OBSERVE: guidelines for the refinement of rodent cancer models.

Existing guidelines on the preparation (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE)) and reporting (Animal Research: Reporting of In Vivo Experiments (ARRIVE)) of animal experiments do not provide a clear and standardized approach for refinement during in vivo cancer studies, resulting in the publication of generic methodological sections that poorly reflect the attempts made at accurately monitoring different pathologies. Compliance with the 3Rs guidelines has mainly focused on reduction and replacement; however, refinement has been harder to implement. The Oncology Best-practices: Signs, Endpoints and Refinements for in Vivo Experiments (OBSERVE) guidelines are the result of a European initiative supported by EurOPDX and INFRAFRONTIER, and aim to facilitate the refinement of studies using in vivo cancer models by offering robust and practical recommendations on approaches to research scientists and animal care staff. We listed cancer-specific clinical signs as a reference point and from there developed sets of guidelines for a wide variety of rodent models, including genetically engineered models and patient derived xenografts. In this Consensus Statement, we systematically and comprehensively address refinement and monitoring approaches during the design and execution of murine cancer studies. We elaborate on the appropriate preparation of tumor-initiating biologicals and the refinement of tumor-implantation methods. We describe the clinical signs to monitor associated with tumor growth, the appropriate follow-up of animals tailored to varying clinical signs and humane endpoints, and an overview of severity assessment in relation to clinical signs, implantation method and tumor characteristics. The guidelines provide oncology researchers clear and robust guidance for the refinement of in vivo cancer models.

COVID-19, Disability, and the International Classification of Functioning, Disability and Health: A Scoping Review of Early-Stage Pandemic Response.

Introduction: This study aimed to systematically identify the environmental factors that impacted people with disability during the COVID-19 pandemic. Methods: A scoping literature review was conducted using LitCOVID (January 1-July 31, 2020). Sixty-six articles met the inclusion criteria that (1) discussed disability and/or health conditions related to functioning and (2) considered environmental factors. A qualitative content analysis was conducted using codes from the WHO International Classification of Functioning, Disability and Health. Results: A total of 212 International Classification of Functioning, Disability and Health codes were used in the coding process. The most frequent codes referred to health services policies and public health guidelines. These policies, although generally considered facilitators for minimizing infection, were frequently identified as barriers to the health, participation, and human rights of people with disability. The lack of disability-specific population data was identified as a key barrier to planning and decision making. Conclusions: The social determinants of health for people with disability were not adequately considered in the acute phase of infection prevention at the population level. Integrating the International Classification of Functioning, Disability and Health in emergency management provides a tool to evaluate functioning and address barriers for those in need.

Diagnostic Accuracy of Radioactive Iodine Seed Placement in the Axilla With Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Node-Positive Breast Cancer.

