Contrast Spread After Erector Spinae Plane Block at the Fourth Lumbar Vertebrae: A Cadaveric Study.

INTRODUCTION: In recent years, the erector spinae plane block (ESPB) has seen widespread use to treat acute and chronic pain in the regions of the thoracic spine. While limited data suggest its increasing utilization for pain management distal to the thoracic, abdomen and trunk, the anesthetic spread and analgesic mechanism of ESPB at the level of the lumbar spine has not been fully described or understood. METHODS: This is an observational anatomic cadaveric study to assess the distribution of solution following an ESPB block performed at the fourth lumbar vertebrae (L4) using ultrasound guidance to evaluate the spread of a 20 ml solution consisting of local anesthetic and methylene blue. The study was performed in an anatomy lab in a large academic medical center. Following injection of local anesthetic with contrast dye, cadaveric dissection was performed to better understand the extent of contrast dye and to determine the degree of staining to further predict analgesic potential. We reviewed the findings of other ESPB cadaveric studies currently available for comparison. RESULTS: Following cadaveric dissection in an anatomy lab, the contrast dye was observed in the ESP space, and staining was found most cranially at L2 and extending caudally underneath the sacrum. Evaluating the depth of its spread, we found it to be confined to the posterior compartment of the spine sparing the nerve roots bilaterally, which is consistent with the only other cadaveric study of ESPB performed at L4. CONCLUSION: Our results demonstrate the clinical utility of lumbar ESPB where posterior confinement of local anesthesia is preferred. However, further investigation is needed to determine the efficacy of ESPB in lower extremity analgesia which is predicated on ventral nerve root involvement.

Prediction of lateral neck lymph node metastasis according to preoperative calcitonin level and tumor size for medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut-off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut-off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut-off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.

The distribution of intratumoral macrophages correlates with molecular phenotypes and impacts prognosis in colorectal carcinoma.

AIMS: The role of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) remains elusive. In this study, we aimed to examine the correlation between TAMs, clinicopathological features, tumour-infiltrating lymphocytes (TILs) and prognosis in CRC by the use of image analysis. METHODS AND RESULTS: Immunohistochemical staining for CD68 and CD163 was performed as pan-macrophage and M2-macrophage markers, respectively. Each marker was analysed separately for intra-epithelial and stromal area densities. All four macrophage densities showed a significant correlation with one another (P = 0.001). Intra-epithelial CD68+ macrophage densities showed a correlation with pTNM stage (P = 0.008), microsatellite instability (MSI) (P < 0.001), CpG island methylator phenotype (CIMP) (P < 0.001) and TIL densities (P < 0.001). Intra-epithelial CD163+ macrophage densities were associated with perineural invasion, MSI, CIMP and TIL densities (P < 0.001). Stromal CD68+ and CD163+ macrophage densities had a significant relationship with intra-epithelial and stromal CD3+ (P = 0.001 and P < 0.001, respectively) and CD8+ (P < 0.001) T cells. High intra-epithelial CD68+ macrophage density was associated with worse overall survival (HR = 1.386, 95% CI = 1.043-1.843, P = 0.025) and progression-free survival (HR = 1.522, 95% CI = 1.146-2.020, P = 0.004). Intra-epithelial CD68+ macrophage density was also an independent prognostic factor of the progression-free survival (HR = 1.447, 95% CI = 1.076-1.947, P = 0.015) of CRC patients regardless of pTNM stage, lymphatic, venous, and perineural invasions and TIL densities. CONCLUSION: Our results indicate that the density of intratumoural macrophages is a useful prognostic indicator for further stratifying T cell populations in CRC.

Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low-level viremia.

