Does Early Chemotherapy Improve Survival in Advanced Endometrial Cancer?

OBJECTIVES: In endometrial cancer, the appropriate sequence of adjuvant chemotherapy (aCT) and adjuvant radiation therapy (aRT) is unclear. We aim evaluated whether early chemotherapy is associated with improved overall survival (OS) and cancer-specific survival (CSS). METHODS: Endometrial cancer patients that received aCT and aRT were selected from the SEER-Medicare database. Early chemotherapy was defined as receiving aCT before aRT, with or without additional aCT ("sandwich" regimens). All other patients received a full course of aRT before chemotherapy with or without concurrent chemotherapy. Univariate and multivariate Cox proportional hazards regression was utilized to assess the impact of clinical and demographic factors on OS. RESULTS: We selected 597 patients for analysis. Median age and was 72 years; 85% of patients were white. Overall, 68% of women had FIGO (International Federation of Gynecology and Obstetrics) stage III disease and 77% received 4 to 6 cycles of chemotherapy. Five-year OS (66.6% vs. 62.4%, P=0.46) and 5-year CSS (71.1% vs. 71.2%, P=0.88) was not significantly improved among those receiving early chemotherapy. In addition, early chemotherapy did not improve OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]: 0.56-1.34, P=0.53) or CSS (HR=1.21; 95% CI: 0.82-1.79, P=0.34) on multivariate analysis. Compared with 1 to 3 cycles, receiving 4 to 6 (HR=0.48, 95% CI: 0.26-0.87, P=0.02), and ≥7 cycles (HR=0.42, 95% CI: 0.20-0.89, P=0.02) of chemotherapy was associated with improved OS. CONCLUSION: No differences in OS or CSS were noted among endometrial patients receiving early chemotherapy. However, the number of chemotherapy cycles was associated with prolonged survival.

Esthesioneuroblastoma: A Patterns-of-Care and Outcomes Analysis of the National Cancer Database.

BACKGROUND: The available literature to guide treatment decision making in esthesioneuroblastoma (ENB) is limited. OBJECTIVE: To define treatment patterns and outcomes in ENB according to treatment modality using a large national cancer registry. METHODS: This study is a retrospective cohort analysis of 931 patients with a diagnosis of ENB who were treated with surgery, radiation therapy, and/or chemotherapy in the United States between the years of 2004 and 2012. Log-rank statistics were used to compare overall survival by primary treatment modality. Logistic regression modeling was used to identify predictors of receipt of postoperative radiotherapy (PORT). Cox proportional hazards modeling was used to determine the survival benefit of PORT. Subgroup analyses identified subgroups that derived the greatest benefit of PORT. RESULTS: Primary surgery was the most common treatment modality (90%) and resulted in superior survival compared to radiation (P < .01) or chemotherapy (P < .01). On multivariate analysis, PORT was associated with decreased risk of death (hazard ratio [HR] 0.53, P < .01). PORT showed a survival benefit in Kadish stage C (HR 0.42, P < .01) and D (HR 0.09, P = .01), but not Kadish A (HR 1.17, P = .74) and B (HR 1.37, P = .80). Patients who received chemotherapy derived greater benefit from PORT (HR 0.22, P < .01) compared with those who did not (HR 0.68, P = .13). Predictors of PORT included stage, grade, extent of resection, and chemotherapy use. CONCLUSION: Best outcomes were obtained in patients undergoing primary surgery. The benefit of PORT was driven by patients with stages C and D disease, and by those also receiving chemotherapy.

Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non-Small-Cell Lung Cancer.

Purpose Although several feasibility studies have demonstrated the safety of adjuvant concurrent chemoradiotherapy (CRT) for locally advanced or incompletely resected non-small-cell lung cancer (NSCLC), it remains uncertain whether this approach is superior to sequential chemotherapy followed by postoperative radiotherapy (C→PORT). We sought to determine the most effective treatment sequence. Patients and Methods Using the National Cancer Database, we selected two cohorts of patients with nonmetastatic NSCLC who had received at least a lobectomy followed by multiagent chemotherapy and radiotherapy; cohort one included patients with R0 resection and pN2 disease, whereas cohort two included patients with R1-2 resection regardless of nodal status. Overall survival (OS) was examined using a propensity score-matched analysis with a shared frailty Cox regression. Results A total of 747 patients in cohort one and 277 patients in cohort two were included, with a median follow-up of 32.8 and 27.9 months, respectively. The median OS was 58.8 months for patients who received C→PORT versus 40.4 months for patients who received CRT in cohort one (log-rank P < .001). For cohort two, the median OS was 42.6 months for patients who received C→PORT versus 38.5 months for patients who received CRT (log-rank P = .42). After propensity score matching, C→PORT remained associated with improved OS compared with CRT in cohort one (hazard ratio, 1.35; P = .019), and there was no statistical difference in OS between the sequencing groups for cohort two (hazard ratio, 1.35; P = .19). Conclusion Patients with NSCLC who undergo R0 resection and are found to have pN2 disease have improved outcomes when adjuvant chemotherapy is administered before, rather than concurrently with, radiotherapy. For patients with positive margins after surgery, there is not a clear association between treatment sequencing and survival.

