Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood.

Background: Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time. Material and methods: Multicenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020). Results: Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3-18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2-24 years]. Six patients died, the median age was 13 years [range, 6-24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6-32 years]. None of them have developed myeloblastic syndrome or cancer. Conclusions: DC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.

“Doctora, me ha salido un huevo en la cabeza”. A propósito de dos casos / “Doctor, I have a bump on my head. Two cases”

El granuloma eosinófilo es un tipo de histiocitosis de células de Langerhans que afecta exclusivamente al hueso. Puede ser uni o multifocal, siendo la forma unifocal la más habitual. El cráneo es el hueso más afectado en niños, y es más frecuente en niños que en niñas, entre los 5 y 10 años. La radiografía convencional es el método diagnóstico más usado visualizando imágenes osteolíticas características de esta patología, aunque se precisa de una confirmación histológica para realizar el diagnóstico definitivo. Se describen dos casos de granuloma eosinófilo (AU)

Eosinophilic granuloma is a Langerhans cell histiocytosis of the bone. Presentacion of eosinophilic granuloma with a single (monostotic) bone lesion is more common than multiple (polyostotic) bone lesions. The most commonly involved bone is the skull in children. In childhood presentations, prevalence is greater in males and it is most common in children 5 to 10 years of age. Conventional radiograpshs have served as the primary imaginng method used to identify LCH lesions. Histologic confirmation is necessary for the diagnosis. (AU)

Relevancia de la cuantificación en los estudios PET cerebrales con 18F-FDG / Relevance of quantification in brain PET studies with 18F-FDG

La inclusión de la PET 18F-FDG como biomarcador en los criterios de diagnóstico clínico de enfermedades neurodegenerativas y su indicación en el estudio precirugía en la epilepsia resistente a los fármacos permiten mejorar la especificidad del diagnóstico. La interpretación clásica de los estudios PET neurológicos se ha abordado de forma cualitativa, aunque en la última década hemos sido testigos del auge en los sistemas de evaluación cuantitativa. Este desarrollo técnico es de vital importancia en la práctica clínica, ya que mejora la especificidad y la reproducibilidad y reduce el efecto dependiente del observador derivado del análisis visual. Consideramos que es conveniente exponer la complejidad de las técnicas de procesamiento de imagen empleadas, lo que permitirá al especialista en Medicina Nuclear conocer sus ventajas e inconvenientes a la hora de incluirlas en la práctica clínica diaria

The inclusion of 18F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice

Relevance of quantification in brain PET studies with 18F-FDG. / Relevancia de la cuantificación en los estudios PET cerebrales con 18F-FDG.

The inclusion of 18F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice.

Capillary electrophoresis and mutational images of hemoglobin sendagi [Β42 (CD1) PHE → VAL; HBB: C.127T→G].

We report two cases of hemoglobin Sendagi in a Romanian family residing in Spain: a four-year-old boy and his mother, who had been previously diagnosed with another type of congenital hemolytic anemia and had undergone splenectomy in her country during childhood. The unstable hemoglobin variant, hemoglobin Sendagi, is characterized by decreased oxygen affinity caused by replacement of one of the critical amino acid residues, phenylalanine beta 42 (CD1) of the beta-chain, with valine in the heme pocket, resulting in methemoglobin formation. As a result of migratory movements in Europe, new disease-causing hemoglobin variants are emerging in our country. Here, capillary electrophoresis enabled the identification of the variant and a molecular study was used to establish an accurate diagnosis.

