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Background: The histopathologic features characterizing the involvement of the bone marrow (BM) in systemic lupus erythematosus (SLE) have not been systematically analyzed to date. Objectives: The aim of this study was to assess morphologic and immunohistochemical characteristics of BM involvement in SLE. Patients and methods: Clinical and serological data of 40 SLE patients with unexplained cytopenias were studied. Ten patients with myelodysplasia of refractory anemia (RA) were used as controls. BM aspiration, BM biopsy (BMB), and immunohistochemistry were carried out in patients and controls. BM fibrosis, BM necrosis, stromal edema, and abnormal localization of immature precursors (ALIP) were assessed according to standard criteria. Results: Dyserythropoiesis and megakaryocytic atypias were uniform findings in SLE patients. The disruption of the normal BM architecture was a predominant SLE BM feature affecting cells of all three hemopoietic lineages, with both erythroid and megakaryocytic precursors tending to assume paratrabecular locations and ALIP aggregates being present in 27 cases. In addition, BM was hypocellular in 23 cases. BM necrotic alterations were evident in 90% of the cases. The density of reticulin content was generally increased. Vascular changes including dilatation of sinuses were manifest and were associated with the presence of necrotic alterations (P = 0.008). Hemoglobin levels correlated inversely with the presence of ALIP (P = 0.016). Upon comparing BMB features between SLE and RA controls there were striking similarities. Conclusions: BMB in patients with SLE and unexplained cytopenias presents a variety of histopathologic findings including BM necrosis, stromal alterations, hypocellularity, dyspoiesis, and distortion of normal BM architecture, characterized primarily by the presence of ALIP aggregates. Am. J. Hematol. 81:590–597, 2006. © 2006 Wiley-Liss, Inc.

We present a case of chronic lymphocytic leukemia associated with nephrotic syndrome. Renal biopsy revealed membranous glomerulonephritis accompanied by interstitial monoclonal lymphocytic infiltration. Combination therapy with cyclophosphamide, vincristine, and prednisone (COP) was successful in inducing an effective response in chronic lymphocytic leukemia. Improvement of renal function and proteinuria was also observed.

It has been suggested that colonization with C. difficile protects from infection. Nevertheless, the association between carriage of toxinogenic strains and ensuing C. difficile infections (CDIs) has not been studied.We searched PubMed and EMBASE databases up to 20 June 2014, using the term "difficile". Our primary outcomes of interest included the prevalence of isolation of toxinogenic C. difficile or its toxins from asymptomatic patients on hospital admission through stool or rectal swab testing and the risk of ensuing infection among colonized and noncolonized patients. Data on previous hospitalization, antibiotic, and proton pump inhibitor (PPI) use and prior CDIs among colonized and noncolonized patients were also extracted.Nineteen out of 26,081 studies on 8,725 patients were included. The pooled prevalence of toxinogenic C. difficile colonization was 8.1% (95% confidence interval (CI) 5.7-11.1%), with an increasing trend over time (P=0.003), and 10.0% (95% CI 7.1-13.4%) among North American studies. Patients colonized upon hospital admission had a 5.9 times higher risk of subsequent CDIs compared with noncolonized patients (relative risk (RR) 5.86; 95% CI 4.21-8.16). The risk of CDI for colonized patients was 21.8% (95% CI 7.9-40.1%), which was significantly higher than that of noncolonized patients (3.4%; 95% CI 1.5-6.0%; P=0.03), with an attributable risk of 18.4%. History of hospitalization during the previous 3 months was associated with a higher risk of colonization (RR 1.63; 95% CI 1.13-2.34), as opposed to previous antibiotic (RR 1.07; 95% CI 0.75-1.53) and PPI use (RR 1.44; 95% CI 0.94-2.23), as well as history of CDI (RR 1.45; 95% CI 0.66-3.18) that had no impact.Over 8% of admitted patients are carriers of toxinogenic C. difficile with an almost 6 times higher risk of infection. These findings update current knowledge regarding the contribution of colonization in CDI epidemiology and stress the importance of preventive measures toward colonized patients.

Purpose The relative effectiveness and tolerability of treatments for type 2 diabetes mellitus (T2DM) is not well understood because few randomized, controlled trials (RCTs) have compared these treatments directly. The purpose of the present study was to evaluate the relative effectiveness and tolerability of treatments of T2DM. Methods We performed a network meta-analysis of available RCTs with pharmacologic interventions in T2DM and compared antidiabetic drugs and combination regimens with metformin (the reference drug). Glycemic control (proportion achieving HbA 1c goal) and tolerability (risk of hypoglycemia) were the primary outcomes of interest. Direct and indirect relative effects (unadjusted) were expressed as odds ratios and 95% CIs. Findings Eight treatments (glucagon-like peptide-1 [GLP-1] agonists plus metformin, sulfonylureas plus metformin, dipeptidyl peptidase-4 [DPP-4] inhibitors] plus metformin, colesevelan plus metformin, thiazolidinediones plus metformin, meglitinides plus metformin, α-glucosidase inhibitor plus metformin, and rosiglitazone monotherapy) outperformed metformin (direct effects). Triple combinations of GLP-1, thiazolinedione, insulin, metiglinide, or sulfonylureas added to a metformin backbone improved glycemic control (indirect effects). Higher risk of hypoglycemia was noted for sulfonylureas, α-glycosidases, and metiglinides when added to metformin (direct effects). Across indirect effects, only 17% of comparisons yielded less risk of hypoglycemia (70% were worse and 13% were comparable). Implications Our results point out the relative superiority of 2- and 3-drug combination regimens over metformin and summarize treatment effects and tolerability in a comprehensive manner, which adds to our knowledge regarding T2DM treatment options.

