Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy.

Systemic administration of interleukin (IL)-12 induces potent anti-tumor immune responses in preclinical cancer models through the systemic activation of effector immune cells and release of proinflammatory cytokines. IL-12-loaded PLGA nanospheres (IL12ns) are hypothesized to improve therapeutic efficacy and thwart unwanted side effects observed in previous human clinical trials. Through the investigation of peripheral blood and local tissue immune responses in healthy BALB/c mice, the immune-protective pharmacodynamics of IL12ns were suggested. Nanospheres increased pro-inflammatory plasma cytokines/chemokines (IFN-γ, IL-6, TNF-α, and CXCL10) without inducing maladaptive transcriptomic signatures in circulating peripheral immune cells. Gene expression profiling revealed activation of pro-inflammatory signaling pathways in systemic tissues, the likely source of these effector cytokines. These data support that nanosphere pharmacodynamics, including shielding IL-12 from circulating immune cells, depositing peripherally in systemic immune tissues, and then slowly eluting bioactive cytokine, thereafter, are essential to safe immunostimulatory therapy.

Capecitabine as Maintenance Therapy for High-Risk, Resected Colorectal Cancer.

INTRODUCTION: In 2020, colorectal cancer will be the fourth most frequently diagnosed malignant neoplasm and the second leading cause of site-specific, cancer-related deaths in the USA. Notably, 80% of the new cases are, by staging criteria, potentially curable even those with completely resected stage 4 disease. If slightly more than half the losses can be attributed to metastatic disease at presentation, then the remaining portion of deaths may be linked to disease relapse after surgery and, if applicable, adjuvant chemotherapy. The inference that these therapies are not curative for a significant number of subjects poses a role for maintenance therapy. OBJECTIVE: To assess event-free survival (EFS) of patients who received capecitabine as maintenance therapy following treatment according to current guidelines. METHODS: Clinical outcomes data were collected for 35 subjects treated with capecitabine as maintenance therapy. Descriptive statistical analyses were conducted on collective data related to duration of maintenance therapy and disease or clinical status from surgery to initial event. Kaplan-Meier method and log-rank test were used to analyze EFS and overall survival. RESULTS: Of the entire cohort, 26 subjects have no evidence of disease (NED), a median of 5.5 years from surgery. Kaplan-Meier analyses indicated a 5-year EFS rate of 74% (95% CI: 60-90%). Eighteen of these 26 patients received capecitabine ≥30 months. Eight of the 17 subjects treated with capecitabine therapy for <30 months developed progressive disease; the majority of the relapses occurred within 20 months of surgery. The difference between the two groups was statistically significant. Six subjects died, only two of who had metastatic disease at the time of death; the other four had NED at least 4 years from surgery. Five patients with resected stage 4 disease who received capecitabine as maintenance therapy were alive >5 years from surgery. CONCLUSION: The findings and analyses of this cohort of patients suggest that maintenance capecitabine therapy reduces the risk of disease progression and cancer-related death.

Smoking is associated with adrenal adenomas and adrenocortical carcinomas: a nationwide multicenter analysis.

MICROABSTRACT: The effect of smoking on adrenal cancer is poorly understood. A clear association of adrenal adenoma and adrenocortical carcinoma with smoking among the United States population is observed. This association points to the possibility of environmental carcinogenic and/or lifestyle factors contributing to adrenal cancer formation. Our results support the association of tobacco use with adrenal adenomas and adrenal cortical carcinoma. BACKGROUND: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but this hypothesis has only been inferred from a single study using all types of adrenal cancers including pheochromocytoma, neuroblastoma, as well as ACC. Given the high rate of tobacco use in West Virginia, we hypothesized that smoking might contribute to increased prevalence of ACC. MATERIALS AND METHODS: De-identified institutional review board-exempted records were analyzed in the Surveillance, Epidemiology, and End Results (SEER) Program from 2001-2016 and in patients from the United States nationwide, multicenter TriNetX database of 41,063,707 patients from 2008-2018. In addition, the state-level ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the Center for Disease Control. West Virginia Health System data from 2008-2018 was extracted to confirm population-level findings. Melanoma was used as a cancer control in both databases. RESULTS: 6,946 ACC cases were identified. West Virginia had the highest smoking rate and the second highest rate of ACC. A significant association was found between smoking and ACC (Pearson correlation coefficient r = 0.4887, p=.0004). From 2008 to 2018 using TriNetX, 846 ACC and 36,434 AA were extracted. Both adrenal neoplasm cohorts had increased prevalence of tobacco use compared with melanoma controls, where 23.5% were smokers compared to 36.4% and 33.9% in the ACC and AA groups, respectively (p<0.0001 each). CONCLUSION: To our knowledge, this is the first United States population-based study supporting smoking as a risk factor for adrenal carcinogenesis and ACC.

