Sarah M. Jenkins

Infective Endocarditis Complicating Permanent Pacemaker and Implantable Cardioverter-Defibrillator Infection

OBJECTIVE To describe management of patients with permanent pacemaker (PPM)- and implantable cardioverter-defibrillator (ICD)-related endocarditis. PATIENTS AND METHODS We retrospectively reviewed all cases of infection involving PPMs and ICDs among patients presenting to Mayo Clinics site in Rochester, MN, between January 1, 1991, and December 31, 2003. Cardiac device-related infective endocarditis (CDIE) was defined as the presence of both vegetation on a device lead or valve and clinical or microbiological evidence of CDIE. Of 189 patients with PPM or ICD infection who were admitted during the study period, 44 met the case definition for CDIE (33 PPM, 11 ICD). RESULTS The mean +/- SD age of patients was 67 +/- 14 years. Staphylococci (36 [82%]) were the most commonly isolated pathogens. Nearly all patients (43 [98%]) were treated with a combined approach of complete hardware removal and parenteral antibiotics. The median duration of antibiotic treatment after infected device explantation was 28 days (interquartile range, 19-42 days). Device leads were removed percutaneously in 34 cases (77%); only 7 cases (16%) required surgical lead extraction. Percutaneous extraction was uncomplicated in 15 patients with lead vegetation greater than 10 mm in diameter. Six patients (14%) died during hospitalization. Twenty-seven (96%) of 28 patients remained infection free at their last visit (median follow-up, 183 days; intraquartile range, 36-628 days). CONCLUSION Prompt hardware removal and prolonged parenteral antibiotic administration decrease mortality among patients with CDIE. The presence of a large (> 10 mm in diameter) vegetation on a lead is not a contraindication for percutaneous lead extraction.

Temporal Trends in Permanent Pacemaker Implantation: A Population-Based Study

BACKGROUND Limited data exist regarding temporal trends in permanent pacemaker (PPM) implantation. To describe trends in incidence and comorbidities of PPM recipients, we conducted a retrospective population-based cohort study over a 30-year period. METHODS All 1291 adult residents of Olmsted County, Minnesota, undergoing PPM implantation between 1975 and 2004 were included in the study. Trends in PPM implantation incidence, pacing mode and indication, and comorbidities (via Charlson Comorbidity Index [CCI]) were assessed through the Rochester Epidemiology Project. Permanent pacemaker recipients were compared with age- and sex-matched PPM-free controls from the population. RESULTS Adjusted implantation incidence rates increased from 36.6 per 100,000 person-years during 1975 to 1979 to 99 per 100,000 person-years during 2000 to 2004 (P < .0001). After adjusting for age (hazard ratio [HR] 1.06 per year), male sex (HR 1.28), and implant year (HR 0.98), the HR for death among PPM recipients by CCI quartiles was 1.0, 1.79, 2.29, and 3.91 for CCI of 0 to 1 (reference), 2 to 3, 4 to 6, and > or = 7, respectively (P < .0001). Overall, PPM recipients had higher CCI than the population-based controls (P = .04), with higher mean CCI noted since 1990. Mean age-adjusted CCI increased from 3.15 to 4.60 among the cases (P < .0001) and from 3.06 to 3.54 among the age- and sex-matched controls (P = .047). CONCLUSIONS There have been significant increases in incidence of PPM implantation over 30 years, and PPM recipients have had an age-independent increase in comorbidities relative to the underlying population, especially over the past 15 years.

Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica

Objective: To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome. Methods: From Mayo Clinic records (2005–2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 “seronegative” patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus. Results: Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly. Conclusions: Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG–seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG–seropositive NMO.

Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression.

The Turin Proposal algorithm defines poorly differentiated carcinoma on the basis of the presence of solid/trabecular/insular growth pattern, absence of conventional nuclear features of papillary carcinoma, and the presence of at least one of the following features: convoluted nuclei, mitotic activity ≥3/10 HPF, or tumor necrosis. IMP3 appears to have diagnostic and prognostic value in many solid tumors, including thyroid carcinomas. We examined a series of follicular-cell carcinomas with prominent solid patterns diagnosed at Mayo Clinic (56 cases) (Rochester, MN, USA) and at the University of Turin (96 cases) (Northern Italy) to validate the Turin consensus criteria defining poorly differentiated carcinoma of the thyroid and to evaluate the prevalence and prognostic behavior of this tumor. On this series, we analyzed the expression of conventional markers by immunohistochemistry and we investigated the expression of IMP3 by both immunohistochemistry and qRT-PCR. The prevalence of poorly differentiated carcinoma among the USA cases was 1.8% (56/3128) and that in the cases of Northern Italy was 6.7% (96/1442). Tumor characteristics were similar in the cases from the USA and from Italy except for extensive vascular invasion and a prevalent insular growth pattern (lower the former, higher the latter in the Italian series). In univariate analysis, the risk of death was higher for age ≥45, tumors ≥4 cm, and IMP3 positivity. Multivariate analysis showed that the risk of death from poorly differentiated carcinoma was higher for age ≥45. The Turin consensus criteria can reliably select poorly differentiated carcinomas. Tumors from the USA and from Italy showed similar overall survival, although the prevalence of poorly differentiated carcinoma was higher in Northern Italy. Expression of IMP3 appears to be an adverse prognostic factor for poorly differentiated thyroid carcinoma.

