A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts ...A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.
Psychologically informed practice emphasizes routine identification of modifiable psychological risk factors being highlighted.
The purpose of this study was to test the predictive validity of the ...STarT Back Screening Tool (SBT) in comparison with single-construct psychological measures for 6-month clinical outcomes.
This was an observational, prospective cohort study.
Patients (n=146) receiving physical therapy for low back pain were administered the SBT and a battery of psychological measures (Fear-Avoidance Beliefs Questionnaire physical activity scale and work scale FABQ-PA and FABQ-W, respectively, Pain Catastrophizing Scale PCS, 11-item version of the Tampa Scale of Kinesiophobia TSK-11, and 9-item Patient Health Questionnaire PHQ-9) at initial evaluation and 4 weeks later. Treatment was at the physical therapist's discretion. Clinical outcomes consisted of pain intensity and self-reported disability. Prediction of 6-month clinical outcomes was assessed for intake SBT and psychological measure scores using multiple regression models while controlling for other prognostic variables. In addition, the predictive capabilities of intake to 4-week changes in SBT and psychological measure scores for 6-month clinical outcomes were assessed.
Intake pain intensity scores (β=.39 to .45) and disability scores (β=.47 to .60) were the strongest predictors in all final regression models, explaining 22% and 24% and 43% and 48% of the variance for the respective clinical outcome at 6 months. Neither SBT nor psychological measure scores improved prediction of 6-month pain intensity. The SBT overall scores (β=.22) and SBT psychosocial scores (β=.25) added to the prediction of disability at 6 months. Four-week changes in TSK-11 scores (β=-.18) were predictive of pain intensity at 6 months. Four-week changes in FABQ-PA scores (β=-.21), TSK-11 scores (β=-.20) and SBT overall scores (β=-.18) were predictive of disability at 6 months.
Physical therapy treatment was not standardized or accounted for in the analysis.
Prediction of clinical outcomes by psychology-based measures was dependent upon the clinical outcome domain of interest. Similar to studies from the primary care setting, initial screening with the SBT provided additional prognostic information for 6-month disability and changes in SBT overall scores may provide important clinical decision-making information for treatment monitoring.
The STarT Back Screening Tool (SBT) was recently developed for primary care providers to use as a screening tool for subgrouping people with low back pain (LBP) on the basis of modifiable prognostic ...factors. The use of the SBT in physical therapy has not been described.
The aims of this study were to describe the use of the SBT in people receiving physical therapy for LBP and to describe patterns of change in clinical outcomes across the episode of care and among SBT categories.
This study was a prospective case series.
A total of 214 patients receiving physical therapy for LBP were administered the SBT at the initial evaluation. Treatment was at the physical therapist's discretion. Clinical outcomes included pain intensity and disability scores collected at each session. Descriptive statistics were calculated, and baseline characteristics among SBT categories were compared. Hierarchical linear mixed models were used to examine patterns of change in predicted outcomes across the episode of care.
The patients' mean age was 44.3 years (SD=15.8), and 56.5% were women. The SBT categorized 33.2% of the patients as being at low risk, 47.7% as being at medium risk, and 19.2% as being at high risk. The high-risk category corresponded to the highest initial pain intensity and disability scores. The low-risk category corresponded to the lowest initial pain intensity and disability scores. Linear mixed models indicated different patterns of change in outcome scores for pain intensity (F=3.99) and disability (F=3.49) among SBT categories. Relative to the low-risk category, the high-risk category had larger improvements in predicted outcomes and the medium-risk category had similar improvements in predicted outcomes. Limitations The SBT was not administered to 24% of eligible patients. The timing of follow-up assessments was variable.
The SBT may provide important prognostic information for physical therapists.
Clinical Practice Guidelines Linked to the International Classification of Functioning, Disability and Health From the Academy of Orthopaedic Physical Therapy of the American Physical Therapy ...Association
Chronic inflammation is a risk factor for lung cancer, and low-dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung ...carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programing changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ≤50% of control levels after 4-6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of insulin-like growth factor-I, CXCL1, IL-6, and CCL2 diminished with clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and clodronate liposome-treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression.
