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Background: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown. Methods: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight’s Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride ( Results: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [ P =0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone. Conclusions: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

Study Objective To compare the accuracy of frozen section diagnosis of borderline ovarian tumors among 3 distinct types of hospital—academic hospital with gynecologic pathologists, academic hospital with nongynecologic pathologists, and community hospital with nongynecologic pathologists—and to determine if surgical staging alters patient care or outcomes for women with a frozen section diagnosis of borderline ovarian tumor. Design Retrospective study (Canadian Task Force classification II-1). Setting Tertiary care, academic, and community hospitals. Patients Women with an intraoperative frozen section diagnosis of borderline ovarian tumor at 1 of 3 types of hospital from April 1998 through June 2016. Interventions Comparison of final pathology with intraoperative frozen section diagnosis. Measurements and Main Results Two hundred twelve women met the inclusion criteria. The frozen section diagnosis of borderline ovarian tumor correlated with the final pathologic diagnosis in 192 of 212 cases (90.6%), and the rate of correlation did not differ among the 3 hospital types (p = .82). Seven tumors (3.3%) were downgraded to benign on final pathologic analysis and 13 (6.1%) upgraded to invasive carcinoma. The 3 hospital types did not differ with respect to the proportion of tumors upgraded to invasive carcinoma (p = .62). Mucinous (odds ratio, 7.1; 95% confidence interval, 2.1–23.7; p = .002) and endometrioid borderline ovarian tumors (odds ratio, 32.4; 95% confidence interval, 1.8–595.5; p = .02) were more likely than serous ovarian tumors to be upgraded to carcinoma. Only 88 patients (41.5%) underwent lymphadenectomy, and only 1 (1.1%) had invasive carcinoma in a lymph node. Conclusions A frozen section diagnosis of borderline ovarian tumor correlates with the final pathologic diagnosis in a variety of hospital types.

The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs.To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer.A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness.At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life-year thresholds.PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost-effective options.This study was unfunded. The authors have nothing to disclose.

Purpose or Objective In March 2020, a 1-week hypofractionated adjuvant breast radiotherapy schedule, 26 Gy in 5 fractions was adopted to reduce the risk of COVID 19 exposure for patients and staff without compromising on cancer outcomes. This study aimed to confirm acceptable acute toxicity rates for patients receiving this 1-week schedule (+/- sequential boost) and to quantify the positive impact of implementing this schedule on linac capacity. Materials and Methods This is a multicentre prospective observational study of consecutive patients receiving 26 Gy in 5 fractions adjuvant breast cancer radiotherapy (+/- boost) Mar-Aug 2020. Consensus was obtained on planning procedure protocols which included dose-volume evaluation and mandatory radiation quality assurance objectives. Standardised virtual consultations assessed acute skin toxicity during treatment and at weeks 1, 2, 3 and 4 post treatment using CTCAE V5 scoring criteria. Toxicity was compared between patients who received a boost and those that did not. The total number of linac minutes saved was estimated accounting for boost and DIBH use Results In total, 135 women were included, 33 (24%) received a boost. 128/135 (95%) patients, including 31/33 boost patients, completed at least 3/5 acute toxicity assessments. 0/128 (0%) reported moist desquamation not confined to skin folds or minor bleeding (grade 3 toxicity). 41/128 (31%) reported brisk erythema, moist desquamation confined to skin folds or breast swelling (Grade 2) and 63/128 (50%) reported faint erythema or dry desquamation (Grade 1) as their worst reported acute skin toxicity. The highest prevalence of grade 2 toxicity occurred at week 1 following treatment (19.5%), which reduced to 2.6% by week 4. There was no statistically significant difference in acute toxicity between boost and no boost patients (p= 1.00). Delivering a 1-week schedule to 135 patients over a six month period led to a saving of 21,300 linac minutes and 1485 hospital visits compared to delivering a moderately hypofractionated regimen of 3 weeks duration. 6,300 LINAC minutes were saved and 462 hospital visits avoided for patients > 70 years and cocooning under national guidance $Φg $Φg Conclusion This study demonstrates the feasibility of rapidly implementing a 1-week hypofractionated adjuvant breast radiotherapy schedule in clinical practice and how this landmark change has a considerable impact on linac capacity. This change in practice has ensured ongoing access to treatment for patients during the COVID-19 pandemic and greatly reduced the risks of infection for patients and staff. It further confirms acceptable acute skin toxicity even when followed by boost.