Pleomorphic Xanthoastrocytoma: Natural History and Long-Term Follow-Up.

Prognostic significance of histological anaplasia and BRAF V600E mutation were retrospectively evaluated in 74 patients with pleomorphic xanthoastrocytoma (PXA). Median age at diagnosis was 21.5 years (31 pediatric, 43 adult) and median follow‐up 7.6 years. Anaplasia (PXA‐AF), defined as mitotic index ≥ 5/10HPF and/or presence of necrosis, was present in 33 cases. BRAF V600E mutation was detected in 39 (of 60) cases by immunohistochemical and/or molecular analysis, all negative for IDH1 (R132H). Mitotic index ≥ 5/10HPF and necrosis were associated with decreased overall survival (OS; P = 0.0005 and P = 0.0002, respectively). In all cases except two, necrosis was associated with mitotic index ≥ 5/10HPF. Patients with BRAF V600E mutant tumors had significantly longer OS compared with those without BRAF V600E mutation (P = 0.02). PXA‐AF patients, regardless of age, had significantly shorter OS compared with those without (P = 0.0003). Recurrence‐free survival was significantly shorter for adult PXA‐AF patients (P = 0.047) only. Patients who either recurred or died ≤3 years from diagnosis were more likely to have had either PXA‐AF at first diagnosis (P = 0.008) or undergone a non‐gross total resection procedure (P = 0.004) as compared with patients who did not. This study provides further evidence that PXA‐AF behaves more aggressively than PXA and may qualify for WHO grade III “anaplastic” designation.

Expanding the spectrum of neuronal pathology in multiple system atrophy

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.

Treatment of Patients With Small Renal Masses: A Survey of the American Urological Association

PURPOSE We surveyed American Urological Association members to determine factors that influence the treatment of patients with small renal masses. MATERIALS AND METHODS In June 2009 American Urological Association members were solicited to complete an online survey. Respondents were asked their preferred treatment for 8 cases and 3 index patients. In each case computerized tomographic axial and schematic coronal images were provided. RESULTS A total of 759 active urologists with varied training backgrounds and clinical practice settings completed the survey. Tumor size (OR 8.4, 95% CI 7.1-10.1), tumor depth (OR 19.2, 95% CI 14.8-25.0) and tumor location (OR 24.0, 95% CI 18.1-31.8) were markedly associated with preference for radical nephrectomy instead of partial nephrectomy. Fellowship trained urologists (OR 0.4, 95% CI 0.2-0.6) and urologists at academic hospitals (OR 0.6, 95% CI 0.4-0.9) were less likely to choose radical nephrectomy. Respondents were more likely to choose active surveillance in an older patient (OR 2.7, 95% CI 2.1-3.6) or in a patient with comorbidities (OR 10.0, 95% CI 8.0-12.4). Urologists were less likely to choose active surveillance for a 4 vs 2 cm tumor (OR 0.18, 95% CI 0.15-0.21). Active surveillance was chosen more often if the tumor was perihilar vs mid kidney (OR 2.0, 95% CI 1.8-2.3) or polar (OR 2.1, 95% CI 1.9-2.5). CONCLUSIONS There is considerable heterogeneity in the treatment of patients with clinical T1a tumors. Several factors explain these differences as selected treatments are independently associated with tumor, patient and urologist factors.

MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of well-characterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sun-exposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2–3+: 6 cases, 16%; 1+: 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2–3+ immunostaining showed high-level gene amplification. One additional case with 3+ immunostaining showed higher level aneusomy of chromosome 8 (5–8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3–5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.

Stress Level, Health Behaviors, and Quality of Life in Employees Joining a Wellness Center

Purpose. Examine the relationship between stress level and quality of life at a worksite wellness center. Design. A survey completed when joining the wellness center. Setting. Employee wellness center. Subjects. Survey that inquired about stress, health behaviors, and quality of life of more than 13,000 employees joining a wellness center. Measures. A series of questions about current health status and health behaviors. Analysis. Two-sample t-tests assuming unequal variances. Results. A total of 2147 of these employees reported having high stress levels. Employees with high stress levels had statistically significant lower quality of life, more fatigue, and poorer health compared with employees with low stress levels. In terms of their ability and motivation to participate in wellness programs, the high-stress employees were also less active and had less healthy nutritional habits, less support, and less confidence in their ability to be active. They also reported having more health problems, including high blood pressure, high blood sugar, high cholesterol, and overweight. Conclusions. It appears that employees with high stress levels—those who might most benefit from participation in wellness programs—may experience the greatest difficulty participating actively in wellness programs because of their lack of support, low confidence, and numerous health problems. Perhaps offering tailored stress reduction programs for these employees would be beneficial.

Primary sclerosing cholangitis with equivocal cytology: Fluorescence in situ hybridization and serum CA 19-9 predict risk of malignancy

Patients diagnosed with primary sclerosing cholangitis (PSC) and dominant strictures often undergo endoscopic retrograde cholangiopancreatography with brush cytology to exclude or confirm the development of malignancy. Equivocal (atypical or suspicious) routine cytologic results may confound patient management decisions, especially in the absence of a mass on imaging. The objective of the current study was to identify independent predictors of malignancy in patients with PSC with an equivocal cytology diagnosis.