The paediatric cancer clinical research landscape in Spain: a 13-year multicentre experience of the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. METHODS: Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. RESULTS: Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. CONCLUSIONS: The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barriers to accessing new drugs for all ranges of age and cancer diseases remain. Additionally, opportunities to improve academic research are still required in Spain.

Measurement of percentage dose at the surface for a 6 MV photon beam.

AIM: To evaluate if a radiochromic film (RF) Gafchromic EBT3 is suitable for surface dose measurements of radiotherapy treatments performed with a 6 MV linear accelerator. Two aspects of RF were analyzed, beam energy dependence and surface dose determination. BACKGROUND: The measurements done at the surface or near the radiation source are done without charged electronic equilibrium and also have contribution of electron contamination. The detectors used for these measurements should not alter the dose to the target. To counteract these dosimetric problems it is proposed to do the measurements with radiochromic films which are thin detectors and have tissue equivalent properties. MATERIALS AND METHODS: The measurements were done using a Novalis linear accelerator (LINAC) with nominal energy of 6 MV. To determine the surface dose, the total scatter factors (TSF) of three different field sizes were measured in a water phantom at 5 cm depth. Energy dependence of EBT3 was studied at three different depths, using a solid water phantom. The surface measurements were done with the RF for the same field sizes of the TSF measurements. The value of the percentage depth dose was calculated normalizing the doses measured in the RF with the LINAC output, at 5 cm depth, and the TSF. RESULTS: The radiochromic films showed almost energy independence, the differences between the curves are 1.7% and 1.8% for the 1.5 cm and 10 cm depth, respectively. The percentage depth doses values at the surface measured for the 10 cm × 10 cm, 5 cm × 5 cm and 1 cm × 1 cm were 26.1 ± 1.3%, 21.3 ± 2.4% and 20.2 ± 2.6%, respectively. CONCLUSIONS: The RF-EBT3 seems to be a detector suitable for measurements of the dose at the surface. This suggests that RF-EBT3 films might be good candidates as detectors for in vivo dosimetry.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.

INTRODUCTION: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. METHODS: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. RESULTS: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. CONCLUSIONS: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Bronchoalveolar lavage to evaluate new pulmonary infiltrates in allogeneic hematopoietic stem cell transplant recipients: impact on antimicrobial optimization.

BACKGROUND: Pulmonary complications cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant (AHSCT). Bronchoscopy with targeted bronchoalveolar lavage (BAL) is often used in AHSCT patients with suspected lower respiratory tract infection (LRTI) to help guide management. AIM: To evaluate how positive BAL results change antimicrobial management of AHSCT recipients with suspected LRTI. METHODS: We performed a retrospective review of BAL results from January 2014 to July 2016 for 54 AHSCT recipients. A positive BAL was determined by culture, multiplex polymerase chain reaction (PCR), Aspergillus galactomannan antigen (AGA), and cytology. FINDINGS: BAL was positive for infectious etiologies in 63%, and antimicrobials were adjusted in 48/54 (89%) of patients. Antibacterial escalation was predicted by a positive BAL bacterial culture (OR 7.61, P=0.017). Antibiotic de-escalation was more likely with an elevated AGA (OR 3.86, P=0.035). Antiviral initiation was more likely with positive BAL multiplex PCR (OR 17.33, P=0.010). Antifungals were more likely to be escalated or changed with an elevated AGA (OR 4.33, P=0.020). The patients with a negative BAL were more likely to be started on steroids (OR 0.19, P= 0.043). CONCLUSIONS: BAL was helpful to determine the etiology of pulmonary complications and optimize antimicrobials. The addition of AGA and multiplex PCR to standard BAL significantly impacted de-escalating antibiotics and adjusting antifungals to provide adequate coverage. The association with an elevated AGA with antibacterial de-escalation highlights a new role for BAL in antimicrobial optimization.

Dos casos de liquen plano con tratamiento de hipnosis: Report of two cases / Lichen planus submitted to hypnosis treatment

El liquen plano es una alteración que afecta la piel, mucosas oral y genital, el cuero cabelludo y uñas. Su etiología incluye factores genéticos, inmunológicos y estrés; puede evolucionar por años y adquirir carácter crónico, presenta alta resistencia a los tratamientos de todo tipo. Se presentan dos casos con diagnósticos de liquen plano múltiple, sometidos a tratamiento de hipnosis con sugerencias terapéuticas directas, en tres direcciones: eliminación de las lesiones, marcas y prevención de nuevos brotes. Se administró una sesión por semana. El tratamiento fue de diez y seis sesiones, respectivamente. Se logró la remisión de los síntomas en ambos casos, el seguimiento no fue suficiente para evaluar la eliminación de las máculas residuales. Aún cuando el control de variables y el número de casos, no permite asegurarlo de manera científica, la hipnosis se perfila como un proceder que puede ser efectivo, en el tratamiento del liquen plano crónico.

