Coexistence of Plasma Cell Dyscrasia with Prefibrotic Stage of Primary Myelofibrosis: A Case Report

Introduction. Coexistence of myeloproliferative neoplasms with lymphoproliferative syndromes has been described in the past, whereas plasma cell dyscrasias seem to be the most common cases. Case Presentation. We present a case of a 59-year-old Caucasian female of Greek origin who presented with thrombocytosis. Clinical and laboratory investigation disclosed the presence of a smoldering myeloma with coexisting histological and molecular characteristics of primary myelofibrosis. The patient had the acquired point mutation V617F in the JAK2 gene but not the bcr-abl rearrangement and was treated for myelofibrosis with subsequent improvement of all haematological parameters without evidence of myelomatic evolution. Conclusion. We present the first case in the literature of a smoldering myeloma coexisting with primary myelofibrosis. The underlying pathogenetic mechanism could be either related to the presence of a pluripotent neoplastic stem cell capable to differentiate into both lymphoid and myeloid cells or be related to two separate nosologic entities

Membranous nephropathy and lupus-like syndrome after hematopoietic cell transplantation: a case report

<p>Abstract</p> <p>Introduction</p> <p>The kidney is increasingly recognised as a target organ of chronic graft-versus-host disease after hematopoietic cell transplantation in the context of the development of the nephrotic syndrome. Chronic graft-versus-host disease is associated with autoimmune phenomena similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of the disease.</p> <p>Case presentation</p> <p>We report the case of a 57-year-old Caucasian man who developed the nephrotic syndrome due to membranous nephropathy in association with recurrent chronic graft-versus-host disease, along with a lupus-like syndrome manifested with pancytopenia, hair loss, positive anti-DNA antibodies and sub-epithelial and mesangial immune deposits. To the best of our knowledge, this is the first case reported in the literature. The nephrotic syndrome subsided soon after he was treated with a short course of cyclosporin with steroids. Unfortunately he died seven months later due to a relapse of leukemia.</p> <p>Conclusions</p> <p>Our case report confirms the notion that chronic graft-versus-host disease is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon.</p

Mutations of the tumor suppressor genes p14ARF, p15INK4b and p16INK4a and genomic instability in actinic keratosis

Actinic keratosis (AK) is a well-established pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). We investigated the involvement of the CDKN2A, CDKN2B and p53 genes in AK and in the progression of AK to SCC. Mutational analysis on exons 1a, 1b and 2 of the CDKN2A locus and exon 1 of the CDKN2B locus as well as allelic imbalance was performed in 26 AK specimens. Expression levels of the genes p14ARF, p15INK4b, p16INK4a and p53 were examined in 16 AKs and 12 SCCs by real-time RT-PCR. A previously-described polymorphism of p16INK4a (Ala148Thr) was detected at an allelic frequency of 12%. Six samples carried novel mutations at codon 71 of the CDKN2A locus and one sample presented an additional mutation at codon 65. Two AK samples carried a notpreviously described non-UV type missense mutation at codon 184 (Val184Glu) of exon 1b in the p14ARF gene. Regarding the CDKN2B locus a new mutation at codon 50 (Ala50Thr) and another at codon 24 (Arg24Arg), were detected. Microsatellite instability (MSI) was found in at 15% of AKs in at least one marker, indicating that genetic instability has some implication in the development of AK. Down-regulation of p16INK4a and p53 mRNA levels was noted in SCC compared to AK. TSGs expression levels in sun-exposed morphologically normal-appearing skin, suggests that abnormal growth stimuli might exist in these tissues as well. Furthermore, we suggest a possible role of p15INK4b, independently from the intracellular pathway mediated by p16INK4a, and of p14ARF in AK development, as well as in the progression of AK to SCC. The deregulation of the expression profiles of the CDKN2A, CDKN2B and p53 genes may, independently of mutations and LOH at 9p21, play a significant role in AK and progression of AK to SCCΗ ακτινική υπερκεράτωση (ΑΚ) αποτελεί μια καθιερωμένη προ-καρκινωματώδη βλάβη του δέρματος που μπορεί να εξαλλαχτεί σε ακανθοκυτταρικό καρκίνο (SCC). Στην παρούσα εργασία, μελετήθηκε η συμμετοχή των γονιδίων CDKN2A, CDKN2B και p53 στην ανάπτυξη της ΑΚ και στην εξέλιξη της σε SCC. Πραγματοποιήθηκε ανάλυση μεταλλάξεων στα εξόνια 1a, 1b και 2 του τόπου CDKN2A και στο εξόνιο 1 του τόπου CDKN2B, καθώς επίσης ανάλυση της αστάθειας της αλληλουχίας μικροδορυφορικού DNA σε 26 δείγματα ΑΚ. Μελετήθηκαν τα επίπεδα έκφρασης των γονιδίων p14ARF, p15INK4b, p16INK4a και p53 σε 16 δείγματα ΑΚ και 12 δείγματα SCC με την μέθοδο της αντίστροφης μεταγραφής – αλυσιδωτής αντίδρασης της πολυμεράσης σε πραγματικό χρόνο (real time RT-PCR). Ένας πολυμορφισμός που έχει ήδη περιγραφεί στο p16INK4a (Ala148Thr) ανιχνεύτηκε σε ένα ποσοστό 12%. Σε έξι δείγματα ΑΚ ανιχνεύτηκαν καινούργιες μεταλλάξεις στο κωδικόνιο 71 του τόπου CDKN2A και ένα δείγμα παρουσίασε μια επιπλέον μετάλλαξη στο κωδικόνιο 65. Δύο δείγματα ΑΚ εμφάνισαν μια μη επαγώμενη από UV μετάλλαξη η οποία δεν έχει αναφερθεί προηγουμένως στο εξόνιο 1b του γονιδίου p14ARF. ΄Οσον αφορά τον τόπο CDKN2B, ανιχνεύτηκαν μια καινούργια μετάλλαξη στο κωδικόνιο 50 (Ala50Thr) και μια άλλη στο κωδικόνιο 24 (Arg24Arg). Μικροδορυφορική αστάθεια ανιχνεύτηκε στο 15% των δειγμάτων της ΑΚ σε έναν δείκτη τουλάχιστον, υποδεικνύοντας ότι η μικροδορυφορική αστάθεια πιθανόν να παίζει κάποιο ρόλο στην ανάπτυξη της ΑΚ. Τα αποτελέσματα μας προτείνουν μείωση της έκφρασης του mRNA των γονιδίων p16INK4a και p53 στο SCC σε σύγκριση με τα αντίστοιχα επίπεδα έκφρασης στην AK. Τα επίπεδα έκφρασης των ογκοκατασταλτικών γονιδίων σε μορφολογικά φυσιολογικούς ιστούς που έχουν εκτεθεί στον ήλιο, προτείνει ότι μη φυσιολογικά ερεθίσματα κυτταρικής ανάπτυξης μπορεί να υπάρχουν επίσης και σε αυτούς τους ιστούς. Επιπλέον, προτείνουμε ένα πιθανό ρόλο για το p15INK4b, ανεξάρτητο από την ενδοκυττάρια οδό μεσολαβούμενη από το p16INK4a και του p14ARF στην ανάπτυξη της ΑΚ, καθώς επίσης στην εξελιχτική πορεία της μετατροπής της AK σε SCC. Εκτός από την παρουσία μεταλλάξεων και γενωμικής αστάθειας (LOH/MSI) στο 9p21, η απορρύθμιση του προφίλ έκφρασης των ογκοκατασταλτικών γονιδίων (TSGs) πιθανόν να παίζει σημαντικό ρόλο στην ανάπτυξη της AK και στην μετατροπή της σε SC

