Leveraging the Consolidated Framework for Implementation Research (CFIR) to Develop the American College of Rheumatology's Toolkit for Implementation of Rheumatoid Arthritis Outcome Measures in Clinical Practice: A Qualitative Study.

OBJECTIVE: Despite the recognized benefits of collecting rheumatoid arthritis (RA) outcomes measures, their use in routine care is inconsistent. Using the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured interviews with United States rheumatologists and practice personnel to assess workflows, opportunities, and challenges in collecting RA outcome measures. Using insights from interviews, we developed the RA Measures Toolkit to enhance their utilization in clinical practice. METHODS: We invited 138 RISE registry practices and 5 academic medical centers with ≥ 30 patients eligible for RA outcome measures to participate in the study. Practices were classified based on their performance in quality payment programs. Recorded interviews were transcribed verbatim and analyzed thematically using deductive and inductive techniques. The findings were used to create the RA Measures Toolkit. RESULTS: We conducted 20 interviews with 38 participants across 20 practices. Key themes within the CFIR domains highlighted the challenges and best practices in RA outcome measure collection and included: 1) Process: the variability in practices' use of RA outcome measures and the importance of streamlined workflows, 2) Intervention: challenges of integrating PROs into electronic health records (EHRs), and 3) Individual characteristics: importance of clinic culture around quality improvement. Using this data, we developed the RA Toolkit, a multimedia online resource, featuring guidelines, best practices, and educational resources to improve the efficiency of current workflows and to enhance patient care. CONCLUSION: This study identifies critical gaps in the collection of RA outcome measures in U.S. rheumatology practices and provides actionable recommendations and resources to address challenges via the RA Toolkit.

A Narrative Review of Chondrocalcinosis: Clinical Presentation, Diagnosis, and Therapies.

Calcium pyrophosphate deposition disease is categorized into radiographic chondrocalcinosis, acute calcium pyrophosphate arthritis, chronic calcium pyrophosphate arthritis, and osteoarthritis with calcium pyrophosphate deposition. These entities collectively are characterized by the deposition of calcium into joints, which then may cause localized and systemic inflammation, resulting in pain and swelling in the affected joints. Patients with the ANKH gene are more susceptible to the development of CPP arthritis as are those with primary hyperparathyroidism, hypomagnesemia, and hemochromatosis. Radiographic chondrocalcinosis is asymptomatic. Acute calcium pyrophosphate arthritis results in self-limited periods of joint pain and swelling in the affected joint. Along with localized inflammation, there may also be systemic inflammation characterized by fever and elevated inflammatory markers. Chronic calcium pyrophosphate arthritis results in periods of quiescence interrupted by flares that are identical to acute periods of disease. Osteoarthritis associated calcium pyrophosphate arthritis presents with chronic pain well described in osteoarthritis with periods of acute flares. In 2023, a joint effort by the American College of Rheumatology and the European League Against Rheumatism developed guidelines meant to aid in the recognition of calcium pyrophosphate deposition diseases. The diagnosis is made if there is proof of either crowned dens syndrome or synovial fluid analysis demonstrating calcium pyrophosphate crystals or when more than 56 points are summed utilizing the criteria described in the guidelines. Radiographic chondrocalcinosis requires no therapy. Acute calcium pyrophosphate arthritis is treated with the goal of aborting the flare. Treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, oral corticosteroids, parenteral corticosteroids, intraarticular corticosteroids, IL-1 inhibitors, or parenteral adrenocorticotropic hormone (ACTH). The goal in treatment for chronic calcium pyrophosphate arthritis is the suppression of acute flares. The drugs used for acute flare treatment may be given as maintenance therapy with the additional options of methotrexate and hydroxychloroquine.

Could Some Patients With Fibromyalgia Potentially Have Hypophosphatasia? A Retrospective Single-Center Study.