Impact of Morbid Obesity on Overnight Stay and Early Complications With Outpatient Arthroplasty.

BACKGROUND: The shift toward outpatient joint arthroplasty is rapidly growing, but concerns still remain on whether certain patients should be excluded from same-day discharge arthroplasty. The purpose of this study is to evaluate whether morbid obesity is a risk factor for perioperative complications after outpatient joint arthroplasty. METHODS: A retrospective review was performed from 2013 to 2017 of all outpatient primary total hip, total knee, partial knee, and revision hip and knee arthroplasties, yielding a cohort of 4863 patients (5988 arthroplasty procedures). Patients were separated and analyzed based on 2 groups: nonmorbidly obese (NMO) (BMI < 40 kg/m2) and morbidly obese (MO) (BMI ≥ 40 kg/m2). The NMO group consisted of 4870 arthroplasties and the MO group consisted of 1118 arthroplasties. Overnight stays, medical complications, and early perioperative complications were assessed between groups. RESULTS: Overnight stays occurred in 5.4% of NMO patients and 9.1% of MO patients (P < .001), with medical reasons for the overnight stay occurring in 3.2% of NMO and 6.4% of MO patients (P < .001). Respiratory/sleep apnea was the leading medical reason leading to overnight stay occurring in 4% of MO patients and 0.8% of NMO patients (P < .001). There was no significant difference between groups in direct facility transfers, emergency room visits/admissions, or medical complications within 90 days. Wound revisions, nonrevision surgery, or revisions within 90 days were significant between groups. CONCLUSION: MO patients did not have an increased risk of 90-day medical complications, readmission, or revisions after outpatient arthroplasty. However, MO patients did have a significantly higher incidence of overnight stay.

Higher Activity Level Following Total Knee Arthroplasty Is Not Deleterious to Mid-Term Implant Survivorship.

BACKGROUND: The impact of a patient's activity level following total knee arthroplasty (TKA) remains controversial, with some surgeons concerned about increased polyethylene wear, aseptic loosening, and revisions. The purpose of this study is to report on implant survivorship and outcomes of high activity patients compared to low activity patients after TKA. METHODS: A retrospective review identified 1611 patients (2038 knees) that underwent TKA with 5-year minimum follow-up. Patients were divided in 2 groups based on their University of California Los Angeles (UCLA) activity level: low activity (LA) (UCLA ≤5) and high activity (HA) (UCLA ≥6). Outcomes included range of motion, Knee Society scores, complications, and reoperations. Parametric survival analysis was performed to evaluate the significance of activity level on survivorship while controlling for age, gender, preoperative pain, Knee Society clinical scores, Knee Society functional scores, and body mass index (BMI). RESULTS: Mean follow-up was 11.4 years (range 5.1-15.9). The LA group had significantly more female patients, were older, had higher BMI, and had lower functional scores preoperatively (all with P < .001). The HA group had significantly higher improvements in Knee Society scores (P < .001) and pain postoperatively (P < .001). Revisions were performed in 4% of the LA group and 1.7% knees of the HA group (P = .003). After controlling for age, gender, preoperative pain, Knee Society clinical scores, Knee Society functional scores, and BMI, a higher postoperative activity level remained a significant factor for improved survivorship with an odds ratio of 2.4 (95% confidence interval 1.2-4.7, P = .011). The all-cause 12-year survivorship was 98% for the HA group and 95.3% for the LA group (P = .003). The aseptic 12-year survivorship was 98.4% for the HA group and 96.3% for the LA group (P = .02). CONCLUSION: Highly active patients had increased survivorship at 5-year minimum follow-up compared to lower activity patients after TKA. Patient activity level after TKA may not need to be limited with modern implants.