Background. Human immunodeficiency virus (HIV)–infected individuals who are colonized with methicillin-resistant Staphylococcus aureus (MRSA) have increased risk for MRSA infection. We conducted a meta-analysis of published studies to estimate the prevalence of MRSA colonization in this population. Methods. We performed a systematic literature review and meta-analysis. The PubMed and Embase databases were searched and studies reporting prevalence of MRSA colonization among HIV-infected individuals were included. Results. Among 7940 citations, 32 studies reporting data on 6558 HIV-infected individuals were considered eligible for our meta-analysis. We found that 6.9% (95% confidence interval [CI], 4.8–9.3) of individuals with HIV infection are MRSA carriers, with the corresponding figure across North American studies being 8.8% (95% CI, 6.0–12.2). History of hospitalization during the previous 12 months was associated with a 3.1 times higher risk of MRSA colonization (risk ratio [RR], 3.11 [95% CI, 1.62–5.98]). Previous or current incarceration was also associated with a higher risk for carriage (RR, 1.77 [95% CI, 1.26–2.48]). Current antiretroviral therapy or use of trimethoprim-sulfamethoxazole did not impact the risk of MRSA carriage (RR, 1.02 [95% CI, .64–1.63] and 1.45 [95% CI, .69–3.03], respectively). Extranasal screening increased the detection of MRSA colonization by at least 31.6% (95% CI, 15.8–50.0). The added yield from groin screening was 19.3% (95% CI, 11.5–28.5), from perirectal screening 18.5% (95% CI, 7.4–33.2), and from throat cultures 17.5% (95% CI, 12.0–24). Conclusions. Individuals with HIV infection constitute a highly vulnerable population for MRSA colonization, and prior exposure to hospital or incarceration are significant factors. Nasal screening alone will underestimate the rate of colonization by at least one-third.

Patients undergoing dialysis are particularly vulnerable to methicillin-resistant Staphylococcus aureus (MRSA) infections. We performed a meta-analysis of published studies to estimate the prevalence of MRSA colonization in dialysis patients, time trends, and long-term risk of subsequent MRSA infections. Our search of the PubMed and Embase databases returned 5743 nonduplicate citations, from which we identified 38 relevant studies that included data on 5596 dialysis patients. The estimated prevalence of MRSA colonization was 6.2% (95% confidence interval [95% CI], 4.2% to 8.5%). The prevalence increased over time but remained stable after 2000. Stratification of patients according to dialysis modality and setting revealed that 7.2% (95% CI, 4.9% to 9.9%) of patients on hemodialysis were colonized with MRSA compared with 1.3% (95% CI, 0.5% to 2.4%) of patients on peritoneal dialysis (P=0.01), and that a statistically significant difference existed in the percentage of colonized inpatients and outpatients (14.2% [95% CI, 8.0% to 21.8%] versus 5.4% [95% CI, 3.5% to 7.7%], respectively; P=0.04). Notably, the risk of developing MRSA infections increased among colonized hemodialysis patients compared with noncolonized patients (relative risk, 11.5 [95% CI, 4.7 to 28.0]). The long-term (6–20 months) probability of developing a MRSA infection was 19% among colonized hemodialysis patients compared with only 2% among noncolonized patients. In summary, 6.2% of dialysis patients are MRSA colonized, and the average prevalence of colonization has remained stable since 2000. Colonization in hemodialysis patients is associated with increased risk of MRSA infection.

Spondylodiscitis is a rare infectious entity that requires multimodal diagnostic procedures. We evaluated the diagnostic performance of 18F-FDG PET on suspected spondylodiscitis based on published literature.We searched the PubMed and EMBASE for pertinent studies up to July 2013. We implemented a patient-based meta-analysis of diagnostic data for FDG PET (the index test) against clinical, laboratory, and/or radiologic evidence of disease (the reference standard). A bivariate analysis was implemented to account for variability beyond the threshold effect. The individual patient data analysis was used to assess confounding factors that moderate diagnostic performance.Twelve studies provided the diagnostic data on FDG PET and spondylodiscitis, comprising 224 patients. The combined sensitivity across studies was 0.97 [95% confidence interval (CI), 0.83-1.00], the specificity was 0.88 (95% CI, 0.74-0.95), and the area under the curve was 0.98 (95% CI, 0.96-0.99). For prior probabilities greater than 0.50, the corresponding positive predictive value was 0.96 (0.93-0.98), and the negative predictive value was 0.85 (0.82-0.88). In the individual patient data analysis, metallic implants, dual PET/CT scanners and the addition of other imaging modalities to confirm disease were significant outcome moderators; only PET/CT remained significant in the adjusted analysis. PET/CT scanners improved the diagnostic performance, as opposed to the clinical data (age, sex, lesion site), which did not alter outcome.FDG PET is a robust diagnostic test when spondylodiscitis is suspected and is excellent for exclusion of infectious spondylodiscitis given its low likelihood ratio negative (0.1). Importantly, this diagnostic test is unaffected by other confounders, including the presence of implants, when PET/CT is used.

Background: Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases. Purpose: To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T) with infectious diseases. Data Sources: We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies. Study Selection: We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed. Data Extraction: Two authors independently extracted study data. Data Synthesis: The generalized odds ratio metric (ORG) was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (ORG 1.59; 95%CI 1.05-2.42), malaria (1.31; 95%CI 1.04-1.66), brucellosis (2.66; 95%CI 1.66-4.27), cutaneous leishmaniasis (7.22; 95%CI 1.91-27.29), neurocysticercosis (4.39; 95%CI 2.53-7.61), Streptococcus pyogenes tonsillar disease (2.93; 95%CI 1.24-6.93) , typhoid fever (2.51; 95%CI 1.18-5.34) and adult urinary tract infections (1.98; 95%CI 1.04-3.98), but was protective for leprosy (0.36; 95%CI 0.22-0.60). TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95%CI 0.31-0.98) and Haemophilus influenzae tonsillar disease (0.42; 95%CI 0.17-1.00). The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations. Conclusions: Depending on the type of infection and population, TLR4 polymorphisms are associated with increased, decreased or no difference in infectious disease. This may be due to differential functional expression of TLR4, the co-segregation of TLR4 variants or a favorable inflammatory response. Citation: Ziakas PD, Prodromou ML, El Khoury J, Zintzaras E, Mylonakis E (2013) The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to

