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Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.
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Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 28 consecutive patients admitted to our hospital between September 2011 and November 2021 for idiopathic hypereosinophilia (HE).Bone marrow (BM) morphology was evaluated in 22 patients: while in six subjects BM was unremarkable, in the remaining cases an increase in BM eosinophils was observed, together with a slight increase in BM fibrosis (MF-1) in 5/22 patients.A total of 4/28 patients had at least one genetic lesion by targeted NGS. In particular, the genes involved were: two each of TET2 and DNMT3A; and one each of JAK2V617F, ASXL1, PPM1D, and ZBTB33. Notably, JAK2V617F and TET2 mutations co-occurred, with the JAK2V617F-mutated sample also carrying TET2 lesions. Median VAF was 21%, with the exception of the oncodriver JAK2V617F, which showed a VAF > 50% in the reported case. Of note, of the four cases bearing lesions, 2/4 had multiple hits in different genes.While in recent years mutational analysis using NGS has proven to be able to differentiate clonal hematopoietic neoplasms from reactive processes in diagnostically difficult cases, we found somatic mutations in only 14.3% of patients who acceded to our hospital for idiopathic HE. More importantly, excluding the JAK2V617F-mutated case with an underlying MPN-Eo diagnosis, NGS was able to identify somatic mutations in only three cases, all older than 70 years. Consequently, the detection of these mutations in idiopathic HE patients should be interpreted with caution and only in the context of other supportive clinical-pathological findings.
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Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Dioxigenasas/genética , Janus Quinasa 2/genética , Médula Ósea/patología , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ADN/genética , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/diagnóstico , ADN Metiltransferasa 3A , Anciano de 80 o más Años , Análisis Mutacional de ADN/métodos , Adulto Joven , Proteínas RepresorasRESUMEN
The last step of ex novo ceramide biosynthesis consists of the conversion of dihydroceramide into ceramide catalyzed by sphingolipid Δ4-desaturase DEGS1. DEGS1 variants were found to be responsible for heterogeneous clinical pictures belonging to the family of hypomyelinating leukodystrophies. To investigate the mechanisms making such variants pathogenic, we designed a procedure for the efficient detection of desaturase activity in vitro using LC-MS/MS and prepared a suitable cell model knocking out DEGS1 in HEK-293T cells through CRISPR-Cas9 genome editing (KO-DES-HEK). Transfecting KO-DES-HEK cells with DEGS1 variants, we found that their transcripts were all overexpressed as much as the WT transcripts, while the levels of cognate protein were 40%-80% lower. In vitro desaturase activity was lost by many variants except L175Q and N255S, which maintain a catalytic efficiency close to 12% of the WT enzyme. Metabolic labeling of KO-DES-HEK with deuterated palmitate followed by LC-MS/MS analysis of the formed sphingolipids revealed that the ceramide/dihydroceramide and sphingomyelin/dihydrosphingomyelin ratios were low and could be reverted by the overexpression of WT DEGS1 as well as of L175Q and N255S variants, but not by the overexpression of all other variants. Similar analyses performed on fibroblasts from a patient heterozygous for the N255S variant showed very low variant DEGS1 levels and a low ratio between the same unsaturated and saturated sphingolipids formed upon metabolic labeling, notwithstanding the residual activity measured at high substrate and homogenate protein concentrations. We conclude that loss of function and reduced protein levels are both relevant in disease pathogenesis.
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Ceramidas , Oxidorreductasas , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Ceramidas/metabolismo , Esfingolípidos/genética , Esfingolípidos/metabolismo , Ácido Graso Desaturasas/genéticaRESUMEN
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are classically represented by polycythemia vera, essential thrombocythemia, and primary myelofibrosis. BCR::ABL1-negative MPNs are significantly associated with morbidity and mortality related to an increased risk of thrombo-hemorrhagic events. They show a consistent association with splanchnic vein thrombosis (SVT), either represented by the portal, mesenteric or splenic vein thrombosis, or Budd-Chiari Syndrome. SVT is also a frequent presenting manifestation of MPN. MPNs associated with SVT show a predilection for younger women, high association with JAK2V617F mutation, low JAK2V617F variant allele frequency (generally <10 %), and low rates of CALR, MPL, or JAK2 exon 12 mutations. Next-Generation Sequencing techniques have contributed to deepening our knowledge of the molecular landscape of such cases, with potential diagnostic and prognostic implications. In this narrative review, we analyze the current perspective on the molecular background of MPN associated with SVT, pointing as well future directions in this field.