Forced vital capacity less than 1: A mark for high-risk patients.

BACKGROUND: Rib fractures (RFx) continue to be a source of morbidity and mortality. A RFx care pathway has been used based on forced vital capacity (FVC). The objective of this study was to test the hypothesis that deterioration of FVC to less than 1 after admission is a marker for high-risk patients and affects outcomes. METHODS: A retrospective study of patients enrolled in an RFx care pathway at a Level 1 trauma center from 2009 to 2014. All patients had an admission FVC greater than 1. 2 groups were analyzed: patients with a lowest inpatient FVC less than 1 (Group A) compared to patients with lowest inpatient FVC of 1 or greater (Group B). Complications [pneumonia, upgrade to the intensive care unit, readmission, and intubation] and demographics were examined. Patients without documented admission FVCs were excluded. p < 0.05 was considered significant. RESULTS: A total of 1,106 patients were analyzed (Group A, 187; Group B, 919). Patients whose FVC dropped less than 1 (Group A) had a higher complication rate [15% (Group A) vs 3.2% (Group B); p < 0.001]. Rates of pneumonia, readmission, unplanned upgrade, and intubation were all significantly higher in Group A [pneumonia: 9% (Group A) vs 1.4% (Group B), p < 0.001; readmission: 4% (Group A) vs 1.7% (Group B), p = 0.04; upgrade; 3.7% (Group A) vs 0.2% (Group B), p < 0.001; intubation: 1.6% (Group A) vs 0.1% (Group B), p = 0.02]. Hospital length of stay was longer in Group A [10 days (Group A) vs 4 days (Group B), p < 0.001]. CONCLUSIONS: Forced vital capacity predicts complications in patients with RFx. Patients whose FVC falls less than 1 during admission are at high risk for pulmonary complications. Daily FVC testing for patients admitted with RFx can predict outcomes. Forced vital capacity less than 1 should be considered as a marker for complications. Once FVC drops less than 1, patients should be considered for increased interventions. Even if the patient has not yet clinically deteriorated, consideration for higher level of care is warranted. LEVEL OF EVIDENCE: Prognostic study, level III.

Undersized Rigid Nonplanar Annuloplasty: The Key to Effective and Durable Repair of Functional Tricuspid Regurgitation.

BACKGROUND: Previous clinical experiences have demonstrated high early and late recurrence rates after repair of functional tricuspid regurgitation (TR). We investigated the results of functional TR repair with undersized rigid nonplanar annuloplasty rings. METHODS: From January 2007 to December 2013, 216 consecutive patients with moderate or greater functional TR were treated with undersized (size 26 mm or 28 mm) rigid nonplanar annuloplasty rings. RESULTS: The mean age was 69 ± 13 years. There was a previous history of cardiac operation in 25% (54 of 216 patients). Tricuspid regurgitation was graded as severe in 47% (102 of 216) and moderate in 53% (114 of 216). Concomitant operations included mitral valve procedures in 92% (198 of 216), coronary artery bypass grafting in 21% (45 of 216), aortic valve procedures in 9% (20 of 216), and cryomaze procedures in 35% (76 of 216). Size 26 mm rings were used in 38% of patients (81 of 216), and size 28 mm in 62% (135 of 216). The perioperative mortality rate was 6% (14 of 216). On predischarge echocardiography, TR grade was none or mild in 94% (176 of 187 patients), moderate in 4% (7 of 187), and severe in 2% (4 of 187). At a mean follow-up of 33.0 ± 24.0 months, TR grade was none or mild in 81% of patients (130 of 160), moderate in 16% (26 of 160), and severe in 2% (4 of 160). There were no reoperations for recurrent TR, and no patients have had tricuspid stenosis or annuloplasty ring dehiscence. CONCLUSIONS: Treatment of functional TR with undersized (26 mm or 28 mm) nonplanar rigid annuloplasty rings is safe and highly effective, with a near absence of recurrent severe TR at midterm follow-up.

The 'pit-crew' model for improving door-to-needle times in endovascular stroke therapy: a Six-Sigma project.