Studies on political knowledge routinely find that women have lower levels of political knowledge than men. This gender gap in political knowledge is usually interpreted as troublesome for democracy, because a lack of political knowledge could imply that women’s participation in politics is less effective and that their interests will be represented less well than those of men. In this short article, we present a direct test of the assumption that women are less effective voters because of this lack of political knowledge. We make use of CSES data to study gender differences in proximity voting and correct voting. Our results do not suggest that women vote less correctly than men—a conclusion that prompts important questions about the role of different forms of political knowledge, and the seemingly gendered nature of the vote choice.

Background Breast cancer is the most commonly diagnosed cancer in women in Ireland. The 5 year net survival is over 80%. Most women diagnosed with breast cancer do not die from the disease and instead cardiovascular disease (CVD) remains the most frequent cause of death. Many breast cancer patients are older and have established CVD risk factors. They are at further risk of a cardiovasular (CV) event due to exposure to anthracyclines, HER2 targeted agents, endocrine therapy and radiotherapy. In this study, we aimed to compare the 10 year risk of breast cancer mortality versus that of a CV event or death in an oncology day ward population at our centre through the use of online prognostic risk calculators. Furthermore, we sought to investigate the predicted outcome of lifestyle changes on their overall CV risk and level of interest in addressing these risk factors. Methods This was a cross cohort study of all breast cancer patients attending for adjuvant chemotherapy at our institution from September 2015 to September 2016. To calculate patients' 10 year CVD risk, we used the JBS3 online calculator. Using this calculator we could also predict patient's lifetime CV risk. To calculate patients' 10 year mortality risk from breast cancer we used NHS predict! These calculators incorporate several variables which we identified from chart review, the use of questionnaires and the performance of a serum lipid test. Results 101 subjects were identified. All patients (pts) completed questionnaires. Eighteen pts were excluded from CV risk analysis due to lack of lipid profile. Of 83 pts, 83% (n=69) were >50 years of age and 17% (n=14) pts were 50 age group (grp) was 59 and 42 in the 50 and 50 grp were smokers/ex smokers and 49% (n=7) were in the 50 grp were on statins and 25% (n=17) were on antihypertensives. Fifty-two percent (n=36) of pts in the >50 grp and 66% (n=10) received anthracyclines. Fifty percent in both grps received left sided radiotherapy. Ninety five percent (n=63) were on endocrine therapy in the >50 grp and 93% (n=13) in the 50 grp (n=28) and 29% (n=4) of patients in the 50 grp, 13% (n=9) were found to have a high 10 year cardiovascular risk (>20% risk of CV event) and 28% were found to be at moderate risk (n=19). Ten percent of patients were found to have a CV risk that exceeded their breast cancer mortality risk (n=7). Even though the 10 year CV risk was low in patients 50 patients in the high risk group post CV risk modification was 8.8% (+/-5.6) versus 28% (+/-8) at baseline. Conclusion This patient population has significant CV risk factors at baseline. Benefits predicted with CV risk intervention model and significant patient interest indicates that formalised CV risk prevention strategy is needed. Citation Format: Prior L, Featherstone H, Nugent K, Lim M, Kelly C. Competing mortality risks: Cardiovascular risk versus risk of metastatic disease in breast cancer patients receiving adjuvant therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-16.

Objective: To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models. Methods: Mice were inoculated with 1 × 10 6 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV 3 -GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days. Results: Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV 3 or TOV-112d orthotopic mouse models. Conclusion: This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway.

Objectives: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. Methods: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways—glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)—were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety and immune modualtion. Results: CYP450 inhibition was observed with FVF. The GST, QOR, and UGT pathways had no changes. UPF and FVF both interacted with COMT. No growth inhibitory activity in cancer cell lines was observed. UPF and FVF had synergistic activity with paclitaxel or tamoxifen and additive activity with topotecan. In vivo, FVF decreased HeLa human cervical tumor growth and both FVF and UPF decreased TOV-112D human ovarian tumor growth. Otherwise, no significant change in tumor growth was observed. FVF immune modulation of IgG and IL-6 was observed (p

ObjectiveThis retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer.MethodsFrom 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ2Test and Studentttest were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival.ResultsThere were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46–5.38;P< 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26–3.98;P< 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56–1.88,P= 0.93).ConclusionsPatients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range.

