorphism after allogeneic hematopoietic stem cell transplantation in a pediatric population with malignancies.

Relapse remains the major pitfall to success for Allo-HSCT in children with malignancies. Ninety-one patients undergoing Allo-HSCT were retrospectively reviewed. Chimerism status was evaluated at days +30, +60, and +100 in PB. VNTR-PCR and STR-PCR were used for this purpose. Thirty-one patients recurred (34%) and none survived. Thirty-two remain alive in CR (35%). Patients who achieved a CC at those days had a significant higher RFS and OS than patients who did not. Twelve patients showing PMC had an increased risk of recurrence (p=0.02. OR 7.7). In the univariate analysis, the probability of death was higher in patients who were not in first CR before transplant (p=0.008.OR 2.09) and in those receiving cells not from PB (p=0.002.OR 2.03). In the multivariate analysis, the absence of CC at day +100 was associated with a higher probability of relapse (p=0.004. OR 10.8) and death (p=0.016. OR 9.3). Serial chimerism PCR-based analyses of polymorphic DNA markers can predict relapse. Patients with PMC are at the highest risk of recurrence. Patients receiving an Allo-HSCT in first CR from PB who achieve a CC at day +100 have a better outcome.

Solid ovarian tumours in childhood: a 35-year review in a single institution.

PURPOSE: Solid ovarian tumours are uncommon in childhood. Our aim is to evaluate the outcomes in a single institution over 35 years. METHODS: We reviewed their clinical presentation, management, pathology and outcomes from 1972 to 2007. RESULTS: Fifty-three patients, with a median age of 9.2 years (range 0.9-14.2), were registered. Common symptoms at presentation were abdominal pain (75.8%) and abdominal mass (57.4%). Histopathological diagnoses were: 26 mature teratoma, 10 immature teratoma, 8 dysgerminoma, 5 granulosa cell tumours, 2 yolk sac tumours, 1 gonadoblastoma and 1 embryonal carcinoma. Staging (FIGO) for malignant/borderline tumours was: 17 stage I, 1 stage II, 8 stage III and 1 stage IV. Unilateral salpingo-oophorectomy was performed in 47 cases. Sixteen patients underwent chemotherapy after surgery (15 with platinum-based regimen) and postoperative radiotherapy was given in 5 cases. Recurrence was observed in 2 patients and one died (stage III immature teratoma) after a second relapse despite multiple chemotherapy, surgery and radiotherapy. Five-year OS and 5-year EFS were 97% and 94% respectively. CONCLUSIONS: Although rare, ovarian tumours must be included in the differential diagnosis of abdominal pain in childhood. Our results confirm their excellent prognosis using conservative surgery and platinum-based chemotherapy. The key point is to maintain excellent outcome while reducing associated morbidity and preserving fertility.

Solid ovarian tumours in childhood: a 35-year review in a single institution

PURPOSE: Solid ovarian tumours are uncommon in childhood. Our aim is to evaluate the outcomes in a single institution over 35 years. METHODS: We reviewed their clinical presentation, management, pathology and outcomes from 1972 to 2007. RESULTS: Fifty-three patients, with a median age of 9.2 years (range 0.9-14.2), were registered. Common symptoms at presentation were abdominal pain (75.8%) and abdominal mass (57.4%). Histopathological diagnoses were: 26 mature teratoma, 10 immature teratoma, 8 dysgerminoma, 5 granulosa cell tumours, 2 yolk sac tumours, 1 gonadoblastoma and 1 embryonal carcinoma. Staging (FIGO) for malignant/borderline tumours was: 17 stage I, 1 stage II, 8 stage III and 1 stage IV. Unilateral salpingo-oophorectomy was performed in 47 cases. Sixteen patients underwent chemotherapy after surgery (15 with platinum-based regimen) and postoperative radiotherapy was given in 5 cases. Recurrence was observed in 2 patients and one died (stage III immature teratoma) after a second relapse despite multiple chemotherapy, surgery and radiotherapy. Five-year OS and 5-year EFS were 97% and 94% respectively. CONCLUSIONS: Although rare, ovarian tumours must be included in the differential diagnosis of abdominal pain in childhood. Our results confirm their excellent prognosis using conservative surgery and platinum-based chemotherapy. The key point is to maintain excellent outcome while reducing associated morbidity and preserving fertility (AU)

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Preservación de la fertilidad en niños y adolescentes con cáncer: situación actual y perspectivas futuras / Preservation of fertility in children and adolescents with cancer: Current situation and future perspectives