Interleukin-6 (IL-6) is implicated in the pathophysiology of hematologic neoplasia.To review the role of IL-6 single nucleotide polymorphisms (SNPs) in hematologic neoplasia.PubMed and EMBASE search of genetic association studies. Effects were summarized using the model-free generalized odds ratio (ORG), and the mode of inheritance was estimated for significant associations.Seventeen articles provided data on 20 distinct SNPs. The IL-6 receptor rs8192284 was associated with an increased risk of hematologic malignancy (combined ORG 1.42, 95%CI 1.03-1.96), including multiple myeloma (ORG 1.39, 95%CI 0.99-1.95). The IL-6 promoter rs1800795 conferred protection against young adult Hodgkin's disease (ORG 0.68, 95%CI 0.48-0.95). Significant single-study effects for four other SNPs-disease associations were estimated. The IL-6 promoter rs1800795 and rs1800797 were not associated with overall susceptibility to non-Hodgkin's lymphomas.There is accumulating evidence that the IL-6 promoter, receptor and signal transducer SNPs can modify disease susceptibility.

Summary What is known and objective The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: ‘patients free of relapse’, ‘patients without disease progression’, ‘patients without MRI progression’ and ‘patients with adverse events’. Methods Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m2) using direct and indirect analyses. Results and discussion The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex (‘patients free of relapse’ and ‘patients without MRI progression’) and for Betaferon compared with Avonex (‘patients without disease progression’ and ‘patients without MRI progression’). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: ‘patients free of relapse’ and ‘patients without MRI progression’. Regarding ‘patients with adverse events’, no data were available for all comparisons to make fair inferences. What is new and conclusion This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments.

Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34+ cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 × 106 cells/kg increase in CD34+ cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P

Background The burden and significance of vancomycin-resistant enterococci (VRE) colonization in the ICU is not clearly understood. Methods We searched PubMed and EMBASE up to May 2013 for studies reporting the prevalence of VRE upon admission to the ICU and performed a meta-analysis to assess rates and trends of VRE colonization. We calculated the prevalence of VRE on admission and the acquisition (colonization and/or infection) rates to estimate time trends and the impact of colonization on ensuing VRE infections. Findings Across 37 studies (62,959 patients at risk), the estimated prevalence of VRE on admission to the ICU was 8.8% (7.1-10.6). Estimates were more consistent when cultures were obtained within 24 hours from admission. The VRE acquisition rate was 8.8% (95% CI 6.9-11.0) across 26 evaluable studies (35,364 patients at risk). Across US studies, VRE acquisition rate was 10.2% (95% CI 7.7-13.0) and demonstrated significant decline in annual trends. We used the US estimate of colonization on admission [12.3% (10.5-14.3)] to evaluate the impact of VRE colonization on admission in overall VRE prevalence. We demonstrated that VRE colonization on admission is a major determinant of the overall VRE burden in the ICU. Importantly, among colonized patients (including admitted and/or acquired cases) the VRE infection rates vary widely from 0-45% (with the risk of VRE bacteremia being reported from 0-16%) and

Mediterranean Kaposi’s sarcoma (MKS), HIV-related KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p < 0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p < 0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence.

We assessed the diagnostic performance of interim 18-fluorodeoxyglucose positron emission tomography (FDG-PET) with regard to the final outcome of adult patients with newly diagnosed Hodgkin lymphoma (HL). The predefined outcome was treatment failure at the end of follow-up. Bivariate meta-analysis of diagnostic data was used to calculate combined (pooled) estimates. Demographics, quality data and study characteristics were used as potential moderators of outcome in subgroup analysis and meta-regression. A total of 14 studies (16 arms stratified by staging or therapy, 1328 evaluable patients) were deemed eligible for final analysis, after excluding intention-to-treat studies (i.e. those where treatment decision was based on interim PET). The combined effect (95% confidence interval) for sensitivity was 0.67 (0.57-0.76) and specificity 0.89 (0.84-0.93). The corresponding likelihood ratios (LRs) were 6.2 (3.9-10.0) for LR + and 0.37 (0.27-0.50) for LR -, with moderate heterogeneity (I(2) =67%). The estimated negative predictive value was 0.93 (0.85-1.00). The diagnostic performance was influenced by most covariates tested, including age, duration of follow-up, criteria used and time of interim PET. Interim PET retains a high specificity for final outcome, but the sensitivity is low. The use of a PET + study as a surrogate marker is hampered by inconsistent interpretation criteria and study populations. However, the high negative predictive value may permit treatment stratification based on a negative outcome.

The aim of this study was to evaluate the aetiology of 'unexplained' cytopenias in patients with autoimmune disorders, as well as to identify parameters that should alert clinicians to the need for bone marrow examination.During the study period (2005-2010), 110 consecutive patients with an underlying systemic autoimmune disease, excluding Sjogren's syndrome, were referred for haematological consultation and bone marrow examination, due to cytopenias without evident cause including blood loss, haemolysis, nutritional deficiencies and haemoglobin disorders.Systemic lupus erythaematosus was the most frequent underlying condition (38/110, 34.5%), and anaemia (haemoglobin12gr/dl) the most common haematologic abnormality (81/110, 74%). Prior to evaluation, more than half of the patients received cytotoxic or immunosuppressive drugs, with methotrexate being the most commonly administrated agent (29/110, 26.4%). Evaluation was informative in 31 (28.2%) of the cases. Twenty-four (21.8%) cases of haematologic clonal disease were diagnosed; 11 myelodysplastic syndromes, 6 lymphoproliferative disorders, 6 plasma cell dyscrasias and one myeloproliferative neoplasm. Seven cases (6.4%) with bone marrow toxicity were also noted. Male gender, serum iron90 μg/dl, mean corpuscular volume (MCV)90fl, and serum monoclonal band were significant predictors of specific diagnosis including clonal haematologic disorder or bone marrow toxicity. All other correlations were insignificant.Clonal haematologic disorders and toxicity are frequent findings in patients with autoimmunity referred for haematologic consultation, owing to otherwise unexplained cytopenias. Patients with high serum iron, high MCV and presence of serum monoclonal band should undergo bone marrow examination to exclude haematologic malignancy or bone marrow toxicity.

Sjogren syndrome (SS) has been associated with the development of non-Hodgkin lymphoma (NHL). From a cohort of 584 SS patients followed in our department from 1980 to 2010, we retrospectively analyzed 53 consecutive NHL cases. Considerations included histologic type, clinical manifestation and NHL staging, treatment, response rate and overall survival (OS), event-free survival (EFS), and standardized mortality ratio (SMR).Mucosa-associated lymphoid tissue (MALT) lymphomas constituted the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (NMZLs) (15%) and diffuse large B-cell lymphomas (DLBCLs) (15%). Six lymphoma patients died during the median follow-up of 40.8 months. The corresponding age/sex-adjusted SMR of SS with and without NHLs versus the general population was 3.25 (95% confidence interval [CI] 1.32-6.76) and 1.08 (95% CI, 0.79-1.45), respectively. A "watch and wait" policy was adopted for 9 patients with asymptomatic localized salivary MALT lymphomas. Eight patients with limited-stage MALT lymphomas and extraglandular manifestations were treated with rituximab. Ten MALT lymphoma patients with disseminated disease received chemotherapy with or without rituximab. The 3-year OS and EFS in patients with MALT lymphomas was 97% and 78%, respectively. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the chosen therapeutic intervention for patients with DLBCLs. A successful outcome was recorded for this group, with 100% OS and EFS at 3 years. Patients with NMZLs had a less favorable outcome, with a 3-year OS of 80% and EFS of 53%. Our results describe the course and prognosis of SS-associated NHL and highlight the need for a risk-stratified treatment approach.

Granulocyte-colony-stimulating factors are helpful for the support of patients receiving autologous hematopoietic stem cell transplantation, resulting in faster neutrophil recovery and lower incidence of febrile neutropenia (FN). Our aim was to evaluate the use of pegfilgrastim vs. filgrastim with regard to absolute neutrophil count (ANC) recovery, risk, and duration of FN and length of hospital stay. Mean difference was the summary effect for continuous data, and odds ratio for binary data, using random-effects modeling. MEDLINE, EMBASE, and the Cochrane Registry of Randomized Controlled Trials were included in the search. Randomized controlled trials (RCTs), case-control studies, and studies with historical control group for filgrastim were eligible. Of the initial 114 studies screened, 12 studies were analyzed (four were RCTs, including one phase III trial). The use of pegfilgrastim resulted in a one d gain in ANC recovery (mean difference -0.82, 95% CI -1.07 to -0.57, p0.001) and duration of FN (-0.67, 95% CI -1.28 to -0.06, p0.001) but had no effect on the risk of FN or length of stay. Pegfilgrastim was more expensive (baseline marginal cost €116.97, p0.001), which was largely determined by the treatment duration and pegfilgrastim cost. Non-randomized setting attenuated the effect on duration of FN whereas delayed onset of filgrastim injections (to pegfilgrastim) overestimated the protective effect on the risk of FN. Both drugs are at least equally effective, though methodology and disease stratification in published trials warrant further improvement.

Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT). Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT. The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome.Fifty-seven cirrhotic patients [43 males; median age 58 (28-87) years] underwent Doppler echocardiography. Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time100 ms were deemed to have PPHT. ET-1, 2, and 3 serum levels were measured with an ELISA assay. All-cause mortality was recorded over a median period of 24 months.Nine out of 57 patients (15.8%) had PPHT. Among various clinical variables, only autoimmune hepatitis was associated with PPHT (OR=11.5; 95% CI, 1.58-83.4; P=0.01). ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL, P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7), P=0.02] were significantly higher in patients with PPHT than in those without. ET-2 and ET-3 levels did not differ between the two groups. There was no difference in survival between the two groups, although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11; 95% CI, 1.02-1.22; P=0.02 per unit increase in ET-1).Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.

Background : Acute lymphoblastic leukemia (ALL) is a complex disease with genetic background. The genetic association studies (GAS) that investigated the association between ALL and the MTHFR C677T and A1298C gene variants have produced contradictory or inconclusive results. Materials and methods : In order to decrease the uncertainty of estimated genetic risk effects, a meticulous meta-analysis of published GAS related the variants in the MTFHR gene with susceptibility to ALL was conducted. The risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (OR G ). Cumulative and recursive cumulative meta-analyses were also performed. Results The analysis showed marginal significant association for the C677T variant, overall [OR=0.91 (0.82–1.00) and OR G =0.89 (0.79–1.01)], and in Whites [OR=0.88 (0.77–0.99) and OR G =0.85 (0.73–0.99)]. The A1298C variant produced non-significant results. For both variants, the cumulative meta-analysis did not show a trend of association as evidence accumulates and the recursive cumulative meta-analysis indicated lack of sufficient evidence for denying or claiming an association. Conclusion : The current evidence is not sufficient to draw definite conclusions regarding the association of MTHFR variants and development of ALL.

Poor nutritional status is associated with high rates of healthcare-associated infections (HCAIs) among hospitalized elderly patients. Early recognition of patients at risk for HCAIs is important. The Geriatric Nutritional Risk Index (GNRI) is a screening tool able to predict nutrition-related complications.To examine the use of GNRI as a predictor of HCAIs in the acute care setting.A total of 248 consecutive patients aged65 years, admitted as emergencies to the medical ward of an acute care hospital, were enrolled. On admission, clinical and laboratory assessment, anthropometric measurements, performance status, and GNRI score estimation were performed. HCAIs were recorded during admission.On admission, 53.8% of the patients were not at risk, 37.2% at low or medium risk and 8.9% at high risk for nutrition-related complications, as stratified by using the GNRI. During hospitalization 23.7% of the patients developed HCAIs. Patients with HCAIs had higher mortality (P0.001) and longer hospital stay (P0.001). In multivariate analysis, a performance status1 [hazard ratio (HR): 2.08; 95% confidence interval (CI): 1.07-4.02; P = 0.03] and diabetes (HR: 2.57; 95% CI: 1.37-4.84; P = 0.003) were associated with increased risk for HCAIs, whereas GNRI score (per unit increase) had a protective effect (HR: 0.97; 95% CI: 0.95-0.99; P = 0.01). Well-nourished patients (GNRI98) were significantly more likely to remain free from HCAIs during hospitalization (P = 0.003).GNRI can accurately stratify hospitalized elderly patients according to risk for developing HCAIs.

Background Invasive fungal infections are responsible for substantial morbidity and mortality among patients with neutropenia after chemotherapy. Objective This meta-analysis was conducted to estimate the effect of systemic antifungal prophylaxis on the frequency of invasive fungal infections in patients with neutropenia and the mortality associated with these infections. Methods MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through September 15, 2010, for English-language publications of randomized controlled trials that compared systemic antifungal prophylaxis with placebo or no treatment in patients with neutropenia. Studies involving nonsystemic antifungal agents, direct comparisons of antifungal agents, and empirical, preemptive, or salvage treatment were excluded. Data were extracted according to European Organization for Research and Treatment of Cancer definitions of proven , possible , or probable fungal infections. Effect measures were reported as odds ratios (ORs) for fungal infection and mortality. Outcomes were pooled using random-effects meta-analysis. Study quality was assessed based on the study setting (single center or multicenter), institutional review board approval/informed consent, randomization, description of allocation concealment, double blinding, and reporting of dropouts. Results Twenty-six trials including a total of 3979 patients were included in the meta-analysis. Antifungal prophylaxis was associated with significant reductions in proven fungal infections (OR = 0.43; 95% CI, 0.31–0.60; number needed to treat [NNT] = 20) and mortality attributed to fungal infections (OR = 0.49; 95% CI, 0.30–0.80; NNT=53). Overall mortality was not affected by antifungal prophylaxis (OR = 0.92; 95% CI, 0.74–1.14). Antifungal prophylaxis was associated with a reduction in risk for proven Candida infections (OR = 0.28; 95% CI, 0.20–0.38), but not for aspergillosis or zygomycosis. Antifungal prophylaxis was also associated with a decreased need for antifungal therapy (OR = 0.64; 95% CI, 0.48–0.86). In an explanatory subgroup analysis of major outcomes, only recipients of a hematopoietic stem cell transplant (HSCT) had a significant likelihood of benefiting from antifungal prophylaxis in terms of reductions in risk for proven infections (OR = 0.27; 95% CI, 0.16–0.44) and mortality attributed to infections (OR = 0.41; 95% CI, 0.21–0.81). A metaregression analysis indicated that a multicenter (vs single-center) design and a double-blind (vs unblinded) design were significant moderators of the effect of antifungal prophylaxis on overall mortality and proven systemic fungal infections, respectively. Conclusions Systemic antifungal prophylaxis was associated with a reduction in proven fungal infections and mortality attributed to these infections in patients with neutropenia after chemotherapy. In the setting of HSCT, antifungal prophylaxis was associated with reductions in both proven infections and mortality attributed to infections. There was no significant association between antifungal prophylaxis and overall mortality.

Objective To estimate the effect of combined heparin and aspirin compared with aspirin monotherapy in pregnant women with antiphospholipid syndrome and recurrent pregnancy loss. Data sources We searched the PubMed database up to December 2009 for English-language studies using the key words "aspirin AND (heparin OR low molecular weight heparin), (antiphospholipid OR anticardiolipin OR aPL) AND pregnancy." Methods of study selection Two hundred ninety- two studies were initially screened. Randomized controlled trials comparing the effect of heparin (unfractionated heparin or low molecular weight heparin) plus aspirin compared with aspirin alone on the live-birth rate in women with a history of at least two miscarriages and antiphospholipid antibodies were eligible. Tabulation, integration, and results The pooled effect of unfractionated heparin and low molecular weight heparin was evaluable in three and two randomized controlled studies, respectively, with regard to live births, which was the major outcome. Overall, treatment effects were in favor of heparin against first-trimester losses (odd ratio [OR] 0.39, 95% confidence interval [CI] 0.24-0.65, number needed to treat 6). More specifically, unfractionated heparin displayed a significant effect (OR 0.26, 95% CI 0.14-0.48, number needed to treat 4), while the pooled effect of low molecular weight heparin was insignificant (OR 0.70, 95% CI 0.34-1.45). Combination therapy of either unfractionated heparin or low molecular weight heparin with aspirin failed to display any significant effect in the prevention of late-pregnancy losses. No significant differences were observed between treatment and control groups for any other outcomes. Conclusion The combination of unfractionated heparin and aspirin confers a significant benefit in live births. However, the efficacy of low molecular weight heparin plus aspirin remains unproven, highlighting the urgent need for large controlled trials.

Background: Despite the advent of combination chemotherapy regimens achieved within the last decade, long term survival of patients with unresectable metastatic disease from colorectal cancer remains poor. Thermal ablation procedures, including radiofrequency ablation (RFA), are considered feasible options in treating unresectable hepatic tumors either primary (hepatocellular carcinoma) or metastatic, the latter mainly arising from colorectal cancer. Percutaneous access is the least invasive RFA procedure. Methods & Results: A MEDLINE review unfolded a significant clinical heterogeneity among published series reporting on percutaneous RFA in hepatic metastatic disease from colorectal cancer, regarding study population, optimal time and treatment schemes pre- and post-RFA intervention. Notwithstanding, percutaneous RFA survival figures were consistently better than front line chemotherapy. Furthermore, a pooled analysis of larger series demonstrated a clear benefit in overall survival (HR 0.51, 95% CI 0.44 to 0.58). Conclusion: Albeit optimal indications are still pending, percutaneous RFA should nonetheless be considered a viable option in patients with unresectable metastatic disease, as it may prolong survival rates achieved with standard chemotherapy.

Background. One-third of the world’s population is infected with tuberculosis, and 9 months of isoniazid monotherapy is the treatment of choice for latent tuberculosis infection. However, this approach has been associated with hepatotoxicity and poor compliance. A shorter (4-month) rifampin regimen has been evaluated in recent clinical trials. Methods. We performed a meta-analysis of the published studies to compare compliance, toxicity, and costeffectiveness between the 2 strategies. Pooled effects were calculated as risk ratios (RRs) by means of randomeffects and fixed-effects models. Results. Pooled data from 3586 patients suggested that 4-month rifampin therapy was associated with a significant reduction in the risk of noncompletion (RR for random-effects model, 0.53; 95% confidence interval [CI], 0.44–0.63). Noncompletion rates were lower among patients who received 4-month rifampin therapy (range, 8.6%–28.4%), compared with noncompletion rates among patients who received 9-month isoniazid therapy (range, 24.1%–47.4%). Also, rates of hepatotoxicity (defined as grade 3 or 4 liver failure leading to drug discontinuation) were lower for patients who received 4-month rifampin therapy (range, 0%–0.7%), compared with the corresponding rates for patients who received 9-month isoniazid therapy (range, 1.4%–5.2%), and rifampin was associated with significant reduction in the risk of hepatotoxicity (RR for fixed-effects model, 0.12; 95% CI, 0.05– 0.30). Notably, with the data from our meta-analysis, we calculated that the 4-month rifampin strategy is also cost-effective and results in $213 savings per patient treated ($90/patient when doctor fees are not included). Conclusions. The improved compliance, safety, and cost associated with the 4-month rifampin therapy suggest that the efficacy of this approach needs to be evaluated in detail. An extended posttreatment follow-up in future studies will clarify the unresolved issue of tuberculosis reactivation rates.

Background: Cirrhosis is associated with elevated levels of acute-phase proteins (APP), irrespective of the presence of infection. This condition limits the clinical application of APP determination in cirrhotic patients with bacterial infections. Aims: To weigh the diagnostic value of several APP in cirrhotics with or without bacterial infection, and to correlate them with the clinical outcome. Methods: We investigated 88 consecutive cirrhotic patients (67 males, 21 females; range 28–85 years) with mean age (SD) 58.9 (13.8) on admission, according to a standard protocol for infection. We measured the following APP: C-reactive protein (CRP), fibrinogen (FIB), haptoglobin (Hpt), ferritin (Fer), β2-microglobulin (β2-mg), C3, C4 and C1 inhibitor. Results: From the 88 patients, 19 (21.6%) had documented infection at the entry based on clinical, radiological and microbiological data. This group of patients did not differ in basic demographics from those without infection. CRP [17.5 (20.7) vs 77.1 (43.9), P55.8 mg/L has high sensitivity (79%) and specificity (96%), with the best diagnostic accuracy (92%).

Lamivudine prophylaxis is an effective strategy in HbSAg-positive patients receiving cancer chemotherapy. Recent data indicate that a lamividune-prophylaxis strategy results in a decrease of hepatitis B virus (HBV) reactivation rates, though its effect on HBV-mortality remains equivocal. This report evaluates the benefits from this strategy among lymphoma patients and develops a management approach for patients with prolonged immunosuppression. A Medline search was conducted to retrieve published trials on HBsAg-positive lymphoma patients receiving prophylactic lamivudine during chemotherapy. Basic inclusion criterion was to report HBV-reactivation rates with and without lamivudine prophylaxis. A meta-analysis of the risk of HBV-reactivation and HBV-related mortality was conducted, and the pooled effect was calculated as risk ratio (RR). We found that lamivudine prophylaxis is associated with a significant reduction in hepatitis B virus reactivation (RR 0.21, 95%CI 0.13–0.35) and a trend in reducing HBV-related mortality (RR 0.68, 95%CI 0.19–2.49). In order to study the long-term effects of anti-HBV prophylaxis when prolonged immunosuppression is needed, we used our findings to model a decision tree. Overall survival was the main outcome used in the analysis. Rituximab maintenance in B-cell lymphomas was used as a paradigm of prolonged immunosuppression. We found that extended anti-HBV prophylaxis can improve survival rates by 2.4% in HBsAg-positive patients. If 1,000 HBsAg-positive lymphoma patients receive prophylaxis, one will die from hepatitis B virus reactivation versus 25/1,000 if no prophylaxis is administered. This effect is probably mediated through a reduction of hepatitis B virus reactivation and HBV-related mortality. The ideal antiviral agent needs to be determined.

We evaluated the safety and efficacy of image-guided radiofrequency ablation (RFA) using a triple-spiral-shaped electrode needle for unresectable primary or metastatic hepatic tumors. Thirty-four patients with 46 index tumors were treated. Ablation zone, morbidity, and complications were assessed. The lesions were completely ablated with an ablative margin of about 1 cm. Five patients (14.7%) with a lesion larger than 4.5 cm had local tumor progression after 1 month and were retreated. Hemothorax, as a major complication, occurred in 1 of 34 patients (3.0%) or 1 of 46 lesions ablated (2.2%). RFA using this new electrode needle can be effective in the treatment of large unresectable hepatic tumors.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired stem cell disorder, with its primary clinical manifestations being hemolytic anemia, marrow failure and thrombophilia. Chronic hemolysis, failures of the fibrinolytic system, increased leukocyte – derived tissue factor levels in plasma, procoagulant microparticles generated through complement-mediated damage of platelets and venous endothelium are related to the acquired hypercoagulable state. Visceral thrombosis (including hepatic veins and mesenteric veins), cerebrovascular events and pulmonary embolism predict a poor outcome. Thrombosis is also associated with significant morbidity during pregnancy. Depending on the sites of thrombosis, a score-based probability to predict outcome can be assigned. Abdominal vein thromboses account for the majority of morbidity and mortality related to thrombosis, and time-dependent trends suggest that mortality rates tend to decline, with the advent of evolution of therapeutic and diagnostic strategies. In contrast, mortality rates from cerebrovascular events display no significant decline. Prompt diagnosis requires both clinical suspicion and sophisticated imaging techniques, along with multidisciplinary therapeutic intervention. In the eculizumab era, a significant reduction of thrombotic events was observed during therapy, and long-term follow up is needed to establish any benefit in rates and pattern of this complication. However, up to now, only bone marrow transplantation permanently abolishes the coagulation defect.

Background The use of positron emission tomography with fluoro-deoxy-glucose (FDG PET) in Hodgkin's disease (HD) is continuing to expand worldwide, with response assessment after completion of therapy being its most widely utilized application. A positive scan has been associated with high relapse rates and disease progression. Methods A decision analysis was performed to determine the long-term impact of FDG PET restaging both with and without computed tomography (CT) in terms of the 5-year progression-free survival (5yrPFS). Outcomes and utilities were based on published data. The first strategy involved CT restaging after first-line therapy, with or without subsequent FDG PET, while the second strategy used FDG PET scan alone. All positive test required histological examination. Upon histological confirmation of active lymphoma, patients were considered candidates for autologous transplantation and long-term outcomes were retrieved. The expected clinical benefit of the two strategies was calculated and depicted, along with the mean costs. One-way and two-way sensitivity analyses were performed to ensure the validity of the results. Results CT restaging plus FDG PET when residual mass is detected, results in a 2% benefit at 5yrPFS at baseline compared to FDG PET-alone restaging and remains positive for a wide range of probabilities. This strategy reduces the average cost by €1863 per patient, including costs of biopsy and autologous transplantation. Conclusion A more conservative approach that includes CT restaging after first-line therapy and FDG PET scan only on residual mass, is the preferred strategy in HD. Furthermore it appears to confer the maximal diagnostic yield along with a substantial reduction in the mean cost.

Low-grade systemic chronic inflammation is a very well-known feature of diabetes mellitus (DM). The purpose of this study was the assessment of the proinflammatory cytokine secretion profile in long-standing diabetes along with the presence of features of systemic inflammation. Metabolic parameters and serum high-sensitivity C-reactive protein, interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels were determined in 20 patients with type 1 DM and 21 patients with type 2 DM and compared to 34 healthy subjects. The number of cytokine-secreting peripheral blood mononuclear cells (PBMCs), before and after mitogenic stimulation, was also determined in the same groups. Adverse lipid profile, higher levels of inflammatory markers, and higher count of cytokine-secreting cells were observed more prevalently in type 2 diabetics than in controls. After stimulation, the increase in number of cytokine-secreting cells was higher in controls. In conclusion, patients with DM have evidence of low-grade inflammation and abnormal PBMC function that could be related to long-term sequelae, the accelerated atherosclerotic process, and the susceptibility to infections.

The objective of this investigation was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment, in low-risk cancer patients with fever and neutropenia. We analysed retrospectively 120 episodes of febrile neutropenia, treated on an outpatient basis at 2 different oncology units; 63 episodes were treated with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 57 were treated with the combination of oral ciprofloxacin plus cefuroxime. 20 treatment failures were recorded-2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group. Univariate analysis showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11, CI 2.42-49.9, p =0.002). In the multivariate model, after adjusting for the absolute number of neutrophils and the duration of neutropenia, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted, although the regimen of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72-31.1, p =0.10). In conclusion, the 2 regimens appeared equally safe and effective but prospective studies are needed to confirm these results.

Objectives The social and economic burden of osteoporosis is important since it concerns a continuously aging population, while the disease is silent until the emergence of fractures. Aim of the study was to assess female population knowledge about osteoporosis risk factors and to identify the risk factors of the studied population. Methods A sample of 99 (aged: 61.59 ± 9.61 years) women under treatment for osteoporosis or osteopenia answered the questionnaire provided by their pharmacists and were included in the study's analysis. Various parameters on osteoporosis awareness and risk factor knowledge of the population sample studied were analyzed. Results It was revealed that 96% of the participants knew osteoporosis definition and sources of this knowledge were one or more of the following: doctors (86.3%), mass media (20%) and friends or relatives (13.7%). It was found that the older age was associated with less knowledge (OR = 0.93, CI: 0.88–0.97, p = 0.004), and higher education with increased knowledge (OR = 1.68, CI: 1.10–2.55, p = 0.014) about osteoporosis. 56.4% of the participants were aware of at least one osteoporosis risk factor. In multivariate analysis, it was revealed that the participants who referred increased milk products consumption in childhood (OR = 3.72, CI: 1.34–10.36, p = 0.012) and current performance of physical activity (OR = 13.06, CI: 3.22–53.05, p 61 years was associated with decreased knowledge of risk factors (OR = 0.27, CI: 0.09–0.82, p = 0.018). Conclusions This study implies that a higher degree of participant's health education may result in the avoidance of osteoporosis risk factors. Increasing knowledge of osteoporosis should be a priority for future intervention programs in order to promote specific behavioural strategies for osteoporosis prevention.

Thrombocytopenia in patients with systemic lupus erythematosus (SLE) requires immunosuppressive treatment to restore normal platelet counts and treat concomitant organ involvement in other systems.1–6 However, relapses are quite common during the course of the disease.7 From 1995 to 2004, 38 consecutive patients with SLE with a first episode of thrombocytopenia (platelet count 150 000). Severe thrombocytopenia (

Hepatocellular cancer ranks fifth among cancers and is related to chronic viral hepatitis, alcohol abuse, steatohepatitis and liver autoimmunity. Surgical resection and orthotopic liver transplantation have curative potential, but fewer than 20% of patients are suitable candidates. Interventional treatments are offered to the vast majority of patients. Radiofrequency (RFA) and microwave ablation (MWA) are among the therapeutic modalities, with similar indications which include the presence of up to three lesions, smaller than 3 cm in size, and the absence of extrahepatic disease. The therapeutic effect of both methods relies on thermal injury, but MWA uses an electromagnetic field as opposed to electrical current used in RFA. Unlike MWA, the effect of RFA is partially limited by the heat-sink effect and increased impedance of the ablated tissue. Compared with RFA, MWA attains a more predictable ablation zone, permits simultaneous treatment of multiple lesions, and achieves larger coagulation volumes in a shorter procedural time. Major complications of both methods are comparable and infrequent (approximately 2%-3%), and they include haemorrhage, infection/abscess, visceral organ injury, liver failure, and pneumothorax. RFA may incur the additional complication of skin burns. Nevertheless, there is no compelling evidence for differences in clinical outcomes, including local recurrence rates and survival.

Objective To determine the ability of initial forced vital capacity (FVC) of patients with scleroderma to predict subsequent pulmonary function deterioration. Methods Data on 78 patients with scleroderma were retrospectively collected and analyzed. FVC (percent predicted), diffusing capacity for carbon monoxide (percent predicted), and various clinical and laboratory parameters were recorded. Pulmonary function decline (outcome) was defined as at least a 15-point sustained decrease in FVC (percent predicted). Kaplan-Meier analyses were performed separately for 60 patients initially assessed within the first 3 years from disease onset (group A) and 16 patients whose FVC values in the fourth or fifth year from disease onset were ascribed as baseline measurements (group B). Results Based on baseline FVC, patients in each group were categorized into those with normal FVC (≥80% predicted) and those with decreased FVC (

Background Graft-versus-host Disease (GvHD) prophylaxis after allogeneic hematopoietic stem-cell transplantation (HSCT) is an ongoing effort but relative effects of different policies are not systematically explored. Methods We systematically reviewed 30-year evidence on GvHD prophylaxis and quantified the relative effect of different policies using a network meta-analysis. We searched PubMed and the Cochrane Library for randomized studies on the topic. The primary outcome of interest was grade II-IV acute GvHD over 0 or I (with odds ratio OR

Background: Invasive aspergillosis (IA) is associated with significant morbidity and mortality among hematopoietic-stem cell transplant (HSCT) recipients. Timely and accurate diagnosis of an active infection is needed in order to initiate targeted antifungal therapy. Although previous studies have assessed the performance of Aspergillusspp. PCR with promising findings, PCR has not yet been incorporated in the diagnostic algorithms by the guideline issuing organizations. Aim: Our goal was to evaluate PCR as a screening or a confirmatory tool for the diagnosis of IA among HSCT patients and to determine the different parameters that could contribute to contradictory reports from the literature regarding PCR performance. Thus, we performed a meta-analysis of clinical trials that evaluated the accuracy of PCR for IA performed on serum and whole blood of HSCT patients. Methods: We performed a bivariate meta-analysis of diagnostic data for Aspergillus spp. PCR on blood specimens across HSCT patients. We included all studies involving human subjects that assessed the performance of any PCR assay for IA on whole blood or serum and that used as reference standard the EORTC/MSG criteria. We performed 2 separate analyses either including or excluding the cases that were defined as “possible”. When possible cases where included they were classified as negative. Out of 37 total studies, 25 met strict quality criteria and were included. Results: 25 studies with 2,595 patients were analyzed. Six studies performed PCR on serum (23%) and the remaining used whole blood assays (77%). The pooled diagnostic performance of whole blood and serum PCR was moderate, with a sensitivity of 84% (95% CI 75%-91%). Specificity was 76% (95% CI 65%-84%) when possible cases were included and 85% (95% CI 74%-91%) when excluded, suggesting that a positive or negative result is unable on its own to confirm or exclude a suspected infection. In subgroup analysis, the performance of PCR on serum was not significantly different from whole blood when possible cases were included. Interestingly, exclusion of possible cases revealed higher specificity of serum PCR (94% vs. 80%, meta-regression p-value=0.05) over whole blood without altering the sensitivity (79% vs. 85%, meta-regression p-value=0.4) and high positive likelihood ratio (LR+=12.6) suggesting that serum PCR could be used as a confirmatory test. No methodological parameter significantly affected the performance of PCR. Importantly, PCR specificity was greatly increased when 2 positive PCR results were used to define positivity (73% vs. 95%, respectively), giving a high positive likelihood ratio of 12.8, whereas sensitivity decreased (85% vs 64%, respectively). Importantly, the European AspergillusPCR Initiative (EAPCRI) recommendations improved even further the performance of PCR when at least two positive specimens were used to define ‘PCR positivity’. Conclusions: Two positive PCR results should be considered highly indicative of an active Aspergillus spp. infection in HSCT patients. Use of the EAPCRI recommendations by clinical laboratories can further enhance PCR performance. Disclosures No relevant conflicts of interest to declare.

We describe a patient with myelofibrosis, giant splenomegaly, and pulmonary hypertension related to increased intra-abdominal pressure. Focusing on alterations in hemodynamic studies, we conclude that in patients with myelofibrosis, dyspnea, and hypoxemia, the measurement of intra-abdominal pressure should be included in the initial evaluation. It is an inexpensive, non-invasive diagnostic tool that can provide crucial information about the cause of dyspnea and disclose the pathogenetic link between massive splenomegaly and pulmonary compromise in myelofibrosis.