Patterns of care and outcomes in gliosarcoma: an analysis of the National Cancer Database.

OBJECTIVE The authors compared presenting characteristics and survival for patients with gliosarcoma (GS) and glioblastoma (GBM). Additionally, they performed a survival analysis for patients who underwent GS treatments with the hypothesis that trimodality therapy (surgery followed by radiation and chemotherapy) would be superior to nontrimodality therapy (surgery alone or surgery followed by chemotherapy or radiation). METHODS Adults diagnosed with GS and GBM between the years 2004 and 2013 were queried from the National Cancer Database. Chi-square analysis was used to compare presenting characteristics. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses. RESULTS In total, data from 1102 patients with GS and 36,658 patients with GBM were analyzed. Gliosarcoma had an increased rate of gross-total resection (GTR) compared with GBM (19% vs 15%, p < 0.001). Survival was not different for patients with GBM (p = 0.068) compared with those with GS. After propensity score analysis for GS, patients receiving trimodality therapy (surgery followed by radiation and chemotherapy) had improved survival (12.9 months) compared with those not receiving trimodality therapy (5.5 months). In multivariate analysis, GTR, female sex, fewer comorbidities, trimodality therapy, and age < 65 years were associated with improved survival. There was a trend toward improved survival with MGMT promoter methylation (p = 0.117). CONCLUSIONS In this large registry study, there was no difference in survival in patients with GBM compared with GS. Among GS patients, trimodality therapy significantly improved survival compared with nontrimodality therapy. Gross-total resection also improved survival, and there was a trend toward increased survival with MGMT promoter methylation in GS. The major potential confounder in this study is that patients with poor functional status may not have received aggressive radiation or chemotherapy treatments, leading to the observed outcome. This study should be considered hypothesis-generating; however, due to its rarity, conducting a clinical trial with GS patients alone may prove difficult.

Anaplastic meningioma: an analysis of the National Cancer Database from 2004 to 2012.

OBJECTIVE Anaplastic meningiomas represent 1%-2% of meningioma diagnoses and portend a poor prognosis. Limited information is available on practice patterns and optimal management. The purpose of this study was to define treatment patterns and outcomes by treatment modality using a large national cancer registry. METHODS The National Cancer Database was used to identify patients diagnosed with anaplastic meningioma from 2004 to 2012. Log-rank statistics were used to compare survival outcomes by extent of resection, use of adjuvant radiotherapy (RT), and use of adjuvant chemotherapy. Least-squares linear regression was used to evaluate the utilization of RT over time. Logistic regression modeling was used to identify predictors of receipt of RT. Cox proportional hazards modeling was used to evaluate the effect of RT, gross-total resection (GTR), and chemotherapy on survival. RESULTS A total of 755 adults with anaplastic meningioma were identified. The 5-year overall survival rate was 41.4%. Fifty-two percent of patients received RT, 7% received chemotherapy, and 58% underwent GTR. Older patients were less likely to receive RT (OR 0.98, p < 0.01). Older age (HR 1.04, p < 0.01), high comorbidity score (HR 1.33, p = 0.02), and subtotal resection (HR 1.57, p = 0.02) were associated with increased risk of death on multivariate modeling, while RT receipt was associated with decreased risk of death (HR 0.79, p = 0.04). Chemotherapy did not have a demonstrable effect on survival (HR 1.33, p = 0.18). CONCLUSIONS Anaplastic meningioma portends a poor prognosis. Gross-total resection and RT are associated with improved survival, but utilization of RT is low. Unless medically contraindicated, patients with anaplastic meningioma should be offered RT.

Toxicity and Outcomes in Patients With and Without Esophageal Stents in Locally Advanced Esophageal Cancer.