Objective: To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models. Methods: Mice were inoculated with 1 × 106 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV3-GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days. Results: Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV3 or TOV-112d orthotopic mouse models. Conclusion: This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway.

Objective. To determine the impact on antitumor activity when active hexose correlated compound (AHCC) in combination with anticancer hormonal agents in orthotopic mouse models of human estrogen receptor positive breast cancer and evaluate impact of AHCC on aromatase activity. Methods. The study consisted of 7 treatment arms (n=10) conducted in 2 breast cancer mouse models: MCF-7 and ZR-75. Treatment groups included untreated, vehicle, AHCC 50 mg/kg, AHCC 50 mg/kg + tamoxifen 10 mg/kg, tamoxifen 10 mg/kg, AHCC 50 mg/kg + letrozole 10 µg/mouse, or letrozole 10 µg/mouse. All treatments were administered daily by oral gavage for 12 weeks. Tumors were measured 3 times a week. In vitro estrone and 17β-estradiol enzyme immunoassay was used to evaluate aromatase activity. Results. There was no difference in the activity with the combination of AHCC + tamoxifen compared with tamoxifen ( P = 0.29). In the ZR-75 model (catechol- O-methyltransferase [COMT] wild-type), there was no difference in activity with the letrozole + AHCC compared with letrozole. However, in the MCF-7 model (COMT variant), AHCC + letrozole resulted in a decrease in activity compared with letrozole ( P < 0.01). Immunoassay data suggested that AHCC is a potential inducer of aromatase activity. In both tumor models, there was cytotoxicity observed with AHCC compared with untreated ( P < 0.02). Conclusion. AHCC did not change the activity of tamoxifen. AHCC may have some interaction with letrozole in patients with COMT variant genotype. AHCC had cytotoxicity that warrents additional studies to evaluate its potential role for consolidation/prevention of breast cancer.

The genome sequence of the obligate chemolithoautotroph Hydrogenovibrio crunogenus paradoxically predicts a complete oxidative citric acid cycle (CAC). This prediction was tested by multiple approaches including whole cell carbon assimilation to verify obligate autotrophy, phylogenetic analysis of CAC enzyme sequences and enzyme assays. Hydrogenovibrio crunogenus did not assimilate any of the organic compounds provided (acetate, succinate, glucose, yeast extract, tryptone). Enzyme activities confirmed that its CAC is mostly uncoupled from the NADH pool. 2-Oxoglutarate:ferredoxin oxidoreductase activity is absent, though pyruvate:ferredoxin oxidoreductase is present, indicating that sequence-based predictions of substrate for this oxidoreductase were incorrect, and that H. crunogenus may have an incomplete CAC. Though the H. crunogenus CAC genes encode uncommon enzymes, the taxonomic distribution of their top matches suggests that they were not horizontally acquired. Comparison of H. crunogenus CAC genes to those present in other 'Proteobacteria' reveals that H. crunogenus and other obligate autotrophs lack the functional redundancy for the steps of the CAC typical for facultative autotrophs and heterotrophs, providing another possible mechanism for obligate autotrophy.

Objectives: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. Methods: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways—glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)—were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety and immune modualtion. Results: CYP450 inhibition was observed with FVF. The GST, QOR, and UGT pathways had no changes. UPF and FVF both interacted with COMT. No growth inhibitory activity in cancer cell lines was observed. UPF and FVF had synergistic activity with paclitaxel or tamoxifen and additive activity with topotecan. In vivo, FVF decreased HeLa human cervical tumor growth and both FVF and UPF decreased TOV-112D human ovarian tumor growth. Otherwise, no significant change in tumor growth was observed. FVF immune modulation of IgG and IL-6 was observed (p

Capsaicin causes direct irritation of the eyes, mucous membranes, and respiratory tract. It is used in self-defense, in crowd control, and as a less lethal weapon in police work. Controlled trials suggest that capsaicin has minimal serious acute effects. Herein, we report a woman who had a 20-minute exposure to capsaicin during a jail riot. She subsequently developed episodic dyspnea and cough, and increased sensitivity to scents, perfumes, and cigarette smoke. She has not had wheezes on physical examination or abnormal pulmonary function tests. Her response to inhaled steroids and long-acting beta-agonists has been incomplete. She appears to have developed airway sensory hyperreactivity syndrome after the inhalation of capsaicin, which likely injured sensory nerves and/or caused persistent neurogenic inflammation.

