Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.

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.

The relationship between second-hand smoke and wheezing in infants from Córdoba, Argentina

Background: Wheezing constitutes a common respiratory symptom in children, and several risk factors have been associated with the prevalence of recurrent wheezing (RW) and its severity, especially viral respiratory infections and second-hand smoke (SHS) exposure. Objective: To analyze the relationship between smoking patterns in the home and wheezing, in infants from the city of Córdoba, Argentina, during their first year of life. Methods: Parents of infants were invited to complete a standardized questionnaire voluntarily and anonymously (WQ-P1-EISL). Wheezing in the first 12 months of life was classified as occasional wheezing (OW) when having one or two episodes during the first 12 months of life; recurrent wheezing (RW) if having three or more, and more frequent wheezing (MFW) ≥ 6 episodes. Results: 409 infants (39.0%) had one or more episodes of wheezing in the first 12 months. Of these, 214 infants (52.3%) presented occasional wheezing (OW), 135 (33%) had recurrent wheezing (RW), and 60 (14.7%) more frequent wheezing (MFW). SHS was significantly related to MFW, especially if the mother smoked (OR = 2.7; IC 95%: 1.4-5.18; p = 0.0009) or if she smoked during pregnancy (OR = 4; IC 95%: 1.8-8.5; p = 0.0001). This group of MFW was also associated with SHS as well as having been to the emergency room for wheezing (40.87%, p = 0.0056). Conclusion: The results indicate that second-hand tobacco smoke is a significant risk factor for the presence of wheezing in infants, and for its severity. Our findings have significant implications for public health, as smoking is a modifiable behavior

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The relationship between second-hand smoke and wheezing in infants from Córdoba, Argentina.

BACKGROUND: Wheezing constitutes a common respiratory symptom in children, and several risk factors have been associated with the prevalence of recurrent wheezing (RW) and its severity, especially viral respiratory infections and second-hand smoke (SHS) exposure. OBJECTIVE: To analyze the relationship between smoking patterns in the home and wheezing, in infants from the city of Córdoba, Argentina, during their first year of life. METHODS: Parents of infants were invited to complete a standardized questionnaire voluntarily and anonymously (WQ-P1-EISL). Wheezing in the first 12 months of life was classified as occasional wheezing (OW) when having one or two episodes during the first 12 months of life; recurrent wheezing (RW) if having three or more, and more frequent wheezing (MFW) ≥6 episodes. RESULTS: 409 infants (39.0%) had one or more episodes of wheezing in the first 12 months. Of these, 214 infants (52.3%) presented occasional wheezing (OW), 135 (33%) had recurrent wheezing (RW), and 60 (14.7%) more frequent wheezing (MFW). SHS was significantly related to MFW, especially if the mother smoked (OR=2.7; IC 95%: 1.4-5.18; p=0.0009) or if she smoked during pregnancy (OR=4; IC 95%: 1.8-8.5; p=0.0001). This group of MFW was also associated with SHS as well as having been to the emergency room for wheezing (40.87%, p=0.0056). CONCLUSION: The results indicate that second-hand tobacco smoke is a significant risk factor for the presence of wheezing in infants, and for its severity. Our findings have significant implications for public health, as smoking is a modifiable behavior.

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.

Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years

Background: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. Patients and methods 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. Results: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. Conclusions: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain

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Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years.

BACKGROUND: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. PATIENTS AND METHODS: 1664 lymphoma cases (1983-2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. RESULTS: In Spain, the ASRw0-14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry-based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. CONCLUSIONS: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain.

Risk factors for recurrent wheezing in the first year of life in the city of Córdoba, Argentina

BACKGROUND: Wheezing is a very common respiratory symptom in infants. The prevalence of wheezing in infants, conducted in developed countries shows prevalence rates ranging between 20% and 30%. However, we do not know the risk factors in our population of wheezing infants. METHODS: A standardised written questionnaire (WQ-P1-EISL) in infants between 12 and 18 months of age residing in the city of Cordoba was used; population/sample included 1031 infants. Recurrent wheezing (RW) was defined as three or more episodes of wheezing reported by the parents during the first 12 months of life. Data obtained were coded in Epi-Info™ (version 7) and statistically analysed with SPSS (version 17.5) software in Spanish. Parametric tests (one-way ANOVA) were performed for identifying significantly associated variables. RESULTS: The prevalence of wheezing infants was 39.7%; recurrent wheezing 33%; and severe wheezing 14.7%; 13.7% had pneumonia before the first year and of these 6.3% were hospitalised, multiple variables as risk factors for wheezing were found such as: >6 high airway infections and bronchiolitis in the first three months of life, smokers who smoke in the home among other risk factors and protective factors in those who have an elevated socioeconomic status. CONCLUSION: It is known that persistent respiratory problems in children due to low socioeconomic status is a risk factor for wheezing, pneumonia and could be a determining factor in the prevalence and severity of RW in infants. Research suggests that there are areas for improvement in the implementation of new educational strategies

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Risk factors for recurrent wheezing in the first year of life in the city of Córdoba, Argentina.