BACKGROUND & AIMS: We tested whether non-invasive tests for liver disease severity can stratify hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV)-infected patients showing low-level viremia (LLV, HBV DNA <2000 IU/mL). METHODS: A retrospective cohort of 1006 chronic hepatitis B patients showing persistently LLV, defined by at least two consecutive assessments in the year before enrolment, was assessed for HCC development. Two non-invasive serum biomarkers, the aspartate aminotransferase to platelet ratio index (APRI) and the Fibrosis-4 (FIB-4), were tested. Cirrhosis was defined with ultrasonography. RESULTS: During a median 5.1 years of follow-up, HCC developed in 36 patients. HCC incidence rate at 5 years was significantly higher for cirrhotic patients (19/139, 13.7%), but was not null for non-cirrhotic patients (17/867, 2.0%, P<.001). APRI at a cut-off of 0.5 was more specific but less sensitive for HCC development, and FIB-4 at a cut-off of 1.45 was more sensitive but less specific. When both APRI and FIB-4 were used to group patients, the 5-year cumulative HCC incidence rate was 13.9%, 1.4% and 1.2% for both high, any high, and both low APRI and FIB-4 score among all patients (n=1006, P<.001), respectively, and was 11.4%, 1.5% and 0.4% in the same respective order among non-cirrhotic patients (n=867, P<.001). CONCLUSIONS: The combined use of two non-invasive serum biomarkers (APRI and FIB-4) could stratify HCC risk for chronic HBV-infected patients with LLV.

Hematopoietic Id Deletion Triggers Endomyocardial Fibrotic and Vascular Defects in the Adult Heart.

Inhibitor of DNA binding (Id) proteins play important roles in regulating cardiac development via paracrine signaling. Id1/Id3 knockout mice die at mid-gestation with multiple cardiac defects. Single Id knockout studies have not reported cardiomyopathies. To bypass embryonic lethality we used Tie2CRE-mediated recombination to conditionally delete Id1 against global Id3 ablation (Id cDKOs), which develops adult-onset dilated cardiomyopathy. We confirm upregulation of thrombospondin-1 (TSP1) in Id cDKO hearts. Colocalization studies reveal increased TSP1 expression in the vicinity of endothelial cells and near regions of endocardial fibrosis/disruption. Downstream fibrotic molecules were upregulated. Endocardial capillary density was reduced with evidence of vascular distention. Treatment of Id cDKO cardiac explants with LSKL, a peptide antagonist of TSP1 activation of TGFß, reversed the increased expression of fibrotic molecules. We conducted bone marrow transplant experiments in which we transferred bone marrow cells from Id cDKO mice into lethally irradiated WT mice. The majority of WT recipients of Id cDKO bone marrow cells phenocopied Id cDKO cardiac fibrosis 4 months post-transplantation. Injection of LSKL into adult Id cDKO mice led to downregulation of fibrotic molecules. The results prompt caution when bone marrow transfers from individuals potentially carrying mutations in the Id axis are applied in clinical settings.

Erectile Dysfunction is Predictive of Endothelial Dysfunction in a Well Visit Population.

PURPOSE: The relationship between erectile dysfunction and endothelial dysfunction has been described and is associated with adverse cardiac events. Endothelial dysfunction is believed to precede erectile dysfunction. Our objective was to characterize the prevalence of subjective erectile dysfunction, endothelial dysfunction and commonly related comorbidities in a population of men undergoing wellness screening. MATERIALS AND METHODS: A total of 205 men presented for wellness screening. They underwent testing for endothelial dysfunction via peripheral arterial tonometry and completed a health screening questionnaire. Reactive hyperemia index scores were generated by peripheral arterial tonometry testing. A reactive hyperemia index score of 1.67 or less defined endothelial dysfunction. The Student t-test and Fisher exact test were performed for continuous and categorical variables, respectively. The association of endothelial dysfunction, erectile dysfunction and various comorbidities was calculated using univariate and multivariable analyses. RESULTS: Of 205 men 47 reported subjective erectile dysfunction. Median age was 44 years old. The mean reactive hyperemia index in patients with erectile dysfunction was significantly lower than in patients without erectile dysfunction (1.63 vs 1.87, p = 0.001). Endothelial dysfunction was more common in men with than without erectile dysfunction (55% vs 36%, p = 0.027). Multivariable analysis revealed that men with erectile dysfunction and obesity were twofold more likely to have concomitant endothelial dysfunction (OR 2.45, 95% CI 1.13-4.24, p = 0.02 and OR 2.08, 95% CI 1.16-3.75, p = 0.01, respectively). CONCLUSIONS: Among middle-aged men presenting for wellness screening erectile dysfunction and obesity independently predicted endothelial dysfunction, a known risk factor for long-term adverse cardiac events.