OBJECTIVE: Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP. Disease presentation is heterogeneous and can present as a chronic pain syndrome like fibromyalgia (FM). Our objective was to determine if there are any potential patients with HPP in the group of patients who were diagnosed with FM. Antiresorptive therapy use can trigger atypical femur fractures in patients with HPP. METHODS: We performed a retrospective chart review of all patients 18 years or older at a single academic center who were diagnosed with FM and had either a low or a normal ALP level. The following characteristics were reviewed: biological sex; age; history of fractures; diagnosis of osteoporosis, osteopenia, osteoarthritis, and chondrocalcinosis; genetic testing; vitamin B6 level testing; and medications. RESULTS: Six hundred eleven patients with FM were identified. Two hundred had at least one low ALP level, and 57 had at least three consecutively low measurements of ALP, 44% of which had a history of fractures. No patients had vitamin B6 levels checked. None of the patients had previous genetic testing for HPP or underwent testing for zinc or magnesium levels. CONCLUSION: The percentage of patients with FM who were found to have consistently low ALP levels was 9.3%. None had vitamin B6 level or genetic testing, suggesting that the diagnosis was not suspected. It is important to diagnose HPP given the availability of enzyme replacement therapy to prevent complications from HPP such as fractures. Our data support screening for this condition as a part of the initial workup of FM.

Polymyositis/dermatomyositis readmissions: analysis of the nationwide readmission database.

BACKGROUND: There is a scarcity of national population-based studies on polymyositis (PM)/dermatomyositis (DM) readmissions in the USA. In this study, we aim to describe the rates, reasons for readmissions, and characteristics of readmissions for adults hospitalized for PM/DM in the USA. METHODS: We analyzed the 2018 Nationwide Readmissions Database (NRD). We included index hospitalizations for all adult DM/PM patients with a principal diagnosis of PM/DM using ICD-10 codes. We excluded elective and traumatic readmissions. Using a "rank" command in STATA, the most common specific principal diagnosis of readmissions was outlined. Chi-square tests were used to compare baseline characteristics between readmissions and index hospitalizations. STATA 16 was used for analysis. RESULTS: A total of 1610, 1286, and 842 index hospitalizations with a principal diagnosis of PM/DM, that were discharged alive, were included in the 30-, 90-, and 180-day readmission analysis, respectively. Among these, 193 (12%), 276 (21.5%), and 240 (28.5%) were readmitted within 30, 90, and 180 days, respectively. PM and sepsis were the most common reasons for reasons across the 3 timeframes. 30-day readmissions were responsible for an aggregate of 4.1 million US dollars in total hospital cost and 1518 hospital days in 2018. Compared to index hospitalizations, 30-day readmissions have higher Charlson Comorbidity Index scores, severe-extreme loss of function, obesity, and deep venous thrombosis. CONCLUSION: About a third of PM/DM hospitalized patients are readmitted within 180 days. Readmissions constitute a significant economic burden to the health care system. PM and sepsis are the main reasons for readmissions. Key points • About a third of polymyositis (PM)/dermatomyositis (DM) hospitalized patients are readmitted within 180 days • PM and sepsis are the main reasons for readmissions. • Readmissions of PM/DM Patients constitute a significant economic burden to the health care system. • Compared to index hospitalizations, 30-day readmissions have higher Charlson comorbidity index scores, severe-extreme loss of function, obesity, and deep venous thrombosis.

Carotid-Cavernous Fistula in a Patient With Unilateral Periorbital Swelling and Proptosis Initially Attributed to Possible Immunoglobulin G4-Related (IgG4-Related) Disease.

The differential diagnosis for proptosis and periorbital swelling is broad and includes infectious, malignant, vascular, and rheumatologic etiologies. In this study, we report a case of carotid-cavernous fistula as the cause of acute-onset unilateral proptosis and periorbital swelling of the right eye in a 44-year-old female patient whose symptoms were initially attributed to possible immunoglobulin G4-related disease (IgG4-RD). The patient initially received antibiotics for presumed cellulitis and steroid treatment for a possible autoimmune cause, however; her autoimmune work-up was negative. Radiologic imaging later confirmed that she had a direct spontaneous carotid-cavernous fistula. She experienced significant improvement in her symptoms and vision after embolization treatment. Due to the risk that a carotid-cavernous fistula will progress quickly and cause neurological damage, this is a key diagnosis that should not be missed in patients with acute-onset periorbital and visual symptoms. Rheumatologists should include this condition in the differential for any patient who presents with periorbital swelling and vision disturbances.

