Effect of Advanced HIV Infection on the Respiratory Microbiome.

RATIONALE: Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population. OBJECTIVES: To measure the lung microbiome in an HIV-infected population with advanced disease. METHODS: 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm(3)) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects. MEASUREMENTS AND MAIN RESULTS: The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting therapy. Population dispersion in the group infected with HIV was significantly greater than in the uninfected cohort and declined after treatment. There were differences in the relative abundance of some bacteria between the two groups at baseline and after 1 year of therapy. After 1 year on HAART, HIV BAL contained an increased abundance of Prevotella and Veillonella, bacteria previously associated with lung inflammation. CONCLUSIONS: The lung microbiome in subjects infected with HIV with advanced disease is altered compared with an uninfected population both in diversity and bacterial composition. Differences remain up to 3 years after starting HAART. We speculate an altered lung microbiome in HIV infection may contribute to chronic inflammation and lung complications seen in the HAART era.

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy.

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2 years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95 %) and Cho (2.61 %) in the FWM; NAA (1.89 %), Cr (1.84 %), Cho (2.19 %), and Glx (6.05 %) in the MFC; and Glx (2.80 %) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Molecular analysis of tumor margins by MALDI mass spectrometry in renal carcinoma.

The rate of tumor recurrence post resection suggests that there are underlying molecular changes in nearby histologically normal tissue that go undetected by conventional diagnostic methods that utilize contrast agents and immunohistochemistry. MALDI MS is a molecular technology that has the specificity and sensitivity to monitor and identify molecular species indicative of these changes. The current study utilizes this technology to assess molecular distributions within a tumor and adjacent normal tissue in clear cell renal cell carcinoma biopsies. Results indicate that the histologically normal tissue adjacent to the tumor expresses many of the molecular characteristics of the tumor. Proteins of the mitochondrial electron transport system are examples of such distributions. This work demonstrates the utility of MALDI MS for the analysis of tumor tissue in the elucidation of aberrant molecular changes in the tumor microenvironment.

Resequencing of the vascular endothelial growth factor promoter reveals haplotype structure and functional diversity.

Our group has previously reported that SNPs in the VEGF promoter are strongly associated with efficacy and toxicity to the anti-VEGF antibody bevacizumab in breast cancer. In order to better understand the biologic mechanism for our previously reported biomarkers, we embarked on a comprehensive evaluation of genetic variation in the VEGF promoter coupled with a study of its intrinsic function. We resequenced 48 Caucasians and 48 African-Americans for the VEGF promoter to identify SNPs and elucidate its haplotype structure. We further cloned the haplotypes into reporter constructs and assessed the role of SNPs on promoter function in breast cancer cell lines. SNPs that were identified included twenty previously reported SNPs/insertions/deletions, one novel SNP, and one novel deletion. Among these variants, we identified five SNPs that tag six haplotypes capturing 74% of the genetic variation of the promoter. Subsequently, assessment of the haplotypes in reporter constructs demonstrates significant variation in promoter induced expression among the haplotypes. In particular, two haplotypes had higher expression and one haplotype had lower expression across cell lines. Haplotypes containing SNPs previously reported to be associated with increased survival with the use of bevacizumab are high-expressing haplotypes, thus lending putative functional evidence to the prior clinical finding.

Estrogen receptor genotype is associated with risk of venous thromboembolism during tamoxifen therapy.

Thromboembolism is a serious complication of tamoxifen therapy in women with breast cancer. Banked DNA from tamoxifen-treated individuals with breast cancer from the Marshfield Clinic Personalized Medicine Research Project, a population-based DNA repository, was tested for association between incidence of tamoxifen-associated thromboembolic events (TTE) and single nucleotide polymorphisms encoding the estrogen receptors 1,2 (ESR1, ESR2) or drug metabolism enzymes cytochrome P450 2D6 (CYP2D6) and aromatase (CYP19). TTE were experienced by 16/220 subjects with risk association noted for XbaI (rs9340799) genotype and ESR1 Xbal/PvuII diplotype (rs9340799 and rs2234693) (hazard ratio 3.47, 95% CI 0.97-12.44, P = 0.035). Association persisted after adjusting for classical risk factors including age at diagnosis and body mass index at enrollment. Initial evidence of association between increased risk for TTE and ESR1 genotype and ESR1 diplotype is presented. Determination of estrogen receptor genotype may identify a subset of women at increased risk for thromboembolism with tamoxifen exposure.