PD-L1 expression in melanocytic lesions does not correlate with the BRAF V600E mutation.

PD-L1 expression in melanoma correlates with response to PD-1 pathway-blocking antibodies. Aberrant tumor-cell PD-L1 expression may be oncogene driven and/or induced by IFNγ. Melanomas express PD-L1 in association with tumor-infiltrating lymphocytes (TIL), but the potential contribution of the BRAF V600E mutation (BRAFmut) to induced PD-L1 expression has not been determined. Fifty-two archival melanocytic lesions were assessed for PD-L1 expression, TIL infiltration, and BRAFmut simultaneously. IFNγ-induced PD-L1 expression in cultured melanomas was assessed in parallel according to BRAF status. Melanocyte PD-L1 expression was observed in 40% of specimens, and BRAFmut was observed in 42% of specimens, but no significant concordance was found between these variables. Almost all melanocytes displaying PD-L1 expression were observed to be adjacent to TILs, irrespective of BRAF status. TIL(-) lesions were not more likely to be associated with BRAFmut, when compared with TIL(+) lesions. Baseline expression of PD-L1 by melanoma cell lines was virtually nil, regardless of BRAFmut status, and the intensity of IFN-induced PD-L1 expression in melanoma cell lines likewise did not correlate with BRAF mutational status. PD-L1 expression in melanocytic lesions does not correlate with the BRAFmut. Thus, distinct populations of melanoma patients will likely benefit from BRAF inhibitors versus PD-1 pathway blockade.

Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.

PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN: Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. RESULTS: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ©2014 AACR.

Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.

BACKGROUND: Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet. RESULTS: Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 µg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. CONCLUSIONS: In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status.

Comprehensive Analysis of ETS Family Members in Melanoma by Fluorescence In Situ Hybridization Reveals Recurrent ETV1 Amplification.

E26 transformation-specific (ETS) transcription factors are known to be involved in gene aberrations in various malignancies including prostate cancer; however, their role in melanoma oncogenesis has yet to be fully explored. We have completed a comprehensive fluorescence in situ hybridization (FISH)-based screen for all 27 members of the ETS transcription factor family on two melanoma tissue microarrays, representing 223 melanomas, 10 nevi, and 5 normal skin tissues. None of the melanoma cases demonstrated ETS fusions; however, 6 of 114 (5.3%) melanomas were amplified for ETV1 using a break-apart FISH probe. For the six positive cases, locus-controlled FISH probes revealed that two of six cases were amplified for the ETV1 region, whereas four cases showed copy gains of the entire chromosome 7. The remaining 26 ETS family members showed no chromosomal aberrations by FISH. Quantitative polymerase chain reaction showed an average 3.4-fold (P value = .00218) increased expression of ETV1 in melanomas, including the FISH ETV1-amplified cases, when compared to other malignancies (prostate, breast, and bladder carcinomas). These data suggest that a subset of melanomas overexpresses ETV1 and amplification of ETV1 may be one mechanism for achieving high gene expression.

A case-matched validation study of anatomic severity grade score in predicting reinterventions after endovascular aortic aneurysm repair.