Cardiovascular disease and bone health in aging female rheumatic disease populations: A review.

Rheumatic diseases cover a wide spectrum of conditions, including primary and secondary degenerative joint diseases and autoimmune inflammatory rheumatic diseases. The risks of cardiovascular disease and osteoporosis and resultant fractures in aging female rheumatic disease populations, especially those with autoimmune rheumatic diseases, are increased. Changes in the immune system in aging populations need to be considered especially among patients with autoimmune rheumatic diseases. Immunosenescence is closely aligned to reduced adaptive immunity and increased non-specific innate immunity leading to chronic inflammation of inflammaging. The effective use of disease-modifying antirheumatic drugs to control autoimmune rheumatic diseases may also mitigate factors leading to cardiovascular disease and osteoporosis. Rheumatic diseases, which largely manifest as arthritis, predispose patients to premature joint degeneration and poor bone health and therefore have a higher risk of developing end-stage arthritis requiring joint arthroplasties sooner or more often than other patients without rheumatic disease.

Clinical Academic Rheumatology: A Boon for Health Systems.

OBJECTIVE: Finding a balance between clinical and scholarly productivity is a challenge for many academic clinician-educator rheumatologists. An examination of workload and downstream revenue determines if the financial value generated by services rendered by rheumatologists are proportionate to the financial value created for a health system. A 2005 study found that academic rheumatologists generate $10.02 for every $1.00 they receive for an office visit. METHODS: A retrospective analysis of ordering and billing practices of 5 full-time clinician-educator rheumatologists from August 2017 to February 2019 was conducted. Individual workload is defined as averaged full-time equivalent workload based on time spent on clinical and academic duties. Academic productivity was reviewed. Revenue-generating activities that benefited the division directly and downstream revenue were collected. Revenue was extrapolated based on volumes of referrals, publicly available drug costs, and estimated Medicare reimbursement values (average sales price) of representative drugs. RESULTS: The total revenue by physician that benefited the division directly was $597,203, with evaluation and management codes accounting for $174,456. Downstream revenue by physician totaled $2,119,437. The largest contributor was from referrals to the hospital-based infusion center, at $1,287,496. The downstream revenue generated by rheumatologist per dollar of evaluation and management services was found to be $12.14 ($9.37 in 2005 dollars). CONCLUSION: For every $1 generated though office visits by 5 practicing academic rheumatologists at our institution, $12.14 was generated through downstream revenue, which, when adjusted for inflation, shows stability in the value generated by academic rheumatologists ($10.02 versus $9.37).

ANCA-associated vasculitis in Caucasian and Hispanics of the Inland Empire of Southern California.

