New techniques are on the horizon for the detection of small leukemic clones in both, acute leukemias and myeloproliferative disorders. A promising approach is based on digital polymerase chain reaction (PCR). Digital PCR (dPCR) is a breakthrough technology designed to provide absolute nucleic acid quantification. It is particularly useful to detect a low amount of target and therefore it represents an alternative method for detecting measurable residual disease (MRD). The main advantages are the high precision, the very reliable quantification, the absolute quantification without the need for a standard curve, and the excellent reproducibility. Nowadays the main disadvantages of this strategy are the costs that are still higher than standard qPCR, the lack of standardized methods, and the limited number of laboratories that are equipped with instruments for dPCR. Several studies describing the possibility and advantages of using digital PCR for the detection of specific leukemic transcripts or mutations have already been published. In this review we summarize the available data on the use of dPCR in acute myeloid leukemia and myeloproliferative disorders.
SUMMARY
Objectives
The purpose of this study was to correlate acute invasive fungal rhinosinusitis (AIFRS) and chronic invasive fungal rhinosinusitis with underlying diseases, aetiological microorganisms, clinical symptoms, radiological findings, and surgical and medical treatment to determine the subset of patients who require more accurate diagnostic investigation and to prevent irreversible complications.
Methods
This retrospective monocentric study included 17 patients who underwent endoscopic sinus surgery evaluated by paranasal computed tomography and magnetic resonance imaging. Age, sex and symptoms, and location of the invasive fungal infection and the causative fungus were analysed.
Results
In total, 4 patients were affected by the AIFRS form, and 13 by the chronic form. Diabetes mellitus was reported in 41.17% of cases, and haematological diseases in 23.52%. The maxillary sinuses were involved in 47.05% of cases and sphenoidal sinuses in 52.94%; Aspergillus fumigatus was the fungus in 76.47% of cases, and Zygomycetes in 23.53%.
Conclusions
An understanding of the different types of fungal sinusitis and knowledge of their features play a crucial role in reaching prompt diagnosis and initiation of appropriate therapy, which is essential to avoid a protracted or fatal outcome.
Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
Discontinuation of tyrosine kinase inhibitors (TKI) is the main goal today in the field of Philadelphia positive chronic myeloid leukemia (Ph + CML) and the criteria to attempt the interruption of therapy are well defined and rely on the possibility to regularly monitor the BCR-ABL1 transcript. Patients harboring atypical transcripts are automatically excluded from protocols due to the absence of a standardized method of quantification of their minimal residual disease (MRD). We report here the outcome of 6 patients with atypical transcripts with a long follow up whose MRD was followed in three cases with digital PCR during their treatment free remission (TFR).
Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis and increased apoptosis in the bone marrow, which cause peripheral cytopenia. Mitochondria are key regulators of apoptosis and a site of iron accumulation that favors reactive oxygen species (ROS) production with detrimental effects on cell survival. Although the energy metabolism could represent an attractive therapeutic target, it was poorly investigated in MDS. The purpose of the study was to analyze how the presence of myelodysplastic hematopoiesis, iron overload and chelation impact on mitochondrial metabolism. We compared energy balance, OxPhos activity and efficiency, lactic dehydrogenase activity and lipid peroxidation in mononuclear cells (MNCs), isolated from 38 MDS patients and 79 healthy controls. Our data show that ATP/AMP ratio is reduced during aging and even more in MDS due to a decreased OxPhos activity associated with an increment of lipid peroxidation. Moreover, the lactate fermentation enhancement was observed in MDS and elderly subjects, probably as an attempt to restore the energy balance. The biochemical alterations of MNCs from MDS patients have been partially restored by the in vitro iron chelation, while only slight effects were observed in the age-matched control samples. By contrast, the addition of iron chelators on MNCs from young healthy subjects determined a decrement in the OxPhos efficiency and an increment of lactate fermentation and lipid peroxidation. In summary, MDS-MNCs display an altered energy metabolism associated with increased oxidative stress, due to iron accumulation. This condition could be partially restored by iron chelation. Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, characterized by a clonal and ineffective hematopoiesis, an increased apoptosis within the bone marrow and risk of transformation into acute myeloid leukemia (AML) 1. MDS affect especially the elderly and are characterized by one or more cytopenias, mainly
A diagnosis of rhino-orbital-cerebral mucormycosis was made in a 59-year-old man with a secondary acute myeloid leukemia a few days after hematopoietic stem cell transplantation.Prompt treatment with combined antifungal therapy (liposomal amphotericin B and isavuconazole) followed by a procedure of endoscopic sinus surgery resulted in the resolution of the infection. Therapeutic drug monitoring of isavuconazole was performed during the year of treatment showing an increment of plasma concentrations in correspondence with the improvement of intestinal GvHD, thus suggesting that in this or similar conditions TDM for isavuconazole can be of value.A literature review of cases of rhino-orbital-cerebral and rhino-cerebral mucormycosis in allogeneic hematopoietic stem cell transplant recipients was carried out.
Philadelphia positive acute lymphoblastic leukemia is well documented nowadays but very little is known about Philadelphia positive lymphoblastic lymphoma (LBL). Only two cases are available in literature and both of them died during treatment whereas the patient treated in our center is still alive 3 years after the initial diagnosis. A chemo-free regimen was used in induction with dasatinib plus steroids with local radiotherapy on the mass, and then the patient underwent bone marrow transplant. Philadelphia positive lymphoblastic lymphoma is a difficult diagnosis to make and the management of this extremely rare disease is very challenging.
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