Rotura extracapsular de prótesis mamaria imitando recidiva neoplásica en PET/TC con 18F-FDG / Extracapsular breast implant rupture mimicking local cancer recurrence on 18F-FDG PET/CT

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Utilidad del estudio metabólico cerebral con PET/TC 18F-fluorodeoxiglucosa para descartar estado vegetativo / The role of 18-F-fluorodeoxyglucose PET/CT in ruling out vegetative state

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Neuropatías y moda en la adolescencia: presentación de 2 casos clínicos / Neuropathy and style in adolescence: Presentation of two cases

Introducción: Las neuropatías localizadas adquiridas, no posquirúrgicas ni postraumáticas (excluida la afectación de pares craneales), son raras en la infancia. Se presentan 2 casos clínicos de adolescentes con neuropatía periférica secundaria a fenómenos compresivos en relación con hábitos estéticos. Casos clínicos: El caso 1 corresponde a una niña de 13 años con neuropatía del ciático poplíteo externo; presenta una pérdida ponderal en un breve periodo de tiempo y practica ejercicio físico intenso a diario. El caso 2 corresponde a una niña de 14 años con meralgia parestésica del nervio femorocutáneo; habitualmente viste pantalones elásticos ajustados. Conclusiones: Ambos casos presentan neuropatías periféricas debido a fenómenos compresivos, favorecidos por la pérdida de peso, el ejercicio físico y el uso de ropa ajustada; ponen de manifiesto los peligros de algunos hábitos estéticos y relacionados con la moda y pueden ocultar otras patologías subyacentes, como trastornos de la conducta alimentaria. El tratamiento conservador es efectivo en la mayoría de los casos, pero en casos refractarios puede desarrollarse una discapacidad, por lo que es importante su identificación precoz (AU)

Introduction: Acquire neuropathies with different post-surgical or post-traumatic etiology (excluding cranial nerves affection) are uncommon in children. Two cases of peripherical neuropathy in teenagers caused by compressive phenomenon as a consequence of aesthetic habits are presented. Clinical cases: Case 1: a 13 year old patient with external popliteal sciatic neuropathy. An important weight loss in few months is referred associated with intense physical activity. Case 2: a 14 year old patient with meralgia paresthetica. She usually wears 'skinny jeans'. Conclusions: Both cases present peripheral neuropathies in teenagers, due to compressive phenomenons, increased by diet, weight loss and tight-fitting clothes. These cases remind us the dangerous effect of aesthetic habits and fashion which can hide important diseases like alimentary disorders. Conservative treatment is effective in most cases, but an early diagnosis is needed because of the important disability they can cause in some refractory cases (AU)

The Epstein-Barr Virus (EBV) in T Cell and NK Cell Lymphomas: Time for a Reassessment.

While Epstein-Barr virus (EBV) was initially discovered and characterized as an oncogenic virus in B cell neoplasms, it also plays a complex and multifaceted role in T/NK cell lymphomas. In B cell lymphomas, EBV-encoded proteins have been shown to directly promote immortalization and proliferation through stimulation of the NF-κB pathway and increased expression of anti-apoptotic genes. In the context of mature T/NK lymphomas (MTNKL), with the possible exception on extranodal NK/T cell lymphoma (ENKTL), the virus likely plays a more diverse and nuanced role. EBV has been shown to shape the tumor microenvironment by promoting Th2-skewed T cell responses and by increasing the expression of the immune checkpoint ligand PD-L1. The type of cell infected, the amount of plasma EBV DNA, and the degree of viral lytic replication have all been proposed to have prognostic value in T/NK cell lymphomas. Latency patterns of EBV infection have been defined using EBV-infected B cell models and have not been definitively established in T/NK cell lymphomas. Identifying the expression profile of EBV lytic proteins could allow for individualized therapy with the use of antiviral medications. More work needs to be done to determine whether EBV-associated MTNKL have distinct biological and clinical features, which can be leveraged for risk stratification, disease monitoring, and therapeutic purposes.