PURPOSE: Esophageal stenting is often considered to relieve dysphagia in patients with locoregionally advanced esophageal cancer. We sought to determine the effects of stenting on the incidence of acute toxicity and oncologic outcomes in patients undergoing chemoradiation therapy (CRT). METHODS AND MATERIALS: The data from patients treated with curative intent CRT for locoregionally advanced esophageal cancer at the University of Utah were retrospectively analyzed. The χ2 or Fisher exact test was used to compare the demographic and tumor characteristics between patients with and without esophageal stenting before RT. Univariate and multivariate analyses using logistic regression modeling were used to identify the predictors of acute toxicities. A propensity score-matched analysis with shared frailty Cox hazard regression was performed according to stent status to identify the stent effect on survival. Acute toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4. RESULTS: From 2005 to 2013, 103 consecutive patients received CRT. Of the 103 patients, 28 had a stent in place during CRT. The median dose was 50.4 Gy for all patients. Grade ≥3 acute toxicities were seen in 71% of the stent versus 27% of the no-stent patients (P<.01), including esophagitis (39% vs 20%; P=.05), dehydration (29% vs 13%; P=.07), and anorexia (14% vs 5%; P=.13). Of the 103 patients, 29% of the stent and 51% of the no-stent patients underwent esophagectomy (P=.05). The only significant predictor for acute toxicity on multivariate analysis was esophageal stenting (odds ratio 8.1; P<.01). After propensity score matching, the stent patients had a worse median overall survival compared with the no-stent patients (11.5 vs 22.0 months; hazard ratio 2.3; P=.016). CONCLUSIONS: In patients undergoing CRT with curative intent, esophageal stenting was associated with significantly increased grade ≥3 acute toxicities, fewer patients proceeding to esophagectomy, and worse overall survival.

Risk of Death from Prostate Cancer with and without Definitive Local Therapy when Gleason Pattern 5 is Present: A Surveillance, Epidemiology, and End Results Analysis.

Purpose The purpose is to evaluate the patterns of care and comparative effectiveness for cause-specific and overall survival of definitive local treatments versus conservatively managed men with a primary or secondary Gleason pattern of 5. Methods and materials Patients diagnosed from 2004 to 2012 with a primary or secondary Gleason pattern of 5 N0M0 prostate cancer were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox regression analyses were used to estimate the survival. Results We identified 20,560 men. Median age and follow-up were 68 years and 4.33 years, respectively. At eight years, cause-specific survival (CSS) was 86.6% and 57.4% of those receiving and not receiving definitive local treatments, respectively. For CSS multivariate analysis, the following were significant: age, race, insurance status, total Gleason Score, T-stage, and type or omission of definitive local treatments. Compared to prostatectomy alone, men not undergoing definitive local treatments had the highest risk of death (HR: 6.07; 95% CI: 5.19-7.10). Those undergoing external beam radiotherapy alone (HR: 2.11; 95% CI: 1.80-2.48) were also at elevated risk of death. The number needed to treat (NNT) to prevent a prostate cancer death at eight years was three persons. Conclusions Death from prostate cancer with a primary or secondary Gleason pattern of 5 histology without definitive local treatment is high. In this hypothesis-generating study, we found that men with a limited life expectancy (less than eight years) and non-metastatic Gleason pattern of 5 disease may benefit from definitive local treatments. Given the high mortality in men with a Gleason pattern of 5, combined modality local therapies and consideration of chemotherapies may be warranted.

Differences in Parotid Dosimetry and Expected Normal Tissue Complication Probabilities in Whole Brain Radiation Plans Covering C1 Versus C2.

