Citations

Background: Neurohospitalists may improve the efficiency and quality of care delivered to hospitalized patients with neurological disease. However, there is limited systematic data to support this hypothesis. The primary purpose of this study was to compare length of stay (LOS) for patients with ischemic stroke cared for by either neurohospitalists or community-based neurologists at a single institution. Methods: A retrospective chart review was performed for all patients with ischemic stroke discharged from St. Luke’s Hospital in Jacksonville, Florida, between January 2006 and December 2007. The LOS for patients cared for by neurohospitalists was compared to the LOS for patients cared for by community neurologists. Compliance with Joint Commission inpatient stroke quality metrics was also compared. Results: A total of 533 patients were discharged with a principal diagnosis of ischemic stroke over the 24-month study period. Neurohospitalists cared for 313 patients with mean (± SD) LOS of 4.9 (5.2) days (95% CI: 4.3-5.5 days), and community-based neurologists cared for 220 patients with a mean LOS of 6.5 (8.2) days (95% CI: 5.4-7.6 days). The mean LOS was significantly less for the neurohospitalists compared to the community-based neurologists ( P = .005). Neurohospitalists achieved a higher compliance rate in 10 of 11 inpatient stroke quality metrics and achieved significantly higher compliance rate of smoking cessation education ( P = .019). Conclusions: Neurohospitalists achieved significantly shorter LOS for patients with ischemic stroke compared to community-based neurologists. These data suggest that neurohospitalists can also improve compliance with quality metrics necessary for Joint Commission Primary Stroke Center designation.

Abstract Objectives. To assess chemo-response of patient derived ovarian cancer cells to first line chemotherapeutic agents as well as targeted therapies. Methods. Ascites was obtained at laparotomy from 14 patients with epithelial ovarian cancer. Short term cultures were established in 11 of these and the cells characterized by morphology and immuno-staining to cytokeratin AE1/AE3 and E-cadherin. MTT assays were done on the 11 samples after 48 hours of exposure to Cisplatin, Paclitaxel, Vandetanib and Flavopiridol. Results. Three samples did not grow well and ultimately showed senescence or were over-run by fibroblasts. In the remaining 11 samples, morphology showed the cells to be arranged in a cobble-stone or rosette pattern. Most of the cells stained positive for cytokeratin AE1/AE3 and E-cadherin. The majority of samples (8/11, 73%) were sensitive to either Cisplatin or Paclitaxel. Of the three resistant samples, one was sensitive to Vandetanib, one to Flavopiridol and one was resistant to all four drugs. Two patients did not receive chemotherapy due to morbidity or mortality. Among those who were treated, 4 (50%) had complete response and are currently free of disease. Conclusions. Short term cultures may be a good method of studying chemo-response of tumor cells ex-vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3544.

Abstract Introduction. PCNSL is an aggressive primary brain tumor characterized by a perivascular accumulation of malignant cells that have lymphoid characteristics. As there is significantly less information regarding the molecular pathogenesis of PCNSL in comparison with systemic lymphomas the aim of this study was to perform a comprehensive high-resolution genomic analysis in a cohort of PCNSL cases to better characterize the disease at chromosomal and gene level. Material and Methods. Specimens from 7 EBV- and HIV-negative and presumed immunocompetent PCNSL patients with sufficient frozen tissue for DNA extraction were studied. Copy-number abnormalities were analyzed by array CGH using SurePrint G3 (1 million probes) microarray (Agilent). B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and CD138. Results. PCNSL cases were characterized by highly complex genomes with a median of 23 copy-number abnormalities per patient (range 16-49). Twenty-four chromosomal regions were affected in recurrent deletions and 19 in copy-number gains. Gain of 12q12-q24.33 and losses of 9p21.3 and 6q were the most common abnormalities, found in five of the seven patients. There was not a deleted region on 6q unique to all cases, with 6q14.1-q14.3, 6q16.3-q22.2 and 6q25.3-q26 losses being found in 4 out of 5 cases with 6q deletions. Two regions of interest were biallelically deleted. CDKN2A was the sole gene included in all cases with 9p21.3, being biallelically deleted in two out of 5 cases. TOX and CD58, genes associated with the development and activation of T cells, were also biallelically affected. Focal monoallelic deletions affecting negative regulators of the NFkB signaling pathway (MAP4K1, TANK, TAX1BP1, TRIB3), cell cycle (RB1) and immune-cell regulation (SIRPB1, CBLB, NFATC2) were also identified. Overall, a total of 22 genes were included in homozygous deletions in at least one case. Several chromosomal breakpoints were identified inside genes that encode transcription factors previously identified as being part of fusion protein in other hematological malignancies (FOXP1, ETV6 and NCOA2). Conclusion. This pilot study showed evidence for a highly complex genome, mainly characterized by abnormalities affecting a plethora of genes involved in lymphocyte development, activation and NF-kB signaling pathways regulation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 331.

