Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) ...and improves physical performance in older individuals who have had recent falls and low muscle strength and power.
In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408.
Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY.
Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers.
Eli Lilly and Company.
Ovarian cancer is the fifth leading cause of cancer-associated mortality among US women with survival disparities seen across race, ethnicity, and socioeconomic status, even after accounting for ...histology, stage, treatment, and other clinical factors. Neighborhood context can play an important role in ovarian cancer survival, and, to the extent to which minority racial and ethnic groups and populations of lower socioeconomic status are more likely to be segregated into neighborhoods with lower quality social, built, and physical environment, these contextual factors may be a critical component of ovarian cancer survival disparities. Understanding factors associated with ovarian cancer outcome disparities will allow clinicians to identify patients at risk for worse outcomes and point to measures, such as social support programs or transportation aid, that can help to ameliorate such disparities. However, research on the impact of neighborhood contextual factors in ovarian cancer survival and in disparities in ovarian cancer survival is limited. This commentary focuses on the following neighborhood contextual domains: structural and institutional context, social context, physical context represented by environmental exposures, built environment, rurality, and healthcare access. The research conducted to date is presented and clinical implications and recommendations for future interventions and studies to address disparities in ovarian cancer outcomes are proposed.
Background
Ixekizumab (IXE) is an interleukin (IL)-17A antagonist approved for the treatment of adults with moderate-to-severe psoriasis.
Objective
The objective of this study was to determine if the ...immune response to tetanus and pneumococcal vaccines in healthy subjects administered IXE was noninferior to control.
Methods
In a randomized, open-label, parallel-group study, adult subjects received vaccinations alone (
N
= 42, control) or in combination with 160 mg IXE subcutaneously 2 weeks prior to vaccination and 80 mg IXE on the day of vaccination (
N
= 41, IXE). Response to tetanus vaccination was defined as anti-tetanus antibodies ≥ 1.0 IU and a ≥ 1.5-fold increase if baseline was ≤ 1.0 IU or a ≥ 2.5-fold increase if baseline was > 1.0 IU. Response to pneumococcal vaccination was defined as a ≥ 2-fold increase from baseline in anti-pneumococcal antibodies against > 50% of the 23 serotypes. The primary outcomes were the percentages of patients with a response to the tetanus and pneumococcal vaccines 4 weeks after vaccination. A noninferiority analysis of IXE to control using a 40% margin was evaluated for the primary outcomes. Safety and pharmacokinetics were also assessed.
Results
IXE (38 completers) was noninferior to control (41 completers) based on the difference in the proportion of responders to tetanus 1.4%; 90% confidence interval (CI) − 16.6 to 19.2 and pneumococcal (− 0.8%; 90% CI − 12.9 to 11.0) vaccines. Twenty subjects (14 IXE, six control) reported 43 mild treatment-emergent adverse events.
Conclusion
IXE does not suppress the humoral immune response to non-live vaccines and was well tolerated in healthy subjects.
ClinicalTrial.gov identifier
: NCT02543918.
Abstract
Understanding the social and environmental causes of cancer in the United States, particularly in marginalized communities, is a major research priority. Population-based cancer registries ...are essential for advancing this research, given their nearly complete capture of incident cases within their catchment areas. Most registries limit the release of address-level geocodes linked to cancer outcomes to comply with state health departmental regulations. These policies ensure patient privacy, uphold data confidentiality, and enhance trust in research. However, these restrictions also limit the conduct of high-quality epidemiologic studies on social and environmental factors that may contribute to cancer burden. Geomasking refers to computational algorithms that distort locational data to attain a balance between effectively “masking” the original address location while faithfully maintaining the spatial structure in the data. We propose that the systematic deployment of scalable geomasking algorithms could accelerate research on social and environmental contributions across the cancer continuum by reducing measurement error bias while also protecting privacy. We encourage multidisciplinary teams of registry officials, geospatial analysts, cancer researchers, and others engaged in this form of research to evaluate and apply geomasking procedures based on feasibility of implementation, accuracy, and privacy protection to accelerate population-based research on social and environmental causes of cancer.