The primary objective of this study was to quantify the impact of treatment delay and dose reductions in an in vivo orthotopic ovarian cancer model. In addition, this study evaluated the role of growth factors in achieving “full dose on time”. HeyA-8 and SKOV3.ip1ovarian cancer orthotopic mouse models were used determine the effect of paclitaxel/carboplatin treatment delays or dose reductions on tumor response and overall survival. The addition of growth factor support with pegfilgrastim and darbepoetin was also evaluated in treatment control arm. The results indicated that full dose of paclitaxel (20 mg/kg) and carboplatin (50 mg/kg) delivered on time (every 21 days) achieved better tumor response in both aggressive (HeyA-8) and metastatic (SKOV3.ip1) human ovarian tumors compared to treatment delay or dose reduction arms. In the HeyA-8 orthotopic model treatment delay (P

EphA2 overexpression predicts poor prognosis in endometrial cancer. To explore mechanisms for this association and assess its potential as therapeutic target, the relationship of EphA2 expression to markers of angiogenesis was examined using patient samples and an orthotopic mouse model of uterine cancer.Expression of EphA2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was evaluated using immunohistochemistry in 85 endometrioid endometrial adenocarcinomas (EEC) by two independent investigators. Results were correlated with clinicopathological characteristics. The effect of EphA2- agonist monoclonal antibody EA5, alone or in combination with docetaxel was studied in vitro and in vivo. Samples were analyzed for markers of angiogenesis, proliferation and apoptosis.Of 85 EEC samples, EphA2 was overexpressed in 47% of tumors and was significantly associated with high VEGF expression (p=0.001) and high MVD counts (p=0.02). High EphA2 expression, high VEGF expression and high MVD counts were significantly associated with shorter disease-specific survival. EA5 led to decrease in EphA2 expression and phosphorylation in vitro. In the murine model, while EA5 (33-88%) and docetaxel (23-55%) individually led to tumor inhibition over controls, combination therapy had the greatest efficacy (78-92%, p.

BACKGROUND: We reviewed local control (LC) and overall survival (OS) post intracranial SRS to cavity post resection of brain metastases at one institution, and factors affecting LC. MATERIAL AND METHODS: A retrospective review was conducted of adjuvant SRS at one institution from 2013 to 2016. Patient records, treatment plans, and diagnostic images were reviewed. Local failure was MRI defined. Categorical variables were analysed using chi-square and Fisher’s exact tests. Continuous variables were analysed using Mann-Whitney tests. The Kaplan-Meier method was used to estimate survival times and the log-rank test was used to compare differences in survival. RESULTS: 47 patients with 48 cavities were treated with SRS post operatively. LC rate was 69%, and the distant intracranial failure rate was 47%. The 12 month freedom from local recurrence (FFLR) was 77% (63–91%). Median OS (95% CI) was 22.7 (14.6–30.8) months. Patients with a single metastasis had longer FFLR (30.1 vs 14.4 months; p = .014). Median interval from surgery to SRS was 6.3 weeks. Patients with interval > 7 weeks had increased local recurrence (LR) (62%) than < 7 weeks (37%), p = 0.025.Patients with a margin < 2mm were more likely to experience LR (48%) than those with margin equal to 2mm (20%); this approached statistical significance (p = 0.063). The median follow up for all patients was 15.4 months (2–41). CONCLUSION: We determined LC and OS using adjuvant SRS at our institution. Based on the findings of this retrospective review SRS should be given promptly post operatively with a 2mm PTV margin.