BACKGROUND: Wheezing is a very common respiratory symptom in infants. The prevalence of wheezing in infants, conducted in developed countries shows prevalence rates ranging between 20% and 30%. However, we do not know the risk factors in our population of wheezing infants. METHODS: A standardised written questionnaire (WQ-P1-EISL) in infants between 12 and 18 months of age residing in the city of Cordoba was used; population/sample included 1031 infants. Recurrent wheezing (RW) was defined as three or more episodes of wheezing reported by the parents during the first 12 months of life. Data obtained were coded in Epi-Info™ (version 7) and statistically analysed with SPSS (version 17.5) software in Spanish. Parametric tests (one-way ANOVA) were performed for identifying significantly associated variables. RESULTS: The prevalence of wheezing infants was 39.7%; recurrent wheezing 33%; and severe wheezing 14.7%; 13.7% had pneumonia before the first year and of these 6.3% were hospitalised, multiple variables as risk factors for wheezing were found such as: >6 high airway infections and bronchiolitis in the first three months of life, smokers who smoke in the home among other risk factors and protective factors in those who have an elevated socioeconomic status. CONCLUSION: It is known that persistent respiratory problems in children due to low socioeconomic status is a risk factor for wheezing, pneumonia and could be a determining factor in the prevalence and severity of RW in infants. Research suggests that there are areas for improvement in the implementation of new educational strategies.

Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología / Review of patients studied for coagulopathy in a Hematology/Oncology unit

INTRODUCCIÓN: Los síntomas/signos indicativos de una coagulopatía son un motivo de consulta frecuente en las unidades de Hematología Pediátrica. Tanto la clínica como los antecedentes familiares son fundamentales para el diagnóstico. PACIENTES Y MÉTODOS: Estudio retrospectivo y descriptivo de los pacientes derivados a una consulta de Hematología Pediátrica de un hospital de tercer nivel por posible coagulopatía durante el año 2012. RESULTADOS: Se estudiaron 47 niños. El 61,7% no había presentado previamente sangrado. El motivo de derivación más frecuente fue un tiempo de tromboplastina parcial activada alargado sin hemorragia (42,5%); de estos, un 25% fue diagnosticado de una coagulopatía con riesgo real de sangrado. En los pacientes derivados por tiempo de tromboplastina parcial activada alargado con clínica hemorrágica se detecta una coagulopatía con riesgo real de sangrado con mayor frecuencia (41,7%). En los niños con antecedentes familiares de sangrado se diagnostica con más frecuencia una coagulopatía con riesgo real de sangrado: 37,5 vs. 14,3% (niños sin antecedentes familiares). Los diagnósticos han sido: sano (48,9%), enfermedad de von Willebrand tipo1 (19,1%), déficit de factor XII (19,1%), déficit de factor XI(4,2%), déficit de precalicreína/cininógeno de alto peso molecular (2,1%), déficit adquirido de factor X (2,1%) y déficit de factor IX (2,1%). CONCLUSIONES: Los antecedentes personales y familiares de sangrado orientan el diagnóstico de una coagulopatía. El motivo de derivación debería basarse en mayor medida en la clínica hemorrágica y no solo en un tiempo de laboratorio alterado. Los diagnósticos más frecuentes han sido enfermedad de von Willebrand tipo 1 y déficit de factor XII

INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor XII deficiency (19.1%), factor XI deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor X (2.1%), and factor IXdeficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor XII deficiency

[Review of patients studied for coagulopathy in a Hematology/Oncology unit]. / Revisión de los pacientes estudiados por coagulopatía en una unidad de Oncohematología.

INTRODUCTION: Symptoms/signs suggestive of coagulopathy is a frequent complaint in Pediatric Hematology units. Both the clinical and family history are essential for diagnosis. PATIENTS AND METHODS: Retrospective and descriptive study of patients referred to a Pediatric Hematology unit of a tertiary hospital for possible coagulopathy during 2012. RESULTS: A total of 47 children were studied, of whom 61.7% had not previously suffered bleeding. The most frequent reason for referral was an eloganted activated partial thromboplastin time without any hemorrhage (42.5%), of these, 25% were diagnosed of a coagulopathy with a real risk of bleeding. While patients referred due to an eloganted activated partial thromboplastin time with bleeding more frequently (41.7%) have a coagulopathy with a real risk of bleeding. Children with a family history of bleeding are diagnosed more frequently with a coagulopathy with a real risk of bleeding: 37.5% (family history) vs. 14.3% (without). The most frequent diagnoses were: healthy children (48.9%), von Willebrand type 1 disease (19.1%), factor xii deficiency (19.1%), factor xi deficiency (4.2%), prekalikrein/high molecular weight kininogen deficiency (2.1%), acquired deficiency of factor x (2.1%), and factor ix deficiency (2.1%). CONCLUSIONS: A thorough personal and family bleeding history and physical examination are the first steps for a correct differential diagnosis. The reason for referral should be based more on clinical bleeding and not just on an abnormal coagulation time. The most frequent diagnoses were type 1 von Willebrand disease and factor xii deficiency.