Lichen planus is an alteration that affects the skin, oral and genital mucous membranes, the scalp and nails. Its etiology is imprecise, it includes genetic, immunological and stress-related factors, it can evolve for years and acquire the characteristic of a chronic disorder, it has a high resistance to treatments, psychotherapeutic methods have not shown efficiency either. Two cases with a diagnosis of multiple lichen planus submitted to hypnosis treatment with direct therapeutic suggestions, in three directions: elimination of lesions, marks, and prevention of new outbreaks are presented. One session per week was administered. The treatment lasted ten and six sessions respectively, the evolution was favorable, the remission of the symptoms was achieved in both cases, which had not been achieved with any previous treatment. The follow-up was not long enough to evaluate the elimination of residual spots. The importance of the cases presented lies in the favorable evolution of both under hypnotherapy, if taken into account their chronic nature and the lack of response to other treatments. Although it can not be ensured scientifically, by the small sample and by the impossibility of controlling variables, that the evolution is a result of the intervention performed, hypnosis is emerging as a procedure that can be effective in the treatment of chronic lichen planus, used as a single procedure or combined with other treatments.

Arthroplasty knee registry of Catalonia: What scientific evidence supports the implantation of our prosthesis? / Registro de artroplastias de rodilla de Cataluña: ¿qué evidencia científica respalda la implantación de nuestras prótesis?

INTRODUCTION: In our environment, it is increasingly necessary to perform an activity based on scientific evidence and the field of prosthetic surgery should be governed by the same principles. The national arthroplasty registries allow us to obtain a large amount of data in order to evaluate this technique. The aim of our study is to analyse the scientific evidence that supports the primary total knee arthroplasties implanted in Catalonian public hospitals, based on the Arthoplasty Registry of Catalonia (RACat) MATERIAL AND METHODS: A review of the literature was carried out on knee prostheses (cruciate retaining, posterior stabilized, constricted and rotational) recorded in RACat between the period 2005-2013 in the following databases: Orthopedic Data Evaluation Panel, PubMed, TripDatabase and Google Scholar. The prostheses implanted in fewer than 10 units (1,358 prostheses corresponding to 62 models) were excluded. RESULTS: 41,947 prostheses (96.86%) were analysed out of 43,305 implanted, corresponding to 74 different models. In 13 models (n = 4,715) (11.24%) no clinical evidence to support their use was found. In the remaining 36 models (n = 13,609) (32.45%), level iv studies were the most predominant evidence. CONCLUSIONS: There was a significant number of implanted prostheses (11.24%) for which no clinical evidence was found. The number of models should be noted, 36 out of 110, with fewer than 10 units implanted. The use of arthroplasty registries has proved an extremely useful tool that allows us to analyse and draw conclusions in order to improve the efficiency of this surgical technique.

Treatment of childhood astrocytomas with irinotecan and cisplatin.

BACKGROUND: Previously we described the outcome of children with spinal cord astrocytoma treated with irinotecan and cisplatin (I/C). We here report the review of the initial institutional experience using this combination for children with low-grade glioma (LGG). PROCEDURE: I/C chemotherapy consisted of weekly cisplatin (30 mg/m2) and irinotecan (50-65 mg/m2) for a total maximum of 16 doses, administered in an outpatient basis. RESULTS: Between November 2002 and December 2009, 46 children (median age 6.3 years; range 0.3-17.7) with glioma were treated. We here report the cohort of 31 patients with LGG. Patients received a median of 16 cycles of I/C (range 8-16). The overall objective response [complete response (CR) + partial response (PR)] and disease control (CR + PR + stable disease) rates to I/C treatment were 6.5% [95% confidence interval (CI), 0.8-21.4%] and 93.5% (95% CI 78.6-99.2%), respectively. Disease control persisted for a median of 65 months. Toxicity was predominantly myelosuppression only seen in heavily pretreated patients. Survival analysis shows 5-year event-free survival (EFS) of 54% and 5-year overall survival (OS) of 80%. CONCLUSION: I/C chemotherapy produced disease control and clinical improvement in a majority of children with low-grade glioma, with manageable toxicity.

