Late perforation of a thoracic aortic dacron graft by a metallic stent-graft component.

PURPOSE: To describe a case involving perforation of a previously placed aortic Dacron graft by the uncovered proximal stent of a thoracic stent-graft. CASE REPORT: A 76-year-old man with a surgically treated type A dissection presented with residual type B dissection. Thoracic stent-grafting of the entry site was performed successfully. After 2 years, the patient was admitted for evaluation of a non-pulsating parasternal mass. Computed tomography showed a large, hypodense liquid-like mass affecting the mediastinum up to the subcutaneous tissue. A false aneurysm at the proximal end of the stent-graft was observed arising from an aortic perforation by the uncovered stent. One week later, the mass had almost completely resolved, and the patient has been scheduled for close surveillance. CONCLUSION: This case illustrated the importance of thoroughly examining the long-term durability and compatibility of prosthetic materials.     

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration 6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).     

Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival,independent of the MCL international prognostic index

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an “indolent” evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra‐hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of “indolent” patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis. © 2013 Wiley Periodicals, Inc.     

Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study

Corticosteroid and central nervous system (CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow‐up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m² in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow‐up is required because of potential very late occurrence.     

Basal peroxisome proliferator activated receptor gamma coactivator 1α expression is independent of calcineurin in skeletal muscle

Both calcineurin-A and peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) are key players in the acquisition and maintenance of slow-oxidative skeletal muscle phenotype. Whether calcineurin can control PGC-1α expression has been proposed but is still controversial. Our aim was to examine the relationship between calcineurin activation and PGC-1α expression in nonexercising skeletal muscles of rats. We first examined PGC-1α and modulatory calcineurin-interacting protein-1 messenger RNA (mRNA) (a marker of calcineurin activity) expression patterns within rat single myofibers, classified according to their phenotype (type I, IIa, IIx, and IIb). Secondly, we measured PGC-1α mRNA and protein in soleus and plantaris muscles of rats treated or not by cyclosporin A or FK506, 2 pharmacological inhibitors of calcineurin activity. In single myofibers, no differences were found in PGC-1α mRNA levels, whereas modulatory calcineurin-interacting protein-1 mRNA was substantially higher in type I and IIa compared with type IIx and IIb fibers. In cyclosporin A- and FK506-treated animals, no decrease in PGC-1α mRNA and protein was found, despite an efficient blockade of calcineurin activity. Taken together, our results show that, in weight-bearing skeletal muscles, basal PGC-1α expression, necessary to maintain slow-oxidative phenotype, is independent of calcineurin activity.     

Coxsackievirus B3 mutator strains are attenuated in vivo

Based on structural data of the RNA-dependent RNA polymerase, rational targeting of key residues, and screens for Coxsackievirus B3 fidelity variants, we isolated nine polymerase variants with mutator phenotypes, which allowed us to probe the effects of lowering fidelity on virus replication, mutability, and in vivo fitness. These mutator strains generate higher mutation frequencies than WT virus and are more sensitive to mutagenic treatments, and their purified polymerases present lower-fidelity profiles in an in vitro incorporation assay. Whereas these strains replicate with WT-like kinetics in tissue culture, in vivo infections reveal a strong correlation between mutation frequency and fitness. Variants with the highest mutation frequencies are less fit in vivo and fail to productively infect important target organs, such as the heart or pancreas. Furthermore, whereas WT virus is readily detectable in target organs 30 d after infection, some variants fail to successfully establish persistent infections. Our results show that, although mutator strains are sufficiently fit when grown in large population size, their fitness is greatly impacted when subjected to severe bottlenecking, which would occur during in vivo infection. The data indicate that, although RNA viruses have extreme mutation frequencies to maximize adaptability, nature has fine-tuned replication fidelity. Our work forges ground in showing that the mutability of RNA viruses does have an upper limit, where larger than natural genetic diversity is deleterious to virus survival.     

Corticotroph deficiency

Corticotroph deficiency usually results from exogenous glucocorticoid therapy or, more rarely, from hypothalamopituitary damages. Its diagnostic may be difficult, especially when the deficit in ACTH secretion is partial. Stimulation tests are then necessary to investigate the integrity of the hypothalamopituitary-adrenal axis. The insulin tolerance test has become the gold standard, but its utilization is limited by several contra-indications. The metyrapone and cosyntropin tests represent currently used alternatives but their sensitivity is not optimal. Measurement of basal plasma dehydroepiandrosterone sulfate may allow excluding corticotroph deficiency when normal. Finally, cortisol replacement in patients with corticotropic deficiency is based on hydrocortisone administration. However, the dose regimens employed in clinical practice do not allow mimicking the nycthemeral rhythm of cortisol secretion and are still disputed.