Immunotherapy with liposome-bound TRAIL overcomes partial protection to soluble TRAIL-induced apoptosis offered by down-regulation of Bim in leukemic cells

Purpose. Human Apo2-Ligand/TRAIL secreted by natural killer cells and cytotoxic T lymphocytes plays an important role immunosurveillance controlling tumor growth and metastasis. Moreover, the fact that Apo2L/TRAIL is capable of inducing cell death in tumor cells but not in normal cells makes this death ligand a promising anti-tumor agent. Previous data from our group demonstrated that Apo2L/TRAIL was physiologically released as transmembrane protein inserted in lipid vesicles, called exosomes. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) resembling the natural exosomes, greatly improved Apo2L/TRAIL activity and were able to induce apoptosis in hematological malignancies. In this study, we have deepened in the underlying mechanism of action of LUV-TRAIL in hematologic cells. Methods/patients. Cytotoxic ability of LUV-TRAIL was assessed on Jurkat cells either over-expressing the anti-apoptotic protein Mcl1 or down-regulating the pro-apoptotic protein Bim previously generated in our laboratory. We also tested LUV-TRAIL cytotoxic ability against primary human leukemic cells from T-cell ALL patient. Results. Silencing Bim but not Mcl-1 over-expression partially protects Jurkat cells from apoptosis induced by sTRAIL. LUV-TRAIL induced caspase-8 and caspase-3 activation and killed Jurkat-Mcl1 and Jurkat-shBim more efficiently than sTRAIL independently of the mitochondrial pathway. On the other hand, LUV-TRAIL were clearly more cytotoxic against primary leukemic cells from a T-cell ALL patient than sTRAIL. Conclusion. Tethering Apo2L/TRAIL to the surface of lipid nanoparticles greatly increases its bioactivity and could be of potential use in anti-tumor therapeutics (AU)

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Immunotherapy with liposome-bound TRAIL overcomes partial protection to soluble TRAIL-induced apoptosis offered by down-regulation of Bim in leukemic cells.

PURPOSE: Human Apo2-Ligand/TRAIL secreted by natural killer cells and cytotoxic T lymphocytes plays an important role immunosurveillance controlling tumor growth and metastasis. Moreover, the fact that Apo2L/TRAIL is capable of inducing cell death in tumor cells but not in normal cells makes this death ligand a promising anti-tumor agent. Previous data from our group demonstrated that Apo2L/TRAIL was physiologically released as transmembrane protein inserted in lipid vesicles, called exosomes. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) resembling the natural exosomes, greatly improved Apo2L/TRAIL activity and were able to induce apoptosis in hematological malignancies. In this study, we have deepened in the underlying mechanism of action of LUV-TRAIL in hematologic cells. METHODS/PATIENTS: Cytotoxic ability of LUV-TRAIL was assessed on Jurkat cells either over-expressing the anti-apoptotic protein Mcl1 or down-regulating the pro-apoptotic protein Bim previously generated in our laboratory. We also tested LUV-TRAIL cytotoxic ability against primary human leukemic cells from T-cell ALL patient. RESULTS: Silencing Bim but not Mcl-1 over-expression partially protects Jurkat cells from apoptosis induced by sTRAIL. LUV-TRAIL induced caspase-8 and caspase-3 activation and killed Jurkat-Mcl1 and Jurkat-shBim more efficiently than sTRAIL independently of the mitochondrial pathway. On the other hand, LUV-TRAIL were clearly more cytotoxic against primary leukemic cells from a T-cell ALL patient than sTRAIL. CONCLUSION: Tethering Apo2L/TRAIL to the surface of lipid nanoparticles greatly increases its bioactivity and could be of potential use in anti-tumor therapeutics.

Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients with locally advanced colon cancer.

AIM: Preoperative chemotherapy followed by radical surgery is an attractive treatment for locally advanced colon cancer (LACC) given the promising results of this approach in other locally advanced tumours. The study evaluates the outcome and treatment-related complications of perioperative oxaliplatin- and capecitabine-based chemotherapy and surgery for clinical Stage III colon cancer. METHOD: Twenty-two consecutive patients with a CT-staged LACC were included. All were staged at baseline and before surgery. Surgery-related complications and oncological outcome were determined. RESULTS: Toxicity was manageable, with 19/22 patients completing the planned chemotherapy protocol. The median time from initial diagnosis to surgery was 65.5 days. The median time from the end of chemotherapy to surgery was 22 days. After neoadjuvant treatment, tumour reduction of 69.5% was observed by CT scan and a 59.9% decrease of SUVmax (standard uptake value) was achieved on positron emission tomography/CT. No progressive disease was reported during preoperative chemotherapy and surgery was performed in all 22 patients. Four patients developed postoperative complications. After a median postoperative follow-up of 14.4 months, the actuarial overall and disease-free survival rates were 100 and 90%. CONCLUSION: Neoadjuvant chemotherapy followed by surgery and chemotherapy for LACC is safe without apparent increase of early and medium-term complications.