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Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Trombosis de la Vena , Humanos , Femenino , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/diagnóstico , Trombosis de la Vena/genética , Policitemia Vera/complicaciones , Trombocitemia Esencial/genética , Mutación , Calreticulina/genética , Janus Quinasa 2/genéticaRESUMEN
Leprosy is a neglected disease sporadically reported in high-income countries. Skin lesion and peripheral nerve involvement represent most common manifestations. Mediastinal lymphadenopathy in the absence of superficial lymph nodes involvement is very rare. Atypical or rare clinical presentations of disease may delay diagnosis and therapy and cause potential life-threatening manifestations and disabilities. We describe the case of a 49-year-old Sinhalese man who was admitted to our hospital with a one-month history of peripheral neurological symptoms and skin lesions on lower limbs. CT scan showed the presence of mediastinal lymphadenopathies without lung parenchymal and superficial lymph nodes involvement. Endobronchial ultrasound-guided transbronchial needle aspiration showed the presence of granulomas while skin biopsy revealed dermo-hypodermic granulomas with perineural lymphohistiocytic inflammatory reaction. Fite-Faraco staining demonstrated the presence of acid-fast bacilli in both lymph nodal and skin biopsy and polymerase chain reaction was positive for Mycobacterium leprae. Multibacillary leprosy was then diagnosed.
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Myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase (TK) gene fusions are a rare group of haematopoietic neoplasms with a broad range of clinical and morphological presentations. Paediatric cases have increasingly been recognised. Importantly, not all appear as a chronic myeloid neoplasm and eosinophilia is not always present. In addition, standard cytogenetic and molecular methods may not be sufficient to diagnose M/LN-eo due to cytogenetically cryptic aberrations. Therefore, additional evaluation with fluorescence in-situ hybridisation and other molecular genetic techniques (array-based comparative genomic hybridisation, RNA sequencing) are recommended for the identification of specific TK gene fusions. M/LN-eo with JAK2 and FLT3-rearrangements and ETV6::ABL1 fusion were recently added as a formal member to this category in the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In addition, other less common defined genetic alterations involving TK genes have been described. This study is an update on M/LN-eo with TK gene fusions with focus on novel entities, as illustrated by cases submitted to the Bone Marrow Workshop, organised by the European Bone Marrow Working Group (EBMWG) within the frame of the 21st European Association for Haematopathology congress (EAHP-SH) in Florence 2022. A literature review was performed including paediatric cases of M/LN-eo with TK gene fusions.
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Eosinofilia , Neoplasias Hematológicas , Linfoma , Trastornos Mieloproliferativos , Humanos , Niño , Eosinofilia/genética , Eosinofilia/patología , Linfoma/patología , Médula Ósea/patología , Neoplasias Hematológicas/patología , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 58 consecutive MPN-SVT patients admitted to our hospital between January 1979 and November 2021. We identified 15.5% of PV, 13.8% of ET, 34.5% of PMF, 8.6% of SMF and 27.6% of MPN-U. Most cases (84.5%) carried JAK2V617F mutation, while seven patients were characterized by other molecular markers, namely MPL in four and CALR mutations in three cases. NGS was performed in 54 (93.1%) cases: the most frequent additional mutations were found in TET2 (27.8%) and DNMT3A (16.7%) genes, whereas 25 (46.3%) patients had no additional mutation. Cases with JAK2V617F homozygosity had a higher median number of additional mutations than those with low allele burden. More importantly, all cases of leukemic evolution were characterized by a higher median number of co-mutations, and a co-mutational pattern of high-risk lesions, such as truncating mutations of ASXL1, bi-allelic TP53 loss, and CSMD1 mutations. Nevertheless, no difference was found between cases with and without additional somatic mutations regarding fibrotic progression, SVT recurrence, other thrombo-hemorrhagic complications, or death. After a median follow-up of 7.1 years, ten deaths were recorded; fibrotic progression/leukemic evolution was ascertained in one (1.7%) and six (10.3%) patients, respectively, while 22 (37.9%) patients suffered from recurrent thrombosis. In conclusion, our data underline the importance of using NGS analysis in the management of MPN-related SVT as it can support the MPN diagnosis, particularly in "triple-negative" cases, and provide additional information with potential consequences on prognosis and therapeutic strategies.