The presence of β-mannans in feed can produce a futile and chronic immune stimulation in fattening pigs. In this trial, a 1-4-endo-D-β-mannanase was added to the feed (HC) during growth and fattening ...(0.03% of Hemicell HT) and physical performance and pathological data were recorded, and intestinal integrity and immune activation were studied by molecular biomarkers, compared to a control group (CON). The treatment diet was reduced in energy content by 40 Kcal/kg NE. From each group, 113 and 112 animals housed in 8 pens were individually identified and weighed three times: at 7th, 63rd and 116th days in feed. The FCR was calculated for groups of two pens and ADG individually. There was no difference in ADG (CON = 0.836, HC = 0.818) nor in FCR between groups (p = 0.486). During growth, there was a higher frequency of normal feces in HC and there were also no differences in the frequency of gastric lesions. A significant increase in Claudin, Occludin, IFN-γ and IL8 was observed in the CON in feces and a significant decrease in IL-6 in HC. In tissues, there were differences for IL-12p40, TNF-alpha in jejunum (increased CON) and TGF-β in ileum and jejunum, (decreased HC). The economic performance was EUR 4.7 better in the treated group. In conclusion, the addition of 1-4-endo-D-β--mannanase to the feed with a 1.6% reduction in net energy compared to the control, allowed the animals to perform as well as the animals on the higher energy diet, with lower prevalence of diarrhea.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
CONTEXT Fibrates are weak agonists of peroxisome proliferator–activated receptor α (PPAR-α). No trials have reported effects of more potent and selective agents. OBJECTIVES To examine the safety and ...efficacy of LY518674, a PPAR-α agonist. DESIGN, SETTING, AND PARTICIPANTS Two multicenter, randomized, double-blind, placebo-controlled trials: 1 in patients with elevated triglycerides and low HDL-C (atherogenic dyslipidemia), the other in patients with elevated LDL-C (hypercholesterolemia). Between August 2005 and August 2006, the dyslipidemia study randomized 309 patients at US centers; the hypercholesterolemia study, 304 patients. INTERVENTIONS Dyslipidemia study: placebo, fenofibrate (200 mg), or LY518674 (10, 25, 50, or 100 μg) for 12 weeks. Hypercholesterolemia study: placebo or atorvastatin (10 or 40 mg) for 4 weeks, then placebo or LY518674 (10 or 50 μg) for 12 more weeks. MAIN OUTCOME MEASURES Dyslipidemia study: percentage change in levels of HDL-C and triglycerides. Hypercholesterolemia study: percentage change in levels of LDL-C. RESULTS Dyslipidemia study: LY518674 (25 μg) and fenofibrate increased HDL-C by 5.9 and 5.5 mg/dL (15.8% and 14.4%) (both P≤.001 vs placebo, P = .79 between treatments). Higher LY518674 doses yielded smaller increases. LY518674 decreased triglycerides by 97.3 to 114.5 mg/dL (34.9% to 41.7%) but was similar to fenofibrate. LY518674 produced a dose-dependent increase in LDL-C, reaching 20.4 mg/dL (19.5%) for the 100-μg dose vs 0.3 mg/dL (2.3%) for fenofibrate (P≤.01). Fenofibrate and LY518674 (50 μg and 100 μg) increased serum creatinine (P≤.001 vs placebo), with 38% and 37.3% of patients exceeding the normal range. Fenofibrate, but not LY518674, increased creatine phosphokinase (P = .004 vs placebo). Hypercholesterolemia study: LY518674 (10 μg or 50 μg) decreased LDL-C by 21.4 to 26.0 mg/dL (13.2%-15.8%) and triglycerides ≈37% for both doses, and increased HDL-C by 6.3 to 6.7 mg/dL (12.5%-15.0%). When added to atorvastatin, LY518674 changed HDL-C by −0.7 to 6.2 mg/dL (−0.6% to 11.9%) and significantly decreased triglycerides but had no additional effect on LDL-C. CONCLUSIONS In patients with dyslipidemia, LY518674 and fenofibrate decreased triglycerides and increased HDL-C but also increased serum creatinine. LY518674, but not fenofibrate, increased LDL-C. In those with hypercholesterolemia, LY518674 reduced triglycerides and increased HDL-C, but did not further reduce LDL-C in combination with atorvastatin. Fenofibrate and LY518674 both raised safety concerns. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00133380 and NCT00116519Published online March 25, 2007 (doi:10.1001/jama.297.12.1362).