Imaging mass spectrometry reveals unique protein profiles during embryo implantation.

A reciprocal interaction between the implantation-competent blastocyst and receptive uterus is an absolute requirement for implantation, a process crucial for pregnancy success. A comprehensive understanding of this interaction has yet to be realized. One major difficulty in clearly defining this discourse is the complexity of the implantation process involving heterogeneous cell types of both the uterus and blastocyst, each endowed with unique molecular signatures that show dynamic changes during the course of pregnancy. Whereas gene expression studies by in situ hybridization or immunohistochemistry have shown differential expression patterns of specific genes during implantation, there is no report how numerous signaling proteins are spatially displayed at specific times and stages of implantation in the context of blastocyst-uterine juxtaposition. Using in situ imaging (matrix assisted laser desorption/ionization) mass spectrometry directly on uterine sections, here we provide molecular composition, relative abundance, and spatial distribution of a large number of proteins during the periimplantation period. This approach has allowed us for the first time to generate in situ proteome profiles of implantation and interimplantation sites in mice in a region- and stage-specific manner with the progression of implantation. This application is reliable because patterns of expression of several proteins displayed by in situ imaging mass spectrometry correlate well with in situ hybridization results. More interestingly, the use of this approach has provided new insights regarding uterine biology of cytosolic phospholipase A(2alpha) null females that show implantation defects.

Enhancement of protein sensitivity for MALDI imaging mass spectrometry after chemical treatment of tissue sections.

MALDI imaging mass spectrometry (IMS) has become a valuable tool for the investigation of the content and distribution of molecular species in tissue specimens. Numerous methodological improvements have been made to optimize tissue section preparation and matrix deposition protocols, as well as MS data acquisition and processing. In particular for proteomic analyses, washing the tissue sections before matrix deposition has proven useful to improve spectral qualities by increasing ion yields and the number of signals observed. We systematically explore here the effects of several solvent combinations for washing tissue sections. To minimize experimental variability, all of the measurements were performed on serial sections cut from a single mouse liver tissue block. Several other key steps of the process such as matrix deposition and MS data acquisition and processing have also been automated or standardized. To assess efficacy, after each washing procedure the total ion current and number of peaks were counted from the resulting protein profiles. These results were correlated to on-tissue measurements obtained for lipids. Using similar approaches, several selected washing procedures were also tested for their ability to extend the lifetime as well as revive previously cut tissue sections. The effects of these washes on automated matrix deposition and crystallization behavior as well as their ability to preserve tissue histology were also studied. Finally, in a full-scale IMS study, these washing procedures were tested on a human renal cell carcinoma biopsy.

Accuracy of uncorrected versus corrected QT interval for prediction of torsade de pointes associated with intravenous haloperidol.

STUDY OBJECTIVE: To determine if the uncorrected QT interval (QT(u)) more accurately predicts drug-induced torsade de pointes than QT intervals corrected using the Bazett's (QT(B)), Fridericia (QT(Frid)), or Framingham (QT(Fram)) methods. DESIGN: Retrospective analysis of a previously reported case-control study of risk factors for haloperidol-induced torsade de pointes. SETTING: Large tertiary care teaching hospital. PATIENTS: Forty-six critically ill patients who received intravenous haloperidol for sedation; seven developed torsade de pointes. MEASUREMENTS AND MAIN RESULTS: The QT intervals were measured manually by one investigator from electrocardiograms performed before and during haloperidol therapy. Logistic regression analysis for prediction of torsade de pointes was performed, incorporating QT(u), QT(B), QT(Frid), QT(Fram), and RR intervals measured during treatment. Receiver operating characteristics (ROC) curves were constructed. Primary outcome measures were proportion of explained variation (maximum-rescaled R2); area under the ROC curves for QT(u), QT(B), QT(Frid), QT(Fram), and RR interval; and sensitivity and specificity for prediction of haloperidol-induced torsade de pointes. The QT(u) was associated with the highest R2 compared with QT(Fram), QT(Frid), QT(B), and RR interval (0.77, 0.73, 0.68, 0.53, and 0.30, respectively). No significant differences in areas under the ROC curves were found between any of the QT-interval methods. Areas under the ROC curves for QT(u) and QT(Fram) trended toward being greater than that associated with the RR interval. All QT-interval methods were highly sensitive (100% for each), whereas the RR interval was less sensitive (86%); QT(u) and QT(Fram) were most specific (82%) compared with the QT(Frid) (72%), QT(B) (64%), and RR interval (36%). CONCLUSION: Compared with QT(B) and QT(Frid), the QT(u) and QT(Fram) best predicted haloperidol-induced torsade de pointes in critically ill patients; the QT(Fram) offered no advantage over the QT(u).