Los avances del tratamiento antineoplásico han llevado a un significativo aumento de las tasas de supervivencia, que en la actualidad y para la población pediátrica son superiores al 70%. Entre los posibles efectos tardíos secundarios al tratamiento oncológico, las alteraciones en la capacidad reproductiva pueden tener un especial impacto en la calidad de vida de los supervivientes. En los últimos años el desarrollo de nuevas técnicas de reproducción asistida, entre las que se incluye la criopreservación de corteza ovárica, ha abierto un camino esperanzador en algunos subgrupos de población, que hasta la fecha contaban con escasas posibilidades para preservar su fertilidad ante la administración de un tratamiento gonadotóxico. Sin embargo, la aplicación de estos avances en el campo de la Pediatría y de los adolescentes tiene todavía un largo camino por delante y algunas consideraciones prácticas y éticas merecen revisarse antes de recomendar su utilización en la práctica médica diaria (AU)

Advances in antineoplastic therapy have considerably increased survival rates, and currently in the setting of paediatric population are higher than 70%. Among the potential long-term late effects due to oncological treatment, reproductive dysfunction may have a particularly deep impact on the survivors’ quality of life. Until recently, limited fertility preservation options were available before gonadotoxic therapies. In the last few years the development of new assisted reproduction techniques, including ovarian cryopreservation, may be promising in selected groups of patients. Although, the feasibility of these advances in the paediatric and adolescent field have a long way to go, several practical and ethical issues deserve a special review before recommending them for routine medical practice (AU)

[Preservation of fertility in children and adolescents with cancer: current situation and future perspectives]. / Preservación de la fertilidad en niños y adolescentes con cáncer: situación actual y perspectivas futuras.

Advances in antineoplastic therapy have considerably increased survival rates, and currently in the setting of paediatric population are higher than 70%. Among the potential long-term late effects due to oncological treatment, reproductive dysfunction may have a particularly deep impact on the survivors' quality of life. Until recently, limited fertility preservation options were available before gonadotoxic therapies. In the last few years the development of new assisted reproduction techniques, including ovarian cryopreservation, may be promising in selected groups of patients. Although, the feasibility of these advances in the paediatric and adolescent field have a long way to go, several practical and ethical issues deserve a special review before recommending them for routine medical practice.

[Clinical and economic repercussions of the use of tunneled haemodialysis catheters in a health area]. / Repercusiones clínicas y económicas del uso de catéteres tunelizados de hemodiálisis en un área sanitaria.

INTRODUCTION: Tunneled catheters in hemodialysis are associated with poor prognosis, however, few prospective studies have been designed to specifically evaluate this aspect. The objective has been evaluate the impact of tunneled catheter in patient mortality and costs attributable to this procedure. METHODS: A seven years prospective cohort study was performed in all patients starting hemodialysis in our health care area adjusting for comorbidity and albumin. The study comprised 260 patients with Charlson index 7.05 +/- 2.8 (age 65.5 years, 62.3% males, 25% with diabetes mellitus and 37.7% with a previous cardiovascular event. RESULTS: The first vascular access was a catheter in 47.3%, PTFE in 11.2% and native arteriovenous fistula in 41.5%. Minimum follow-up was one year, with an average of 2.31 years/patient. The mortality risk adjusted for comorbidity was greater among the patients that started with catheterization, HR: 1.86 [1.11-3.05]. This negative effect was observed in 57.30% of those subjected to catheterization at any stage (HR: 1.68 [1.00-2.84] and proved to be time dependent, i.e., the longer catheterization, the greater the risk: HR: 7.66 [3.34-17.54] third versus first tertil. The cost directly attributable to catheter use was 563.31 euros/month. All poor prognosis groups showed lower albumin and hemoglobin levels, without differences in efficacy. CONCLUSION: Tunneled catheter use at any time is associated with an increased risk of death. This effect increases with the duration of catheterization, both circumstances are independent of patient comorbidity at time start of hemodialysis and implies a higher net cost.

Repercusiones clínicas y económicas del uso de catéteres tunelizados de hemodiálisis en un área sanitaria / No disponible

Introducción: el uso de catéteres en hemodiálisis se asocia a un gran número de complicaciones. Sin embargo, se han realizado pocos estudios diseñados específicamente para evaluar este problema. Los objetivos del estudio han sido conocer el impacto en la supervivencia del paciente y el gasto económico que implica la utilización de catéteres. Métodos: estudio observacional y prospectivo histórico de siete años de duración en 260 pacientes incidentes en hemodiálisis en nuestra área de salud, ajustado a la comorbilidad y albúmina al inicio de la hemodiálisis. La media de edad fue de 65,5 ± 15,2 años, 62,3% varones, 25% diabéticos. La media del índice de comorbilidad de Charlson fue de 7,05 ± 2,8. Resultados: el 47,3% de los pacientes inicia hemodiálisis con catéter, el 41,5% con FAV-auto y 11,2% con FAV-PTFE. El seguimiento medio fue 2,31 años/paciente. El riesgo de mortalidad ajustado por comorbilidad fue mayor para los que inician hemodiálisis con un catéter, HR:1,86 (1,11-3,05). Este efecto negativo también se observó en el 57,3% de pacientes que a lo largo del seguimiento requirieron un catéter, HR: 1,68 (1,00-2,84) y, además, fue tiempo dependiente; a mayor tiempo con catéter, mayor mortalidad: HR 7,66 (3,34-17,54), tertil 3 vs. tertil 1. El coste del empleo mes/catéter fue de 561,31 euros. Conclusiones: el uso de catéteres tunelizados es un factor independientemente asociado con la mortalidad de los pacientes, tanto al inicio como a lo largo del seguimiento, es tiempo dependiente y conlleva un elevado coste económico (AU)