To explore the yield and impact of perioperative imaging on management among patients undergoing surgical resection and treatment of uterine sarcomas.A retrospective chart review was done for women with histologically confirmed uterine sarcomas treated at Barnes Jewish Hospital/Washington University from 2001 to 2007. Descriptive statistics, Cox multivariate models, and Kaplan-Meier plots were used to evaluate associations and survival.A total of 92 patients were identified and 55 (60%) were diagnosed with stage III-IV disease. Perioperative imaging was obtained in 84 (91%) cases, including chest X-ray in 66 (72%), computerized tomography (CT) of the abdomen and pelvis in 59 (64%), chest CT in 33 (36%), positron emission tomography (PET) in 8 (9%), and CT of the head, pelvic magnetic resonance imaging (MRI), or bone scan in a total of 2 (2.2%). Imaging identified abnormalities concerning for metastases in 30 (32%) studies. Thirty-four recurrences have been documented, and 21 (62%) of these treatment failures were extrapelvic. Multivariate analysis of this series noted that tomographic evidence of extrauterine disease predicted recurrence (p=0.028) and incomplete surgical resection (p=0.003, HR 6.0 95% CI 1.9-19.9) predicted disease-free survival. Imaging contributed to change in surgical and post-surgical treatment decisions in 8 (9%) patients.Pretreatment imaging studies change management in a minority of patients with newly diagnosed uterine sarcomas.

BACKGROUND: EphA2 is a tyrosine kinase receptor in the ephrin family that is implicated in oncogenesis and angiogenesis. The objective of the current investigation was to study the role of EphA2 in endometrial cancer and its relation to steroid hormone receptor expression. METHODS: EphA2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression levels were evaluated using immunohistochemistry in 139 endometrioid endometrial carcinoma (EEC) samples and in 10 benign endometrial samples. Samples were scored by 2 investigators who were blinded to clinical outcome. The results were correlated with clinicopathologic characteristics using univariate and multivariate analysis. A P value

Purpose: Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial cancer is not fully known. Therefore, we examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model. Experimental Design: Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation. Results: Of 111 endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation between VEGF expression and MVD (P < 0.001). On multivariate analysis, stage (P = 0.04), grade (P = 0.003), VEGF levels (P = 0.03), and MVD (P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97% inhibition over controls; P < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls; P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001). Conclusions: Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.

Purpose Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies. Methods The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies. Results In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone. Conclusion Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy.

Leflunomide, a disease modifying anti-rheumatic drug in use since 1998, causes interstitial lung disease (ILD) and other pulmonary complications.We undertook a systematic review of literature of PubMed (March 2013) to identify the published literature pertaining to pulmonary toxicity associated with leflunomide.We identified 41 relevant articles detailing four population studies and case reports/series on an additional 42 patients. Available data were reviewed and summarized.Leflunomide can cause ILD. Most of these patients present within three months of starting leflunomide with acute symptoms for a week or less. Bilateral ground glass opacities and diffuse alveolar damage are the most common radiologic and histopathologic findings, respectively. Patients with pre-existing ILD are particularly at risk for this complication, and leflunomide should be avoided in this population. Activated charcoal and cholestyramine significantly decrease the half-life of the drug because of its enterohepatic circulation and should be considered in cases with acute toxicity.

Conductive electronic devices (CED), such as Taser and stun guns, are sold worldwide for use by security services, although they have also been used for self-defence and even for torture. CED are promoted as non-lethal weapons which can potentially save lives. However, there are multiple reports of deaths temporally associated with CED use. These weapons have definite physiological effects in normal volunteers, especially when accompanied by exertion. Medical examiners often report that deaths followed physical encounters which included the use of CED were due to natural causes, excited delirium and/or drug intoxication. These cases present complex situations in which multiple factors potentially contribute to the death, including electric shocks which cause neuromuscular incapacitation, severe pain and anxiety. Public health officials, physicians and hospital personnel need to be aware that individuals controlled with CED are at increased risk of death. We need better recording of incidents worldwide to understand the extent and outcomes of CED use.استخدام وسلامة الأجهزة الإلكترونية المكهربة، ما هي المعارف المتاحة؟كينيث نوغنت، جيهان شفيقإن الأجهزة الإلكترونية المكهربة مثل التأزر وبنادق الصعق، تباع في جميع أرجاء العالم لاستخدامها في الخدمات الأمنية، رغم أنها تستخدم أيضاً في الدفاع عن النفس، بل حتى في التعذيب، ويروَّج لها على أنها أسلحة غير فتاكة يمكنها أحياناً أن تنقذ الحياة. إلا أن هناك تقارير عديدة عن حالات وفيات ارتبطت بتوقيت استخدام تلك الأجهزة. ولهذه الأجهزة آثار فيزيولوجية محددة لدى المتطوعين العاديين، ولاسيَّما عندما تترافق مع بذل المجهود. وقد يَكْتُب الطبيب الفاحص في تقريره أن الوفاة التي تَلَت التعرُّض لعامل فيزيائي يتضمَّن استخدام الأجهزة الإلكترونية المكهربة، إنّما هي ناجمة عن أسباب طبيعية، أو عن هَذَيان الإثارة، أو عن التسمم بالمخدرات. وتمثِّل هذه الحالات أوضاعاً معقّدة قد تساهم فيها عوامل متعددة في الوفاة؛ بما فيها الصدمات الكهربية التي تسبب عجزاً عصبياً عضلياً وألماً شديداً وقلقاً. وينبغي أن يكون الأطباء والموظفون في الصحة العمومية والعاملون في المستشفيات على علم بأن الأفراد الذين يتم التحكم فيهم بالأجهزة الإلكترونية المكهربة يتعرّضون لاختطار مرتفع للوفاة. ونحن بحاجة لتسجيل أفضل للحوادث التي تقع في شتى أنحاء العالم، حتى نفهم مدى استخدام الأجهزة الإلكترونية المكهربة والحصائل الناجمة عنها.Utilisation et sécurité des dispositifs à impulsions électriques : quel est l'état des connaissances ?Les dispositifs à impulsions électriques comme le Taser