OBJECTIVES: There is no consensus standard regarding the placement of the inferior field border in whole brain radiation therapy (WBRT) plans, with most providers choosing to cover the first versus (vs.) second cervical vertebrae (C1 vs. C2). We hypothesize that extending coverage to C2 may increase predicted rates of xerostomia. METHODS: Fifteen patients underwent computed tomography (CT) simulation; two WBRT plans were then produced, one covering C2 and the other covering C1. The plans were otherwise standard, and patients were prescribed doses of 25, 30 and 37.5 gray (Gy). Dose-volume statistics were obtained and normal tissue complication probabilities (NTCPs) were estimated using the Lyman-Burman-Kutcher model. Mean parotid dose and predicted xerostomia rates were compared for plans covering C2 vs. C1 using a two-sided patient-matched t-test. Plans were also evaluated to determine whether extending the lower field border to cover C2 would result in a violation of commonly accepted dosimetric planning constraints. RESULTS: The mean dose to both parotid glands was significantly higher in WBRT plans covering C2 compared to plans covering C1 for all dose prescriptions (p<0.01). Normal tissue complication probabilities were also significantly higher when covering C2 vs. C1, for all prescribed doses (p<0.01). Predicted median rates of xerostomia ranged from <0.03%-21% for plans covering C2 vs. <0.001%-12% for patients treated with plans covering C1 (p<0.01), dependent on the treatment dose and NTCP model. Plans covering C2 were unable to constrain at least one parotid to <20 Gy in 31% of plans vs. 9% of plans when C1 was covered. A total parotid dose constraint of <25 Gy was violated in 13% of plans covering C2 vs. 0% of plans covering C1. CONCLUSIONS: Coverage of C2 significantly increases the mean parotid dose and predicted NTCPs and results in more frequent violation of commonly accepted dosimetric planning constraints.

Brachytherapy Improves Survival in Stage III Endometrial Cancer With Cervical Involvement.

PURPOSE: To evaluate the survival benefit of adding vaginal brachytherapy (BT) to pelvic external beam radiation therapy (EBRT) in women with stage III endometrial cancer. METHODS AND MATERIALS: The National Cancer Data Base was used to identify patients with stage III endometrial cancer from 2004 to 2013. Only women who received adjuvant EBRT were analyzed. Women were grouped according to receipt of BT. Logistic regression modeling was used to identify predictors of receiving BT. Log-rank statistics were used to compare survival outcomes. Cox proportional hazards modeling was used to evaluate the effect of BT on survival. A propensity score-matched analysis was also conducted among women with cervical involvement. RESULTS: We evaluated 12,988 patients with stage III endometrial carcinoma, 39% of whom received EBRT plus BT. Women who received BT were more likely to have endocervical or cervical stromal involvement (odds ratios 2.03 and 1.77; P<.01, respectively). For patients receiving EBRT alone, the 5-year survival was 66% versus 69% with the addition of BT at 5 years (P<.01). Brachytherapy remained significantly predictive of decreased risk of death (hazard ratio 0.86; P<.01) on multivariate Cox regression. The addition of BT to EBRT did not affect survival among women without cervical involvement (P=.84). For women with endocervical or cervical stromal invasion, the addition of BT significantly improved survival (log-rank P<.01). Receipt of EBRT plus BT was associated with improved survival in women with positive and negative surgical margins, and receiving chemotherapy did not alter the benefit of BT. Propensity score-matched analysis results confirmed the benefit of BT among women with cervical involvement (hazard ratio 0.80; P=.01). CONCLUSIONS: In this population of women with stage III endometrial cancer the addition of BT to EBRT was associated with an improvement in survival for women with endocervical or cervical stromal invasion.

A Case of Complete Abscopal Response in High-Grade Pleiomorphic Sarcoma Treated with Radiotherapy Alone.

BACKGROUND: "Abscopal response" refers to the spontaneous involution of untreated metastatic disease following local primary tumor-directed therapy. We report a case of an abscopal response of untreated lung metastasis in a man with pleomorphic sarcoma of the head and neck treated with hypofractionated radiotherapy. METHODS: An inoperable pleomorphic sarcoma of the postauricular soft tissue was treated with 40 Gy of radiation in eight fractions. Untreated disease in the lungs was followed with CT scans. RESULTS: At the two-month post-treatment follow-up, clinical exam and restaging CT demonstrated complete primary tumor involution. Additionally, CT chest images showed a dramatic disease response in the untreated pulmonary disease, which progressed to complete and persistent clinical response at one-year post-treatment follow-up. CONCLUSIONS: We report the first described case of a complete abscopal resolution of untreated lung metastases in a patient with a primary pleomorphic sarcoma of the head and neck treated with hypofractionated radiotherapy.

Postoperative Radiotherapy in Locally Invasive Malignancies of the Thymus: Patterns of Care and Survival.