INTRODUCTION: ANCA-associated vasculitis is a disease with high morbidity and mortality which has shown to have different phenotypes in different ethnic and racial groups. This disease has been most frequently studied in Caucasians. We studied a group in Southern California where the Hispanics make up half of the population. We believe there will be different phenotypes between the two. METHODS: A retrospective study of 114 patients was conducted at two tertiary care centers between 2003 and 2019. Demographic data, ICU admission, ANCA antibody status, BVAS on presentation, VDI per the last clinic visit, the number of hospitalizations, the number of follow-up years, and treatment were recorded. We calculated odds ratios for the categorical data and ran independent sample T test for the continuous data with alpha equal to 0.05 for statistical significance. RESULTS: Difference was found in antibody status, disease presentation, morbidity, and age at diagnosis. Hispanics had greater number of AAV flares despite BVAS and VDI being comparable. Caucasians had more frequent follow-up. Hispanics had a 4.39 increase in odds of being admitted to the ICU, a 1.33 increased odds of developing acute respiratory failure, and a 67% increased odds of developing hemoptysis or pulmonary alveolar hemorrhage. Further, Hispanics had a 1.22 increase in odds of having ESRD. CONCLUSIONS: Clinicians treating Hispanic patients with AAV should have a high index of suspicion for severe disease in this patient population. Further, epidemiologic and disparities research should be conducted to evaluate the discrepancy in outcomes in these groups. Key Points • This is the first study to examine the phenotype and severity of ANCA associated vasculitis in Southern California, a population which is comprised largely of Hispanics. • Hispanics in this population were found to be more likely to be admitted to the ICU, have more flares, reach end-stage renal disease, have severe pulmonary manifestations, and had fewer outpatient follow-up visits than their Caucasian counterparts. • Clinicians should have a high suspicion for more severe disease in Hispanics in this region when compared to Caucasians. • More research is needed to assess the degree social determinants of health contribute to these findings and if progress can be made with decreasing health disparities between these populations in this disease.

The Development of the Rheumatology Informatics System for Effectiveness Learning Collaborative for Improving Patient-Reported Outcome Collection and Patient-Centered Communication in Adult Rheumatology.

OBJECTIVE: Patient-reported outcomes (PROs) are an integral part of treat-to-target approaches in managing rheumatoid arthritis (RA). In clinical practice, however, routine collection, documentation, and discussion of PROs with patients are highly variable. The RISE LC (Rheumatology Informatics System for Effectiveness Learning Collaborative) was established to develop and share best practices in PRO collection and use across adult rheumatology practices in the United States METHODS: The goals of the RISE LC were developed through site surveys and in-person meetings. Participants completed a baseline survey on PRO collection and use in their practices. RISE LC learning sessions focused on improving communication around PROs with patients and enhancing shared decision-making in treatment plans. During the coronavirus disease 2019 (COVID-19) pandemic, the RISE LC pivoted to adapt PRO tools for telehealth. RESULTS: At baseline, all responding sites (n = 15) had established workflows for collecting PROs. Most sites used paper forms alone. PRO documentation in electronic health records was variable, with only half of the sites using structured data fields. To standardize and improve the use of PROs, participants iteratively developed a Clinical Disease Activity Index-based RA Disease Activity Communication Tool to solicit treatment goals and improve shared decision-making across sites. The COVID-19 pandemic necessitated developing a tool to gauge PROs via telehealth. CONCLUSION: The RISE LC is a continuous, structured method for implementing strategies to improve PRO collection and use in rheumatological care, initially adapting from the Learning Collaborative model and extending to include features of a learning network. Future directions include measuring the impact of standardized PRO collection and discussion on shared decision-making and RA outcomes.

Screening for acquired latent tuberculosis in rheumatoid arthritis patients on tumor necrosis factor inhibition therapy in Southern California.

BACKGROUND: There are no studies assessing the development of latent tuberculosis infection (LTBI) in patients on tumor necrosis factor inhibitors (TNFα-I) in high TB prevalence areas of the USA. Our objective was to assess the rate of LTBI development in rheumatoid arthritis (RA) patients on TNFα-I therapies in San Bernardino and Riverside Counties of California, high TB prevalence areas in the US. METHODS: Data were extracted from the electronic health record for 217 adult RA patients across three health centers from January 2010 to January 2017 who have had at least 1 year of TNFα-I use and negative initial QuantiFERON Gold status. Demographics, TNFα-I type, duration of use, TB risk factors, QuantiFERON results, rates of re-screening, TB test seroconversion, and its association with drug use and other factors were assessed. RESULTS: Of the 217 patients, 115 (53%) received baseline and annual screening for LTBI. LTBI was diagnosed in 9.4% (10) of patients. Four patients were on infliximab, three on golimumab, two on adalimumab, and one on etanercept. Hispanic patients tended to have a greater than 200% increase in odds of seroconversion compared to non-Hispanic patients. Infliximab and golimumab were associated with a 92% and 400% increase in odds of seroconversion, respectively. CONCLUSION: The LTBI developed in 9.4% of the patients. This is higher than what is reported for previous US studies. Screening for LTBI in the US should take into consideration TB prevalence, ethnicity, drug type, and duration of use. For our local population and similar populations, annual screening should be practiced. Key Points • Although patients on TNFα inhibitor (TNFα-I) therapy are at high risk of latent tuberculosis infection (LTBI), few studies report the rate of LTBI in patients living in high prevalence areas of the US. • The rate of LTBI was 9.4% in patients on TNFα-I therapy in Southern California. The risk of seroconversion was higher in patients of Hispanic ethnicity and also higher for those on infliximab and golimumab compared to those on other TNFα-I therapies. • Screening guidelines for LTBI screening on TNFα-I should consider local TB prevalence, drugs used, duration of use and ethnicity for cost efficient, and optimal healthcare.