Abstract
Background: Black women experience the worst survival after an ovarian cancer diagnosis, compared to any racial and ethnic group, and the mortality gap between non-Hispanic Black (NHB) and ...non-Hispanic White (NHW) women has continued to widen over the years. Standard of care for ovarian cancer has historically included surgical cytoreduction followed by platinum and taxane-based chemotherapy, with some minor variations over the years in the recommendations for agents, dosing patterns, and treatment sequence, which may affect disparities in adherence to treatment guidelines. The most drastic changes in National Comprehensive Cancer Network (NCCN) guidelines were released in 2016, with the incorporation of histotype in decision trees to guide care. Our study aimed to evaluate racial and ethnic differences in receipt of guideline concordant care in an integrated health system. Methods: This analysis included 4,197 California residents in the KP ROCS (Kaiser Permanente Research on Ovarian Cancer Survival) Study, age 18 years or older when diagnosed between 2000 and 2018 with invasive ovarian, fallopian or peritoneal cancer at Kaiser Permanente Northern California, and with available key information to assess guideline concordant care. Detailed surgery and chemotherapy data, as well as clinical characteristics (e.g., grade, stage, histotype), were obtained from electronic medical records. We evaluated concordance with year-specific NCCN guidelines for surgery and chemotherapy according to the year of diagnosis, with independent consideration of recommendations for neoadjuvant and adjuvant therapies. Results: Our study included 2,822 NHW women, 231 NHB women, 558 Asian American and Pacific Islander (AAPI) women, 512 Hispanic women, and 74 women of other races. Overall, we found that NHB women were less likely to receive guideline concordant care than any other groups (37.2% compared to 44.6% for NHW, 55.4% for NHA, and 48.6% for Hispanic women). NHB women were less like to receive surgery, and guideline concordant chemotherapy, including having early discontinuation. Annual trends also revealed persistently lower receipt of guideline treatment among NHB compared with all other groups over time. We also observed for all groups, except AAPI women a lower percentage of concordant care after 2016, most pronounced for NHB women, at 33%, when histotype was incorporated into NCCN guidelines. Conclusions: We found that in a setting with similar insurance coverage, treatment disparities persisted. Our next step will be to further explore the reasons for these treatment differences, including neighborhood context and geographic medical accessibility, as well as other patient characteristics (e.g., comorbidity burden, biological factors), that may also have an impact in disease progression and mortality outcomes.
Citation Format: Elisa V. Bandera, Lindsay J. Collin, Valerie Lee, Juraj Kavecansky, Christine Garcia, Carola Sanchez Diaz, Farzin Khosrow-Khavar, Jennifer A. Doherty, Scarlett Lin Gomez, Lawrence H. Kushi. Racial and ethnic disparities in receipt of guideline concordant care among ovarian cancer patients abstract. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B007.
Abstract
Background: Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality among women in the US. Racial and ethnic disparities in ovarian ...cancer outcomes exist, wherein non-Hispanic Black (NHB) women are 40% more likely to die compared with non-Hispanic White (NHW) women. Comorbidity burden is differential by race and ethnicity and has the potential to affect treatment and outcomes. Our objective was to evaluate the association between comorbidities, present at the time of diagnosis, and mortality, and to evaluate if comorbidities contributed to racial and ethnic disparities in mortality. Methods: The KP ROCS (Kaiser Permanente Research on Ovarian Cancer Survival) Study includes women diagnosed with invasive ovarian, fallopian, or peritoneal cancer between 2000 and 2018 at KP Northern California, older than 18 years and residing in California at diagnosis. Comorbidities were identified using ICD-9/10 and procedural codes up to five years preceding the ovarian cancer diagnosis. We computed hazard ratios (HRs) and 95% confidence intervals (CIs) associating individual comorbidities and the Charlson Comorbidity Index (CCI) with all-cause mortality, and the racial disparities (Hispanic, non-Hispanic Asian, and NHB vs. NHW) in all-cause mortality by comorbidity, adjusting for age and stage. Results: Of 4,910 ovarian cancer patients in the KP ROCS cohort, 605 (12%) are Hispanic, 672 (13%) are non-Hispanic Asian, 282 (5.5%) are NHB, and 3,321 (74%) are NHW. At diagnosis, NHB and Hispanic ovarian cancer patients were more likely