In situ assessment of PI3K and PTEN alterations in mycosis fungoides: correlation with clinicopathological features

Deregulated signalling through phosphatidylinositol 3‐kinase (PI3K) pathway plays a critical role in tumour initiation and progression. We have already shown that AKT is activated in skin lesions in Mycosis Fungoides (MF) and we herein further investigate the frequency and clinical significance of PTEN and PI3K at the protein and at the DNA level as well as the presence of AKT1 mutations in skin lesions from 50 patients with MF clinical stages I‐IV in relation to clinicopathological features. Increased p‐AKT expression correlated with poor prognosis in plaques (P = 0.0198), whereas p‐AKT was an independent predictor of poor survival in the entire cohort (P = 0.017, HR = 1.012). PTEN cytoplasmic expression was found low or absent in all 77.3% of cases and inversely correlated with advanced clinical stages (P = 0.0744). Molecular analysis showed no AKT1 mutation, no PI3KCA copy number gain, only 1 case with PI3KCA mutation in exon 9 and 3 cases with PTEN mutations (7%) in exons 7, 8 and 5. The latter correlated with disease (P = 0.0253) and progression (P < 0.0001) free survival in tumour stage. Although activation of PI3K/AKT signalling pathway due to PTEN alterations is rarely attributed to abnormalities in PTEN, PI3K, and AKT1 genes, PTEN mutations exert a negative effect on patients’ prognosis with tumours.     

Prognostic value of C-reactive protein,fibrinogen, interleukin-6, and macrophage colony stimulating factor in severe unstable angina

BACKGROUND: Inflammatory process plays an important role in the pathogenesis of acute coronary syndromes. HYPOTHESIS: The study was undertaken to evaluate whether admission levels of C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6). and macrophage colony stimulating factor (MCSF) can predict short-term prognosis in patients with unstable angina. METHODS: C-reactive protein, fibrinogen, IL-6, and MCSF were measured on admission in 141 consecutive patients, aged 59 +/- 10 years, with unstable angina (Braunwald class IIIb). Patients were divided into two groups according to their in-hospital outcome: Group 1 comprised 77 patients with a complicated course (2 died, 15 developed nonfatal myocardial infarction, and 60 had recurrence of angina), and Group 2 comprised 64 patients with an uneventful course. RESULTS: Admission median levels of CRP (8.8 vs. 3.1 mg/l, p = 0.0002). fibrinogen (392 vs. 340 mg/dl, p = 0.008), IL-6 (8.8 vs. 4.5 pg/ml, p = 0.03), and MCSF (434 vs. 307 pg/ml, p = 0.0001) were higher in Group I than in Group 2. The MCSF levels were an independent risk factor for in-hospital events, with an adjusted odds ratio for eventful in-hospital outcome of 3.3 (95% confidence interval 1-10.9, p = 0.04), and correlated with levels of IL-6 (r(s) = 0.52, p = 0.0001), CRP (r(s) = 0.43, p = 0.0001), and fibrinogen (r(s) = 0.25, p = 0.004). CONCLUSIONS: These findings suggest that among the studied inflammatory indices only increased admission levels of MCSF are strongly and independently related with adverse short-term prognosis in patients with severe unstable angina.     

The prolyl‐hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia

EGLN1 and EGLN3 are members of the egg‐laying‐defective 9 (EglN) prolyl‐hydroxylases which during normoxia catalyse hydroxylation of the hypoxia‐inducible factor (HIF)‐1α, thereby promoting its ubiquitination by a complex containing the von Hippel–Lindau (VHL) tumour suppressor. EGLN3 also has pro‐apoptotic activity in some cell types. Analyses of a well‐characterised series of cases of plasma cell dyscrasias, including multiple myeloma (MM), Waldenström’s macroglobulinaemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) surprisingly demonstrated that the CpG island of EGLN3, and not EGLN1, is frequently methylated in these disorders. Multiple myeloma patients with a methylated EGLN3 promoter showed trends towards an increased risk of death, bone lytic lesions, anaemia, advanced stage of disease and the presence of extramedullary disease. Those individuals with methylation in the EGLN3 CpG island also had significantly lower albumin levels. These data suggest that the prolyl‐hydroxylases may be a novel class of potential tumour suppressors in plasma cell neoplasia that warrant further investigation with regard to their potential utility as biomarkers. Moreover, we observed that EGLN3 is also methylated at high frequency in B‐cell lymphoma subtypes, implying that loss of EGLN3 is an important epigenetic event not only in plasma cell neoplasias but also in B‐cell neoplasias.     

Phantom cytomegalovirus infection in vasculitis patients: what it means and what to do

We report our experience and hypothesis on the diagnosis and treatment of patients with vasculitis who are simultaneously diagnosed with serum-positive cytomegalovirus (CMV) immunoglobulin (Ig)M antibodies and negative CMV DNA polymerase chain reaction (PCR). It remains unknown how to treat this kind of phantom CMV infection. In a patient diagnosed with Henoch-Schönlein vasculitis, CMV IgM titers were increased while angiitis and renal function deteriorated. Empiric treatment of phantom CMV infection with ganciclovir in this CMV IgM-positive and PCR-negative patient resulted in complete vasculitis remission, serum CMV antibody seroconversion, and renal function improvement. These results imply something more than coincidence.     

Thyroid function in humans with morbid obesity.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.     

Imported Klebsiella pneumoniae carbapenemase-producing K. pneumoniae clones in a Greek hospital: impact of infection control measures for restraining their dissemination

The recent emergence of carbapenemase-producing Enterobacteriaceae strains represents a major threat for hospitalized patients. We document the dissemination and control of carbapenemase-producing Klebsiella pneumoniae clones in a Greek hospital. During a 3-year study period (January 2009 to December 2011), carbapenemase-producing K. pneumoniae strains were isolated from clinical samples from 73 individual patients. Phenotyping and molecular testing confirmed that 52 patients were infected with K. pneumoniae carbapenemase 2 (KPC-2) producers, 12 were infected with VIM-1 producers, and the remaining 9 were infected with isolates producing both KPC-2 and VIM-1 enzymes. Twenty-eight of these clinical cases were characterized as imported health care associated, and 23 of these were attributed to KPC producers and 5 were attributed to KPC and VIM producers. The remaining 45 cases were deemed hospital acquired. In the second year of the study, intensified infection control intervention was implemented, followed by active surveillance and carrier isolation in the third year. The incidence of carbapenemase-producing K. pneumoniae patient cases decreased from 0.52/1,000 patient days in 2009 to 0.32/1,000 patient days in 2010 (P = 0.075). Following these additional infection control measures, the incidence fell to 0.21/1,000 patient days in 2011 and differed significantly from that in 2009 (P = 0.0028). Despite the fact that the imported cases of carbapenemase-producing K. pneumoniae were equally distributed over this 3-year period, the incidence of hospital-acquired cases decreased from 0.36/1,000 patient days in 2009 to 0.19/1,000 patient days in 2010 (P = 0.058) and to 0.1/1,000 patient days in 2011 (P = 0.0012). Our findings suggest that rigorous infection control measures and active surveillance can effectively reduce the incidence of secondary transmission due to KPC-producing pathogens.