BACKGROUND: Delays in delivering endovascular stroke therapy adversely affect outcomes. Time-sensitive treatments such as stroke interventions benefit from methodically developed protocols. Clearly defined roles in these protocols allow for parallel processing of tasks, resulting in consistent delivery of care. OBJECTIVE: To present the outcomes of a quality-improvement (QI) process directed at reducing stroke treatment times in a tertiary level academic medical center. METHODS: A Six-Sigma-based QI process was developed over a 3-month period. After an initial analysis, procedures were implemented and fine-tuned to identify and address rate-limiting steps in the endovascular care pathway. Prospectively recorded treatment times were then compared in two groups of patients who were treated 'before' (n=64) or 'after' (n=30) the QI process. Three time intervals were measured: emergency room (ER) to arrival for CT scan (ER-CT), CT scan to interventional laboratory arrival (CT-Lab), and interventional laboratory arrival to groin puncture (Lab-puncture). RESULTS: The ER-CT time was 40 (±29) min in the 'before' and 26 (±15) min in the 'after' group (p=0.008). The CT-Lab time was 87 (±47) min in the 'before' and 51 (±33) min in the 'after' group (p=0.0002). The Lab-puncture time was 24 (±11) min in the 'before' and 15 (±4) min in the 'after' group (p<0.0001). The overall ER-arrival to groin-puncture time was reduced from 2 h, 31 min (±51) min in the 'before' to 1 h, 33 min (±37) min in the 'after' group, (p<0.0001). The improved times were seen for both working hours and off-hours interventions. CONCLUSIONS: A protocol-driven process can significantly improve efficiency of care in time-sensitive stroke interventions.

Intravenous thrombolysis of large vessel occlusions is associated with higher hospital costs than small vessel strokes: a rationale for developing stroke severity-based financial models.

BACKGROUND: Owing to their severity, large vessel occlusion (LVO) strokes may be associated with higher costs that are not reflected in current coding systems. This study aimed to determine whether intravenous thrombolysis costs are related to the presence or absence of LVO. METHODS: Patients who had undergone intravenous thrombolysis over a 9-year period were divided into LVO and no LVO (nLVO) groups based on admission CT angiography. The primary outcome was hospital cost per admission. Secondary outcomes included admission duration, 90-day clinical outcome, and discharge destination. RESULTS: 119 patients (53%) had LVO and 104 (47%) had nLVO. Total mean±SD cost per LVO patient was $18,815±14,262 compared with $15,174±11,769 per nLVO patient (p=0.04). Hospital payments per admission were $17,338±13,947 and $15,594±16,437 for LVO and nLVO patients, respectively (p=0.4). A good outcome was seen in 33 LVO patients (27.7%) and in 69 nLVO patients (66.4%) (OR 0.2, 95% CI 0.1 to 0.3, p<0.0001). Hospital mortality occurred in 31 LVO patients (26.1%) and in 7 nLVO patients (6.7%) (OR 0.2, 95% CI 0.08 to 0.5, p<0.0001). 31 LVO patients (32.6%) were discharged to home versus 64 nLVO patients (61.5%) (OR 4.5, 95% CI 2.6 to 8, p<0.0001). Admission duration was 7.5±6.9 days in LVO patients versus 4.9±4.2 days in nLVO patients (p=0.0009). Multivariate regression analysis after controlling for comorbidities showed the presence of LVO to be an independent predictor of higher total hospital costs. CONCLUSIONS: The presence or absence of LVO is associated with significant differences in hospital costs, outcomes, admission duration, and home discharge. These differences can be important when developing systems of care models for acute ischemic stroke.

Effect of Head Position on Intraocular Pressure During Lumbar Spine Fusion: A Randomized, Prospective Study.