Abstract Background. Vitamin K1 (phylloquinone) is a fat soluble vitamin found mainly in green leafy vegetables, with smaller amounts found in other vegetables, vegetable oils, and some fruits. Vitamin K-dependent gamma-carboxylation of specific glumatic acid residues is critical to the functioning of several key proteins in the coagulation cascade. Vitamin K compounds also inhibit IL-6 and other inflammatory cytokines and serve as transcription factors that foster cell-cycle arrest and apoptosis, pathways relevant to lymphomagenesis. We tested the hypothesis that dietary and supplemental intake of Vitamin K was inversely associated with risk of NHL and the common subtypes of diffuse large B cell, follicular, and chronic lymphocytic leukemia/small lymphocytic lymphomas. Methods. We evaluated dietary and supplemental intake of vitamin K and NHL risk in a clinic-based study of 603 newly diagnosed NHL cases and 1007 frequency-matched controls enrolled at the Mayo Clinic from 2002-2008. Usual diet two years before case diagnosis or control enrollment was assessed using a self-administered, 128-item food frequency questionnaire. Dietary intake of vitamin K was estimated using the Food Processor SQL system. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, and total energy. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results. The mean age at diagnosis was 60.8 years for cases and 57% were male; for controls, the mean age at enrollment was 60.1 years and 53% were male. Median intake of vitamin K from diet among controls was 63.5 ug/day; 16% used a multivitamin supplement that included vitamin K. NHL risk was inversely associated with intake of dietary vitamin K (p-trend=0.001); compared to intake <39.3 ug/d, risk was decreased for intakes of 39.3-63.4 ug/d (OR=0.76; 95% CI 0.57-1.02), 63.5-107.7 ug/d (OR=0.74; 95% CI 0.55-1.00), and >107.7 (OR=0.56; 95% CI 0.40-0.77). There was an U-shaped association for supplemental intake of Vitamin K and NHL risk; compared to no use, supplemental intake of <5.9 ug/d (OR=0.63; 95% CI 0.37-1.08) and 5.9-17.6 ug/d (OR=0.53; 95% CI 0.30-0.93) were inversely associated with NHL risk, while intake of >17.6 ug/d (OR=1.13; 95% CI 0.73-1.74) showed no association. There was no evidence of heterogeneity by NHL subtype (p=0.4). Further adjustment for education, family history of NHL, pack-years of smoking, body mass index, and alcohol consumption did not alter these results, nor did adjustment for a food-frequency questionnaire-based estimate of total antioxidant intake. Conclusion: Higher intake of vitamin K from the diet was inversely associated with risk of NHL overall and for the major subtypes. These first results, which require replication, suggest that the coagulation pathway or other biologic effects of vitamin K may play a role in lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2811.

Abstract Background: Cell cycle dysregulation is a common molecular finding in ovarian cancer and the cyclin-D kinases (CDK) represent an attractive target in this pathway. PD 0332991 (Pfizer Inc.) is an orally active potent and highly selective inhibitor of CDK 4 and CDK6 kinases with the ability to block pRb phosphorylation at serine 780 and 795 in the low nanomolar range. To identify predictors of response to PD 0332991, we determined the in vitro sensitivity to PD 0332991 in a large panel of molecularly characterized ovarian cancer cell lines, and then used baseline expression profiles and Western blot analyses to identify biomarkers associated with response to PD 0332991. These biomarkers were then validated in a large cohort of 324 ovarian cancer patients by immunohistochemistry. Methods: 40 human ovarian cancer cell lines were treated with PD 0332991 using two-fold dilutions over 12 concentrations. Dose response curves were generated using a cell count assay to calculate the IC50 across the panel. These data were then analyzed against baseline gene expression data to identify genes associated with sensitivity to PD 0332991. Western blot analysis was performed to validate these markers and to study the effects of PD 0332991 on pRb phosphorylation. Cell cycle analysis was performed using flow-cytometry. Combination studies were performed to analyze the interaction between PD 0332991 and paclitaxel or carboplatin chemotherapy. Tissue microarrays were constructed from 324 ovarian cancer patients and IHC was performed for p16 and Rb expression. Long-term clinical follow up was available for all patients. Results: Concentration-dependent anti-proliferative effects of PD 0332991were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC50s (IC50 range: 0.02 to >20 μmol/L). Cell lines with high Rb expression and low p16 expression by gene expression array and Western blot analyses were most sensitive to inhibition by PD 0332991. Cell lines treated with PD 0332991 showed clear G0/G1 arrest and a decrease in S-phase fraction in sensitive but not in resistant cell lines. In addition, Western blot showed that pRb phosphorylation is blocked in a concentration and time dependent manner. IHC for Rb and p16 allows the identification of ovarian cancer patients most likely to benefit from CDK4/6 inhibition. Outcome analyses are ongoing. Conclusion: PD 0332991 shows promising biologic activity in ovarian cancer cells. Assessment of Rb and p16 expression may help select patients who benefit from therapeutic strategies targeting CDK4/6 in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 25.