Microcalcificaciones y focos ecogénicos puntiformes, ¿qué tan bien sabemos lo que estamos viendo? / Microcalcifications and punctate echogenic foci, how well do we know what we are seeing?

Resumen: La presencia de microcalcificaciones en nódulos tiroideos es un signo muy específico de malignidad, al corresponder a cuerpos de Psammoma. No existen suficientes estudios que demuestren una correlación entre su presencia histológica y su aspecto ecográfico real. Materiales y Métodos: Se seleccionaron todos los nódulos con tamaño mayor a 3 cm puncionados en el Hospital Clínico Universidad Católica entre los años 2010-2015 y se clasificó el aspecto ecográfico según la presencia de 3 tipos de focos ecogénicos con una definición más estricta a lo usual. Se correlacionó lo anterior con hallazgos en biopsias. Resultados: 44 nódulos correspondieron a cáncer papilar de tiroides. Hubo relación estadísticamente significativa entre una nueva definición ecográfica de las microcalcificaciones (focos ecogénicos puntiformes) y la presencia histológica de cuerpos de psamomma. Discusión: Habría una buena correlación entre una definición más estricta y la presencia real de microcalcificaciones en histología, mejorando la alta tasa de sobrediagnóstico advertido recientemente por algunos autores.

Abstract: The presence of microcalcifications in thyroid nodules is a very specific sign of malignancy, as it corresponds to Psammoma bodies. There are not enough studies that demonstrate a correlation between their histological presence and their actual ultrasound appearance. Materials and Methods: All nodules larger than 3 cm punctured at the Universidad Católica Clinical Hospital between 2010-2015 were selected, and the sonographic appearance was classified according to the presence of 3 types of echogenic foci according to a stricter definition than usual. The above was correlated with findings in biopsies. Results: 44 nodules corresponded to papillary thyroid cancer. There was a statistically significant relationship between a new ultrasound definition of the microcalcifications (punctate echogenic foci) and the histological presence of psamomma bodies. Discussion: There would be a good correlation between a stricter definition and the actual presence of microcalcifications in histology, improving the high rate of over diagnosis recently noticed by some authors.

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS).

BACKGROUND: First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients. METHODS: This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734). RESULTS: Forty-three patients were enroled, median age 17 years (range, 3-40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41-74%) with an EFS of 50.0% (95% CI, 36-68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57-100%) and 71.0% (CI, 54-94%); for HR 36.0% (CI, 20-65%) and 29.0% (CI, 15-56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56-97%) and 31.0% for >18 years (95% CI, 15-66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively). CONCLUSIONS: Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.

The tumor suppressor phosphatase and tensin homolog protein (PTEN) is negatively regulated by NF-κb p50 homodimers and involves histone 3 methylation/deacetylation in UROtsa cells chronically exposed to monomethylarsonous acid.

UROtsa cells have been accepted as a model to study carcinogenicity mechanisms of arsenic-associated human bladder cancer. In vitro continuous exposure to monomethylarsonous acid (MMAIII), leads UROtsa cells to commit to malignant transformation. In this process, NF-κß-associated inflammatory response seems to play an important role since this transcription factor activates some minutes after cells are exposed in vitro to MMAIII and keeps activated during the cellular malignant transformation. It is known that a slight decrease in the protein phosphatase and tensin homologue (PTEN) gene expression is enough for some cells to become malignantly transformed. Interestingly, this tumor suppressor has been proven to be negatively regulated by NF-κß through binding to its gene promoter. Based on these observations we propose that NF-κß may be involved in arsenic associated carcinogenesis through the negative regulation of PTEN gene expression. Changes in PTEN expression and the binding of p50 NF-κß subunit to PTEN promoter were evaluated in UROtsa cells exposed for 4, 12, 20, or 24 wk to 50nM MMAIII. Results showed that MMAIII induced a significant decrease in PTEN expression around 20 wk exposure to MMAIII,which correlated with increased binding of p50 subunit to the PTEN promoter. Consistent with these results, ChIP assays also showed a significant decrease in H3 acetylation (H3ac) but an increase in the repression marks H3k9me3 and H327me3 in PTEN promoter when compared with not treated cells. These results suggest that the activation of NF-κß by MMAIII may participate in UROtsa cells malignant transformation through the negative regulation of PTEN expression involving p50 homodimers-mediated chromatin remodeling around the PTEN promoter.

Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort.

BACKGROUND/OBJECTIVES: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (⩾15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction <0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction <0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction <0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future.

Assessment of an image-guided neurosurgery system using a head phantom.

OBJECTIVE: To acknowledge the challenges and limitations of image-guided neurosurgery systems, we compared the application accuracy of two different image registration methods for one commercial system. (VectorVision, BrainLab, Germany). METHODS: We used an anthropomorphic head phantom for radiosurgery and a custom built add-on to simulate surgical targets inside the brain during an image-guided neurosurgery. We used two image registration methods, fiducial registration using attachable surface markers for computed tomography (CT) and surface registration using infrared laser face scanning. After simulation, we calculated the three-dimensional (3D) distance between the predicted position of a target, and its actual position using a registered pointer and an infrared camera. Deviations were measured for both superficial fiducial markers and internal surgical targets by five different users. RESULTS: Deviations from the location of fiducial markers after each registration method were 2.15 ± 0.93 mm after CT surface marker registration and 1.25 ± 0.64 mm after infrared face scanner registration. The mean target registration errors were 2.95 ± 1.4 mm using fiducial registration and 2.90 ± 1.3 mm using surface registration. The largest deviations (6.2 mm) were found for the targets in the skull base and posterior cranial fossa. Fiducial deviations and target registration errors were statistically uncorrelated. The total application accuracy was 4.87 ± 0.97 mm after CT surface marker registration and 4.14 ± 0.64 mm after infrared face scanner registration. CONCLUSIONS: Despite others have reported differences, we did not find significant variations between both registration methods for the target registration error, although application accuracy was slightly better after surface face registration. Superficial registration errors, but not the target registration error, can be routinely evaluated in the operating room. Since both errors were uncorrelated, surgeons may neglect the achievable accuracy of the procedure. The described method is recommended to assess application accuracy in the operating room.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Safety of bevacizumab in patients younger than 4 years of age.

PURPOSE: Limited data exist regarding the safety and efficacy of bevacizumab in pediatric patients under the age of 4 years. Here, we report a large cohort of pediatric patients under 4 years of age treated with bevacizumab. METHODS: The primary objective was to document adverse events with a possible relationship to bevacizumab. Patients (n = 16) were identified through retrospective chart review and harbored a variety of conditions (44% central nervous system (CNS) tumors, 31% vascular anomalies, 13% neuroblastoma, 12% other). RESULTS: The median age was 34.3 months (range 4.9-47.3), including five patients <2 years of age. Patients received bevacizumab for a median duration of 6.2 months, alone or with chemotherapy, and a median dose of 9.25 mg/kg (range 7.0-11.8). Partial responses were seen in 19% of patients, and clinical improvements were seen in 69%. Adverse events known to be associated with bevacizumab occurred in 37%. Outcomes observed in this population resemble those reported for bevacizumab in older pediatric patients. The overall pattern and frequency of adverse events observed was similar to those seen in reports of older pediatric patients with a variety of conditions. The highest level of efficacy observed was seen among patients with vascular malformations or with low-grade CNS tumors. CONCLUSIONS: Our results suggest that the use of bevacizumab is safe for the youngest children.

Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

p21-activated kinases (Paks) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1-amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13-amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21(Cip) and decreased expression of cyclin B1. These findings suggest that small-molecule inhibitors of Pak1 may have a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification.

Stereotactic radiosurgery for pediatric patients with intracranial arteriovenous malformations: variables that may affect obliteration time and probability.