BACKGROUND: Ischemic optic neuropathy resulting in visual loss is a rare but devastating complication of spine surgery. Elevated intraocular pressure (IOP) results in decreased perfusion and possibly ischemic optic neuropathy. We performed a randomized, prospective trial to evaluate the effect of head positioning on IOP during lumbar spine fusion. METHODS: The study included fifty-two patients treated at one institution. Inclusion criteria were a lumbar spine fusion and an age of eighteen to eighty years. Exclusion criteria were a diagnosis of tumor, infection, or traumatic injury or a history of eye disease, ocular surgery, cervical spine surgery, chronic neck pain, or cervical stenosis. The control group underwent the surgery with the head in neutral and the face parallel to the level operating room table whereas, in the experimental group, the neck was extended so that the face had a 10° angle of inclination in relation to the table. IOP measurements were recorded along with the corresponding blood pressure and PCO2 values at the same time points. The primary outcome measure was the change in intraocular pressure (ΔIOP, defined as the maximum IOP minus the initial IOP). RESULTS: Analysis of covariance (ANCOVA) was used for categorical risk factors, and regression analysis was used for continuous risk factors. The mean ΔIOP, corrected for duration of surgery, was significantly (p = 0.0074) lower in the group treated with the head elevated than it was in the group treated with the head in neutral (difference between the two groups, 4.53 mm Hg [95% confidence interval, 1.29 to 7.79 mm Hg]). No patient sustained visual loss or any cervical-spine-related complications. CONCLUSIONS: Head elevation for adult lumbar spine fusion performed with the patient prone resulted in significantly lower IOP measurements than those seen when the operation was done with the patient's head in neutral. As lower IOP correlates with increased optic nerve perfusion, this intervention could mitigate the risk of perioperative blindness after spine surgery done with the patient prone.

High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer.

Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile.

PURPOSE: Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. METHODS: Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy-Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-α, IL-6), and adipokine profile (leptin, adiponectin, insulin). RESULTS: Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p < 0.05) than the control group. The intervention group also improved quality of life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p < 0.05). CONCLUSIONS: Exercise and dietary counseling led to loss of body fat and improved quality of life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a change in adiposity with intervention. Exercise and healthy eating may be equally effective in this high-risk population as in other breast cancer survivors and should be encouraged as a part of a cancer survivorship program.

A comparison of risk factors associated with suicide ideation/attempts in American Indian and White youth in Montana.

We examined racial/ethnic and gender-specific associations between suicide ideation/attempts and risky behaviors, sadness/hopelessness, and victimization in Montana American Indian and White youth using 1999-2011 Youth Risk Behavior Survey data. Logistic regression was used to calculate odds ratios and 95% confidence intervals in stratified racial/ethnic-gender groups. The primary results of this study show that although the American Indian youth had more statistically significant suicidal thoughts and attempts than the White youth, they had fewer statistically significant predictors compared to the White youth. Sadness/hopelessness was the strongest, and the only statistically significant, predictor of suicide ideation/attempts common across all four groups. The unhealthy weight control cluster was a significant predictor for the White youth and the American Indian/Alaska Native girls; the alcohol/tobacco/marijuana cluster was a significant predictor for the American Indian boys only. Results show important differences across the groups and indicate directions for future research targeting prevention and intervention.

Promoting oral health as part of an interprofessional community-based women's health event.

Heart disease is the number one killer of women, and studies have shown connections between cardiovascular and oral health. However, interprofessional community-based participatory initiatives promoting women's oral health have received little research attention. This study evaluated the effectiveness of personalized oral health education (POHE) during a free one-day interprofessional women's health promotion event. The objectives were to 1) assess the participants' knowledge about the connection between oral health and heart disease; 2) disseminate information about oral-systemic linkages; 3) encourage comprehensive dental examinations; and 4) evaluate POHE outcomes. West Virginia University School of Dentistry faculty and students delivered POHE to the participants. These POHE instructors were calibrated with a standardized script regarding periodontal disease, health impact of tobacco, xerostomia-inducing medications, and oral hygiene instruction. Immediately prior to and following each POHE session, all the participants (N=165; 100 percent response rate) completed a number-coded questionnaire. The findings showed that the participants' knowledge of oral-systemic health linkages had increased following the POHE. The respondents received oral health kits and were offered discount vouchers toward the cost of a comprehensive oral examination at the dental school. This replicable model may prove useful to other dental schools in promoting women's oral health.

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer.

PURPOSE: This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. METHODS: Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. RESULTS: Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). CONCLUSION: Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

Breast cancer pathology, receptor status, and patterns of metastasis in a rural appalachian population.

