Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature.

The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

Quadriceps tendon rupture in maintenance haemodialysis patients: results of surgical treatment and analysis of risk factors.

BACKGROUND: Reports of spontaneous quadriceps ruptures in end-stage renal disease (ESRD) patients are scarce, and the assessment of risk factors for tendon rupture is poorly addressed in the majority of the studies. The purpose of the present study is to report a series of patients on haemodialysis with spontaneous quadriceps tendon ruptures operated at our institution. The results of the surgical treatment are described and the potential risk factors associated with the rupture are analyzed. METHODS: Our study consisted of retrospective analysis of patient's charts. Clinical and laboratory findings of the operated group were compared to the ones of a control group of haemodialysis patients matched by age, gender, and time on haemodialysis, but without tendon rupture. RESULTS: Between 1998 and 2010, six ESRD patients with 11 spontaneous ruptures of the quadriceps tendon were treated at our institution. On postoperative evaluation all patients were able to walk without crutches after six months of follow-up, and there were no new ruptures. Positive serology for Hepatitis C was present in two cases (33%) but in none of the controls (p = 0.034). Mean serum levels of intact parathormone (iPTH) and alkaline phosphatase were both higher in cases (p = 0.013 and p = 0.034, respectively). In contrast, mean serum levels of albumin, ferritin and haemoglobin were all lower in cases (p = 0.008, p = 0.043 and p = 0.016, respectively). CONCLUSION: Reconstructive surgery is a good way to restore knee function in ESRD patients with quadriceps tendon ruptures. Our cases exhibited higher levels of iPTH and alkaline phosphatase than control patients, reinforcing the role of secondary hyperparathyroidism in tendon weakening. They also had a higher frequency of hepatitis C and lower levels of albumin and haemoglobin compared to controls, possibly implicating chronic inflammation as a potential risk factor for tendon rupture.

Methylation status of nine tumor suppressor genes in multiple myeloma.

Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a, 42.8%; p15 INK4b, 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RAR beta, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P < 0.001) and RAR beta (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RAR beta (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P < 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RAR beta hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.