Citations

A 33-year-old elite female runner presented to a tertiary care sports medicine clinic with a 2-year history of progressive anterior thigh and circumferential leg pain with associated foot paresthesias brought on by high-intensity running. She had both external iliac artery vasospasm and chronic exertional compartment syndrome. External iliac artery vasospasm is a rare cause of exertional leg pain, particularly in the running population. This case highlights the unique features of this condition, addresses the multidisciplinary approach that led to the accurate diagnoses, and demonstrates that more than 1 etiology for exertional leg pain can coexist in an athlete.

Objectives To determine the rate of perioperative complications and cost associated with Mayo-McCall culdoplasty (MMC), open abdominal sacrocolpopexy (ASC), and robotic sacrocolpopexy (RSC) for posthysterectomy vaginal vault prolapse. Methods We retrospectively searched for the records of patients undergoing posthysterectomy apical vaginal prolapse surgery (MMC, ASC, or RSC) between January 1, 2000, and June 30, 2012, at our institution. For all patients identified, perioperative complications, length of hospital stay, and inpatient costs to patients were abstracted from the medical records and compared by procedure. Inverse–probability-of-procedure weighting using propensity scores was used to obtain less-biased comparisons of outcomes between procedures. Results A total of 512 patients met the inclusion criteria (174 MMC, 237 ASC, and 101 RSC). Using inverse-probability weighting, the MMC group had a significantly lower intraoperative complication rate (3.3% vs 11.6% for ASC, 3.4% vs 24.1% for RSC), median operative time (94 vs 217 min for ASC, 100 vs 228 min for RSC), and median cost (US $8,776 vs $12,695 for ASC, US $8,773 vs $13,107 for RSC) than the ASC and RSC groups (all P < 0.01). In addition, the MMC group had significantly fewer postoperative grade 3+ complications than the RSC group (1.1% vs 9.4%, P < 0.01). Conclusions In the treatment of posthysterectomy vaginal vault prolapse, MMC is associated with decreased non–urinary tract infection, less perioperative morbidity, and lower cost to patients compared with sacrocolpopexy.

Abstract Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P &lt; 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry–European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10−7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. ©2016 AACR.

Abstract BACKGROUND Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS Neurosurgeons’ individual surgical goals varied significantly ( P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor ( R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes ( P < .01) and nonresectable residual ( P < .01), but not resectable residual. CONCLUSION In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.

AbstractBackgroundGlioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments.MethodsWe collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV).ResultsWe collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32).ConclusionMRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.

Abstract Background: The immune response has been shown to impact the course of colorectal cancer (CRC). Our goal was to examine the survival of CRC patients in relation to tumor-infiltrating cytotoxic (CD8+) T lymphocytes (CTL). We quantified CTLs in tumor epithelial and stromal tissues and correlated them with clinicopathological characteristics and survival of CRC patients in the Iowa Women's Health Study. Methods: Paraffin-embedded tissue samples were available from 465 post-menopausal women diagnosed with incident CRC in 1986-2002. Tumor microarrays were constructed and immunostained with a CD8 antibody (Clone 144B; Dako). CTLs in tumor epithelial and stromal tissues were categorized by an experienced pathologist into non-detected; mild (1-10 cells per core); moderate (11-29 cells); and strong infiltration (≥30 cells per core), and averaged over cores per each person. We used Cox regression to estimate the hazard ratio (HR) and 95% CI for total and CRC death in relation to each CTL score after adjusting for age of diagnosis, SEER stage, grade, body mass, smoking history and integrated molecular pathway for CRC. The tumors were categorized by integrated pathway (traditional, alternate, serrated, unassigned) based on the combination of phenotypes: microsatellite instability (MSI) status, CpG island methylator (CIMP) phenotype; and mutations in BRAF and/or KRAS genes (described in Samadder, 2013). Results: During follow-up until 2011, 31% of participants died from CRC, 36% from all other causes, and 33% were alive (median follow-up: 8.4 y). The Spearman correlation coefficient between epithelial and stromal CTL scores was 0.52. Both scores were inversely correlated with stage at diagnosis and were higher in tumors characterized by MSI-high, CIMP-high and BRAF mutation-positive status. The highest categories in the epithelial and stromal scores were associated with statistically significant decreases in total death (by 44% and 40%, respectively) and CRC death (by 68% and 56%, respectively) compared to lowest categories. After summing epithelial and stromal CTL scores, the combined HRs (95% CI) in the highest versus lowest category were 0.55 (0.38-0.78) for total death (p-trend = 0.0002) and 0.36 (0.20-0.63) for CRC death (p-trend&lt;0.0001). Additional adjustment for surgery, chemotherapy, radiation, and comorbidities did not markedly change the associations. Finally, there was a statistically significant quantitative interaction between stromal score and MSI status in relation to total and CRC death (P for interaction were 0.02 and 0.0001, respectively); HRs were lower for MSI-high than for MS-stable tumors. There was also a significant interaction between smoking status (current versus never) and epithelial CTL score: the HRs for total and CRC death were lowest among never smokers with the highest score. Conclusions. Our study further supports infiltration of tumors with CTLs as an important prognostic factor in CRC. Citation Format: Anna E. Prizment, Robert A. Vierkant, Thomas C. Smyrk, Lori S. Tillmans, Heather H. Nelson, Charles F. Lynch, Stephen N. Thibodeau, Timothy R. Church, James R. Cerhan, Kristin E. Anderson, Paul J. Limburg. Tumor-infiltrating cytotoxic T-cells are associated with improved survival of colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2636.

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P &lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P &lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

Abstract Diagnostic testing is an integral component of patient evaluation in the emergency department ( ED ). Emergency clinicians frequently use diagnostic testing to more confidently exclude “worst‐case” diagnoses rather than to determine the most likely etiology for a presenting complaint. Increased utilization of diagnostic testing has not been associated with reductions in disease‐related mortality but has led to increased overall healthcare costs and other unintended consequences (e.g., incidental findings requiring further workup, unnecessary exposure to ionizing radiation or potentially nephrotoxic contrast). Shared decision making ( SDM ) presents an opportunity for clinicians to discuss the benefits and harms associated with diagnostic testing with patients to more closely tailor testing to patient risk. This article introduces the challenges and opportunities associated with incorporating SDM into emergency care by summarizing the conclusions of the diagnostic testing group at the 2016 Academic Emergency Medicine Consensus Conference on SDM . Three primary domains emerged: 1) characteristics of a condition or test appropriate for SDM , 2) critical elements of and potential barriers to SDM discussions on diagnostic testing, and 3) financial aspects of SDM applied to diagnostic testing. The most critical research questions to improve engagement of patients in their acute care diagnostic decisions were determined by consensus.

Improving early detection and treatment of atrial fibrillation (AF) is critical because untreated AF is a major contributor to stroke and heart failure. We sought to generate knowledge about the feasibility of conducting a randomized controlled trial to test the effect of the Alert for AFib intervention on knowledge, attitudes, and beliefs about treatment-seeking for signs and symptoms of AF. Adults ≥65 years old (96% White) at risk for developing AF were randomized to receive the Alert for AFib intervention ( n = 40) or an attention control session ( n = 40). Feasibility goals for recruitment, participant retention, adherence, perceived satisfaction and burden, and intervention fidelity were met. From baseline to study completion, knowledge ( p = .005) and attitudes ( p < .001) about treatment-seeking improved more in the intervention group compared with the control group. Results support testing the effectiveness of the Alert for AFib intervention in a large trial.