Citations

Background— Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with LV filling patterns through speckle-tracking strain echocardiography. Methods and Results— Echocardiography was performed in 71 adults with a new diagnosis of PAH. To analyze LV and RV function separately, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed >2 years. Patients had dilated right-sided chambers (right atrial volume index, 44±19 mL/m 2 ; RV end-diastolic area, 34±9 cm 2 ), and reduced RV function (RV fractional area change, 28±12%). Speckle-tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (−15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension, 42±6 mm; ejection fraction, 65±8%; cardiac index, 2.6±0.8 L/min per m 2 ), patients had reduced LV free wall systolic strain (−15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, P =0.0002. During 2-year follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted hazard ratio, 2.40 per 5% decrease in LV free wall strain, 1.22–4.68), which remained significant when adjusted for age, sex, World Health Organization functional class, and PAH pathogenesis (hazard ratio, 3.11, 1.38–7.20). Conclusions— The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LV ejection fraction, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Objectives/HypothesisTo determine the incidence of level IIB lymph node metastasis in patients with laryngeal or hypopharyngeal squamous cell carcinoma and to evaluate the need for elective and therapeutic neck dissection of level IIB.Study DesignRetrospective cohort study and review of the literature.MethodsPatients with laryngeal or hypopharyngeal squamous cell carcinoma (N = 65) were primarily treated with surgery at Mayo Clinic (Rochester, Minnesota) from 2004 through 2010. Neck dissection specimens were analyzed by a pathologist, and metastases to level IIB were reported. In addition, 18 previously published studies, totaling 1,114 neck dissections, were reviewed.ResultsLevel IIB lymph node metastases were present in 4% and 17% of elective and therapeutic neck dissections, respectively. Ipsilateral IIB metastasis was more common than contralateral IIB metastasis in elective and therapeutic neck dissection specimens. Level IIB lymph node metastasis was not significantly associated with level IIA nodal metastasis, level III nodal metastasis, clinical primary tumor stage, clinical nodal stage, or pathologic confirmation of extracapsular spread in either laryngeal or hypopharyngeal squamous cell carcinoma.ConclusionsThe rate of occult IIB metastasis in laryngeal and hypopharyngeal squamous cell carcinoma is exceedingly low. In a clinically node‐negative case, the ipsilateral and contralateral level IIB nodal packet should not be dissected. For clinically node‐positive cases, ipsilateral level IIB dissection should be performed; contralateral IIB dissection should be performed only when indicated.Level of Evidence4. Laryngoscope, 123:3032–3036, 2013

Abstract Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27+IgD− memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40–CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27+IgD− memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.

Objectives/HypothesisTo determine the incidence of level IIB lymph node metastasis in patients with oropharyngeal squamous cell carcinoma (OPSCC) and to evaluate the necessity of level IIB dissection for elective and therapeutic neck dissections.Study DesignRetrospective cohort study.MethodsPatients with OPSCC (N = 348) were surgically managed at our institution from 2004 through 2010. Neck dissection specimens were reviewed by a pathologist, and level IIB metastases were analyzed with respect to clinical and pathologic data.ResultsLevel IIB lymph node metastases were present in 2.5% and 25% of elective and therapeutic neck dissections, respectively. Level IIA metastasis, clinical tumor stage, clinical nodal stage, extracapsular spread, and primary tumor location in the tonsil were significantly associated with level IIB metastasis.ConclusionsThis study uniquely demonstrated a statistically significant association between clinical tumor stage and tonsil subsite with level IIB metastasis in OPSCC. Considering the predicted incidence of nodal metastasis, we conclude that level IIB neck dissection can be omitted in early stage (T1 or T2) clinically node negative (cN0) OPSCC. In patients with a cN0 neck and advanced OPSCC (T3 or T4), primary tumor in the tonsil, or ipsilateral clinically node positive (cN+) and contralateral cN0 neck, level IIB dissection should be considered. Level IIB dissection should be performed routinely in patients with cN+ OPSCC.Level of Evidence4. Laryngoscope, 123:2700–2705, 2013