Breast cancer patients in rural Appalachia have a high prevalence of obesity and poverty, together with more triple-negative phenotypes. We reviewed clinical records for tumor receptor status and time to distant metastasis. Body mass index, tumor size, grade, nodal status, and receptor status were related to metastatic patterns. For 687 patients, 13.8% developed metastases to bone (n = 42) or visceral sites (n = 53). Metastases to viscera occurred within five years, a latent period which was shorter than that for bone (P = 0.042). More women with visceral metastasis presented with grade 3 tumors compared with the bone and nonmetastatic groups (P = 0.0002). There were 135/574 women (23.5%) with triple-negative breast cancer, who presented with lymph node involvement and visceral metastases (68.2% versus 24.3%; P = 0.033). Triple-negative tumors that metastasized to visceral sites were larger (P = 0.007). Developing a visceral metastasis within 10 years was higher among women with triple-negative tumors. Across all breast cancer receptor subtypes, the probability of remaining distant metastasis-free was greater for brain and liver than for lung. The excess risk of metastatic spread to visceral organs in triple-negative breast cancers, even in the absence of positive nodes, was combined with the burden of larger and more advanced tumors.

Repeat sternotomy: no longer a risk factor in mitral valve surgical procedures.

BACKGROUND: The incidence of reoperative mitral valve (MV) surgical procedures is increasing, representing more than 10% of all MV operations in the United States. Previous clinical series have reported mortality rates of 5% to 18% and reentry injury rates of 5% to 10% for reoperative MV operations. METHODS: Between January 2004 and June 2012, 1,312 MV operations were performed on 1,275 patients. We excluded 234 patients who underwent small incision primary right thoracotomy, 11 redo operations with first or second operation other than sternotomy, and 10 emergent operations, leaving 1,056 MV operations for analysis (first-time sternotomy, 926 [88%]; repeat sternotomy, 130 (12%]). Preoperative computed tomography was performed for all repeat sternotomy patients. Patients at risk for reentry injury were identified, and protective strategies were applied systemically before resternotomy procedures. RESULTS: Among 130 patients undergoing reoperative MV operations, 35% (46/130) had prior coronary artery bypass grafting (CABG), 15% (19/130) aortic valve operations, and 61% (80/130) MV operations. Sixteen percent (21/130) had more than one previous sternotomy. Operative mortality was 4.6% (43/926) for first-time procedures and 4.6% (6/130) for reoperative MV operations. Intraoperative injury (innominate vein) occurred during repeat sternotomy in 2 (1.5%) patients. Stroke occurred in 3 patients (2%) who underwent repeat sternotomy and in 22 (2%) who underwent first-time sternotomy. On multivariable analysis, preoperative New York Heart Association function class, concomitant CABG, dialysis, and higher pulmonary artery pressures were associated with operative mortality, and repeat sternotomy was not. CONCLUSIONS: With careful planning and execution, outcomes for reoperative MV operations in contemporary practice are favorable and are identical with those for first-time operations.

Endovascular therapy yields significantly superior outcomes for large vessel occlusions compared with intravenous thrombolysis: is it time to randomize?

BACKGROUND AND PURPOSE: We compared outcomes between endovascular (EV) therapy and intravenous (IV) thrombolysis in large vessel strokes. METHODS: 223 patients who had received either IV (n=100) or EV (n=123) therapy were analyzed. Only patients with strokes involving the internal carotid artery terminus (ICA-T, n=45), the middle cerebral artery (M1, n=107) or the bifurcation branches (M2, n=71) were included. The primary endpoint was 3 month outcome based on the modified Rankin Scale (mRS) score, good-outcome defined as mRS ≤2. RESULTS: The good outcome was 44.7% in the EV group and 26% in the IV group (p=0.003, OR 2.3, 95% CI 1.3 to 4.1). There was no difference in mortality or hemorrhage. For ICA-T occlusions, the good outcome was 27.6% in the EV and 0% in the IV group (p=0.004); for M1 occlusions, 40.6% in the EV versus 10.5% in the IV group (p=0.0006, OR 5.8, 95% CI 1.9 to 18.2); and for M2 occlusions, 76% in the EV versus 47.8% in the IV group (p=0.01, OR 3.5, 95% CI 1.2 to 10.2). For M1 occlusions, the death rate was 27.5% for the EV compared with 57.9% for the IV group (p=0.002, OR 3.6, 95% CI 1.6 to 8.3) with no difference observed in mortality for ICA-T or M2 occlusions. In the univariate analysis, age, National Institutes of Health Stroke Scale score and occlusion site were significant predictors of outcome and mortality (p<0.0001 for all). In the multivariable analysis, EV therapy (p=0.0004, OR 3.9, 95% CI 1.8 to 9) and younger age (p<0.0001, OR 0.96, 95% CI 0.9 to 0.98) were significant independent predictors of good outcome. CONCLUSIONS: There are significantly higher odds of a favorable outcome with EV compared with IV therapy for large vessel strokes. The data support the rationale of a randomized trial for large vessel occlusions.