A hard X‐ray full field microscope from Xradia Inc. has been installed at SSRL on a 54‐pole wiggler end station at beam line 6‐2. It has been optimized to operate from 5–14 keV with resolution as high as 30 nm. High quality images are achieved using a vertical beam stabilizer and condenser scanner with high efficiency zone plates with 30 nm outermost zone width. The microscope has been used in Zernike phase contrast, available at 5.4 keV and 8 keV, as well as absorption contrast to image a variety of biological, environmental and materials samples. Calibration of the X‐ray attenuation with crystalline apatite enabled quantification of bone density of plate‐like and rod‐like regions of mouse bone trabecula. 3D tomography of individual lacuna revealed the surrounding cell canaliculi and processes. 3D tomography of chiral branched PbSe nanowires showed orthogonal branches around a central nanowire.

The Surface/Interface: Microscopy beamline of the Swiss Light Source started operation in 2001. In 2007 the beamline has been significantly upgraded with a second refocusing section and a blazed grating optimized for high photon flux. Two Apple II type undulators with a plane grating monochromator using the collimated light scheme deliver photons with an energy from 90eV to about 2keV with variable polarization for the photoemission electron microscope (PEEM) as the primary user station. We measured a focus of (45×60) μm(ν×h) and a photon flux > 1012 photon/s for all gratings. Polarization switching within a few seconds is realized with the small bandpass of the monochromator and a slight detuning of the undulator.

The SuperXAS beamline at the Swiss Light Source (SLS) features a permanently installed monochromator for quick scanning EXAFS (QEXAFS) spectroscopy in series with a conventional double crystal monochromator (DCM). All installed optical components like collimating and focussing mirrors can be used by both devices. The remote exchange of the monochromators is possible in less than five minutes while maintaining the beam geometry on the sample. The QEXAFS system allows fast absorption scans down to the millisecond range for the investigation of time dependent processes. Using a Si(111) channel cut crystal the energy range from 5–16 keV can be covered, with a Si(311) cut the range 9.5–30 keV. Usually a quick scanning interval of 0.1°–2° in Bragg angle is selected, thus covering XANES, full EXAFS or multiple edge scans of e.g. all L‐edges of a heavy element. Up to about 80 spectra per second can be collected, corresponding to a time resolution of 12.5 ms. The high intensity of the beamline even facilitates fluorescence measurements on dilute samples.

The HEMS Beamline at the German high‐brilliance synchrotron radiation storage ring PETRA III is fully tunable between 30 and 250 keV and optimized for sub‐micrometer focusing. Approximately 70 % of the beamtime will be dedicated to Materials Research. Fundamental research will encompass metallurgy, physics and chemistry with first experiments planned for the investigation of the relationship between macroscopic and micro‐structural properties of polycrystalline materials, grain‐grain‐interactions, and the development of smart materials or processes. For this purpose a 3D‐microsctructure‐mapper has been designed. Applied research for manufacturing process optimization will benefit from high flux in combination with ultra‐fast detector systems allowing complex and highly dynamic in‐situ studies of micro‐structural transformations, e.g. during welding processes. The beamline infrastructure allows accommodation of large and heavy user provided equipment. Experiments targeting the industrial user community will be based on well established techniques with standardized evaluation, allowing full service measurements, e.g. for tomography and texture determination. The beamline consists of a five meter in‐vacuum undulator, a general optics hutch, an in‐house test facility and three independent experimental hutches working alternately, plus additional set‐up and storage space for long‐term experiments. HEMS is under commissioning as one of the first beamlines running at PETRA III.

