Citations

Abstract BACKGROUND Patients recovering from decompressive laminectomy without fusion may require assistance with activities of daily living and physical/occupational therapy upon hospital discharge. OBJECTIVE To examine comorbidities and perioperative characteristics of patients undergoing lumbar decompression for associations with discharge status using a multicenter database. METHODS A multicenter database was used for this retrospective cohort analysis. Patients admitted from home with degenerative spine disease for lumbar decompression without fusion were included. Thirty-day outcomes and operative characteristics were compared as a function of patient discharge using chi-square and Wilcoxon Rank Sum tests. Multivariable logistic regression was used to determine factors associated with discharge to a nonhome facility. RESULTS Of the 8627 patients included for analysis, 9.7% were discharged to a nonhome facility. On multivariable analysis, age (85+ vs <65, odds ratio [OR] 13.59), number of levels of decompression (3+ vs 1, OR 1.75), African American race vs Non-Hispanic or Hispanic White (OR 1.87), female vs male gender (OR 1.97), body mass index (BMI) (40+ vs 18.5-24.9, OR 1.74), American Society of Anesthesiologists physical classification status (4 vs 1 or 2, OR 2.35), hypertension (OR 1.29), dependent functional status (OR 3.92), diabetes (OR 1.47), smoking (OR 1.40), hematocrit (<35 vs 35+, OR 1.76), international normalized ratio (≥1.3 vs <1.3, OR 2.32), and operative time (3+ h vs <1 h, OR 5.34) were significantly associated with an increased odds of discharge to nonhome facilities. CONCLUSION Preoperative status and operative course variables can influence discharge disposition in lumbar decompression patients. Identifying specific factors that contribute to a greater likelihood of dismissal to skilled facility or rehabilitation unit can further inform both surgeons and patients during preoperative counseling and disposition planning.

OBJECTIVEThe mechanism by which greater institutional case volume translates into improved outcomes after surgical clipping of unruptured intracranial aneurysms (UIAs) is not well established. The authors thus aimed to assess the effect of case volume on the rate of various types of complications after clipping of UIAs.METHODSUsing information on the outcomes of inpatient admissions for surgical clipping of UIAs collected within a national database, the relationship of institutional case volume to the incidence of different types of complications after clipping was investigated. Complications were subdivided into different categories, which included all complications, ischemic stroke, intracerebral hemorrhage, medical complications, infectious complications, complications related to anesthesia, and wound complications. The relationship of case volume to different types of complications was assessed using linear regression analysis. The relationships between case volume and overall complication and stroke rates were fit with both linear and quadratic equations. The numerical cutoff for institutional case volume above and below which the authors found the greatest differences in mean overall complication and stroke rate was determined using classification and regression tree (CART) analysis.RESULTSBetween October 2012 and September 2015, 125 health care institutions reported patient outcomes from a total of 6040 cases of clipping of UIAs. On linear regression analysis, increasing case volume was negatively correlated to both overall complications (r2 = 0.046, p = 0.0234) and stroke (r2 = 0.029, p = 0.0557) rate, although the relationship of case volume to the complication (r2 = 0.092) and stroke (r2 = 0.067) rate was better fit with a quadratic equation. On CART analysis, the cutoff for the case number that yielded the greatest difference in overall complications and stroke rate between higher- or lower-volume centers was 6 cases/year and 3 cases/year, respectively.CONCLUSIONSAlthough the authors confirm that increasing case volume is associated with reduced complications after clipping of UIAs, their results suggest that the relationship between case volume and complications is not necessarily linear. Moreover, these results indicate that the effect of case volume on outcome is most evident between very-low-volume centers relative to centers with a medium-to-high volume.

OBJECTIVE With improving medical therapies for chronic conditions, elderly patients increasingly present as candidates for operative intervention for degenerative diseases of the spine. To date, there is a paucity of studies examining complications in lumbar decompression, without fusion, that include patients older than 80 years. Using a multicenter national database, the authors of this study evaluated lumbar decompression in the elderly, including octogenarians, to evaluate for associations between age and patient outcomes. METHODS The 2011–2013 American College of Surgeons' National Surgical Quality Improvement Program data set was queried for patients 65 years and older with diagnosis and procedure codes inclusive of degenerative spine disease and lumbar decompression without fusion. Morbidity and mortality within the 30-day postoperative period were the primary outcomes. Secondary outcomes of interest included unplanned readmission within 30 days or discharge to a nonhome facility. Outcomes and operative characteristics were compared using chi-square tests, Kruskal-Wallis tests, and multivariable logistic regression models. RESULTS A total of 8744 patients were identified; of these patients 4573 (52.30%) were 65 years and older. Elderly patients were stratified into 3 age categories: 85 years or older (n = 314), 75–84 years (n = 1663), and 65–74 years (n = 2596). Univariate analysis showed that, compared with age younger than 65 years, increased age was associated with the number of levels (≥ 3), readmissions within 30 days, nonhome discharge, any complication, length of stay, and blood transfusion (all p < 0.001). On multivariable analysis and with younger than 65 years as the reference, increased age was associated with any minor complication (p < 0.001; ≥ 85 years: OR 3.47, 95% CI 1.69–7.13; 75–84 years: OR 2.34, 95% CI 1.45–3.78; and 65–74 years: OR 1.44, 95% CI 0.94–2.20), as well as discharge location other than home (p < 0.001; ≥ 85 years: OR 13.59, 95% CI 9.47–19.49; 75–84 years: OR 5.64, 95% CI 4.33–7.34; and 65–74 years: OR 2.61, 95% CI 2.05–3.32). CONCLUSIONS The authors' high-powered, multicenter analysis of lumbar decompression without fusion in the elderly, specifically including patients older than 80 years, demonstrates that increased age is associated with more extensive operations, resulting in longer hospital stays, increased rates of nonhome discharge, and minor complications.