INTRODUCTION: Our purpose was to determine the overall survival (OS) benefit of postoperative radiotherapy (PORT) in patients with advanced thymic malignancies and the associated predictors of PORT receipt. METHODS: We queried the National Cancer Data Base for all stage II to III thymic malignancies. Trends in PORT use over time were analyzed using least squares linear regression. Factors predictive of PORT and OS were identified by using multivariate logistic and Cox regression analysis, respectively. RESULTS: We identified 1156 patients between 2004 and 2012 who met the inclusion criteria. The utilization of PORT was found to increase over the study period by 41% (37% to 52% [p = 0.01]). On multivariate analysis, the factors found to be the most predictive of receipt of PORT were positive surgical margins (adjusted OR = 1.98 [p < 0.01]) and treatment at a nonacademic facility (adjusted OR = 1.44 [p = 0.01]). The 5-year OS was superior for patients receiving PORT compared with for those who did not (83% versus 79%, p = 0.03). Receipt of PORT was associated with a trend toward decreased risk for death on multivariate analysis (hazard ratio = 0.75 [p = 0.09]). In addition, a positive macroscopic margin was the most important predictor of survival (hazard ratio = 3.48 [p < 0.01]). On subgroup analysis, patients with thymic carcinoma and WHO histologic types A and AB were associated with an OS benefit with PORT, whereas types B1, B2, and B3 were not. Patients with positive margins were not associated with an OS benefit with PORT. CONCLUSIONS: The use of PORT in patients with advanced thymic malignancies is increasing over time and is determined by both clinical and demographic factors. Receipt of PORT was associated with improved OS. The OS benefit with PORT was dependent on the WHO histologic type.

The "decay" of brachytherapy use in tumors of the oral cavity: A population-based patterns of care and outcomes analysis from 1973 to 2012.

PURPOSE: We aimed to evaluate if use of brachytherapy (BT) is associated with improved survival in patients with oral cavity cancer who do not receive surgery and to analyze patterns of care. METHODS AND MATERIALS: We queried the Surveillance, Epidemiology, and End Results database for patients who received radiation therapy for squamous cell carcinoma of the oral cavity between 1973 and 2012. Patients were grouped by treatment modality: external beam radiotherapy alone vs. external beam radiotherapy + BT. Surgical patients were excluded. Trends in BT utilization over the study period and patterns of care were analyzed. Propensity scores were generated, and a nearest-neighbor matching algorithm was used to balance the 2 groups. Cox regression modeling was used to estimate the effect of BT on overall survival. Sensitivity analysis was conducted to estimate the effect of unmeasured confounders on the analysis. RESULTS: Of 5,161 patients with squamous cell carcinoma of the oral cavity who received radiotherapy, 12% of patients received BT. The rate of BT use has decreased by 0.58% per year (p < 0.001). Factors that predicted for omission of radiation therapy included age ≥ 65 years (adjusted odds ratio [aOR], 0.56; p < 0.001), regional nodal disease (aOR, 0.57; p < 0.001), and black race (aOR, 0.45; p < 0.001). Use of BT was associated with a decreased risk of death (hazard ratio, 0.75; p < 0.001). CONCLUSIONS: The use of BT is associated with improved survival in oral cavity tumors treated with definitive radiotherapy. Rates of BT utilization have declined by 0.58% per year and are currently very low.

Brachytherapy improves survival in primary vaginal cancer.

PURPOSE: Prospective, randomized data does not exist to guide treatment in primary vaginal cancer (PVC). We evaluated the impact of brachytherapy on survival in women with PVC. METHODS AND MATERIALS: Women who received radiotherapy for PVC were identified using the Surveillance, Epidemiology, and End Result database. Two retrospective cohorts were created; women who received external beam radiotherapy (EBRT) alone and those who received brachytherapy (alone or in combination of EBRT). Nearest-neighbor propensity score matching was used to balance the groups according to measured covariates. Cox proportional hazard regression modeling was used to estimate the effect of receipt of brachytherapy on survival. RESULTS: Two thousand five hundred seventeen vaginal cancer patients were identified. Squamous cell carcinoma made up 75% of tumors. Median overall survival (OS) for patients receiving EBRT alone was 3.6years (95% CI, 3.0-4.2years) versus 6.1years (95% CI 5.2-7.2years) for patients receiving brachytherapy (p=<0.001). Cox proportional hazard model revealed decrease risk of death among patients that received brachytherapy in the matched cohort (HR 0.77; 95% CI 0.68-0.86). Brachytherapy reduced risk of death among patients in all stage groups. No patient demographic or tumor variables favored the use of EBRT alone. Brachytherapy was associated with a decreased risk of death for all FIGO stages. Brachytherapy benefited patients with squamous cell carcinoma (HR 0.80; 95% CI 0.70-0.92) and adenocarcinoma (HR 0.69; 95% CI 0.49-0.95). Tumors larger than 5cm had the greatest benefit from brachytherapy (HR 0.68; 95% CI 0.50-0.91). CONCLUSIONS: Brachytherapy should be encouraged for all suitable patients with PVC.