Abstract Background: Obesity has been linked to NHL risk in some studies, and may be stronger for obesity in early adulthood (ages 18-20). There has only been limited evaluation of physical activity and risk of NHL, particularly physical activity earlier in life. The purpose of this study was to evaluate the association of body mass index (BMI), physical activity (PA), and NHL risk during adulthood and at age 18. Methods: Self-reported anthropometrics and PA were collected in a clinic-based study of 954 newly diagnosed NHL cases and 1146 controls enrolled at the Mayo Clinic from 2002-2008. PA variables included duration and frequency of mild, moderate, and strenuous PA two years prior to case diagnosis or control selection, strenuous activity at age 18 (any vs. none), and height and weight at both time periods. An overall PA index was estimated by weighting the reported duration and frequency of each PA intensity by the average energy requirement (defined in METs) to obtain an average MET-minutes/week for each participant. BMI was calculated as weight (kg) divided by height (m) squared. Odds Ratios (OR), 95% confidence intervals (CI), and test for trend were estimated using unconditional logistic regression adjusted for the age, gender, and residence. Continuous variables were divided into quartiles according to the distribution among the controls; results are reported for the highest vs. lowest category or quartile unless otherwise specified. Results: The mean age at diagnosis/enrollment was 61 for both cases and controls; 47% and 43% of the cases and controls, respectively, were female. The most common NHL subtypes were CLL/SLL (32%), follicular lymphoma (FL; 26%), and diffuse large B-cell lymphoma (DLBCL; 21%). BMI 2 years prior to diagnosis was not associated with NHL risk (OR=1.21, p-trend=0.13), while there was a positive association with BMI at age 18 (OR=1.40, p-trend=0.001). There was no association of the PA index with risk (OR=0.91, p-trend=0.29). Furthermore, frequency of walking (OR=0.71, p-trend 0.43), mild (OR=1.30, p-trend=0.64), moderate (OR=0.99, p-trend=0.75), and strenuous (OR=0.77, p-trend=0.20) PA were not associated with NHL risk when evaluated individually. However, there was a suggestive weak inverse association between strenuous activity at age 18 and NHL risk (OR=0.85, 95% CI 0.71-1.05). On exploratory analysis, the association of BMI at age 18 with NHL risk was specific to DLBCL (OR=1.84, p-trend=0.002) and CLL/SLL (OR=1.25, p-trend=0.044) but not FL; all other results were similar across these subtypes. Conclusions: We did not observe an association between adult BMI and NHL risk; however a higher BMI in early adulthood was associated with NHL risk, consistent with limited prior reports. We found little evidence to support an association between PA in either early adulthood or later in life and NHL risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1833.