The Fracture Liaison Service to close the osteoporosis care gap: a leadership educational model for undergraduate and postgraduate trainees.

Osteoporotic fractures have been rising and are a cause of severe morbidity and mortality. Care gaps exist in osteoporosis treatment and diagnosis, which presents an opportunity for education. A number of healthcare systems in the world have developed a fracture liaison service (FLS) to combat osteoporotic fractures. The Rheumatology division at Loma Linda University Health (LLUH) developed an FLS not only to address osteoporosis care gaps but to also develop a new educational model. An interdisciplinary model of osteoporosis care has been implemented along with a revamp of educational focus on osteoporosis and bone health in the rheumatology fellowship and internal medicine residency. Pre-LLUH FLS studies showed that 85% of patients pre-fracture were never screened nor treated for osteoporosis; post-fracture, only 10% of patients were treated, and only 6% had dual x-ray absorptiometry (DXA). Notably, 30% had a prior fracture. We discuss how the FLS has served as a catalyst for education, not only at our academic center but also as an outreach for our community in order to elevate the care of osteoporosis in our community.Key Points• Care gaps exist in osteoporosis treatment and are addressed by the Fracture Liaison Service.• The Loma Linda University Health Fracture Liaison Service is an interdisciplinary program.• The Fracture Liaison Service is an educational model that gives hands on learning through an amalgam of processes, namely quality improvement through the Plan-Do-Study-Act cycle and medical education through Kolb's learning cycle and cognitive apprenticeship.

Education and Professional Development in Rheumatology: Translating Quality Improvement and Education to Clinical Practice.

Academic institutions play an essential role in providing physicians with the necessary skills needed to improve the quality and value of care provided. The Accreditation Council for Graduate Medical Education has several milestones in the curriculum of fellowship programs that prioritize involvement in quality improvement (QI) and patient safety efforts. This article reviews the unique benefits and challenges of involving and teaching fellows to conduct QI initiatives. Strategies and resources available to overcome these challenges and develop a successful quality driven training environment are outlined in this article.

Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-ß.

Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0-80 mmHg increased extracellular pressure for 24 h on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure-stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca(2+) channel Cav3.3, which stimulated PKC-ß to invoke the IKK-IkB-NF-kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca(2+)]i via Cav3.3, driving a PKC-ß- IKK- IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors.

Perfectionistic cognitions and eating disturbance: distinct mediational models for males and females.