PARCS: A Safety Net Community-Based Fitness Center for Low-Income Adults.

BACKGROUND: Physical activity (PA) and fitness are critical to maintaining health and avoiding chronic disease. Limited access to fitness facilities in low-income urban areas has been identified as a contributor to low PA participation and poor fitness. OBJECTIVES: This research describes community-based fitness centers established for adults living in low-income, urban communities and characterizes a sample of its members. METHODS: The community identified a need for physical fitness opportunities to improve residents' health. Three community high schools were host sites. Resources were combined to renovate and staff facilities, acquire equipment, and refer patients to exercise. The study sample included 170 members older than age 18 who completed demographic, exercise self-efficacy, and quality of life surveys and a fitness evaluation. Neighborhood-level U.S. Census data were obtained for comparison. RESULTS: The community-based fitness centers resulted from university, public school, and hospital partnerships offering safe, accessible, and affordable exercise opportunities. The study sample mean body mass index was 35 + 7.6 kg/m(2) (class II obesity), mean age was 50 ± 12.5 years, 66% were Black, 72% were female, 66% completed some college or greater, and 71% had an annual household income of less than $25,000 and supported 2.2 dependents. Participants had moderate confidence for exercise participation and low fitness levels. When compared with census data, participants were representative of their communities. CONCLUSION: This observational study reveals a need for affordable fitness centers for low-income adults. We demonstrate a model where communities and organizations strategically leverage resources to address disparities in physical fitness and health.

Relationships between renal parameters and serum and urine markers of inflammation in those with and without HIV infection.

We sought to determine the relationships among intrarenal and systemic inflammation and renal disease in HIV. We compared paired serum and urinary levels (normalized to urine creatinine) of monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), interferon-γ-induced protein-10 (IP-10), interleukin-8 (IL-8), and ß2-microglobulin (B2M) between two groups of HIV-infected subjects not receiving antiretroviral therapy (ART) [A: not expecting to initiate ART immediately due to having CD4 cell counts ≥350/µl, N=26; B: about to initiate ART, N=19], a group of HIV-infected subjects receiving virologically suppressive antiretroviral therapy [C, N=30], and a group of HIV-uninfected, healthy volunteers [D, N=45]. We then correlated these inflammatory biomarker levels with urine protein/creatinine ratios (uPCR), urine albumin/creatinine ratios (uACR), and estimated glomerular filtration rates (eGFR). Urine inflammatory biomarker levels were highest in Group B. When combining all four study groups, statistically significant positive correlations included uPCR with urine IL-8, urine MCP-1, urine IP-10, and serum IP-10 and uACR with urine IL-8, urine B2M, serum IP-10, and serum B2M. eGFR was statistically significantly negatively correlated with serum MCP-1 and serum B2M. Paired serum and urine levels of IP-10 and B2M (but not IL-8, RANTES, or MCP-1) were significantly correlated with each other in the overall group. The levels of urine inflammatory markers tested differed by HIV status and use of virologically suppressive ART. These urine and serum inflammatory markers were differentially correlated with uPCR, uACR, and eGFR, suggesting that different intrarenal and systemic inflammatory pathways may contribute to different measures of nephropathy.

Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy.