Aportación del tiempo de vuelo y de la modelización de la respuesta a una fuente puntual a las características de funcionamiento del tomógrafo PET/TAC Biograph mCT / Contribution of time of flight and point spread function modeling to the performance characteristics of the PET/CT Biograph mCT scanner

Objetivo. Caracterizar el funcionamiento del tomógrafo PET/TAC Biograph mCT TrueV que incorpora el tiempo de vuelo (TOF) y modeliza la respuesta a una fuente puntual (PSF). Material y métodos. El tomógrafo combina un TAC de 64 cortes y un PET que reconstruye tomográficamente con TOF y PSF. Las características de funcionamiento PET se evaluaron siguiendo el estándar NEMA NU-2-2007, ampliando algunas pruebas. Adicionalmente se evaluaron diferentes algoritmos de reconstrucción y se midieron la radiación intrínseca y la uniformidad tomográfica. Resultados. La resolución espacial (FWHM) a 1 y 10cm del eje fue de 4,4 y 5,3mm, mejorando al introducir la PSF a 2,6 y 2,5mm. La sensibilidad fue de 10,9 y 10,2 kcps/MBq a 0 y 10cm del eje. La fracción de dispersión fue inferior al 34% a bajas concentraciones y la tasa de sucesos equivalentes al ruido (NECR) fue máxima en 182 kcps a 27,8 kBq/mL. La radiación intrínseca produjo 4,42 coincidencias verdaderas por segundo. El coeficiente de variación de la uniformidad del volumen y del sistema fue del 4,7 y 0,8%. La prueba de calidad de imagen mostró mejores resultados al incluir conjuntamente PSF y TOF. Específicamente, la PSF mejoró el contraste de las esferas calientes y la variabilidad del fondo, mientras que el TOF aumentó el contraste de las esferas frías. Conclusiones. El tomógrafo tiene muy buenas características de funcionamiento, además la calidad de la imagen mejora al incorporar la información de la PSF y del TOF en la reconstrucción tomográfic (AU)

Objective. To characterize the performance of the Biograph mCT PET/CT TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. Material and methods. The PET/CT scanner combines a 64-slice CT and PET scanner that incorporates in the reconstruction the TOF and PSF information. PET operating characteristics were evaluated according to the standard NEMA NU 2-2007, expanding some tests. In addition, different reconstruction algorithms were included, and the intrinsic radiation and tomographic uniformity were also evaluated. Results. The spatial resolution (FWHM) at 1 and 10cm was 4.4 and 5.3mm, improving to 2.6 and 2.5mm when PSF is introduced. Sensitivity was 10.9 and 10.2 Kcps/MBq at 0 and 10cm from the axis. Scatter fraction was less than 34% at low concentrations and the noise equivalent count rate (NECR) was maximal at 27.8 kBq/mL with 182 Kcps, the intrinsic radiation produced a rate of 4.42 true coincidences per second. Coefficient of variation of the volume and system uniformity were 4.7 and 0.8% respectively. The image quality test showed better results when PSF and TOF were included together. PSF improved the hot spheres contrast and background variability, while TOF improved the cold spheres contrast. Conclusions. The Biograph mCT TrueV scanner has good performance characteristics. The image quality improves when the information from the PSF and the TOF is incorporated in the reconstruction (AU)

[Contribution of time of flight and point spread function modeling to the performance characteristics of the PET/CT Biograph mCT scanner]. / Aportación del tiempo de vuelo y de la modelización de la respuesta a una fuente puntual a las características de funcionamiento del tomógrafo PET/TAC Biograph mCT.