BACKGROUND: In 2002, the Society for Vascular Surgery created the anatomic severity grading (ASG) score to classify abdominal aortic aneurysms (AAAs). Our objective was to identify the predictive capability and cutoff value of preoperative ASG score for reintervention after endovascular aneurysm repair (EVAR). METHODS: We completed a retrospective review of AAA patients treated with elective EVAR from 2007 through 2011. Patients who had reinterventions as well as preoperative M2S (M2S Inc, West Lebanon, NH) three-dimensional reconstructions were identified and compared with a case-matched control group of patients without reintervention. ASG component scores (neck, aortic, and iliac) and total ASG scores were calculated using M2S software. RESULTS: Of the 623 patients treated with EVAR, 79 (13%) had reinterventions of which 45 had preoperative M2S three-dimensional reconstructions available for ASG score calculation. The reintervention group (mean age, 74 ± 8; 80% male) had a mean ASG score of 18 ± 5 (range, 8-30) compared with a cohort of 45 EVAR patients (mean age, 74 ± 7; 80% male) who had a mean ASG score of 13 ± 4 (range, 6-21; P < .0001). The mean AAA diameter for all patients was 52 mm ± 14 and was not significantly different between the groups. After area under the receiver-operating curve analysis, an ASG score of 17 was highly predictive for reintervention (area = 0.8; sensitivity = 60%; specificity = 78%; positive predictive value = 73%; negative predictive value = 66%). An ASG score of 13 was highly predictive for freedom from reintervention (sensitivity = 93%; specificity = 47%; positive predictive value = 64%; negative predictive value = 88%). The lowest ASG score that yielded a 100% reintervention rate was 22. The majority of reinterventions fell into three categories: proximal extension cuff (n = 18; 40%), distal extension limb (n = 7; 16%), and type II endoleak embolization (n = 13; 29%). Those that received proximal extensions had significantly higher mean total ASG score (19 vs 15; P = .0005), mean neck score (3.28 vs 2.36; P = .047), and mean aorta score (7.39 vs 2.36; P = .004). Those that received distal extensions had a significantly higher mean iliac score (9.00 vs 6.86; P = .013), and those that required an embolization had a significantly higher mean aorta branch score (1.92 vs 1.19; P = .017). CONCLUSIONS: Preoperative total ASG score strongly predicts reintervention after EVAR. Use of a cutoff ASG value predictive of prohibitive reintervention rates could help guide the decision between endovascular vs open AAA repair.

Atherectomy offers no benefits over balloon angioplasty in tibial interventions for critical limb ischemia.

BACKGROUND: Endovascular adjuncts, like atherectomy, were developed to improve outcomes of endovascular arterial interventions. The true impact of atherectomy on endovascular outcomes remains to be determined, and little data exist on the influence of atherectomy on tibial interventions. Our study compares early and late outcomes of tibial intervention with angioplasty vs atherectomy-assisted interventions. METHODS: We completed a retrospective review of all tibial interventions between 2008 and 2010. Outcomes were analyzed using single and multivariate analysis, Cox regression, and Kaplan-Meier curves. Primary outcomes were primary, primary assisted, and secondary patency rates, as well as limb salvage and survival rates. RESULTS: Over a 2-year period, 480 tibial interventions were completed for 421 patients. Eighty-seven percent (n = 418) of interventions were performed for critical limb ischemia (CLI) and 13% (n = 62) for claudication. The CLI cohort of 418 interventions was analyzed. These patients had a mean age of 71 years with a mean follow-up time of 16 ± 15 months (range, 0-59 months). Of the 418 interventions, 339 underwent percutaneous transluminal angioplasty (PTA): 333 PTA alone, six PTA + stent. The remaining 79 interventions received atherectomy: 33 laser, 13 directional, and 33 orbital either alone or in conjunction with PTA (11 atherectomy only, 68 atherectomy + PTA). The groups did not differ significantly in terms of demographics, risk factors, or technical success. The atherectomy group had more TASC B lesions (54% vs 38%; P = .013), while the PTA-alone group had more TASC D lesions (25% vs 13%; P = .004). TASC A and C lesions did not differ significantly between the groups. No significant differences existed with respect to the early (30-day) outcomes of loss of patency (11% vs 13%; P = .699), complications (8% vs 13%; P = .292), or major amputation (17% vs 13%; P = .344) in the PTA-alone group vs the atherectomy-assisted group. Kaplan-Meier analysis revealed no difference for all primary outcomes of PTA alone vs the atherectomy-assisted group at 12 and 36 months: primary patency (69%, 55% vs 61%, 46%; P = .158), primary assisted patency (83%, 71% vs 85%, 67%; P = .801), secondary patency (94%, 89% vs 95%, 89%; P = .892), limb salvage (79%, 70% vs 81%, 77%; P = .485), or survival (77%, 56% vs 80%, 50%; P = .944). CONCLUSIONS: The adjunctive use of atherectomy offered no improvement in primary outcomes over PTA alone in either early or late outcomes in CLI patients who underwent endovascular tibial interventions. Considering the additional cost and increased procedural time, these findings put into question the routine use of adjunctive atherectomy.