In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed an evaluation of the inhalation carcinogenicity of ethylene oxide (EtO) in ...December 2016. This article reviews key findings and scientific issues regarding the carcinogenicity of EtO in EPA's Carcinogenicity Assessment. EPA's assessment critically reviewed and characterized epidemiologic, laboratory animal, and mechanistic studies pertaining to the human carcinogenicity of EtO, and addressed some key scientific issues such as the analysis of mechanistic data as part of the cancer hazard evaluation and to inform the quantitative risk assessment. The weight of evidence from the epidemiologic, laboratory animal, and mechanistic studies supports a conclusion that EtO is carcinogenic in humans, with the strongest human evidence linking EtO exposure to lymphoid and breast cancers. Analyses of the mechanistic data establish a key role for genotoxicity and mutagenicity in EtO-induced carcinogenicity and reveal little evidence supporting other mode-of-action hypotheses. In conclusion, EtO was found to be carcinogenic to humans by inhalation, posing a potential human health hazard for lymphoid and breast cancers.
Observational cohort.
To describe changes in STarT Back Tool (SBT) categorization following 4 weeks of outpatient physical therapy and to evaluate predictive capabilities of SBT categorization when ...administered at multiple time points.
Initial assessment information is commonly used to predict long-term outcomes but does not account for changes that occur following initiation of treatment. Changes in SBT categorization during the course of treatment have potential to provide additional prognostic information that could positively impact management of low back pain.
Patients (n = 123) receiving nonstandardized physical therapy care for low back pain were administered the SBT at intake and 4 weeks later to evaluate SBT changes, which were described as improved (SBT categorization changed from medium to low, high to low, or high to medium risk), stable (SBT categorization remained low or medium risk), or worsened (SBT categorization changed from low to medium, low to high, medium to high, or remained high risk). Clinical outcomes consisted of pain intensity and self-reported disability. Relative contributions of SBT categorization (at intake and 4 weeks) and SBT change patterns as predictors of 6-month clinical outcomes were assessed using separate multiple-regression models, while controlling for other prognostic variables.
Most patients (81.8%) initially categorized as SBT high risk were categorized differently by the SBT at 4 weeks. Eleven percent of patients were described as worsened, based on SBT-category change patterns at 4 weeks. Prediction of 6-month disability scores was improved when considering intake, 4-week, or 4-week change for SBT categorization, with SBT high risk consistently providing unique contributions.
Repeated SBT assessment during the episode of physical therapy has potential to provide additional information for prediction of disability at 6 months. Future studies should investigate optimal management strategies for patients who have worsened SBT risk following physical therapy intervention.
Prognosis, level 2b.
To identify patient- and physical therapist-level predictors for therapeutic alliance at the end of an episode of physical therapy for knee or low back pain (LBP).
Secondary analysis of observational ...cohort.
Outpatient physical therapy clinics.
Patients receiving physical therapy for knee (n=189) or LBP (n=252) and physical therapists (n=19). Candidate predictor variables included demographics, patient clinical characteristics, and physical therapist attitudes and beliefs (Pain Attitudes and Beliefs Scale for Physical Therapists) and confidence in providing patient-centered care (Self-Efficacy in Patient-Centeredness Questionnaire).
Not applicable.
Patient-reported therapeutic alliance was measured using the 12-item Work Alliance Inventory-Short Revised (WAI-SR).
Final linear mixed models indicated different patient- and physical therapist-level factor contributions in predicting final WAI-SR scores across cohorts with knee and LBP. Female sex was a consistent patient-level predictor for both knee (estimated β=1.57, P<.05) and LBP (β=1.42, P<.05), with age (β=-0.07, P<.01) and baseline function (β=0.06, P<.01) contributing to cohorts with knee and LBP, respectively. Physical therapist-level predictors included female sex (β=6.04, P<.05), Pain Attitudes and Beliefs Scale for Physiotherapists behavioral (β=0.65, P<.01), and Self-Efficacy in Patient-Centeredness Questionnaire (SEPCQ) Exploring Patient Perspective (β=-0.75, P<.01) subscale scores for LBP, with SEPCQ Sharing Information and Power subscale scores (β=0.56, P<.05) contributing to both cohorts with knee (β=0.56, P<.05) and LBP (β=0.74, P<.01). Random effects for patients nested within physical therapists were observed for both cohorts.