A prospective biological study in relation to a family with Li-Fraumeni syndrome

INTRODUCTION: The Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disorder associated with different tumor types in childhood and young adults. Approximately 70% of LFS cases contain germline mutations in the TP53 gene. We report a case of a family suspected of LFS. MATERIALS AND METHODS: The proband and four members of the family affected were diagnosed with cancer at an early age and they all died except the proband. Exons 5-9 from TP53 gene were analysed by direct amplification and sequencing in 7 family members. RESULTS: The analysis revealed a germline nonsense mutation in exon 8 at codon 306 of the codified region of the TP53 gene, causing a change of CGA to TGA (Arg→Stop) in the proband, her mother, her cousin and her maternal uncle. Proband's maternal grandmother and aunt do not have the mutation. CONCLUSIONS: The members of this family that were studied meet the criteria of classic LFS and the described mutation increases their susceptibility to develop cancer. The proband's maternal grandfather died of lung cancer in 1993, and we believe that he was the carrier of the mutation in this family (AU)

SU-E-T-264: New Concrete Designed and Evaluation for Megavoltage X Radiotherapy Facilities (CONTEK-RFH2).

PURPOSE: The most common material for shielding is concrete, which can be made using various materials of different densities as aggregates. New techniques in radiotherapy, as IMRT and VMAT, require more monitor units and it is important to develop specifically designed shielding materials. METHODS: Arraela S.L. has developed new concrete (CONTEK®-RFH2), which is made from an arid with a high percentage in iron (> 60%), and using the suitable sieve size, enables optimum compaction of the material and a high mass density, about 4.1-4.2 g/cm3 . Moreover, aluminate cement, used as base, gives high resistance to high temperatures what makes this product be structurally resistant to temperatures up to 1200 ° C. The measurements were made in a LINAC Elekta SL18 to energies 6MV and 15 MV with a field size of 10×10 cm2 for concrete samples in the form of tile 25cm×25cm with variable thickness. RESULTS: The linear attenuation coefficient, µm, was determined for each energy by fitting the data to Eq. 1, where Xxm is the exposure in air behind a thickness xm of the material, and X0 is the exposure in the absence of shielding. These results are compared with the ordinary concrete (2.35 g cm-3) for 6MV and 15MV energies (Ref. NCRP Report No.151). Results are tabulated in Table1. Results of attenuation are compared with ordinary concrete in Fig. 1. CONCLUSIONS: The new concrete CONTEK®-RFH2 increases photon attenuation and reduces the size of a shielded wall. A very high percentage in iron and a suitablesieve size approximately double the density of ordinary concrete. High mass attenuation coefficient makes this concrete an extremely desirable material for use in radiation facilities as shielding material for photon beam, and for upgrading facilities designed for less energy or less workload.

From the limits of the classical model of sensitometric curves to a realistic model based on the percolation theory for GafChromic EBT films.

PURPOSE: Modern radiotherapy uses complex treatments that necessitate more complex quality assurance procedures. As a continuous medium, GafChromic EBT films offer suitable features for such verification. However, its sensitometric curve is not fully understood in terms of classical theoretical models. In fact, measured optical densities and those predicted by the classical models differ significantly. This difference increases systematically with wider dose ranges. Thus, achieving the accuracy required for intensity-modulated radiotherapy (IMRT) by classical methods is not possible, plecluding their use. As a result, experimental parametrizations, such as polynomial fits, are replacing phenomenological expressions in modern investigations. This article focuses on identifying new theoretical ways to describe sensitometric curves and on evaluating the quality of fit for experimental data based on four proposed models. METHODS: A whole mathematical formalism starting with a geometrical version of the classical theory is used to develop new expressions for the sensitometric curves. General results from the percolation theory are also used. A flat-bed-scanner-based method was chosen for the film analysis. Different tests were performed, such as consistency of the numeric results for the proposed model and double examination using data from independent researchers. RESULTS: Results show that the percolation-theory-based model provides the best theoretical explanation for the sensitometric behavior of GafChromic films. The different sizes of active centers or monomer crystals of the film are the basis of this model, allowing acquisition of information about the internal structure of the films. Values for the mean size of the active centers were obtained in accordance with technical specifications. In this model, the dynamics of the interaction between the active centers of GafChromic film and radiation is also characterized by means of its interaction cross-section value. CONCLUSIONS: The percolation model fulfills the accuracy requirements for quality-control procedures when large ranges of doses are used and offers a physical explanation for the film response.