Importance: Several less-invasive staging procedures have been proposed to replace axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) in patients with initially clinically node-positive (cN+) breast cancer, but these procedures may fail to detect residual disease. Owing to the lack of high-level evidence, it is not yet clear which procedure is most optimal to replace ALND. Objective: To determine the diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy (RISAS), a targeted axillary dissection procedure. Design, Setting, and Participants: This was a prospective, multicenter, noninferiority, diagnostic accuracy trial conducted from March 1, 2017, to December 31, 2019. Patients were included within 14 institutions (general, teaching, and academic) throughout the Netherlands. Patients with breast cancer clinical tumor categories 1 through 4 (cT1-4; tumor diameter <2 cm and up to >5 cm or extension to the chest wall or skin) and pathologically proven positive axillary lymph nodes (ie, clinical node categories cN1, metastases to movable ipsilateral level I and/or level II axillary nodes; cN2, metastases to fixed or matted ipsilateral level I and/or level II axillary nodes; cN3b, metastases to ipsilateral level I and/or level II axillary nodes with metastases to internal mammary nodes) who were treated with NAC were eligible for inclusion. Data were analyzed from July 2020 to December 2021. Intervention: Pre-NAC, the marking of a pathologically confirmed positive axillary lymph node with radioactive iodine seed (MARI) procedure, was performed and after NAC, sentinel lymph node biopsy (SLNB) combined with excision of the marked lymph node (ie, RISAS procedure) was performed, followed by ALND. Main Outcomes and Measures: The identification rate, false-negative rate (FNR), and negative predictive value (NPV) were calculated for all 3 procedures: RISAS, SLNB, and MARI. The noninferiority margin of the observed FNR was 6.25% for the RISAS procedure. Results: A total of 212 patients (median [range] age, 52 [22-77] years) who had cN+ breast cancer underwent the RISAS procedure and ALND. The identification rate of the RISAS procedure was 98.2% (223 of 227). The identification rates of SLNB and MARI were 86.4% (197 of 228) and 94.1% (224 of 238), respectively. FNR of the RISAS procedure was 3.5% (5 of 144; 90% CI, 1.38-7.16), and NPV was 92.8% (64 of 69; 90% CI, 85.37-97.10), compared with an FNR of 17.9% (22 of 123; 90% CI, 12.4%-24.5%) and NPV of 72.8% (59 of 81; 90% CI, 63.5%-80.8%) for SLNB and an FNR of 7.0% (10 of 143; 90% CI, 3.8%-11.6%) and NPV of 86.3% (63 of 73; 90% CI, 77.9%-92.4%) for the MARI procedure. In a subgroup of 174 patients in whom SLNB and the MARI procedure were successful and ALND was performed, FNR of the RISAS procedure was 2.5% (3 of 118; 90% CI, 0.7%-6.4%), compared with 18.6% (22 of 118; 90% CI, 13.0%-25.5%) for SLNB (P < .001) and 6.8% (8 of 118; 90% CI, 3.4%-11.9%) for the MARI procedure (P = .03). Conclusions and Relevance: Results of this diagnostic study suggest that the RISAS procedure was the most feasible and accurate less-invasive procedure for axillary staging after NAC in patients with cN+ breast cancer.

Symptom-based clusters in patients with advanced chronic organ failure identify different trajectories of symptom variations.

BACKGROUND: Healthcare needs are complex and heterogeneous in advanced chronic organ failure. However, based on symptom clusters, groups of patients with similar quality of life, care dependency and life-sustaining treatment preferences can be identified. AIMS: To evaluate the stability of symptom-based clusters over time, and whether and to what extent the clusters are able to predict patients' 2-year survival and hospitalization rates. METHODS: This is a secondary analysis of a longitudinal observational study including 95 outpatients with chronic obstructive pulmonary disease (COPD) GOLD stage III-IV, 80 outpatients with chronic heart failure (CHF) NYHA stage III-IV and 80 outpatients with chronic renal failure (CRF) requiring dialysis. Patients were clustered into three groups applying K-means algorithm on baseline symptoms' severity and were then longitudinally evaluated. 2-year survival and hospital admissions during 1 year were estimated using Kaplan-Meier curves and Cox models. 1-year tendencies in symptom variation, using mixed linear models, and clusters comparison over time were performed. RESULTS: The three clusters were unable to predict patients' survival and hospital admissions. Noteworthy, they show different trajectories of symptom variation, with Cluster 1 patients experiencing a worsening of symptoms, associated with an increased care dependency, and Cluster 2 and Cluster 3 patients being stable or having a relief in some symptoms. Although Cluster 1 is becoming more similar to Cluster 2, the three clusters preserve the overall characteristics and differences. DISCUSSION: Symptom-based clusters might help to identify patients with different trajectories of symptom variations. CONCLUSION: Symptom clusters do not predict survival and hospital admissions and are stable over time.

A single-center, randomized, non-inferiority study evaluating seroma formation after mastectomy combined with flap fixation with or without suction drainage: protocol for the Seroma reduction and drAin fRee mAstectomy (SARA) trial.