Pre-intervention cerebral blood volume predicts outcomes in patients undergoing endovascular therapy for acute ischemic stroke.

BACKGROUND: Pre-intervention perfusion imaging is increasingly becoming part of stroke triage. Small studies supporting imaging based patient selection have been published. The goal of this larger study was to determine if perfusion imaging could impact on functional outcomes in patients undergoing stroke interventions. METHODS: All patients who had undergone endovascular therapy for anterior circulation strokes over a 7 year period were retrospectively analyzed. The pre-intervention perfusion imaging was assessed for size of cerebral blood volume (CBV), cerebral blood flow and mean transit time (MTT) abnormalities. A perfusion mismatch for irreversible versus reversible ischemia was based on CBV and MTT. Clinical outcome and mortality were based on the 90 day modified Rankin Scale. An analysis of the pre-intervention perfusion parameters was then performed to determine any impact on functional outcomes. RESULTS: 110 patients underwent endovascular therapy for anterior circulation strokes. A younger age and lower National Institutes of Health Stroke Scale score were important clinical predictors of favorable outcome (modified Rankin Scale ≤ 2). The extent of the CBV abnormality and percentage of CBV/MTT mismatch were the strongest imaging predictors of outcome and mortality. A CBV area of 229.5 mm(2) (± 290) was seen for favorable outcomes versus 968 mm(2) (± 1173) for poor outcomes (p<0.0001). A CBV/MTT mismatch of 91% (± 10.7) was seen for favorable outcomes versus 72.5% (± 31.6) for poor outcomes (p=0.0001). The CBV area was 273 mm(2) (± 392) in patients without mortality versus 1401.1 mm(2) (± 1310) in patients with mortality (p<0.0001). Patients who survived had a mean CBV/MTT mismatch of 90.2% (± 12.5) versus 61.1% (± 35.2) for those who did not (p<0.0001). A CBV lesion approximately greater than one-third of the middle cerebral artery distribution predicted a poor outcome and mortality. CONCLUSION: The extent of pre-intervention CBV abnormality is a strong predictor of functional outcomes following endovascular stroke therapy. This information can aid in patient selection and improve procedure efficacy.

Cerebrovascular geometry in the anterior circulation: an analysis of diameter, length and the vessel taper.

BACKGROUND: A study was undertaken to determine the typical length, diameter and taper of vessels in the anterior cerebral circulation. METHODS: The sample size was calculated at 100 patients based on similar measurements in the literature and divided into cohorts based on gender and side. These patients were consecutively collected from a population that had undergone CT angiography and did not have any vascular abnormality. The arterial diameter was measured at the proximal cavernous internal carotid artery (ICA), the ICA terminus, the middle cerebral artery (MCA) origin and an M2 origin. The length between these endpoints was calculated along the center line. The vessel taper was calculated for the ICA as the change in caliber per unit length. RESULTS: The mean length of the ICA from the proximal cavernous segment to the ICA terminus was 33.1 ± 6.1 mm. The mean diameter at the cavernous ICA and the ICA terminus was 5 ± 0.6 mm and 3.6 ± 0.4 mm, respectively. The mean ICA taper was 0.04 ± 0.02 mm/1 mm. For the MCA, the diameter at the MCA and M2 origins measured 3.1 ± 0.4 mm and 2.4 ± 0.4 mm, respectively. The mean MCA length was 22.5 ± 8.1 mm. There was no significant difference based on gender or between right and left sides. Patients aged >60 years had longer ICAs (p=0.02), larger cavernous ICA (p=0.003), ICA terminus (p<0.0001) and MCA origin (p=0.01) diameters than those aged 40-60 years. The ICA vessel taper did not change with age. CONCLUSION: ICA and MCA vessel size did not change based on gender or side. Older patients had more redundant vessels based on diameter and length. The ICA has a gentle taper from its proximal cavernous segment to the ICA terminus. This information can be important in planning interventions or designing endovascular devices.