The mechanical design and performance of a device to suppress higher orders of a spherical grating monochromator at a constant deviation angle is described. The higher order suppressor (HOS) is used for a scanning transmission x‐ray microspectroscope beamline (PolLux) at a bending magnet of the Swiss Light Source (SLS). The instruments allow microspectroscopy in polymer science, of biological samples in the water window as well as the study of magnetic materials with circular or linear polarized light in a photon energy range of 200 eV to 1400 eV. The HOS uses three mirrors acting as a low pass filter for soft x‐rays to improve the absorption spectroscopy of carbon, oxygen and nitrogen 1s core levels. The successful installation and operation of the HOS located after the monochromator is reported. First results obtained using samples from materials research and environmental sciences exemplify the improved spectroscopy capabilities of the instrument.

The penetrating power of X‐rays coupled with the high flux of 3rd generation synchrotron sources makes X‐ray tomography to excel among fast imaging methods . To exploit this asset of synchrotron sources is the motivation for setting up an ultra‐fast tomography endstation at the TOMCAT beamline. The state of the art instruments at synchrotron sources offer routinely a temporal resolution of tens of seconds in tomography. For a number of applications, for example biomedical studies, the relevant time scales (breathing, heartbeat) are rather in the range of 0.5–2 seconds. To overcome motion artifacts when imaging such systems a new ultra‐fast tomographic data acquisition scheme is being developed at the TOMCAT beamline. We can acquire a full set of projections at sub‐second timescale in monochromatic or white‐beam configuration. We present a feasibility study with the ultimate aim to achieve sub‐second temporal resolution in 3D without significant deterioration of the spatial resolution. For the first time, ...

The Micro‐ and Nanofocus X‐ray Scattering Beamline (MINAXS) of the new 3rd generation source PETRA III is equipped with two endstations, out of which the farthest from the high beta undulator source is designed to provide a high flux, monochromatic X‐ray beam focused to a size in the order of 100 nm×100 nm routinely used for microdiffraction experiments (nanofocus endstation). This contribution presents an overview on the current status of the nanofocus endstation and outlines the to‐be‐used experimental setup.

This study examines the molecular form of cadmium (Cd) present in mine wastes by X-ray Absorption Spectroscopy (XAS; Cd>20 mg/kg) using the K-edge of Cd at the Photon Factory Advanced Ring (PF-AR), NW10A beam line at KEK-Tsukuba-Japan. Mine waste materials and zinc concentrate were analyzed for Cd by ICPMS prior to undertaking XAS (range 21-452 mg/kg). Model compounds (CdO, Cd(OH){sub 2}, CdCO{sub 3}, Cdacetate, CdS, Cdstearate, CdDEDTC) and samples were examined in solid form at 20 K. The XANES spectra showed similar E max values for both model compounds and samples. The EXAFS showed that Cd-S in CdS, gives a flatter spectrum in the extended region compared to Cd-O found with CdCO{sub 3}, CdO and Cd Stearate. Linear combination fitting with model Cd compounds did not give clear assignments of composition, indicating that more detailed EXAFS spectra is required as mineral forms containing Cd were present rather than simple Cd compounds such as CdCO{sub 3}. The Cd bond for a single shell model in mine waste sample matrices appears to be either Cd-O or Cd-S, or a combination of both. Comparison of molecular data from the XAS studies with bioaccessibility data giving a prediction of bioavailability for mine waste materialsmore » provides useful information about the significance of the cadmium form as a contaminant for health risk assessment purposes.« less

We present a X‐ray training course for students. The course covers fundamental properties of synchrotron radiation and basic techniques like scattering and absorption. We prepared ten experiments together with a tutorial. The whole course takes about a week. A first student group from the University of Copenhagen passed the course in June 2009. The experiments were performed at the optics beamline of the Swiss Light Source which can be part‐time allocated for training purposes. Two experiments are described in more detail: scattering from a hanging drop of water turning into ice and measurement of the power of a pink synchrotron beam using a simple calorimeter.