BACKGROUND: Seroma formation is a common complication after breast cancer surgery and can lead to delayed wound healing, infection, patient discomfort and repeated visits to the outpatient clinic. Mastectomy combined with flap fixation is becoming standard practice and is currently combined with closed-suction drainage. There is evidence showing that closed-suction drainage may be insufficient in preventing seroma formation. There is reasonable doubt whether there is still place for closed-suction drainage after mastectomy when flap fixation is performed. We hypothesize that mastectomy combined with flap fixation and closed suction drainage does not cause a significant lower incidence of seroma aspirations, when compared to mastectomy and flap fixation alone. Furthermore, we expect that patients without drainage will experience significantly less discomfort and comparable rates of surgical site infections. METHODS: This is a randomized controlled trial in female breast cancer patients undergoing mastectomy and flap fixation using sutures with or without sentinel lymph node biopsy (SLNB). Patients will be eligible for inclusion if they are older than 18 years, have an indication for mastectomy with or without sentinel procedure. Exclusion criteria are modified radical mastectomy, direct breast reconstruction, previous history of radiation therapy of the unilateral breast, breast conserving therapy and inability to give informed consent. A total of 250 patients will be randomly allocated to one of two groups: mastectomy combined with flap fixation and closed-suction drainage or mastectomy combined with flap fixation without drainage. Follow-up will be conducted up to six months postoperatively. The primary outcome is the proportion of patients undergoing one or more seroma aspirations. Secondary outcome measures consist of the number of invasive interventions, surgical site infection, quality of life measured using the SF-12 Health Survey, cosmesis, pain and number of additional outpatient department visits. DISCUSSION: To our knowledge, no randomized controlled trial has been conducted comparing flap fixation with and without closed-suction drainage with seroma aspiration as the primary outcome. This study could result in finding evidence that supports performing mastectomy without closed-suction drainage. TRIAL REGISTRATION: This trial was approved by the medical ethical committee of Zuyderland Medical Center METC-Z on 20 March 2019 (METCZ20190023). The SARA Trial was registered at ClinicalTrials.gov as per July 2019, Identifier: NCT04035590 .

Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience.

PURPOSE: We assessed the uptake of fertility preservation (FP), recovery of ovarian function (OFR) after chemotherapy, live birth after breast cancer, and breast cancer outcomes in women with early-stage breast cancer. METHODS: Women aged below 41 years and referred to our center for FP counseling between 2008 and 2015 were included. Data on patient and tumor characteristics, ovarian function, cryopreservation (embryo/oocyte) and transfer, live birth, and disease-free survival were collected. Kaplan-Meier analyses were performed for time-to-event analyses including competing risk analyses, and patients with versus without FP were compared using the logrank test. RESULTS: Of 118 counseled women with a median age of 31 years (range 19-40), 34 (29%) chose FP. Women who chose FP had less often children, more often a male partner and more often favorable tumor characteristics. The 5-year OFR rate was 92% for the total group of counseled patients. In total, 26 women gave birth. The 5-year live birth rate was 27% for the total group of counseled patients. Only three women applied for transfer of their cryopreserved embryo(s), in two combined with preimplantation genetic diagnosis (PGD) because of BRCA1-mutation carrier ship. The 5-year disease-free survival rate was 91% versus 88%, for patients with versus without FP (P = 0.42). CONCLUSIONS: Remarkably, most women achieved OFR, probably related to the young age at diagnosis. Most pregnancies occurred spontaneously, two of three women applied for embryo transfer because of the opportunity to apply for PGD.

Reducing seroma formation and its sequelae after mastectomy by closure of the dead space: The interim analysis of a multi-center, double-blind randomized controlled trial (SAM trial).

OBJECTIVE: The main objective of this double-blind randomized controlled trial (RCT) was to assess seroma formation and its sequelae in patients undergoing mastectomy. Patients were randomized into one of three groups in which different wound closure techniques were applied: 1) conventional wound closure without flap fixation (CON) 2) flap fixation using sutures (FF-S) and 3) flap fixation using an adhesive tissue glue (FF-G). BACKGROUND: Seroma formation is still a bothersome complication after mastectomy. Flap fixation seems promising in reducing seroma formation. Various flap fixation techniques remain to be analyzed, including long-term outcome measures. METHODS: This trial was conducted in three different hospitals between June 2014 and November 2016. Patients were allocated to one of three groups. The primary outcome was the number of seroma needle aspirations. Secondary outcomes were (surgical site) infections, number of outpatient clinic visits, shoulder function, postoperative pain, patient-reported cosmesis and skin dimpling. RESULTS: A total of 187 patients were randomly assigned to CON (n = 61), FF-S (n = 64) and FF-G (n = 62). The number of seroma aspirations was significantly higher in CON when compared to both flap fixation groups (p = 0.032), with no difference between FF-S and FF-G. Secondary outcomes showed no statistical differences between all groups. The higher number of outpatient clinic visits in CON was considered to be of clinical importance (CON = 27 (44.3%), FF-S = 19 (30.6%) and FF-G = 21 (34.4%)). CONCLUSIONS: Mastectomy followed by flap fixation with either sutures or adhesive tissue glue reduces the number of seroma aspirations when compared to simple wound closure.

Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study.

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78-1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71-1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06-2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95-2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab.

Using a participatory action strategic approach to enhance accessibility and participation in arts and cultural events: results of four focus groups.

BACKGROUND: Cultural events are abundant in a midwestern college town; however, individuals with disabilities have expressed concerns about their accessibility. Policymakers, business owners, and managers often ignore disability-related issues. Research shows accessibility is the main environmental barrier to participation in arts and cultural events. Individuals with disabilities are disconnected from managers of cultural organizations and city leaders. The lack of awareness about accessibility, including access to the built environment, impedes participation in cultural events in this college town. OBJECTIVES: To encourage the participation of people with disabilities in cultural events in a midwestern college town, a bold strategic project was initiated to conduct a community-based needs assessment as a foundation for an action plan. Participation in arts and culture was selected as a unique focal point for exploring ways to enhance accessibility. METHODS: Thirty-nine stakeholders participated in four different focus groups: individuals with disabilities, managers of cultural organizations, caregivers and health care providers, and other stakeholders including politicians. Critical problem areas identified were mapped onto the environmental factors in the International Classification of Functioning, Disability, and Health (ICF). RESULTS: Three themes emerged: 1) limited awareness about accessibility among the residents with disabilities and a lack of awareness about disability-related issues and accessibility among the managers of cultural organizations; 2) the need for a "central information clearinghouse" to share, provide, and retrieve information; 3) the need for inclusive city-level policies. CONCLUSIONS: Raising awareness about disabilities and accessibility, providing a clearinghouse for information sharing and implementing inclusive policies are crucial to strengthen participation in community life.

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma.

PURPOSE: Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM. METHODS: This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM. RESULTS: The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM. CONCLUSIONS: Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.

Chemoprevention for keratinocytic (pre)cancers: balancing the risks and benefits.

QUESTION: Can celecoxib reduce the incidence of actinic keratoses (AKs) and keratinocytic cancers? DESIGN: Randomized, double-blind, placebo-controlled phase 2-3 clinical trial. SETTING: Eight centers in the United States participated and included 240 patients from January 2001 to November 2006, when the Food and Drug Administration requested termination of this trial after the worldwide withdrawal of rofecoxib. PATIENTS: The study population comprised individuals 18 years or older with Fitzpatrick skin type I to III, with 10 to 40 AKs on the upper extremities, neck, face, and scalp at baseline and a previous histological diagnosis of a keratinocytic (pre)malignant neoplasm. INTERVENTION: Celecoxib (200 mg) or placebo twice daily. MAIN OUTCOME MEASURE: The ratio of new AKs per patient at completion of the study to the number of AKs at randomization. EXPLORATORY POST HOC ANALYSIS: The mean cumulative number of keratinocytic skin cancers per patient. RESULTS: There was no difference in the incidence of AKs between the 2 groups at month 9 after randomization. The adjusted rate ratios for the celecoxib arm compared with the placebo arm were 0.41 (95% CI, 0.23-0.72) for keratinocytic skin cancers, 0.40 (95% CI, 0.18-0.93) for basal cell carcinomas (BCCs), and 0.42 (95% CI, 0.19-0.93) for squamous cell carcinomas (SCCs). CONCLUSION: Celecoxib might be effective for prevention of keratinocytic cancers but not for actinic keratoses.

Differential effect of drug interference in immunogenicity assays.