OBJECTIVE: Perfectionism has long been known to correlate with eating disturbance (ED). One mechanism through which this personality tendency may lead to ED is through increasing one's daily perfectionistic thoughts. This study examined the mediating role of perfectionistic thinking in the personality perfectionism-ED relationship among both male and female college students, and included measures assessing both typically-male and typically-female ED symptoms. METHOD: A majority-White sample of 140 males and 329 females completed online versions of the Multidimensional Perfectionism Scale (Hewitt & Flett, 1991), Perfectionism Cognitions Inventory (Flett, Hewitt, Blankstein, & Gray, 1998), Drive for Muscularity Scale (McCreary, Sasse, Saucier, & Dorsch, 2004), items from the Eating Disorder Examination Questionnaire (Fairburn, 2008), and other measures. Regression tests examined the hypothesized role of perfectionistic cognitions as a mediator, including participant age, BMI, and positive and negative affect as covariates. RESULTS: Among women, relationships between both self-oriented (Sobel's statistic=-4.63, p<.001) and socially prescribed perfectionism (Sobel's statistic=-5.77, p<.001) and dieting behavior were fully mediated by increased perfectionistic thinking. Among men, however, the relationship between only self-oriented perfectionism and bulimic (but not dieting) behavior, was fully mediated by increased perfectionistic thinking (Sobel's statistic=-2.53, p=.01). CONCLUSIONS: Perfectionistic cognitions play an important linking role between personality perfectionism and ED, and can illuminate important differences by gender in eating disturbance. Such findings can improve validity of ED assessment in both genders, and provide a clear pathway to interventions to decrease ED in both genders.

Perceptions of adolescent bullying: attributions of blame and responsibility in cases of cyber-bullying.

Cyber-bullying (where victims are targeted via online social networking or other electronic means) has gained increased attention in research and the broadcast media, but previous research has not investigated attribution of blame in such cyber-bullying events. This experiment hypothesized that participants would assign higher ratings of blame to bullying perpetrators when the bullying situations were depicted as having highly foreseeable outcomes (vs. unforeseeable outcomes), and as occurring in school (vs. online). In addition, a significant interaction was predicted between outcome foreseeability and bullying situation, with highly foreseeable in-school events being rated as the most predictable and attributable to the bully's actions. One-hundred sixty-three participants completed surveys containing demographic items, items regarding their past experiences of victimization, and one of four randomly-assigned vignettes detailing a bullying situation (which participants rated). While hypotheses regarding outcome foreseeability were supported, no cyber-bullying vs. in-school main effects (or corresponding interaction effects) were detected. Implications for future research and practice, as well as study limitations, are discussed.

Assessment of everyday beliefs about health: the lay concepts of health inventory, college student version.

This research investigated lay conceptualisations about health using a progressive mixed-method approach, culminating in a new self-report measure of lay concepts of health. In Study 1, 223 community and college-aged adults provided everyday descriptors of healthy people. These open-ended qualitative responses were narrowed to 259 distinct descriptors, and subsequently rated on their importance to health by a second lay sample (Study 2). The health descriptors rated as most important were then subjected to exploratory factor analysis in Study 3, resulting in five distinguishable factors. Proposed scale items were then administered again (to college students, in Study 4), and a confirmatory factor analysis (CFA) was performed. The CFA supported a four-factor model, comprised of Social-Emotional Health, Positive Health Practices, Absence of Stress and Anxiety, and Adequate Rest, presented as the college student version of the Lay Concepts of Health Inventory. The measure, as well as limitations and recommendations for future research, are presented.

Isoform-specific modulation of pressure-stimulated cancer cell proliferation and adhesion by α-actinin.