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Trastornos Mieloproliferativos , Neoplasias , Trombosis de la Vena , Humanos , Trastornos Mieloproliferativos/genética , Trombosis de la Vena/genética , Mutación , Genómica , Janus Quinasa 2/genética , Calreticulina/genéticaRESUMEN
CONTEXT.: Extramedullary hematopoiesis (EMH) is an uncommon occurrence, usually associated with hematologic disorders, but it rarely presents as an isolated finding. OBJECTIVE.: To determine the frequency, immunomorphologic features, and clinicopathologic background of EMH in orchiectomies from pediatric patients. DESIGN.: All orchiectomy specimens removed from children from 2008 to 2020 in our institution were retrospectively reviewed. Biopsies and neoplasias were excluded. The EMH diagnosis was rendered when hematopoietic cell precursors were present. Immunohistochemical stainings were performed to characterize the hematopoietic components. RESULTS.: Seventy-nine orchiectomies from 77 children (mean age, 5 years; range, 0-17 years) were included in our study. Forty-three patients (55.8%) underwent surgery for testicular atrophy, 30 (39.0%) for torsion, and 4 (5.2%) for intersex conditions. EMH was identified in 6 of 79 orchiectomies (7.6%), all performed for testicular torsion. All patients but one were newborns, and the remaining patient was 15 years old. No patient had evidence of a hematologic disorder. All EMH foci were in a background of reactive changes with a variable extension, either in the epididymis (4 cases) or in the deferens duct (2 cases). Immunostaining confirmed an association of myeloid (myeloperoxidase+) and erythroid precursors (E-cadherin+) in all 6 cases. One case also presented rare megakaryocytes, and one showed benign TdT+ B-cell precursors. CONCLUSIONS.: To our knowledge, this is the first study that demonstrates EMH as a common finding in orchiectomy samples, especially from newborns. Despite the lack of pathologic potential, it is important to recognize EMH in order to avoid misdiagnosis.
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Enfermedades Hematológicas , Hematopoyesis Extramedular , Masculino , Humanos , Niño , Recién Nacido , Preescolar , Adolescente , Estudios Retrospectivos , Biopsia , Diagnóstico DiferencialRESUMEN
Fibroblastic reticulum cell tumor (FRCT) is a rare dendritic neoplasm arising from fibroblastic reticulum cells (FBRCs) and exhibiting peculiar cytokeratin expression. FRCTs usually involve the lymph nodes, although they can also be encountered in the spleen and soft tissues. FRCTs are composed of mildly atypical spindle or ovoid cells, arranged in loose whorls, which express almost invariably low-weight cytokeratins, smooth muscle actin, and CD68. An admixed lymphoplasmacytic infiltrate is also frequently present in solid organ sites. The clinical picture may vary from very indolent to aggressive disease exhibiting features of malignancy, such as cytological pleomorphism, necrosis, or high mitotic rate and metastatic potential. FRCT is a challenging diagnosis, due to its rarity and deceptive cytokeratin expression. Hereafter, we revise the most recent literature regarding such condition and report the case of an extremely indolent splenic FRCT, with no features of malignancy.
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Trastornos Histiocíticos Malignos , Neoplasias , Neoplasias del Bazo , Humanos , Neoplasias del Bazo/patología , QueratinasRESUMEN
OBJECTIVES: Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up. METHODS: We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients. RESULTS: Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. CONCLUSIONS: Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality.
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Enfermedad Celíaca , Hipoalbuminemia , Linfoma , Humanos , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/terapia , Enfermedad Celíaca/diagnóstico , Estudios Retrospectivos , Hipoalbuminemia/complicaciones , Linfoma/complicaciones , AtrofiaRESUMEN
A group of international experts, including hematopathologists, oncologists, and geneticists were recently summoned (September 2021, Chicago, IL, USA) to update the 2016/17 World Health Organization classification system for hematopoietic tumors. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukemias. This current in-depth review focuses on the ICC-2022 category of JAK2 mutation-prevalent myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. The ICC MPN subcommittee chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication.
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Leucemia , Trastornos Mieloproliferativos , Policitemia Vera , Humanos , Consenso , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Leucemia/patología , Policitemia Vera/genética , Médula Ósea/patología , Janus Quinasa 2/genética , MutaciónRESUMEN
The recently published International Consensus Classification (ICC) of myeloid neoplasms summarized the results of an in-depth effort by pathologists, oncologists, and geneticists aimed to update the 2017 World Health Organization classification system for hematopoietic tumors. Along these lines, several important modifications were implemented in the classification of myeloproliferative neoplasms (MPNs). For chronic myeloid leukemia, BCR::ABL1-positive, the definition of accelerated and blast phase was simplified, and in the BCR::ABL1-negative MPNs, the classification was slightly updated to improve diagnostic specificity with a more detailed and better validated morphologic approach and the recommendation of more sensitive molecular techniques to capture in particular early stage diseases. In this regard, high sensitive single target (RT-qPCR, ddPCR) or multi-target next-generation sequencing assays with a minimal sensitivity of VAF 1% are now important for a proper diagnostic identification of MPN cases with low allelic frequencies at initial presentation. This review discusses the updated diagnostic criteria of MPN according to the ICC, particularly by highlighting the new concepts and how they can be applied in clinical settings to obtain an appropriate prognostic relevant diagnosis.