to present with diabetes than non-Hispanic Asian and NHW women (NHB=16%, Hispanic=13% vs non-Hispanic Asian=10%, NHW=8%). Cardiovascular disease was more common among NHB women compared with other racial and ethnic groups (NHB=37% vs. Hispanic=26%, non-Hispanic Asian=19%, NHW=32%). Moreover, the net burden of comorbidities (CCI=3+) was higher among NHB women compared with other racial and ethnic groups (NHB=22% vs non-Hispanic Asian=9%, Hispanic=13%, NHW=13%). In the multivariable-adjusted models, ovarian cancer patients with diabetes (HR=1.16, 95%CI 1.03, 1.31), cardiovascular disease (HR=1.32, 95% CI 1.22, 1.44), hypertension (HR=1.07, 95%CI 0.99, 1.16), or renal disease (HR=1.25, 95%CI, 1.14, 1.38 at the time of their diagnosis were more likely to die than those without the corresponding comorbidity. NHB ovarian cancer patients had an increased hazard of mortality across nearly all comorbid conditions compared with NHW patients, whereas Hispanic women had equivalent mortality rates as NHW patients, and non-Hispanic Asian patients had reduced mortality rates compared with NHW patients across each individual comorbidity. Conclusions: These analyses indicate that the presence of comorbid conditions negatively impacts survival among ovarian cancer patients. Moreover, NHB ovarian cancer patients are more likely to present with comorbidities at the time of their ovarian cancer diagnosis compared with other racial and ethnic groups, which may partially explain the observed disparities.
Citation Format: Lindsay J. Collin, Jia Li, Valerie S. Lee, Juraj Kavecansky, Christine Garcia, Carola Sanchez Diaz, Scarlett Lin Gomez, Jennifer A. Doherty, Elisa V. Bandera, Lawrence H. Kushi. Contribution of comorbid conditions to racial and ethnic disparities in ovarian cancer survival abstract. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B102.
Abstract
Purpose: Ovarian cancer is the most lethal gynecologic cancer in North America, yet our understanding of ovarian cancer risk factors in Mexican women is limited. The aim of the present study ...was to prospectively evaluate associations between reproductive and lifestyle factors and incident ovarian cancer risk among Mexican women.
Methods: The Mexican Teachers′ Cohort (ESMaestras) is a large, prospective, population-based cohort of women (n=115,306) living in a culturally, geographically, and economically diverse 12-state area in Mexico. Reproductive and lifestyle factors were collected on baseline questionnaires administered between 2006-2008, with additional questionnaires collected from the cohort in 2011, and 2014. During follow-up, 187 incident ovarian cancer cases were identified, including 101 via self-report on 2011 and 2014 questionnaires, as well as an additional 85 through linkage with mortality databases, and 3 via other administrative- and cancer registry-based linkages (2 of 3 were also identified via the mortality database linkage). Of the self-reported incident cases, 5 have been validated via mortality databases and 4 via linkage with an administrative database; validation of the remaining self-reported cases is ongoing. Primary analyses examined associations between established ovarian cancer risk factors and incident ovarian cancer. Age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression.
Results: Women in the Mexican Teachers′ Cohort that used hormonal contraceptives (HC), were parous, or had a tubal ligation experienced reduced ovarian cancer risks during follow-up (ever HC use vs. never HR 0.70 95% CI 0.51-0.95, parous vs. nulliparous 0.48 0.35-0.68, ever tubal ligation vs. never 0.87 0.59-1.28). Ovarian cancer risk was elevated among women with a positive family history of breast cancer (1.34 0.76-2.36). Women with a history of endometriosis were at increased ovarian cancer risk (3.43 1.41-8.34). Taller adult height (>159 cm vs <150 cm) was not associated with ovarian cancer risk among women in this cohort. Risk estimates were consistent and, in some instances, more pronounced (i.e., HC use and tubal ligation) when limited to incident ovarian cancer cases confirmed via linkage with mortality databases (n=90).
Conclusions: Ovarian cancer risk factors identified in the Mexican Teachers′ Cohort were generally consistent with associations reported in predominantly non-Hispanic white populations. More research is needed to better understand ovarian cancer etiology among populations under-represented in cancer research.
Citation Format: Britton Trabert, Liliana Gómez Flores Ramos, Marion Brochier, Elisa V. Bandera, Jennifer A. Doherty, Scarlett L. Gomez, Lawrence H. Kushi, Alejandro Mohar, Martín Lajous. Evaluating ovarian cancer risk factors in the Mexican Teachers′ Cohort abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2204.
PDF