The presence of anti-drug antibodies (ADA) in adalimumab-treated patients is associated with reduced serum adalimumab levels and a lower clinical response. Currently, there is no standard for measurement of anti-drug antibodies and many factors influence the results. Consequently, the incidence of ADA as reported in different studies varies considerably. Here we investigated the differential effect of drug interference in two common types of assays used to measure anti-adalimumab: an antigen binding test (ABT) and a more often-used bridging elisa. We measured ADA to adalimumab in a cohort of 216 rheumatoid arthritis patients treated with adalimumab for 28 weeks. Only 15 samples (7%) were positive in the bridging elisa, compared to 29 (13%) in the ABT, despite the fact that the bridging elisa was the most sensitive assay. Furthermore, in an ABT specific for IgG4, 48 samples (22%) were found positive. The bridging elisa was found to detect only the bivalent form of (drug-specific) IgG4, resulting in an underestimation of ADA levels. However, the predominant reason for the different outcomes of these assays was a differential susceptibility to drug interference. In particular, the bridging elisa only detected ADA in the absence of detectable amounts of circulating adalimumab and is therefore not suited for measurement of ADA in complex with the drug. In summary, we showed that a bridging elisa is susceptible to drug interference and typically measures ADA only in absence of detectable drug levels.

Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-α (EORTC 18952) and prognostic value on treatment outcome.

Adjuvant therapy with interferon-α (IFN) only benefits a small subgroup of melanoma patients and a predictive marker selecting responders does not exist. IFN induces increased ferritin and decreased C-reactive protein (CRP) levels; however, an association with treatment effect was not studied. Serum was collected from patients participating in the European Organization for Research and Treatment of Cancer 18 952 trial comparing adjuvant treatment with IFN to observation. Serial ferritin and CRP levels were determined using enzyme-linked immunosorbent assays, before treatment and up to 24 months. Ferritin levels are influenced by sex and age; therefore ratios of serial ferritin and CRP values with corresponding pretreatment values were calculated. Cox regression model and landmark method at end of induction and 6 months were used to evaluate the association between ferritin, CRP and distant metastasis-free survival (DMFS). Baseline ferritin levels were comparable in the two treatment groups (P=0.92). However, ferritin ratios were significantly higher in IFN-treated patients (N=96) compared with untreated patients (N=21) at end of induction (mean: 2.88 vs. 0.75; P=0.0003) and at 6 months (mean: 3.18 vs. 1.02; P=0.009). In the IFN arm, higher ferritin ratios at end of induction and at 6 months were not associated with improved outcome (respectively, P=0.66 and 0.86). Concerning CRP ratios, no differences between the treatment groups, neither an association with DMFS, were observed. Administration of IFN in melanoma patients induced increase in ferritin levels but not in CRP levels. Ferritin and CRP ratios have no prognostic value regarding DMFS.

Participation among adults with disability: the role of the urban environment.

Increasing attention is being paid to the importance of built environment characteristics for participation, especially among people with various levels of impairment or activity limitations. The purpose of this research was to examine the role of specific characteristics in the urban environment as they interact with underlying impairments and activity limitations to either promote or hinder participation in life situations. Using data from the Chicago Community Adult Health Study (2001-2003) in the United States, we used logistic regression to examine the effect of built environment characteristics on three indicators of participation (interpersonal interaction, obtaining preventive health care, and voting) among adults age 45+ (N = 1225). We examined effects across two levels of spatial scale: the census tract and block group. One in five adults reported difficulty walking 2-3 blocks unaided, but their odds of engaging in regular interpersonal interaction was 45% higher when they lived in areas with higher residential security. For the thirty-six percent of adults who reported visual impairment, and the odds of obtaining preventive health care were over 20% lower when living in an area with heavy traffic. Residing in an area with a high proportion of streets in poor condition was associated with 60% lower odds of voting among those with underlying difficulty with mobility activities. Results varied across levels of spatial scale. Simple changes in urban built environments may facilitate the full participation of all persons in society.

Epidemiology of extracutaneous melanoma in the Netherlands.