INTRODUCTION: It is debatable whether pediatric patients diagnosed with arteriovenous malformations (AVMs) should be treated as adults. Several indexes to classify AVMs have been proposed in the literature, and most try to predict the outcome for each specific treatment. The indexes differ in the variables considered, but they are all based in adult populations. In this study, we analyzed the variables that influence the obliteration time and probability of occurrence in a Mexican pediatric population diagnosed with an AVM and treated with stereotactic radiosurgery (SRS). METHODS: We analyzed 45 pediatric patients (<18 years) with a minimum follow-up of 10 months and a maximum of 112 months. We used logistic regression analysis and Kaplan-Meier curves to evaluate the influence of age, AVM volume, prescribed dose, minimum dose, maximum dose, time of follow-up, sex, previous hemorrhage, venous drainage, treatment technique, previous treatment and location. We also evaluated the predictive power of the following indexes: Spetzler-Martin, RBAS, or K index dose deviation. RESULTS: We found that the radiation technique used may influence the obliteration occurrence (p=0.057). The data suggests that circular arcs are a more efficient treatment technique than dynamic arcs. However, no relationship of dose or volume with treatment technique could be found. Obliteration was also dependent on follow-up time and after three years of follow-up, the obliteration probability decreases (p=0.024). According to Kaplan-Meier analysis, the nidus obliteration time was related with the location according to the Spetzler-Martin index. If the nidus was located in a non-eloquent region, there was a tendency of a shorter obliteration time (p=0.071). CONCLUSION: None of the previously proposed indexes for adults predict obliteration in this pediatric population. Treatment technique, eloquence and follow up time were the only variables that showed influence in obliteration. Since the highest probability of obliteration occurs during the first three years, if the nidus has not been obliterated after this time then another treatment option could be considered.

Results of induction chemotherapy in children older than 18 months with stage-4 neuroblastoma treated with an adaptive-to-response modified N7 protocol (mN7).

PURPOSE: We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol. METHODS: From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs. RESULTS: After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, (123)I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival. CONCLUSIONS: mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival.

Effect of dosimeter type for commissioning small photon beams on calculated dose distribution in stereotactic radiosurgery.

PURPOSE: To assess the impact of the detector used to commission small photon beams on the calculated dose distribution in stereotactic radiosurgery (SRS). METHODS: In this study, six types of detectors were used to characterize small photon beams: three diodes [a silicon stereotactic field diode SFD, a silicon diode SRS, and a silicon diode E], an ionization chamber CC01, and two types of radiochromic film models EBT and EBT2. These detectors were used to characterize circular collimated beams that were generated by a Novalis linear accelerator. This study was conducted in two parts. First, the following dosimetric data, which are of particular interest in SRS, were compared for the different detectors: the total scatter factor (TSF), the tissue phantom ratios (TPRs), and the off-axis ratios (OARs). Second, the commissioned data sets were incorporated into the treatment planning system (TPS) to compare the calculated dose distributions and the dose volume histograms (DVHs) that were obtained using the different detectors. RESULTS: The TSFs data measured by all of the detectors were in good agreement with each other within the respective statistical uncertainties: two exceptions, where the data were systematically below those obtained for the other detectors, were the CC01 results for all of the circular collimators and the EBT2 film results for circular collimators with diameters below 10.0 mm. The OAR results obtained for all of the detectors were in excellent agreement for all of the circular collimators. This observation was supported by the gamma-index test. The largest difference in the TPR data was found for the 4.0 mm circular collimator, followed by the 10.0 and 20.0 mm circular collimators. The results for the calculated dose distributions showed that all of the detectors passed the gamma-index test at 100% for the 3 mm/3% criteria. The aforementioned observation was true regardless of the size of the calculation grid for all of the circular collimators. Finally, the dose volume histogram results were independent of the size of the calculation grid used. CONCLUSIONS: The results of this study showed that all of the studied detectors produced similar commissioned data sets for the TPS dose calculations. However, this result only validated the dose distribution calculation in the TPS and could not be used to assess the dose delivery to the target in which the TFS data were used to calculate the monitor units (the TFS data were not used in the TPS dose distribution calculation). Therefore, this study could not be used to determine the most accurate detector commissioning data set; however, all of the detectors exhibited superior performance for the relative dosimetry of small photon beams.

[Respiratory treatments in neuromuscular disease]. / Tratamientos respiratorios en la enfermedad neuromuscular.

In a previous article, a review was presented of the respiratory pathophysiology of the patient with neuromuscular disease, as well as their clinical evaluation and the major complications causing pulmonary deterioration. This article presents the respiratory treatments required to preserve lung function in neuromuscular disease as long as possible, as well as in special situations (respiratory infections, spinal curvature surgery, etc.). Special emphasis is made on the use of non-invasive ventilation, which is changing the natural history of many of these diseases. The increase in survival and life expectancy of these children means that they can continue their clinical care in adult units. The transition from pediatric care must be an active, timely and progressive process. It may be slightly stressful for the patient before the adaptation to this new environment, with multidisciplinary care always being maintained.