OBJECTIVES: HIV-associated brain injury persists despite combination antiretroviral therapy, but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy in chronically HIV-infected subjects. METHODS: Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1ß, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate + Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter, and basal ganglia (BG). Predictive models were built through linear regression, and the best models were chosen using the Akaike Information Criterion. RESULTS: Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG, whereas metabolite changes in the frontal white matter for NAA/Cr, GlxCr, and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1ß. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the 3 models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and magnetic resonance spectroscopy metabolites. CONCLUSIONS: Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region-dependent manner in chronically HIV-infected patients on stable combination antiretroviral therapy.

Risk factors for early hospital readmission in low-income elderly adults.

OBJECTIVES: To identify risk factors for early hospital readmission in low-income community-dwelling older adults. DESIGN: Prospective cohort study. SETTING: University-affiliated urban safety-net healthcare system in Indianapolis, Indiana. PARTICIPANTS: Community-dwelling adults aged 65 and older with annual income less than 200% of the federal poverty level and enrolled in the Geriatric Resources for Assessment and Care of Elders (GRACE) randomized controlled trial (N = 951). MEASUREMENTS: Participant health and functional status at baseline and 6, 12, 18, and 24 months. Early readmission was defined as a repeat hospitalization occurring within 30 days of a prior hospital discharge. Candidate risk factors included sociodemographic characteristics, health and functional status, prior care, lifestyle, and satisfaction with care. RESULTS: Of 457 index admissions in 328 participants, 85 (19%) were followed by an early readmission. The independent risk factors for early readmission identified according to regression analysis were living alone (odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.02-2.87), fair or poor satisfaction with primary care physician (OR = 2.12, 95% CI = 1.01-4.46), not having Medicaid (OR = 1.80, 95% CI = 1.05-3.11), receiving a new assistive device in the past 6 months (OR = 2.26, 95% CI = 1.26-4.05), and staying in a nursing home in the past 6 months (OR = 5.08, 95% CI = 1.56-16.53). Age, race, sex, education, and chronic diseases were not associated with early readmission. CONCLUSION: A broad range of nonmedical risk factors played a greater role than previously recognized in early hospital readmission of low-income seniors.

Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial.

We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation.

Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial.

BACKGROUND: Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy. METHODS: We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed. RESULTS: The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [-1.06 (1.45)%] and PTX [-1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated. CONCLUSIONS: PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00796822.

Bacterial communities of the coronal sulcus and distal urethra of adolescent males.

Lactobacillus-dominated vaginal microbiotas are associated with reproductive health and STI resistance in women, whereas altered microbiotas are associated with bacterial vaginosis (BV), STI risk and poor reproductive outcomes. Putative vaginal taxa have been observed in male first-catch urine, urethral swab and coronal sulcus (CS) specimens but the significance of these observations is unclear. We used 16 S rRNA sequencing to characterize the microbiota of the CS and urine collected from 18 adolescent men over three consecutive months. CS microbiotas of most participants were more stable than their urine microbiotas and the composition of CS microbiotas were strongly influenced by circumcision. BV-associated taxa, including Atopobium, Megasphaera, Mobiluncus, Prevotella and Gemella, were detected in CS specimens from sexually experienced and inexperienced participants. In contrast, urine primarily contained taxa that were not abundant in CS specimens. Lactobacilllus and Streptococcus were major urine taxa but their abundance was inversely correlated. In contrast, Sneathia, Mycoplasma and Ureaplasma were only found in urine from sexually active participants. Thus, the CS and urine support stable and distinct bacterial communities. Finally, our results suggest that the penis and the urethra can be colonized by a variety of BV-associated taxa and that some of these colonizations result from partnered sexual activity.

Endothelial, inflammatory, coagulation, metabolic effects and safety of etravirine in HIV-uninfected volunteers.

The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [-3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.

Protein signatures for survival and recurrence in metastatic melanoma.