Introducction: Tunneled catheters in hemodialysis are associated with poor prognosis, however, few prospective studies have been designed to specifically evaluate this aspect. The objective has been evaluate the impact of tunneled catheter inpatient mortality and costs attributable to this procedure. Methods: A seven years prospective cohort study was performed in all patients starting hemodialysis in our health care area adjusting for comorbidity and albumin. The study comprised 260patients with Charlson index 7.05 ± 2.8 (age 65.5 years, 62.3%males, 25% with diabetes mellitus and 37.7% with a previous cardiovascular event. Results: The first vascular access was a catheter in 47.3%, PTFE in 11.2% and native arteriovenous fistula in 41.5%. Minimum follow-up was one year, with an average of 2.31 years/patient. The mortality risk adjusted for comorbidity was greater among the patients that started with catheterization, HR: 1.86 [1.11-3.05]. This negative effect was observed in 57.30% of those subjected to catheterization at any stage (HR: 1.68 [1.00-2.84] and proved to be time dependent, i.e., the longer catheterization, the greater the risk: HR:7.66 [3.34-17.54] third versus first tertil. The cost directly attributable to catheter use was 563.31 euros/month. All poor prognosis groups showed lower albumin and hemoglobin levels, without differences in efficacy. Conclusion: Tunneled catheter use at any time is associated with an increased risk of death. This effect increases with the duration of catheterization, both circumstances are independent of patient comorbidity at time start of hemodialysisand implies a higher net cost (AU)

Could other viruses cause pediatric posttransplant lymphoproliferative disorder?

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) constitutes a heterogeneous group of diseases. We summarize the experience of our hospital, one of Spain's largest series of renal (294), liver (47) and allogeneic stem cell transplants (67), where four cases of PTLD have developed related to complex viral infections. METHODS: Case 1 was a 24-month-old boy diagnosed with acute lymphoblastic leukemia who underwent allogeneic stem-cell transplantation (SCT). He was seropositive for Epstein-Barr virus (EBV) and developed an aggressive Bcell non-Hodgkin's lymphoma (B-NHL) related to EBV reactivation and human herpesvirus 6 (HHV-6) infection. Cases 2, 3, and 4 developed after kidney transplantation and were all EBV seronegative. Case 2 had associated cytomegalovirus (CMV) and EBV infection. Cases 3 and 4 only revealed EBV viral load. Cases 1, 3, and 4 progressed rapidly, with fatal outcome. Global incidence of PTLD in our series is 1.1%. CONCLUSION: PTLD is a rare but life-threatening condition. Although EBV plays a clear role in its pathogenesis, other associated viral infections could trigger this situation. Current therapies include rituximab, decreasing immunosuppressive drugs. and conventional chemotherapy.

Could other viruses cause pediatric posttransplant lymphoproliferative disorder?

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) constitutes a heterogeneous group of diseases. We summarize the experience of our hospital, one of Spain's largest series of renal (294), liver (47) and allogeneic stem cell transplants (67), where four cases of PTLD have developed related to complex viral infections. METHODS: Case 1 was a 24-month-old boy diagnosed with acute lymphoblastic leukemia who underwent allogeneic stem-cell transplantation (SCT). He was seropositive for Epstein-Barr virus (EBV) and developed an aggressive Bcell non-Hodgkin's lymphoma (B-NHL) related to EBV reactivation and human herpesvirus 6 (HHV-6) infection. Cases 2, 3, and 4 developed after kidney transplantation and were all EBV seronegative. Case 2 had associated cytomegalovirus (CMV) and EBV infection. Cases 3 and 4 only revealed EBV viral load. Cases 1, 3, and 4 progressed rapidly, with fatal outcome. Global incidence of PTLD in our series is 1.1%. CONCLUSION: PTLD is a rare but life-threatening condition. Although EBV plays a clear role in its pathogenesis, other associated viral infections could trigger this situation. Current therapies include rituximab, decreasing immunosuppressive drugs. and conventional chemotherapy (AU)

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