Abstract Objective: Mullerian inhibiting substance type II receptor (MISRII) is a tissue-specific target for therapy in gynecologic cancers. MISRII plays a specialized role in regression of the mullerian tracts embryologically. Analogous to other TGF-β family members, ligand (MIS) binding to the type II receptor leads to a heteromeric complex with type I receptors, downstream Smad signaling, cell cycle arrest and regression. We previously published that the majority of epithelial ovarian cancers (EOC) and endometrial cancers (EC) express MISRII in a tissue specific manner. The purpose of these studies was to investigate the biologic significance of MISRII expression in EOC. Methods: For in vitro studies, we developed both chimeric and endogenous cell models to study MISRII. Chimeric MIS type I and II receptors were created by fusing the ligand binding domain of GM-CSF (α or β subunit) to the transmembrane and cytoplasmic domains of the type I/II receptor; these receptors were stably transfected into Ovcar8 cells. The chimera system allows specific signaling of the receptor complex and the ability to separately analyze candidate type I receptors. The endogenous cell model was created in SKOV3 (MISRII- EOC cell line) by stably expressing full-length MISRII. Growth inhibition was assessed by colony formation in soft agar in response to receptor activation and cisplatin. A BRE-luciferase reporter construct was used to measure Smad 1/5 activation after exposure to MIS. FACS analysis was used to assess cell cycle progression. Results: In the chimeric model, receptor activation resulted in up to 60% inhibition of colony formation (dependent on which candidate type I receptor was targeted). Additionally, receptor activation sensitized cells to the effects of cisplatin (1μM) with nearly 4-fold inhibition of colony formation. In the endogenous MISRII expressing EOC cell model, functional signaling was first confirmed using a BRE-luciferase reporter assay to document induction of Smad activation after exposure to rhMIS (3.2 relative light units increase after 20nM MIS). This model was then assessed for cell cycle progression in the presence of MIS. We observed a strong G1 arrest (62% vs. 43% untreated) after 15h exposure to 25nM MIS in cells expressing the receptor with no change in the MIS- parental cell line. These in vitro data are consistent with our survival results in EOC demonstrating a significantly improved overall survival (p=0.04) in MISRII expressing cancers. Conclusions: The majority of gynecologic cancers express MISRII. Our in vitro studies demonstrate that receptor activation results in cell cycle arrest, reduced colony formation, and sensitization to cisplatin. Confirming this in vitro data is the observation that EOC expressing MISRII have improved response to therapy and longer survival. Together, these results support further targeting of the MISRII pathway as an anticancer strategy in gynecologic malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1586.

Object Synovial cysts of the cervical spine are rare. Further, synovial cysts of the C1–2 articulation, or retroodontoid cysts, are very rare, with fewer than 20 cases reported overall. The authors report on a single-institution series of 10 patients with C1–2 retroodontoid synovial cysts. Methods The charts of 10 patients with pathologically confirmed synovial cysts following resection between January 1998 and June 2009 were reviewed. The clinical presentation, radiographic findings, surgical management, and pre- and postoperative functional levels (reported as a modified Rankin outcome) are reported. Results All 10 patients underwent attempts at complete resection of the synovial cyst; none of the lesions were simply aspirated. All 4 patients with an initial recommendation of observation alone ultimately underwent surgery because of their swift neurological deterioration. The mean age at surgery was 75.4 ± 4.6 years (range 54–81 years). The mean presenting cyst volume was 4.6 ± 1.7 cm3. Nine of 10 patients underwent transoral resection of the cyst with posterior fusion. Six of the 10 patients underwent additional posterior laminectomy for decompression. The hospital length of stay varied from 2 to 45 days, with a mean of 19 ± 7 days. All patients undergoing transoral decompression had varying degrees of difficulty with postoperative dysphagia, diagnosed using videofluoroscopy. All patients improved in their modified Rankin Scale score after surgical intervention with a mean follow-up of 42 months (95% CI 12–72 months). Conclusions Synovial cysts of the atlantoaxial joint are rare. They occur in older patients in whom clinical deterioration is likely to occur. In most cases, these cysts can be diagnosed preoperatively. Transoral decompression with posterior fusion is an effective treatment for C1–2 degenerative cysts and can be accomplished with few complications. However, the ideal treatment for these lesions remains unknown.

Background— Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI. Methods and Results— We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P <0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively, P <0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (χ 2 6.0, P <0.014), and symptom onset-to-hospital arrival (χ 2 9.8, P <0.007) remained independent determinants. Conclusions— Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00091637.

Abstract Background Outcomes for patients with hepatocellular carcinoma (HCC) without cirrhosis and factors associated with disease progression remain unclear. The goals of this single-institution study were to define the outcomes for such patients, and to determine factors associated with survival and disease progression. Methods This was a retrospective review of consecutive patients with HCC without cirrhosis who underwent hepatic resection between 1985 and 2003. Survival was estimated by the Kaplan–Meier method and risk factors were identified by Cox proportional hazards models. Results A total of 143 patients were enrolled, of whom 29·4 per cent had identifiable risk factors for chronic liver disease. Major resection (at least three segments) was undertaken in 63·6 per cent of patients. The operative mortality rate was 3·5 per cent. Median disease-free survival was 2·4 years. Multivariable analysis revealed presence of multiple tumours as the only independent predictor of tumour recurrence. Median overall survival was 3·3 years. Factors independently associated with decreased overall survival were multiple tumours, high histological grade, perioperative transfusion, male sex and age at least 66 years. Conclusion Patients with HCC but without cirrhosis have acceptable outcomes after resection. Specific risk factors for the development of HCC in these patients have yet to be defined.