Mediastinitis secundaria a perforación esofágica yatrogénica / No disponible

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Role of food allergy in asthma in childhood.

Atopy is the major predisposing factor for asthma identified up to now, and allergen exposure, particularly indoor allergens, is considered as a causal factor for asthma. Food allergy is frequently underestimated in association with asthma, however food allergy has been shown to trigger or exacerbate broncho-obstruction in 2 to 8.5% of children with asthma. There is also evidence that double-blind placebo-controlled oral challenge is able to increase unspecific bronchial hyperresponsiveness. Sensitization to food can occur early in life involving T cell response, mainly of the Th2 phenotype, but also IgE-mediated hypersensitivity. Moreover, it has been shown that sensitization to food allergens early in life is a risk factor for sensitization to inhalent allergens and respiratory symptoms later on. Epidemiological studies suggest that changes in the dietary composition, such as trans-fatty acids, could be involved in the increase of asthma prevalence. The introduction of formula during the first trimester of life increases the risk of having asthma. The diagnosis of food allergy associated with asthma is not easy, nevertheless is important for allergists, pulmonologists and paediatricians to consider food allergy in children with respiratory symptoms, especially when asthma symptoms start early in life and when they are associated with other manifestations of food allergy. Children sensitized to cow's milk proteins and also having atopic eczema are at higher risk for asthma. Since avoidance of the offending food is the first step in the management of children with asthma associated with food allergy, a careful identification should be done in order to avoid unnecessary elimination of foods.

Evaluation of heart involvement in gamma-sarcoglycanopathy (LGMD2C). A study of ten patients.

Thorough non-invasive cardiovascular studies were conducted in a series of ten gamma-sarcoglycanopathy Gypsy patients with the founder C283Y mutation in 13q12. Results were compared with those obtained in an age-matched group of normal boys and girls. The studies included electrocardiographic and echocardiographic evaluations using pulsed wave Doppler tissue imaging to assess regional diastolic function and myocardial velocities at various levels. This study confirms the significant electrocardiographic abnormalities described in previous studies. Furthermore, measurement of myocardial velocity at different levels demonstrated an abnormal relaxation pattern in the tricuspid annulus in four of the oldest patients, which strongly suggests intrinsic myocardial involvement of the right ventricle. To our knowledge, these specific studies have not been previously performed in a clinically and genetically homogeneous group of gamma-sarcoglycanopathy patients and suggest primary myocardial involvement probably due to gamma-sarcoglycan deficiency in cardiac muscle fibres. Our results could be of interest in the follow-up of these patients and the prevention and treatment of late cardiological complications.

A novel missense mutation (W797R) in the myophosphorylase gene in Spanish patients with McArdle disease.

OBJECTIVE: To investigate the degree of genetic heterogeneity of myophosphorylase deficiency (McArdle disease) in Spain through molecular studies of 10 new patients. DESIGN: The coding sequence of the entire myophosphorylase gene was sequenced in DNA extracted from muscle and blood. Restriction fragment length polymorphism analysis of polymerase chain reaction fragments was used to confirm and simplify detection of a novel mutation. SETTING: A collaborative study between 2 university laboratories in Spain and the United States. RESULTS: Five of the 10 patients harbored a novel missense mutation in exon 20, converting a tryptophan to an arginine (W797R). Three patients were homozygous for the "common" R49X mutation, and the remaining 2 patients were compound heterozygotes for R49X and a previously described missense mutation, G204S. CONCLUSIONS: The W797R missense mutation is the third novel mutation to be identified among Spanish patients. Its relative frequency suggests that it should be added to the R49X mutation in the molecular screening of McArdle disease in Spain.

Adult glycogenosis II with paracrystalline mitochondrial inclusions and Hirano bodies in skeletal muscle.

Hirano bodies constitute eosinophilic intracytoplasmic inclusions, typically seen in the central nervous system, where they are related to senility and certain dementias such as Alzheimer's disease or the Parkinson-dementia complex. They have been found in different tissues of experimental animals and, on rare occasions, in extraocular muscles of elderly individuals. However, to our knowledge they have not been described in skeletal muscle in locations other than extraocular muscles or associated with muscle pathology. Glycogenosis II or Pompe's disease, is a metabolic disorder caused by acid maltase deficiency and is characterized by glycogen accumulation in lysosomes in various tissues, including skeletal muscle. There are three clinical forms depending on age at onset, the most frequent being the childhood form. We present the histopathological and ultrastructural findings of a muscle biopsy performed in a case of the adult form of glycogenosis II which showed, in addition to characteristic lysosomal glycogen storage, paracrystalline mitochondrial inclusions and, as an exceptional finding, intracytoplasmic Hirano bodies in some muscle fibres.