BACKGROUND: Reliable population-based incidence and survival data on extracutaneous melanoma (ECM) are sparse. METHODS: Incidence data (1989-2006) from the Netherlands Cancer Registry were combined with vital status on January 1, 2008. Age-adjusted annual incidence rates were calculated by direct standardization, and the estimated annual percentage change was estimated to detect changing trends in incidence. Additionally, we carried out cohort-based relative survival analysis. RESULTS: Ocular melanomas were the most common ECM subsite with European standardized incidence rates (ESR) of 10.7 and 8.2 per 1,000,000 person-years for males and females, respectively. In comparison, for cutaneous melanoma (CM), the ESRs for men and women were 122 and 155 per million person-years, respectively. No statistically significant trends in the incidence of ECM were detected, whereas an annual increase of 4.4% for men and 3.6% for women was detected in the incidence of CM. Relative survival for ECM was poor, but differed largely between anatomic subtypes ranging from a 5-year relative survival of 74% for ocular melanomas to 15% for certain subsites of mucosal melanomas. CONCLUSIONS: Of all ECM subsites, ocular melanomas had the highest incidence and the best survival. Mucosal melanomas were the second most frequent subsite of ECM. Five-year relative survival for all ECM subtypes was worse if compared with CM. No statistically significant trends in the incidence of (subsites of) ECM were determined. IMPACT: This study gives insight into the relative sizes of the different subgroups of ECM as well as an estimate of 5-year survival, which varies substantially by subsite.

Environments for healthy ageing: a critical review.

Population health outcomes are shaped by complex interactions between individuals and the environments in which they live, work and play. Environments encompass streets and buildings (physical environment), attitudes, supports and relationships with others (social environment), as well as social and political systems and policies. The impact of environments on the physical, mental health and functioning of individuals has emerged as a growing body of research in population health and health disparities. Yet, the majority of studies in this area do not focus on older adults even though older adults are particularly susceptible to the characteristics of their local environments. In this paper we review the current state of the health literature on physical environments for healthy ageing, using the International Classification of Functioning Disability and Health as a framework. Collectively, the literature emphasizes the role of supportive, barrier-free environments particularly for older adults who are at greater risk for disability and poor health. As part of our review we identify conceptual as well as methodological limitations in the current literature, including (i) a theoretical and empirical neglect of the underlying mechanisms behind the person-environment relationship; (ii) a lack of studies using nationally representative samples; (iii) over-reliance on cross-sectional data; and (iv) a need for better definition and measurement of person-centered environments. We conclude by offering some suggestions and directions for future research in this area.

Diet-dependent mucosal colonization and interleukin-1beta responses in preterm pigs susceptible to necrotizing enterocolitis.

OBJECTIVES: Intestinal colonization challenges the neonatal innate immune system, especially in newborns with an immature immune response lacking the supportive bioactive components from mother's milk. Accordingly, formula-fed preterm pigs frequently show bacterial overgrowth, mucosal atrophy, and gut lesions reflecting necrotizing enterocolitis (NEC) within the first days after birth. We hypothesized that NEC development is related to a diet-dependent bacterial adherence and a subsequent proinflammatory cytokine response in the gut mucosa immediately after introduction of enteral food. MATERIALS AND METHODS: Premature piglets (92% gestation) received 2 to 3 days of total parenteral nutrition followed by 0, 8, or 17 hours of enteral formula or sow's colostrum feeding. RESULTS: Following 8 hours, but not 17 hours, of colostrum feeding, a reduced number of intestinal samples with adherent bacteria (both Gram-negative and Gram-positive bacteria) was counted compared with 0 or 8 hours of formula feeding. Besides a more dense colonization, formula feeding leads to higher intestinal interleukin-1beta (IL-1beta) levels and more NEC-like lesions from 8 hours onward. The load of adherent bacteria was especially high in NEC lesions. Toll-like receptor 4 was detected in enteroendocrine, neuronal, and smooth muscle cells, potentially mediating the increase in IL-1beta levels by Gram-negative bacteria. CONCLUSIONS: Formula feeding facilitates bacterial adherence and the development of a proinflammatory state of the intestine, which may be among the key factors that predispose formula-fed preterm neonates to NEC.