Patients with melanoma metastatic to regional lymph nodes exhibit a range in tumor progression, survival, and treatment. Current approaches to stratify patients with this stage of disease predominantly involve clinical and histological methods. Molecular classification thus far has focused almost exclusively on genetic mutations. In this study, proteomic data from 69 melanoma lymph node metastases and 17 disease free lymph nodes acquired by histology-directed MALDI imaging mass spectrometry were used to classify tumor from control lymph node and to molecularly sub-classify patients with stage III disease. From these data, 12 survival associated protein signals and 3 recurrence associated signals in the acquired mass spectra were combined to generate a multiplex molecular signature to group patients into either poor or favorable groups for recurrence and survival. Proteins represented in the signature include cytochrome c, s100 A6, histone H4, and cleaved forms of thymosin ß-4, thymosin ß-10, and ubiquitin. In total over 40 protein signals from the tissue were identified.

Results of superior vena cava reconstruction with externally stented-polytetrafluoroethylene vascular prostheses.

BACKGROUND: Resection and reconstruction of the superior vena cava (SVC) is occasionally required in the surgical treatment of intrathoracic neoplasms or symptomatic occlusion secondary to benign causes. We reviewed our institutional experience with SVC reconstruction using externally stented-polytetrafluoroethylene vascular prostheses. METHODS: From 1991 to 2009, medical records of 38 patients who underwent SVC resection and reconstruction with externally stented-polytetrafluoroethylene vascular prostheses were reviewed. Indications for surgery were malignancy in 34 (89%) patients (germ cell, 13; thymoma, 10; lung cancer, 9; sarcoma, 2) and benign symptomatic occlusion in 4 (11%) patients. RESULTS: Eighteen patients (47%) underwent right innominate vein to SVC interposition graft reconstruction, which became the favored approach during the study interval when resection of the innominate confluence was necessary. Eight patients (21%) had left innominate vein to SVC interposition grafts, earlier in the series or when the right innominate vein was unavailable. Nine patients (24%) received graft interposition of the proximal to distal SVC. The remaining 3 patients had a Y reconstruction. There were 2 perioperative mortalities. Follow-up averaged 15 months (range, 1 to 113 months), including 11 (29%) patients who died of disease. All patients demonstrated minimal to no brachiocephalic swelling at last follow-up. Twenty (53%) patients underwent imaging after an average of 24 months (range, 1 to 113 months) with only two grafts demonstrating complete occlusion. CONCLUSIONS: Although several SVC reconstructive techniques have been described, externally stented-polytetrafluoroethylene vascular prostheses are readily available for off-the-shelf use. In our experience, patency rates are high, and patients who do demonstrate graft thrombosis have minimal to no symptoms.

Prognostic indicators after surgery for thymoma.

BACKGROUND: We undertook a 20-year retrospective institutional study to investigate prognostic indicators after surgery for thymoma. METHODS: From 1989 to 2009, 83 patients underwent surgical resection of thymoma or thymic carcinoma at our institution. Twelve of these patients were determined to have either World Health Organization type C disease or Masaoka stage IV-B disease and were excluded from analysis. The remaining 71 patients were reviewed. RESULTS: The majority of patients in this series were female 64.7% (n=46) with an overall average age of 51.0 years. The distribution of Masaoka stages I, II, III, and IV-A was 40.8% (n=29), 19.7% (n=14), 18.3% (n=13), and 21.1% (n=15), respectively. Thirteen of the 28 (46.2%) patients who presented with stage III or IV-A disease received preoperative chemotherapy. After a mean follow-up of 66 months (range, 6 to 241 months), 54 (75.3%) patients are alive and well while six are alive with disease. Eleven (16.0%) patients have died, but only 3 (4.3%) of these patients died of thymoma. The overall disease-specific survival was 97% and 89% at 5 and 10 years. Of the variables analyzed, only age was predictive of overall survival (p=0.03). Masaoka stages I to III as compared with stage IV-A was significantly predictive of disease-free survival (p<0.01). CONCLUSIONS: Long-term disease-specific survival can be expected not only after surgery for early stage thymoma but also after surgery for advanced disease, including patients with pleural metastases. However, patients who undergo surgery for stage IV-A disease have reduced disease-free survival. Late mortality due to secondary cancers and associated immunologic disorders was more frequent than mortality from thymoma in this series.

Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation.

PURPOSE: To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies. EXPERIMENTAL DESIGN: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR). RESULTS: Proteomic and validation immunohistochemical analyses revealed that alpha-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery. CONCLUSION: We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane-based therapy.