Abstract Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012–23. ©2016 AACR.

Abstract Breast density represents the stromal and epithelial tissue in the breast and is a strong risk factor for breast cancer. Reductions in breast density attributable to tamoxifen (TAM) and aromatase inhibitors (AI) may be associated with reduced risk of first primary and subsequent breast cancer. Studies assessing breast density changes have principally used two-dimensional measures. We assess changes in breast density following initiation of TAM and AI using two automated volumetric density measures that have shown strong associations to breast cancer risk. Breast cancer cases with a full field digital mammogram (FFDM) prior to diagnosis (index mammogram) and after initiation of TAM (n = 379) or AI (n = 425) were identified from the Mayo Clinic Mammography Practice and the San Francisco Mammography Registry. Volumetric percent density (VPD) and dense volume (DV) were measured on 4-view FFDM using VolparaTM (Matakina Technology) and QuantraTM (Hologic) automated software. We used linear regression to assess the effect of treatment on mean annualized change in VPD and DV (change from index to last mammogram divided by time interval) for each software type, adjusting for age, body mass index (BMI) and density at index mammogram. The median time between index mammogram and cancer diagnosis was 0.6 months (IQR: 0.2, 2.2) and median time between index and last mammogram was 3 years (IQR: 2.0, 3.9). Women on TAM were younger, had lower BMI and higher baseline VPD and DV relative to women on AI (Table). An annual decrease in VPD and DV was observed with both TAM and AI. Both Volpara and Quantra estimated a similar magnitude of change in VPD in women on TAM and AI, and a greater change in DV with TAM. Our findings suggest that both Volpara and Quantra can assess volumetric changes in breast density among women on hormone therapy. If declines in volumetric density correlate with a reduction in breast cancer risk, these automated measures could be used in clinical practice to assess response to therapy. Annualized changes in volumetric breast density estimated by linear regression.Tamoxifen (n = 379)Aromatase Inhibitors (n = 425)Baseline Median (IQR)Annualized Change (95% CI)*Baseline Median (IQR)Annualized Change (95% CI)*Age at Diagnosis50.0 (45.0, 60.0)–63.0 (58.0, 71.0)–Body Mass Index (BMI)23.6 (21.5, 26.8)–25.7 (22.7, 29.9)–Time Interval¥3.0 (2.1, 3.9)–3.0 (2.1, 3.9)–VolparaPercent Density (VPD,%)11.6 (6.8, 18.8)-0.17 (-0.27, -0.10)7.2 (5.0, 11.0)-0.19 (-0.29, -0.12)Dense Volume (DV, cm3)64.7 (45.4, 90.9)-0.90 (-1.45, -0.48)51.9 (38.9, 69.9)-0.52 (-0.93, -0.23)QuantraPercent Density (VPD,%)14.5 (9.2, 20.2)-0.42 (-0.59, -0.28)9.9 (7.1, 14.5)-0.38 (-0.54, -0.25)Dense Volume (DV, cm3)94.0 (58.0, 144.0)-2.20 (-3.52, -1.19)80.0 (49.0, 128.0)-0.95 (-1.85, -0.35)IQR = Interquartile range ¥ Median number of years between index mammogram and last mammogram post-initiation of therapy. *Annualized change estimated as change from index to last mammogram divided by time interval and adjusted for study site, age at diagnosis, BMI and density at index mammogram. Citation Format: Natalie J. Engmann, Celine M. Vachon, Christopher G. Scott, Matthew R. Jensen, Lin Ma, Kathleen R. Brandt, Amir P. Mahmoudzadeh, Serghei Malkov, Dana H. Whaley, Carrie B. Hruska, Fang F. Wu, Stacey J. Winham, Diana L. Miglioretti, Aaron D. Norman, John J. Heine, John Shepherd, V Shane Pankratz, Karla Kerlikowske. Longitudinal changes in volumetric breast density with adjuvant endocrine therapy among women with breast cancer. [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 3424.

