Citations

Abstract The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Background— Measurement of hospital quality has traditionally focused on processes of care and postprocedure outcomes. Appropriateness measures for percutaneous coronary intervention (PCI) assess quality as it relates to patient selection and the decision to perform PCI. The association between patient selection for PCI and processes of care and postprocedural outcomes is unknown. Methods and Results— We included 203 531 patients undergoing nonacute (elective) PCI from 779 hospitals participating in the National Cardiovascular Data Registry (NCDR) CathPCI Registry between July 2009 and April 2011. We examined the association between a hospital's proportion of nonacute PCIs categorized as inappropriate by the 2009 Appropriate Use Criteria (AUC) for Coronary Revascularization and in-hospital mortality, bleeding complications, and use of optimal guideline-directed medical therapy at discharge (ie, aspirin, thienopyridines, and statins). When categorized as hospital tertiles, the range of inappropriate PCI was 0.0% to 8.1% in the lowest tertile, 8.1% to 15.2% in the middle tertile, and 15.2% to 58.6% in the highest tertile. Compared with lowest-tertile hospitals, mortality was not significantly different at middle-tertile (adjusted odds ratio [OR], 0.93; 95% confidence interval [CI], 0.73–1.19) or highest-tertile hospitals (OR, 1.12; 95% CI, 0.88–1.43; P =0.35 for differences between tertiles). Similarly, risk-adjusted bleeding did not vary significantly (middle-tertile OR, 1.13; 95% CI, 1.02–1.16; highest-tertile OR, 1.02; 95% CI, 0.91–1.16; P =0.07 for differences between tertiles) nor did use of optimal medical therapy at discharge (85.3% versus 85.7% versus 85.2%; P =0.58). Conclusions— In a national cohort of nonacute PCIs, a hospital's proportion of inappropriate PCIs was not associated with in-hospital mortality, bleeding, or medical therapy at discharge. This suggests PCI appropriateness measures aspects of hospital PCI quality that are independent of how well the procedure is performed. Therefore, PCI appropriateness and postprocedural outcomes are both important metrics to inform PCI quality.

Noncyclic breast pain is a common breast disorder prompting women to seek medical evaluation. We aimed to perform a pilot study on the relief of noncyclic breast pain using acupuncture. Thirty-seven women seen at a diagnostic breast clinic between April 2003 and January 2009 were enrolled. Treatment consisted of four acupuncture sessions over two weeks, with three months of follow-up. Response to treatment was measured with use of a breast pain questionnaire, a quality of life (QOL) questionnaire, and the Cleeland Brief Pain Inventory (BPI) assessed at baseline, end of treatment, and three months after treatment. Data were analyzed using standard descriptive statistics. Twenty-two patients completed four acupuncture sessions. Pain described as throbbing and heavy decreased significantly after acupuncture (p = 0.04 and p = 0.03, respectively). After treatment, pain scores (on the 10-point BPI scale) decreased by an average of 3.5 points for the worst pain during the previous month (p = 0.001), by 2.7 points for average pain (p < 0.001), and by 2.3 points for pain interference (p = 0.002). The percentage of patients reporting a clinically meaningful decrease of 2 points from baseline to the end of treatment included 67% (12/18) for the worst pain, 65% (11/17) for average pain, and 56% (10/18) for pain interference. QOL data showed no improvement in QOL measures (mental, physical, emotional, social, or spiritual well-being). The results of this preliminary study suggest that a randomized controlled trial may be warranted to evaluate the effect of acupuncture on noncyclic breast pain, as well as the optimal frequency of acupuncture treatments.

Background— Clinical trials have shown that statin therapy reduces cardiovascular morbidity and mortality in patients with coronary artery disease (CAD), even among patients with low-density lipoprotein cholesterol levels <100 mg/dL. We sought to determine the extent to which patients with obstructive CAD in routine outpatient care are treated with statins, nonstatins, or no lipid-lowering therapy. Methods and Results— Within the American College of Cardiology's Practice Innovation and Clinical Excellence (PINNACLE) outpatient registry, we examined rates of treatment with statin and nonstatin medications in 38 775 outpatients with obstructive CAD (history of myocardial infarction or coronary revascularization) and without documented contraindications to statin therapy. Among these patients, 30 160 (77.8%) were prescribed statins, 2042 (5.3%) were treated only with nonstatin lipid-lowering medications, and 6573 (17.0%) were untreated. Lack of medical insurance was associated with no statin treatment, and male sex, coexisting hypertension, and a recent coronary revascularization were associated with statin treatment. Among those not on any lipid-lowering therapy, low-density lipoprotein cholesterol levels were available for 51.2% (3365/6573). Among these untreated patients, low-density lipoprotein cholesterol levels were <100 mg/dL in 1794 patients (53.3%) and ≥100 mg/dL in 1571 patients (46.7%). Conclusions— Despite robust clinical trial evidence, a substantial number of patients with obstructive CAD remain untreated with statins. A small proportion were treated with nonstatin therapy, and 1 in 6 patients was simply untreated; half of the untreated patients had low-density lipoprotein cholesterol values <100 mg/dL. These findings illustrate important opportunities to improve lipid management in outpatients with obstructive CAD.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15 , in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila , with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Abstract Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%–90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of IgH or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.