OBJECTIVE: To characterize the performance of the Biograph mCT PET/CT TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. MATERIAL AND METHODS: The PET/CT scanner combines a 64-slice CT and PET scanner that incorporates in the reconstruction the TOF and PSF information. PET operating characteristics were evaluated according to the standard NEMA NU 2-2007, expanding some tests. In addition, different reconstruction algorithms were included, and the intrinsic radiation and tomographic uniformity were also evaluated. RESULTS: The spatial resolution (FWHM) at 1 and 10cm was 4.4 and 5.3mm, improving to 2.6 and 2.5mm when PSF is introduced. Sensitivity was 10.9 and 10.2 Kcps/MBq at 0 and 10cm from the axis. Scatter fraction was less than 34% at low concentrations and the noise equivalent count rate (NECR) was maximal at 27.8 kBq/mL with 182 Kcps, the intrinsic radiation produced a rate of 4.42 true coincidences per second. Coefficient of variation of the volume and system uniformity were 4.7 and 0.8% respectively. The image quality test showed better results when PSF and TOF were included together. PSF improved the hot spheres contrast and background variability, while TOF improved the cold spheres contrast. CONCLUSIONS: The Biograph mCT TrueV scanner has good performance characteristics. The image quality improves when the information from the PSF and the TOF is incorporated in the reconstruction.

Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning.

PURPOSE: The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade. METHODS: We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by (11)C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately. RESULTS: Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, κ = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5). CONCLUSION: The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.

Disfunción autonómica paroxística desde el periodo neonatal y meduloblastoma / Paroxysmal autonomic dysfunction of neonatal onset and medulloblastoma

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PET de doble fase con 18F-FDOPA como instrumento para la caracterización de tumores cerebrales / Dual time point 18F-FDOPA PET as a tool for characterizing brain tumors

La 18F-FDOPA es un análogo de aminoácidos empleado en la evaluación de la función dopaminérgica presináptica, que ha despertado gran interés en neuro-oncología. Evaluamos 5 estudios PET con 18F-FDOPA de pacientes remitidos para estudio por síndrome parkinsoniano. Dos de ellos tuvieron tumores cerebrales de alto grado previamente tratados, uno una lesión cerebral inespecífica y dos tenían un hallazgo incidental de tumor cerebral. Para cada lesión se calculó el SUVmáx, el tiempo a SUVmáx y el índice SUVmáx entre la lesión y la sustancia gris (T/N), y se analizó el perfil de la cinética de captación. Las lesiones tumorales correspondieron a tres neurocitomas malignos, un meningioma, un pineocitoma y un hemangioma intrasinusal. Todas las lesiones tumorales mostraron una captación de 18F-FDOPA superior al córtex sano. El análisis de la curva cinética de la 18F-FDOPA mostró una doble fase de máxima captación que facilitó la caracterización tumoral: una fase inicial a los 10 minutos en lesiones malignas, y una fase tardía a los 60-90 minutos en las benignas o de bajo grado(AU)

18F-FDOPA is an amino acid analogue used to evaluate presynaptic dopaminergic activity, which has aroused great interest in neuro-oncology. We have evaluated five 18F-FDOPA PET studies of patients referred for study of parkinsonian syndrome. Two subjects had previously treated high-grade brain tumors, one nonspecific brain injury, and 2 subjects presented unexpected tumoral lesions. For all lesions SUVmax, time to SUVmax and tumor-to-normal grey matter SUVmax rate (T/N) were calculated, and 90minutes 18F-FDOPA kinetics were analyzed. Tumor lesions corresponded to three malignant neurocytomas, one meningioma, one pineocytoma and one intrasinusal hemangioma. Both malignant and benign tumors exhibited high uptake of 18F-FDOPA well above the normal cortex. However, the analysis of the curve uptake displayed characteristic patterns that facilitate the characterization of tumor lesions. A dual phase maximum uptake was observed, with an early 10minutes uptake in malignant lesions, and a late 60 to 90minutes uptake in benign or low grade lesions(AU)