These findings provide preliminary evidence for inconsistent relationships among patient- and physical therapist-level factors and therapeutic alliance across cohorts with knee and LBP.
Statins have been reported to reduce the rates of recurrence and improve the resolution of chronic subdural hematomas (cSDHs) treated surgically or conservatively. No studies have investigated the ...effect of statins in patients treated with middle meningeal artery embolization.
We performed a retrospective search of our cSDH database to identify patients treated with middle meningeal artery embolization alone. Only patients with at least 1 noncontrast computed tomography scan obtained 3–12 weeks after embolization were included. Hematoma volumes were measured at baseline and last noncontrast computed tomography available. The volumes, volume reduction, speed of resolution, and recurrence were compared between patients already receiving statin therapy when admitted and those who were not.
Forty-six patients with 50 cSDHs were included (statins, 17 patients with 18 cSDHs vs. nonstatins, 29 patients with 32 cSDHs). The statin group had a significantly higher rate of hyperlipidemia (statin, 64.7% vs. nonstatin, 31%, P = 0.03) but similar demographics, remaining comorbidities, medications, and hematoma thickness, axial and coronal lengths, and baseline volumes. The time between procedure and last noncontrast computed tomography scan was similar between groups. There were no differences between the groups regarding volume reduction, final volume, speed of resolution, complete resolution, and recurrence.
Patients treated with middle meningeal artery embolization alone who were on statin therapy had no differences in cSDH resolution or recurrence compared to those who were not on statin therapy. It is possible that the anti-inflammatory effects of statins may not be relevant when supply to the dura is interrupted by treatment with embolization.
Worldwide, lung cancer kills more people than breast, colon and prostate cancer combined. Alterations in macrophage number and function during lung tumorigenesis suggest that these immune effector ...cells stimulate lung cancer growth. Evidence from cancer models in other tissues suggests that cancer cells actively recruit growth factor-producing macrophages through a reciprocal signaling pathway. While the levels of lung macrophages increase during tumor progression in mouse models of lung cancer, and high pulmonary macrophage content correlates with a poor prognosis in human non-small cell lung cancer, the specific role of alveolar macrophages in lung tumorigenesis is not clear.
After culturing either an immortalized lung macrophage cell line or primary murine alveolar macrophages from naïve and lung-tumor bearing mice with primary tumor isolates and immortalized cell lines, the effects on epithelial proliferation and cellular kinase activation were determined. Insulin-like growth factor-1 (IGF-1) was quantified by ELISA, and macrophage conditioned media IGF-1 levels manipulated by IL-4 treatment, immuno-depletion and siRNA transfection.
Primary macrophages from both naïve and lung-tumor bearing mice stimulated epithelial cell proliferation. The lungs of tumor-bearing mice contained 3.5-times more IGF-1 than naïve littermates, and media conditioned by freshly isolated tumor-educated macrophages contained more IGF-1 than media conditioned by naïve macrophages; IL-4 stimulated IGF-1 production by both macrophage subsets. The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF-1 levels, and recombinant IGF-1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated. Macrophage-conditioned media and IGF-1 stimulated lung tumor cell growth in an additive manner, while EGF had no effect. Macrophage-derived factors increased p-Erk1/2, p-Akt and cyclin D1 levels in neoplastic cells, and the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth.
Macrophages produce IGF-1 which directly stimulates neoplastic proliferation through Erk and Akt activation. This observation suggests that combining macrophage ablation therapy with IGF-1R, MEK and/or PI3K inhibition could improve therapeutic response in human lung cancer. Exploring macrophage-based intervention could be a fruitful avenue for future research.
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