C-reactive protein elicits white blood cell activation in humans.

OBJECTIVE: Consistent epidemiologic evidence suggests that acute infections increase the risk for acute cardiovascular events. We tested in humans whether activation of peripheral leukocytes in reaction to the administration of recombinant human C-reactive protein (rhCRP) may provide a mechanism for infectious diseases to promote atherosclerotic disease. METHODS AND RESULTS: By using quantitative real-time polymerase chain reaction analysis, whole-blood expression profiles were analyzed for 95 inflammatory markers before and after infusion of 1.25 mg/kg rhCRP in 5 male volunteers. Relevant transcript levels were measured at baseline and 4 and 8 hours after rhCRP-infusion. CRP caused significant up-regulation of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, plasminogen activator urokinase, macrophage inflammatory protein 1 alpha, and nuclear factor of kappa B inhibitor mRNAs in peripheral leukocytes. mRNA up-regulation of MMP-9 and MCP-1 was 17- and 11-fold, respectively. The corresponding increase in plasma protein levels of MMP-9 (78+/-32 ng/mL to 109+/-41 ng/mL; P=.014) and MCP-1 (312+/-92 pg/mL to 2590+/-898 pg/mL; P=.007) closely mirrored mRNA findings. Also, in whole-blood culture stimulation assays, CRP induced proinflammatory changes. Notably, heat inactivation abolished the capacity of CRP to evoke these proinflammatory changes, excluding a role for contaminants within the purified CRP preparation. CONCLUSION: CRP elicits activation of peripheral leukocytes with ensuing secretion of plaque-destabilizing mediators. These findings are consistent with the hypothesis that infectious diseases trigger manifestations of atherosclerosis, in which CRP elevation might contribute to the onset of cardiovascular events.

Development and validation of an enzyme-linked immunosorbent assay for the quantification of trastuzumab in human serum and plasma.

Trastuzumab, a humanized monoclonal antibody, is used for the treatment of breast cancer patients who overexpress the HER2 receptor. To optimize therapy, pharmacokinetic studies are necessary. The aim of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for trastuzumab to support these pharmacokinetic studies. For this immunoassay, we raised anti-idiotype antibodies in rabbits. After purification of the rabbit material, the anti-idiotype antibodies are used as capturing antibodies on the ELISA plate. After trastuzumab has bound to the catcher antibody, a sandwich ELISA procedure is followed whereby biotinylated anti-idiotype antibodies can bind to trastuzumab. Detection is performed by streptavidin-polyHRP (poly-horseradish peroxidase) conjugate and (3,5,3',5')-tetramethylbenzidine (TMB) substrate. The reaction is stopped using sulfuric acid, and the absorbance is measured at 450 nm. The calibration range of the assay is 0.039 to 5 ng/ml in well. Because samples are analyzed in multiple dilutions, the validated range corresponds to 1.6 to 1600 ng/ml in undiluted serum. Samples above the upper limit of quantification (ULOQ) can be diluted before transfer to the assay plates. Validation results demonstrate that trastuzumab can be accurately and precisely quantified in human serum and plasma. The assay is now used to support pharmacokinetic studies with trastuzumab in human serum and plasma.

An insider's view on person-centred rehabilitation: a case study.

PURPOSE: The author, a rehabilitation specialist of more than 30 years, presents her observations of the medical and rehabilitation services her husband received after a ruptured abdominal aortic aneurysm. Building on the person-centred approach, she identified several problems and describes theory-based strategies how she and her husband (patient) addressed these problems. In addition, she provides insight in the complex role she fulfilled as family caregiver: liaison, advocate and as personal health manager (taking care of her own health). METHOD: A qualitative analysis and interpretation based on personal observations and discussions with medical and rehabilitation professionals. RESULTS: The author argues that the culture of the institution (knowledge and compassion) and the role of the patient advocate have major implications on the outcome of a patient's functional gains. The International Classification of Functioning, Disability and Health can be a useful tool to enhance transparency within the patient-centred approach. CONCLUSION: Although this case study is described from the perspective of one case, the information shared in this paper may stimulate further discussion and research in the concept and implementation of person-centred rehabilitation.