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status.

Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n=220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m+), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m+, and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m+ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m+, were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m+ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m+ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features, although the proportion of discordant subtypes is low. The microsatellite-unstable colorectal cancers of the same CIMP status tended to exhibit different clinicopathological features depending on MLH1 methylation status.

Endovascular foreign body retrieval.

OBJECTIVE: The number of endovascular procedures performed is increasing exponentially as technology improves. A serious complication of endovascular therapy is loss of a foreign body in the vasculature. We reviewed our experience and evaluated the cause, management, and outcomes of intravascular foreign body (IVFB) misplacement. METHODS: We completed a retrospective review of patients who underwent endovascular retrieval of IVFBs between 2005 and 2010. Patients were identified by current procedural terminology code or by our hospital's risk management team. Patients undergoing routine endovascular retrieval of temporary vena cava filters were excluded. RESULTS: Twenty-seven IVFBs were identified in 26 patients. Twenty patients were asymptomatic (76.9%). Six patients were symptomatic (22.2%) with either pain (n = 4) or abnormal physical findings (n = 2). There were 13 (48.1%) catheter fragments, six (22.2%) guidewires, five (18.5%) inferior vena cava (IVC) filter (embolisms), two (7.4%) stents, and one (3.7%) sheath fragment. There were five (15.6%) embolizations of an IVFB into the right heart, three (9.4%) into a pulmonary artery, eight (25%) into the vena cava, eight (25%) into peripheral veins, five (15.6%) into peripheral arteries, one (3.1%) into a coronary artery, one (3.1%) into a hepatic vein, and one (3.1%) into adjacent soft tissue. The mechanism of endovascular loss was device fracture in 16 (59.3%) cases, loss of control in six cases (22.2%), migration in four (14.8%) cases, and incorrect device deployment in one case (3.7%). The probable cause of foreign body loss was technical error in eight (29.6%) cases. In three cases, IVFB retrieval was not attempted. The misplacement and retrieval were completed during the same procedure in 13 (48%) cases. Twenty-four endovascular retrievals were performed. Fifteen (62.5%) procedures used a snare to remove the IVFB and two (8.2%) used balloon catheters. Three IVFBs could not be removed and two cases were converted to open procedures. Technical success was achieved in 19/24 cases (79.2%). There were no immediate complications related to the retrieval of the IVFB; however, there was a single late complication of pulmonary embolism after failed endovascular retrieval (1/24, 4.2%). Thirty-day survival was 100%. CONCLUSIONS: Intravascular foreign bodies are a serious complication of endovascular therapy that can be minimized with proper device selection and deployment. When an intravascular foreign body is identified, endovascular retrieval should be attempted due to its high success rate and minimal morbidity.

Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer.

Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.

Primary central nervous system B-cell lymphoma in a young dog.

This report describes a primary central nervous system B-cell lymphoma in a 3-year-old intact female Maltese dog. Canine primary central nervous system lymphomas constitute about 4% of all intracranial primary neoplasms, but comprehensive histopathologic classifications have rarely been carried out. This is the first report of this disease in a young adult dog.

Identifying the target lesions for 245 laser angioplasty cases and a review of the literature.

OBJECTIVE: To provide a detailed report of our experience with laser atherectomy in a large patient population with an extensive follow-up period. METHOD: A retrospective chart review was conducted on 222 patients who underwent laser atherectomy. RESULTS: Overall primary patency rates at 1 and 3 years were 48% and 37%, primary-assisted rates were 53% and 40%, and secondary patency rates were 69% and 51%, respectively. Limb salvage rates were 91% and 83%. The 1- and 3-year primary patency rates were significantly different between the native (51% and 39%) and the in-stent group (20% and 20%; P = .027). There were no differences in primary-assisted patency (P = .11), secondary patency (P = .094), and limb salvage rates (P= .83) between the 2 groups. CONCLUSIONS: Although the primary patency of laser angioplasty was higher in native vessels versus the in-stent stenosis, there were no differences in the primary-assisted patency, secondary patency, or limb salvage rates between the 2 groups.