Chemoradiation versus chemotherapy or radiation alone in stage III endometrial cancer: Patterns of care and impact on overall survival.

PURPOSE: We aimed to investigate the patterns-of-care and overall survival (OS) benefit of aCRT versus adjuvant monotherapy (aMT), defined as either chemotherapy or radiation alone, utilizing a large national registry of patients. PATIENTS AND METHODS: Adult patients with stage III endometrial adenocarcinoma diagnosed from 2004 to 2013 were included. Logistic and Cox regression modeling was used to identify factors predictive of receipt of aCRT and OS, respectively. Survival analysis was performed with Kaplan Meier and log-rank analysis. Propensity score matching and sensitivity analysis was performed to address selection bias and presence of potential confounding variables. RESULTS: A total of 21,027 patients were identified: 11,435 (54.4%) patients received aMT, while 9592 (45.6%) received aCRT. Utilization of aCRT increased over the study period (p<0.01). Factors predictive of receiving aCRT include private insurance (OR: 1.67, 95% CI: 1.30-2.14), Medicare (OR: 1.33, 95% CI: 1.01-1.75), FIGO stage IIIC disease (OR: 1.36, 95% CI: 1.19-1.54), lymphovascular space invasion (OR: 1.14, 95% CI: 1.03-1.27), and lymph node surgery performed (OR: 1.42, 95% CI: 1.15-1.74). Median survival in years for aCRT, RT, and CT was 10.3, 7.1, and 5.6, respectively (p<0.001). Compared to aMT, aCRT was associated with a decrease risk of death on multivariate analysis (HR: 0.62, 95% CI: 0.56-0.70). The benefit of aCRT over aMT persisted after propensity score matching. CONCLUSION: The use of aCRT for stage III endometrial cancer is increasing. Multiple clinical and demographic factors were predictive of aCRT use. When compared to chemotherapy or radiation alone, aCRT is associated with an OS benefit.

Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.

Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastase-specific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease.

Density gradients in packed columns: I. Effects of density gradients on retention and separation speed.

Density gradients in packed capillary columns operating under the extreme pressure drops typical for solvating gas chromatography were investigated by on-column spectroscopic measurements and compared to a theoretical model. Laser-induced fluorescence was used to follow the elution of various analytes, and Raman spectroscopy was used to measure the density of the mobile phase, each with respect to column position. Mobile phase linear velocity initially increases gradually, and then rises rapidly near the column outlet. High flow rates near the column outlet are offset by a loss of mobile phase solvating power which ultimately limits the speed of separation. These results represent an extreme case for illuminating factors affecting supercritical fluid separation techniques in general.

Density gradients in packed columns: II. Effects of density gradients on efficiency in supercritical fluid separations.

To investigate how fluid compressibility affects efficiency in supercritical fluid separations, band dispersion along a packed capillary column was measured from on-column elution rate profiles obtained under solvating gas chromatography (SGC) conditions; this allowed efficiency to be determined with respect to position along the column. Theoretical efficiency was also modeled. The model indicates that the primary cause of band broadening in SGC is high mobile phase velocity near the column outlet. However, the experimental results show that significant band broadening also occurs near the column inlet in a region that corresponds to high elution rates of the analyte. On-column detection also revealed spatial focusing of the analyte as it moves down the column density gradient.

Characterization of carbon dioxide mobile phase density profiles in packed capillary columns by Raman microscopy.

Efforts to understand and optimize separations employing compressible mobile phases have been limited by a lack of understanding of the mobile phase density gradient. Mobile phase compressibility leads to gradients in linear velocity and solute retention and affects separation speed and efficiency, especially in packed columns. Gas chromatography (GC), supercritical fluid chromatography (SFC), and solvating gas chromatography (SGC) each rely on compressible mobile phases. This work describes the on-column density measurement of carbon dioxide, a common carrier fluid for SFC and SGC, in packed capillary columns using Raman microspectroscopy of the position of the Fermi doublet. Correlation of the spectrum with density was calibrated over a pressure range of 15 to 290 atm at 125 and 150 degrees C, which then allowed for determination of the density gradient of fluid flowing through a packed capillary column. The results of this work will be used to model the flow behavior of compressible fluids to understand the effects of mobile phase compressibility on separation speed and efficiency.