BACKGROUND: Intratumoral pressure may stimulate cancer proliferation whereas intravascular pressure promotes metastatic adhesion. α-Actinin proteins facilitate focal adhesion formation and link focal adhesion complexes to the cytoskeleton. We hypothesized that α-actinin is the mechanotransducer that mediates the effects of pressure on cancer cell proliferation and adhesion. METHODS: We treated SW620 colon cancer cells with specific short interfering RNA to reduce α-actinin-1 and/or α-actinin-4, the 2 key epithelial isoforms. Proliferation was measured in adherent cells by microculture tetrazolium (MTT) assay after 24 hours at ambient or 40 mm Hg increased pressure. For comparison, we evaluated the effects of 30 minutes of ambient or 15-mm Hg increased pressure on adhesion of suspended SW620 cells. Because the transcription factor nuclear factor-κB (NF-κB) influences proliferation, we used co-immunoprecipitation to evaluate NF-κB-α-actinin association and a lentiviral reporter assay for NF-κB activity. RESULTS: A total of 40 mm Hg increased pressure increased SW620 proliferation 41% ± 6% (n = 10; P < .05) versus ambient pressure controls. Reducing α-actinin-1 and α-actinin-4 together or α-actinin-4 alone blocked this effect, but reducing α-actinin-1 alone did not (n = 6; P < .05). We observed a 72% ± 11% increase in NF-κB activity (n = 6; P < .05), and increased association between NF-κB and α-actinin-4 in adherent cells under pressure. NF-κB and α-actinin-1 did not co-immunoprecipitate. However, reducing α-actinin-4 did not prevent pressure-induced NF-κB activation (n = 8). CONCLUSIONS: α-actinin-4 may mediate pressure stimulation of proliferation within large rapidly growing tumors, perhaps by binding transcription factors such as NF-κB. α-actinins may be important targets to inhibit cancer proliferation and metastasis.

Colchicine inhibits pressure-induced tumor cell implantation within surgical wounds and enhances tumor-free survival in mice.

Iatrogenic tumor cell implantation within surgical wounds can compromise curative cancer surgery. Adhesion of cancer cells, in particular colon cancer cells, is stimulated by exposure to increased extracellular pressure through a cytoskeleton-dependent signaling mechanism requiring FAK, Src, Akt, and paxillin. Mechanical stimuli during tumor resection may therefore negatively impact patient outcome. We hypothesized that perioperative administration of colchicine, which prevents microtubule polymerization, could disrupt pressure-stimulated tumor cell adhesion to surgical wounds and enhance tumor-free survival. Ex vivo treatment of Co26 and Co51 colon cancer cells with colchicine inhibited pressure-stimulated cell adhesion to murine surgical wounds and blocked pressure-induced FAK and Akt phosphorylation. Surgical wound contamination with pressure-activated Co26 and Co51 cells significantly reduced tumor-free survival compared with contamination with tumor cells under ambient pressure. Mice treated with pressure-activated Co26 and Co51 cells from tumors preoperatively treated with colchicine in vivo displayed reduced surgical site implantation and significantly increased tumor-free survival compared with mice exposed to pressure-activated cells from tumors not pretreated with colchicine. Our data suggest that pressure activation of malignant cells promotes tumor development and impairs tumor-free survival and that perioperative colchicine administration or similar interventions may inhibit this effect.

SiRNA-mediated reduction of alpha-actinin-1 inhibits pressure-induced murine tumor cell wound implantation and enhances tumor-free survival.

Viable cancer cells can commonly be recovered from surgical sites and venous blood during tumor resection. The adhesion of these cells to surrounding tissues may impact patient outcomes. Iatrogenic exposure to increased extracellular pressure modulates integrin binding affinity and stimulates colon cancer cell adhesion in vitro through an alpha-actinin-1-dependent signaling pathway. We hypothesized that preoperative small interfering RNA-mediated silencing of alpha-actinin-1 in tumor tissue could disrupt pressure-stimulated cancer cell adhesion to murine surgical wounds and thereby enhance subsequent tumor-free survival. Reducing alpha-actinin-1 in CT26 murine adenocarcinoma cells blocked cell adhesion to collagen in vitro and similarly inhibited pressure-induced CT26 implantation in murine surgical wounds in vivo. Surgical wound contamination with pressure-activated CT26 cells significantly reduced tumor-free survival compared to contamination with tumor cells maintained under ambient pressure. However, mice treated with pressure-activated CT26 cells preoperatively transfected with alpha-actinin-1-specific small interfering RNA displayed reduced surgical site implantation and increased tumor-free survival compared to mice exposed to pressure-activated cells expressing normal levels of alpha-actinin-1 protein. These results suggest that pressure activation of malignant cells promotes tumor development and impairs tumor-free survival. alpha-Actinin-1 may be an effective therapeutic target to inhibit perioperative pressure-stimulated tumor cell implantation.