LRpath analysis reveals common pathways dysregulated via DNA methylation across cancer types.

BACKGROUND: The relative contribution of epigenetic mechanisms to carcinogenesis is not well understood, including the extent to which epigenetic dysregulation and somatic mutations target similar genes and pathways. We hypothesize that during carcinogenesis, certain pathways or biological gene sets are commonly dysregulated via DNA methylation across cancer types. The ability of our logistic regression-based gene set enrichment method to implicate important biological pathways in high-throughput data is well established. RESULTS: We developed a web-based gene set enrichment application called LRpath with clustering functionality that allows for identification and comparison of pathway signatures across multiple studies. Here, we employed LRpath analysis to unravel the commonly altered pathways and other gene sets across ten cancer studies employing DNA methylation data profiled with the Illumina HumanMethylation27 BeadChip. We observed a surprising level of concordance in differential methylation across multiple cancer types. For example, among commonly hypomethylated groups, we identified immune-related functions, peptidase activity, and epidermis/keratinocyte development and differentiation. Commonly hypermethylated groups included homeobox and other DNA-binding genes, nervous system and embryonic development, and voltage-gated potassium channels. For many gene sets, we observed significant overlap in the specific subset of differentially methylated genes. Interestingly, fewer DNA repair genes were differentially methylated than expected by chance. CONCLUSIONS: Clustering analysis performed with LRpath revealed tightly clustered concepts enriched for differential methylation. Several well-known cancer-related pathways were significantly affected, while others were depleted in differential methylation. We conclude that DNA methylation changes in cancer tend to target a subset of the known cancer pathways affected by genetic aberrations.

Cancer epigenetics: a brief review.

Cancer is a disease that results from the successive accumulation of genetic and epigenetic alterations. Despite intense study, many unanswered questions about the nature of the contribution of epigenetic changes to carcinogenesis remain. In this review, we describe principles of epigenetics as they relate to our current understanding of carcinogenesis. There are a number of in vivo models of specific pathways of carcinogenesis that are very useful for the characterization of epigenetic mechanisms that link environmental exposures or genetic susceptibility and cancer progression. Because epigenetic alterations are thought to be reversible, they offer great promise for treatment of cancer. The use of animal models to evaluate the effects of decitabine and zebularine has elucidated the mechanisms of action and indicated the potential for these types of treatment. Ultimately, the greatest challenge lies in the integration of laboratory and epidemiologic data to best prevent and treat this deadly disease.

Cortisol, estradiol-17ß, and progesterone secretion within the first hour after awakening in women with regular menstrual cycles.

Cortisol concentration in both serum and saliva sharply increases and reaches a peak within the first hour after waking in the morning. This phenomenon is known as the cortisol awakening response (CAR) and is used as an index of hypothalamus-pituitary-adrenal (HPA) axis function. We examined whether ovarian steroid concentrations increased after awakening as with the CAR in the HPA axis. To do this, cortisol, estradiol-17ß (E(2)), and progesterone (P(4)) concentrations were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening in women with regular menstrual cycles and postmenopausal women. We found that both E(2) and P(4) concentrations increased during the post-awakening period in women with regular menstrual cycles, but these phenomena were not seen in any postmenopausal women. The area under the E(2) and P(4) curve from the time interval immediately after awakening to 60 min after awakening (i.e. E(2)auc and P(4)auc) in women with regular menstrual cycles were greater than those in the postmenopausal women. E(2) and P(4) secretory activity during the post-awakening period was influenced by the phase of the menstrual cycle. E(2)auc in the peri-ovulatory phase and P(4)auc in the early to mid-luteal phase were greater than in the menstrual phase. Meanwhile, cortisol secretory activity during the post-awakening period was not influenced by menstrual status or the phase of menstrual cycle. These findings indicate that, as with the CAR in the HPA axis function, ovarian steroidogenic activity increased after awakening and is closely associated with menstrual status and phase of menstrual cycle.