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Neoplasias Hematológicas , Linfoma , Trastornos Mieloproliferativos , Humanos , Consenso , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genéticaRESUMEN
Disseminated tuberculosis is a rare form of tuberculosis that can cause severe illness if diagnosed and treated late. We present the case of a young Senegalese woman who had a miscarriage due to a pelvic inflammatory disease, followed by the development of a left pleural effusion. Despite laparoscopic findings and a salpinx biopsy that revealed necrotizing granulomas, only microbiological examinations of pleural biopsies revealed the final diagnosis of disseminated, drug-sensitive tuberculosis.
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Derrame Pleural , Tuberculosis Pleural , Femenino , Humanos , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/etiología , Pleura/patología , Tuberculosis Pleural/complicaciones , Tuberculosis Pleural/diagnóstico , Tuberculosis Pleural/tratamiento farmacológico , Biopsia , Genitales/patologíaRESUMEN
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
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Neoplasias Hematológicas , Leucemia , Trastornos Mieloproliferativos , Enfermedad Aguda , Consenso , Genómica , Neoplasias Hematológicas/patología , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patología , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Organización Mundial de la SaludRESUMEN
The 2016 WHO classification recognized pre-fibrotic primary myelofibrosis (pre-PMF) as a distinct entity. Nevertheless, a prognostic model specific for pre-PMF is still lacking. Our aim was to identify the most relevant clinical, histological, and driver mutation information at diagnosis to evaluate outcomes in pre-PMF patients in the real-world setting. We firstly assessed the association between IPSS or DIPSS at diagnosis and response variables in 378 pre-PMF patients. A strict association was observed between IPSS and DIPSS and occurrence of death. Other analyzed endpoints were not associated with IPSS or DIPSS as thrombo-hemorrhagic events at diagnosis or during follow-up, or did not show a clinical plausibility, as transformation into acute leukemia or overt PMF. The only covariates which were significantly associated with death were diabetes and second neoplasia, and were therefore included in two different prognostic settings: the first based on IPSS at diagnosis [class 1 vs. 0, OR (95%CIs): 3.34 (1.85-6.04); class 2 vs. 0, OR (95%CIs): 12.55 (5.04-31.24)], diabetes [OR (95%CIs): 2.95 (1.41-6.18)], and second neoplasia [OR (95%CIs): 2.88 (1.63-5.07)]; the second with DIPSS at diagnosis [class 1 vs. 0, OR (95%CIs): 3.40 (1.89-6.10); class 2 vs. 0, OR (95%CIs): 25.65 (7.62-86.42)], diabetes [OR (95%CIs): 2.89 (1.37-6.09)], and second neoplasia [OR (95%CIs): 2.97 (1.69-5.24)]. In conclusion, our study underlines the importance of other additional risk factors, such as diabetes and second neoplasia, to be evaluated, together with IPSS and DIPSS, to better define prognosis in pre-PMF patients.
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Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.
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Trasplante de Riñón , Obtención de Tejidos y Órganos , Muerte Encefálica , Muerte , Funcionamiento Retardado del Injerto/etiología , Funcionamiento Retardado del Injerto/patología , Supervivencia de Injerto , Humanos , Isquemia , Riñón/patología , Riñón/fisiología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Estudios Retrospectivos , Donantes de TejidosRESUMEN
High-risk Myelodysplastic syndromes (MDS) represent therapeutical challenges and are usually managed with hypomethylating agents such as azacitidine. Given the lack of data in the literature concerning azacitidine effects on bone marrow, we retrospectively analyzed 57 high-risk MDS cases in order to identify any changes induced by azacitidine therapy or relevant correlations between therapy response and pre- or post-treatment features. Azacitidine treatment had no significant impact on bone marrow cellularity or morphological dysplastic features. On the contrary, although not statistically significant, we observed a slight decrease in CD34+ and CD117+ blasts and p53+ precursors after treatment. Moreover, pre-treatment IPSS-R cytogenetic score (p = 0.004), lymphocytic infiltrate (p = 0.017) and p53+ elements (p = 0.001) correlated with AML progression; pre-treatment lymphocytic infiltrate was also linked to better response to therapy (p = 0.004), suggesting an anti-tumoral role of bone marrow microenvironment. Post-treatment blast count impacted negatively on overall survival (p = 0.035) and risk of leukemic progression (p = 0.04), while both post-treatment lymphocytic infiltrate and p53+ elements showed significant correlation with treatment response (p = 0.004 and p = 0.003 respectively). Higher post-treatment p53+ elements correlated also with risk of leukemic progression (p = 0.013). Our results suggest the possible role of lymphocytic infiltrate and p53+ elements as predictive markers in MDS treated with azacitidine, disclosing new chapters in the understanding of MDS evolution and treatment.