Single crystal, high purity synthetic diamond is used as photoabsorption and carrier transport medium in x‐ray photodiodes. While the thermal / mechanical robustness and high x‐ray transmission of diamond make such devices attractive for synchrotron instrumentation, state‐of‐the‐art quality material and electrical interfaces further make such detectors feasible. The present work develops methodology for attaining calculable responsivity (photocurrent yield) over a wide range of photon energies (0.2 to 28 keV) to within 5% accuracy. These methods achieve linear response for up to 0.2 W absorbed x‐ray power and response time as low as 1 ns. Details of contact formation / robustness and bias configuration are explored.

We describe a revolutionary new approach to high spectral resolution soft x-ray optics. Conventionally in the soft x-ray energy range, high spectral resolution is obtained by use of a relatively low line density grating operated in 1st order with small slits. This severely limits throughput. This limitation can be removed by use of a grating either in very high order, or with very high line density, if one can maintain high diffraction efficiency. We have developed a new technology for achieving both of these goals which should allow high throughput spectroscopy, at resolving powers of up to 106 at 1 keV. Such optics should provide a revolutionary advance for high resolution lifetime free spectroscopy, such as RIXS, and for pulse compression of chirped beams. We report recent developmental fabrication and characterization of a prototype grating optimized for 14.2 nm EUV light. The prototype grating with a 200 nm period of the blazed grating substrate coated with 20 Mo/Si bilayers with a period of 7.1 nm demonstrates good dispersion in the third order (effective groove density of 15,000 lines per mm) with a diffraction efficiency of more than 33percent.

Direct examination by XANES and EXAFS of metal bonding in tissue can be demonstrated by examining cadmium uptake and bonding in animal tissue maintained at cryogenic temperatures. XANES at the K‐edge of cadmium were collected at the Photon Factory Advanced Ring (PF‐AR), NW10A beam line at KEK‐Tsukuba‐Japan. Rats fed with 1g mine waste containing 8–400 mg/kg cadmium per 200g body weight (b.w.) or dosed by oral gavage with either cadmium chloride solution alone (at 6 mg/kg b.w.) or in combination with other salts (As, Cu or Zn), 5 days/week for 6 weeks, had 0.1–7.5 and 8–86 mg/kg cadmium in the liver or kidney, respectively. Rats given intraperitoneally (ip) or intravenously (iv) 1–4 times with 1 mg/kg b.w. cadmium solution had 30–120 mg/kg cadmium in the liver or kidney. Tissues from rats were kept and transferred at cryogenic temperature and XANES were recorded at 20 K. The spectra for rat liver samples suggested conjugation of cadmium with glutathione or association with the sulfide bond (Cd‐S) of proteins and peptides. EXAFS of rat liver fed by Cd and Zn solutions showed that Cd was clearly bound to S ligands with an inter‐atomic distance of 2.54 A for Cd‐S that was similar to cadmium sulfide with an inter‐atomic distance of 2.52 A for Cd‐S. Liver or kidney of rats fed with mine wastes did not give an edge in the XANES spectra indicating little uptake of cadmium by the animals. Longer and higher dosing regimen may be required in order to observe the same Cd‐S bond in the rat tissue from mine wastes, including confirmation by EXAFS.

We report on the design and construction of a higher energy Scanning Transmission X‐ray Microscope on a new bend magnet beam line at the Advanced Light Source. Previously we have operated such an instrument on a bend magnet for C, N and O 1s NEXAFS spectroscopy. The new instrument will have similar performance at higher energies up to and including the S 1s edge at 2472eV. A new microscope configuration is planned. A more open geometry will allow a fluorescence detector to count emitted photons from the front surface of the sample. There will be a capability for zone plate scanning in addition to the more conventional sample scanning mode. This will add the capability for imaging a massive sample at high resolution over a limited field of view, so that heavy reaction cells may be used to study processes in‐situ, exploiting the longer photon attenuation length and the longer zone plate working distances available at higher photon energy. The energy range will extend down to include the C1s edge at 300eV, to allow high energy NEXAFS microscopic studies to correlate with the imaging of organics in the same sample region of interest.