Abstract Percent mammographic density (PMD) is a risk factor for estrogen receptor (ER)-positive and ER-negative invasive breast cancer (BC). Gene expression profiling has identified molecular signatures that classify invasive BC into distinct subtypes that vary in their clinical behavior, response to treatment and likely, etiology. Immunohistochemical (IHC) staining of tumor sections using antibody panels can be used to classify these ‘intrinsic’ molecular subtypes. We evaluated whether density measures [PMD, absolute dense area (DA) and non-dense area (NDA)], are associated equally with all ‘intrinsic’ molecular subtypes. Pooled analysis of six cohort or case-control studies included 3492 women with invasive BC and 10,148 without, who underwent screening mammography a median 4 years prior to diagnosis (for cases). PMD, DA, and NDA were assessed from digitized film-screen mammograms using a computer-assisted thresholding technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+ (PMD) or into quartiles (DA and NDA). Receptor status was abstracted from pathology records and supplemented by IHC staining. We classified tumors as Luminal A (ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (TN) (ER-/PR-/HER2-). For TN, we also differentiated basal-like tumors (positive for EGFR and/or CK 5/6) from unclassified (negative on both markers). We used polytomous logistic regression to calculate the odds ratio (OR) of each ‘intrinsic’ subtype of BC by categories of PMD, DA or NDA, adjusting for age, body mass index and study. We tested for statistical heterogeneity of associations by subtype. Of 3492 invasive BC cases, 2217 (63%) were classified as Luminal A, 747 (21%) as Luminal B, 159 (5%) as HER2 expressing, and 369 (11%) as TN. Of TN, 203 were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) unclassified. PMD was associated with BC risk across all subtypes. For Luminal A, compared to women with 11-25% PMD (reference), women with 0-10% had a reduced risk of BC (OR = 0.63 [95% confidence interval: 0.55, 0.74]) while women with 26-50% had an OR = 1.5 [1.3, 1.7] and women with 51%+ had the highest risk, OR = 2.3 [2.0, 2.7]. Similar BC associations were seen across PMD categories when comparing the five subtypes (P-heterogeneity = 0.63). Similar trends were seen for DA and BC across the five subtypes (P-het = 0.25). NDA was inversely associated with BC across subtypes, and there was suggestion of a stronger inverse trend among HER2-expressing BC compared to other subtypes (P-het = 0.09). Our results suggest mammographic density measures are associated with all ‘intrinsic’ molecular subtypes. However, NDA may be more strongly inversely associated with HER2-expressing than other subtypes. Understanding the importance of density measures for BC subtypes has significance for subtype-specific risk models. Citation Format: Aaron D. Norman, Rulla M. Tamimi, Christopher G. Scott, Kimberly A. Bertrand, Matthew R. Jensen, Daniel W. Visscher, Fergus J. Couch, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew Beck, Vernon S. Pankratz, Karla Kerlikowske, Celine M. Vachon. Association of mammographic density measures and breast cancer ‘intrinsic’ molecular subtypes. [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 2593.

In humans, intra-arterial ATP infusion in limbs mimics many features of exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore, we addressed two questions during a continuous 3-h brachial artery infusion of ATP [20 μg·100 ml forearm volume (FAV) −1 ·min −1 ]: 1) would skeletal muscle blood flow remain robust or wane over time (tachyphylaxis); and 2) would the hyperemic response to moderate-intensity exercise performed during the ATP administration be blunted compared with that during control (saline) infusion. Nine participants (25 ± 1 yr) performed one trial consisting of seven bouts of rhythmic handgrip exercise (20 contractions/min at 20% of maximum), two bouts during saline (control), and five bouts during 180 min of continuous ATP infusion. Five minutes of ATP infusion resulted in a 710% increase in forearm vascular conductance (FVC) from control (4.8 ± 0.77 vs. 35.0 ± 5.7 ml·min −1 ·100 mmHg −1 ·dl FAV −1 , P < 0.05). Contrary to our expectations, FVC did not wane over time with values of 35.0 ± 5.7 and 36.0 ± 7.7 ml·min −1 ·100 mmHg −1 ·dl FAV −1 ( P > 0.05), seen prior to the exercise bouts at 5 vs. 150 min, respectively. During superimposed exercise, FVC increased from 35.0 ± 5.7 to 49.6 ± 5.4 ml·min −1 ·100 mmHg −1 ·dl FAV −1 at 5 min and 36.0 ± 7.7 to 54.5 ± 5.0 at 150 min ( P < 0.05). Our findings demonstrate ATP vasodilation is prolonged over time without tachyphylaxis; however, exercise hyperemia responses remain intact. Our results challenge the metabolic theory of exercise hyperemia, suggesting a disconnect between matching of blood flow and metabolic demand.