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.

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.

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.

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.

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

(18)F-FDOPA is an amino acid analogue used to evaluate presynaptic dopaminergic activity, which has aroused great interest in neuro-oncology. We have evaluated five (18)F-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 90 minutes (18)F-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 (18)F-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 10 minutes uptake in malignant lesions, and a late 60 to 90 minutes uptake in benign or low grade lesions.

[Neuroimaging in brain tumors]. / Neuroimagen de los tumores cerebrales.

Advances in neuroimaging have modified diagnosis, treatment and clinical management of brain tumors. However, neuropathological study remains necessary in order to get the best clinical management. Surgery and radiotherapy planning are imaging-dependent procedures, and MRI is the standard imaging modality for determining precisely tumor location and its anatomical relationship with surrounding brain structures. In high-grade tumors it has been accepted that tumoral areas with contrast uptake in CT, or T1-weighted MRI contrast enhancement corresponds to solid tumor. However, relationship between MRI and invasive tumor areas remains less defined. Therefore, it is generally accepted that conventional MRI is not sufficient to delineate the real extension of brain tumors. In recent years, PET using 18FDG and amino acid radiotracers ((11)C-Methionine, (18)FDOPA, (18)FET) and SPECT with (201-)Thallium, as well as advanced MRI sequences (Perfusion, Diffusion-weighted, Diffusion tensor imaging and tractography), and functional MRI, have added important complementary information in the characterization, therapy planning and recurrence differential diagnosis of brain tumors. In this continuing education review of neuroimaging in brain tumors, technical aspects and clinical applications of different imaging modalities are approached in a multidisciplinary way.