Reversal of tumor resistance to apoptotic stimuli by alteration of membrane fluidity: therapeutic implications.

International audienceIn recent years, significant development and improvement have been observed in the treatment of cancer; however, relapses and recurrences occur frequently and there have not been any current therapies to treat such cancers. Cancers resistant to conventional therapies develop several mechanisms to escape death-inducing stimuli. A poorly understood mechanism is the involvement of the cancer cell plasma membrane composition and architecture and their involvement in regulating drug-inducing stimuli leading to cell death. Although the basic structure of the biological membrane was established 80 years ago, study of the physical properties of lipid bilayers still provides significant information regarding membrane organization and dynamics. Membrane fluidity is probably the most important physicochemical property of cell membranes. Alterations of membrane fluidity can seriously affect functional properties of the cell and induction of apoptotic pathways resulting in cell death. The role of membrane fluidity in the apoptotic process is clearly exemplified as it is seriously disrupted as a result of cell injury. The molecular signaling pathways leading to apoptosis are currently promising areas of research investigation and lead to unravel the underlying molecular mechanisms of tumor cells resistance to apoptotic stimuli and hence the development of new effective therapeutic agents. Recent findings indicate that most anticancer agents induce apoptosis, directly or indirectly, through alterations of tumor cell membrane fluidity. The present chapter summarizes the relationship between alterations of tumor cell membrane fluidity and tumor cell response to apoptotic-inducing stimuli. Several potential therapeutic applications directed at tumor cell membrane fluidity are proposed

Incidence and Prognosis of Clonal Hematopoiesis in patients with Chronic Idiopathic Neutropenia

The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. In the present study we sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next generation sequencing, in CIN patients (n=185) with a long follow-up. We found that 21/185 patients (11.35%) carried totally 25 somatic mutations in 6 genes with median variant allele frequency (VAF) 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving more than 80% of patients followed by IDH1/2, SRSF2 and ZRSR2. The frequency of transformation to a myeloid malignancy was low in the total group of patients (5/185 patients; 2.70%). However, from the transformed patients four belonged to the clonal (4/21; 19.05%) and one to the non-clonal (1/164; 0.61%) group, indicating that the presence of mutation(s) confers a relative risk for transformation 31.24 (P = 0.0017). The VAF of the mutant clones in the transformed patients was higher than 10% in all cases and the genes most frequently associated with malignant transformation were the SRSF2 and IDH1. No significant differences were identified between clonal and non-clonal groups in the severity of neutropenia. Patients with clonal disease were older compared to non-clonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of the mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias