Infectious diseases are important causes of morbidity and mortality in patients with cancer. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This portion of the guidelines highlights the sections on antifungal and antiviral prophylaxis. Antifungal and antiviral prophylaxis recommendations have expanded over the past few years. New agents for the treatment of fungal infections and incorporation of therapeutic drug monitoring are presented. Antiviral prophylaxis for hepatitis B and management considerations for hepatitis C and HIV have been further developed.

Individuals with blood lead levels of 20 to 29 micro g/dL in 1976 to 1980 (15% of the US population at that time) experienced significantly increased all-cause, circulatory, and cardiovascular mortality from 1976 through 1992. Thus, we strongly encourage efforts to reduce lead exposure for occupationally exposed workers and the 1.7 million Americans with blood lead levels of at least 20 micro g/dL (> or = 1.0 micromol/L).

Glioblastoma (GBM) is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric di-methylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell cycle arrest, apoptosis and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Lastly, PRMT5 attenuation enhanced GBM cell survival in a mouse xenograft model of aggressive GBM. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in GBM, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.

ContextLead exposures have been shown to be associated with increased blood pressure and risk of hypertension in older men. In perimenopausal women, skeletal lead stores are an important source of endogenous lead exposure due to increased bone demineralization.ObjectiveTo examine the relationship of blood lead level with blood pressure and hypertension prevalence in a population-based sample of perimenopausal and postmenopausal women in the United States.Design, Setting, and ParticipantsCross-sectional sample of 2165 women aged 40 to 59 years, who participated in a household interview and physical examination, from the Third National Health and Nutrition Examination Survey conducted from 1988 to 1994.Main Outcome MeasuresAssociations of blood lead with blood pressure and hypertension, with age, race and ethnicity, cigarette smoking status, body mass index, alcohol use, and kidney function as covariates.ResultsA change in blood lead levels from the lowest (quartile 1: range, 0.5-1.6 µg/dL) to the highest (quartile 4: range, 4.0-31.1 µg/dL) was associated with small statistically significant adjusted changes in systolic and diastolic blood pressures. Women in quartile 4 had increased risks of diastolic (>90 mm Hg) hypertension (adjusted odds ratio [OR], 3.4; 95% confidence interval [CI], 1.3-8.7), as well as moderately increased risks for general hypertension (adjusted OR, 1.4; 95% CI, 0.92-2.0) and systolic (>140 mm Hg) hypertension (adjusted OR, 1.5; 95% CI, 0.72-3.2). This association was strongest in postmenopausal women, in whom adjusted ORs for diastolic hypertension increased with increasing quartile of blood lead level compared with quartile 1 (adjusted OR, 4.6; 95% CI, 1.1-19.2 for quartile 2; adjusted OR, 5.9; 95% CI, 1.5-23.1 for quartile 3; adjusted OR, 8.1; 95% CI, 2.6-24.7 for quartile 4).ConclusionsAt levels well below the current US occupational exposure limit guidelines (40 µg/dL), blood lead level is positively associated with both systolic and diastolic blood pressure and risks of both systolic and diastolic hypertension among women aged 40 to 59 years. The relationship between blood lead level and systolic and diastolic hypertension is most pronounced in postmenopausal women. These results provide support for continued efforts to reduce lead levels in the general population, especially women.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmu-notherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatu-zumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malig-nancies. Because rituximab and milatu-zumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochon-drial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-B pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL. (Blood. 2011; 117(17):4530-4541) Introduction Mantle cell lymphoma (MCL) is a B-cell malignancy with a variable histology and clinical course, distinguished by the characteristic translocation t(11;14)(q13, q32) that results in overexpres-sion of cyclin D 1 and consequent dysregulation of cell-cycle control. 1 In addition, MCL exhibits alterations in cell survival pathways, including constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling 2 and nuclear factor-B (NF-B). 3 Despite the hallmark genetic translocation in MCL, the clinical course of MCL is variable with some patients experiencing indolent disease, 4 whereas others exhibit rapid progression. 5 MCL patients have a median overall survival (OS) of approximately 3 years, and no consensus exists for standard first-line therapy. 6-9 Although aggressive therapies including chemoimmunotherapy 10,11 or stem cell transplantation 12,13 have been shown to improve outcomes, no therapy offers the potential for cure. Given the absence of curative therapy and the limited number of options for patients with relapsed/refractory MCL, novel treatment approaches are essential. Rituximab (Genentech), a chimeric anti-human CD20 monoclo-nal antibody (mAb), has been used in multiple strategies to treat patients with MCL. 14 As a single agent, rituximab has been tested in patients with newly diagnosed and relapsed/refractory MCL with response rates (RR) of 27% to 38% and a median response duration of 6 to 12 months. 15,16 Interestingly, the RR obtained in untreated patients was not higher than in relapsed...

IntroductionWe set a goal to reduce the incidence rate of catheter-related bloodstream infections to rate of <1 per 1,000 central line days in a two-year period.MethodsThis is an observational cohort study with historical controls in a 25-bed intensive care unit at a tertiary academic hospital. All patients admitted to the unit from January 2008 to December 2011 (31,931 patient days) were included. A multidisciplinary team consisting of hospital epidemiologist/infectious diseases physician, infection preventionist, unit physician and nursing leadership was convened. Interventions included: central line insertion checklist, demonstration of competencies for line maintenance and access, daily line necessity checklist, and quality rounds by nursing leadership, heightened staff accountability, follow-up surveillance by epidemiology with timely unit feedback and case reviews, and identification of noncompliance with evidence-based guidelines. Molecular epidemiologic investigation of a cluster of vancomycin-resistant Enterococcus faecium (VRE) was undertaken resulting in staff education for proper acquisition of blood cultures, environmental decontamination and daily chlorhexidine gluconate (CHG) bathing for patients.ResultsCenter for Disease Control/National Health Safety Network (CDC/NHSN) definition was used to measure central line-associated bloodstream infection (CLA-BSI) rates during the following time periods: baseline (January 2008 to December 2009), intervention year (IY) 1 (January to December 2010), and IY 2 (January to December 2011). Infection rates were as follows: baseline: 2.65 infections per 1,000 catheter days; IY1: 1.97 per 1,000 catheter days; the incidence rate ratio (IRR) was 0.74 (95% CI = 0.37 to 1.65, P = 0.398); residual seven CLA-BSIs during IY1 were VRE faecium blood cultures positive from central line alone in the setting of findings explicable by noninfectious conditions. Following staff education, environmental decontamination and CHG bathing (IY2): 0.53 per 1,000 catheter days; the IRR was 0.20 (95% CI = 0.06 to 0.65, P = 0.008) with 80% reduction compared to the baseline. Over the two-year intervention period, the overall rate decreased by 53% to 1.24 per 1,000 catheter-days (IRR of 0.47 (95% CI = 0.25 to 0.88, P = 0.019) with zero CLA-BSI for a total of 15 months.ConclusionsResidual CLA-BSIs, despite strict adherence to central line bundle, may be related to blood culture contamination categorized as CLA-BSIs per CDC/NHSN definition. Efforts to reduce residual CLA-BSIs require a strategic multidisciplinary team approach focused on epidemiologic investigations of practitioner- or unit-specific etiologies.

We analyzed data from 798 lead workers to determine whether polymorphisms in the genes encoding delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR) were associated with or modified relations of lead exposure and dose measures with renal outcomes. Lead exposure was assessed with job duration, blood lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and tibia lead. Renal function was assessed with blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, calculated creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG), and retinol-binding protein. Mean (+/- SD) tibia lead, blood lead, and DMSA-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0 +/- 15.0 microg/dL, and 767.8 +/- 862.1 microg/g creatinine, respectively. After adjustment, participants with the ALAD(2) allele had lower mean serum creatinine and higher calculated creatinine clearance. We observed effect modification by ALAD on associations between blood lead and/or DMSA-chelatable lead and three renal outcomes. Among those with the ALAD(1-2) genotype, higher lead measures were associated with lower BUN and serum creatinine and higher calculated creatinine clearance. Participants with the eNOS variant allele were found to have higher measured creatinine clearance and BUN. In participants with the Asp allele, longer duration working with lead was associated with higher serum creatinine and lower calculated creatinine clearance and NAG; all were significantly different from relations in those with the Glu/Glu genotype except NAG (p = 0.08). No significant differences were seen in renal outcomes by VDR genotype, nor was consistent effect modification observed. The ALAD findings could be explained by lead-induced hyperfiltration.

Our purpose was to compare fluoroscopy time during endoscopic retrograde cholangiopancreatography (ERCP) between endoscopists with different levels of experience. We performed a cross-sectional analysis of 269 consecutive ERCPs at an academic hospital during 1 year. Median fluoroscopy time was significantly longer in more complex cases, such as in therapeutic (406.5 s [IQR, 235.5-685]) compared to diagnostic (202 s [IQR, 141-481]; P = 0.002) procedures. The experience (number of prior ERCPs) of gastroenterology fellows involved in procedures was an independent predictor of shorter fluoroscopy time when controlling for patient and procedure characteristics (P < 0.0001). Median fluoroscopy time was 2.73 min shorter after at least 50 procedures had been performed (P = 0.039). Time for ERCPs involving fellows was not significantly longer than cases by attending physicians alone (P = 0.23). Increased experience is associated with lower radiation exposure during ERCP training. Radiation reduction methods should be prospectively investigated and integrated into training programs.