Abstract Introduction: Multivariable models that predict biochemical recurrence (BCR) can indicate patients at higher risk for developing clinical progression after prostatectomy. However, most patients that experience BCR do not metastasize or die from prostate cancer, making BCR an unreliable surrogate endpoint. In this study we compared the clinical and genomic characteristics of prostatectomy patients in order to better delineate the relationship between BCR and aggressive prostate cancer. Methods: Postoperative patients were retrospectively classified into three outcome groups: NED (no evidence of disease recurrence); BCR-only (patients that experienced BCR but didn't have progressive disease as evidenced by bone or CT scans); and CP (clinical progression with BCR plus positive CT or bone scans). Patient specimens were from the Mayo Clinic Radical Prostatectomy Registry, selected using a nested case-control design with 14 years median follow-up. RNA expression levels from FFPE tumor specimens were measured with 1.4 million feature whole-transcriptome oligonucleotide microarrays on 106 matching patients from each outcome group (total 318 patients). We analyzed the clinical covariates of the outcome groups in a pairwise manner (NED vs. BCR-only; NED vs. CP; CP vs. BCR-only), using a conditional logistic model in univariable and multivariable analyses. We performed feature reduction for the genomic data set using Kruskal-Wallis tests and regularized logistic regression. Principal Component Analysis (PCA) was used to quantify the variance of the genomic data with respect to the patient outcome groups. Results: Our initial hypothesis was that all three outcome groups would have different clinical and genomic characteristics. Univariable analysis of clinical variables failed to show statistically significant differences between NED and BCR-only groups. Multivariable analysis of the clinical variables also failed to show statistically significant differences between NED and BCR-only groups. Among the clinical variables only pathological Gleason score was statistically significant when comparing the BCR-only vs. CP and NED vs. CP groups. Genomic analysis found 363 coding and non-coding features that passed thresholds for differential expression between the three outcome groups. PCA established that the primary source of variance in the genomic data stemmed from the separation of CP from NED and BCR-only patients; whereas only a small amount of variance separates NED and BCR-only groups. The 363 features were further compared in the three outcome groups using Wilcoxon tests, adjusting for false-discovery using Benjamini-Hochberg. At a cutoff of p < 0.001 there were no features differentially expressed between NED and BCR-only, while 52 and 34 statistically significant features were found in the NED vs. CP and CP vs. BCR-only comparisons, respectively. Conclusion: Considering the clinical and genomic results together, we find that: 1) Patients that developed clinical progression were significantly different from those that did not, irrespective of whether they experienced BCR or not; 2) the NED and BCR-only groups were statistically very similar to each other. We therefore conclude that BCR may not be the most appropriate endpoint for predictive models that attempt to stratify patients at risk for progression. This abstract is also presented as Poster B44. Citation Format: Anamaria Crisan, Elai Davicion, R. Jeffery Karnes, Robert B. Jenkins, Mercedeh H. Ghadessi, Christine Buerki, Eric J. Bergstrahl, Nicholas Erho, Ismael A. Vergara, Karla V. Ballman, Peter C. Black, Timothy J. Triche. Biochemical recurrence is not a definitive surrogate endpoint for development of clinically useful predictive models for post-prostatectomy patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr PR4.

ABSTRACT We previously showed that culture of samples obtained by prosthesis vortexing and sonication was more sensitive than tissue culture for prosthetic joint infection (PJI) diagnosis. Despite improved sensitivity, culture-negative cases remained; furthermore, culture has a long turnaround time. We designed a genus-/group-specific rapid PCR assay panel targeting PJI bacteria and applied it to samples obtained by vortexing and sonicating explanted hip and knee prostheses, and we compared the results to those with sonicate fluid and periprosthetic tissue culture obtained at revision or resection arthroplasty. We studied 434 subjects with knee ( n = 272) or hip ( n = 162) prostheses; using a standardized definition, 144 had PJI. Sensitivities of tissue culture, of sonicate fluid culture, and of PCR were 70.1, 72.9, and 77.1%, respectively. Specificities were 97.9, 98.3, and 97.9%, respectively. Sonicate fluid PCR was more sensitive than tissue culture ( P = 0.04). PCR of prosthesis sonication samples is more sensitive than tissue culture for the microbiologic diagnosis of prosthetic hip and knee infection and provides same-day PJI diagnosis with definition of microbiology. The high assay specificity suggests that typical PJI bacteria may not cause aseptic implant failure.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

Study ObjectiveTo identify specific risk factors for excessive anticoagulation, defined as an international normalized ratio (INR) higher than 5, in hospitalized adults receiving warfarin therapy using a pharmacist‐managed dosing protocol.DesignRetrospective nested case‐control study.SettingLarge academic tertiary care medical center.PatientsHospitalized nonsurgical patients 18 years or older who received at least one dose of warfarin according to the pharmacist‐managed protocol from January 1, 2009, to January 31, 2012, were included. Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR goal, and type of warfarin therapy (new start or continuation).Measurements and Main ResultsA total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin's effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation.ConclusionEven in a highly standardized system for warfarin dosing by a pharmacist‐managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin's effect or the occurrence of diarrheal illness may predict increased risk.