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Importance: Decisions about whether to stop colorectal cancer (CRC) screening tests in older adults can be difficult and may benefit from shared decision-making (SDM). Objective: To evaluate the effect of physician training in SDM and electronic previsit reminders (intervention) vs reminders only (comparator) on receipt of the patient-preferred approach to CRC screening and on overall CRC screening rates of older adults at 12 months. Design, Setting, and Participants: This was a secondary analysis of the Promoting Informed Decisions About Colorectal Cancer Screening in Older Adults (PRIMED) cluster randomized clinical trial. In the PRIMED trial, primary care physicians (PCPs) from 36 primary care practices in Massachusetts and Maine were enrolled between May 1 and August 30, 2019, and were randomized to the intervention group or the comparator group. Patients aged 76 to 85 years who were overdue for CRC screening and did not have a prior diagnosis of CRC enrolled between October 21, 2019, and April 8, 2021. Data analysis was performed between May 24, 2022, and May 10, 2023. Interventions: Primary care physicians in the intervention group completed an SDM training course and received previsit reminders of patients eligible for CRC testing discussion, whereas PCPs in the comparator group received reminders only. Main Outcomes and Measures: The primary outcome was concordance, or the percentage of patients who received their preferred screening approach. Postvisit surveys were administered to assess patient preference for testing, and electronic health record review was used to assess CRC testing at 12 months. Heterogeneity of treatment effect analyses examined interaction between study groups and different factors on concordance rates. Results: This study included 59 physicians and 466 older adults. Physicians had a mean (SD) age of 52.7 (9.4) years and a mean (SD) of 21.6 (10.2) years in practice; 30 (50.8%) were women and 16 (27.1%) reported prior training in SDM. Patients had a mean (SD) age of 80.3 (2.8) years; 249 (53.4%) were women and 238 (51.1%) reported excellent or very good overall health. Patients preferred stool-based tests (161 [34.5%]), followed by colonoscopy (116 [24.8%]) or no further screening (97 [20.8%]); 75 (16.1%) were not sure. The distribution of patient preferences was similar across groups (P = .36). At 12 months, test uptake was also similar for both the intervention group (29 [12.3%] for colonoscopy, 62 [26.3%] for stool-based tests, and 145 [61.4%] for no testing) and the comparator group (32 [13.9%] for colonoscopy, 35 [15.2%] for stool-based tests, and 163 [70.9%] for no testing; P = .08). Approximately half of patients in the intervention group received their preferred approach vs the comparator group (115 of 226 [50.9%] vs 103 of 223 [46.2%]; P = .47). Heterogeneity of treatment effect analyses found significantly higher rates with the intervention vs the comparator for patients with a strong intention to follow through with the preferred approach (adjusted odds ratio [AOR], 1.79 [95% CI, 1.11-2.89]; P = .02, P = .05 for interaction) and for patients who reported more than 5 minutes (AOR, 3.27 [95% CI, 1.25-8.59]; P = .02, P = .05 for interaction) of discussion with their PCP regarding screening. Higher rates were also observed among patients who reported 2 to 5 minutes of discussion with their PCP, although this finding was not significant (AOR, 1.89 [95% CI, 0.93-3.84]; P = .08, P = .05 for interaction). Conclusions and Relevance: In this secondary analysis of a cluster randomized clinical trial, approximately half of older patients received their preferred approach to CRC screening. Physician training in SDM did not result in higher concordance rates overall but may have benefitted some subgroups. Future work to refine and evaluate clinical decision support (in the form of an electronic advisory or reminder) as well as focused SDM skills training for PCPs may promote high-quality, preference-concordant decisions about CRC testing for older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT03959696.
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Neoplasias Colorrectales , Toma de Decisiones Conjunta , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Anciano , Femenino , Masculino , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Anciano de 80 o más Años , Sistemas Recordatorios , Massachusetts , Atención Primaria de Salud , Médicos de Atención Primaria/educación , Médicos de Atención Primaria/estadística & datos numéricos , MaineRESUMEN
OBJECTIVE: Understand how physicians' uncertainty tolerance (UT) in clinical care relates to their personal characteristics, perceptions and practices regarding shared decision making (SDM). METHODS: As part of a trial of SDM training about colorectal cancer screening, primary care physicians (n = 67) completed measures of their uncertainty tolerance in medical practice (Anxiety subscale of the Physician's Reactions to Uncertainty Scale, PRUS-A), and their SDM self-efficacy (confidence in SDM skills). Patients (N = 466) completed measures of SDM (SDM Process scale) after a clinical visit. Bivariate regression analyses and multilevel regression analyses examined relationships. RESULTS: Higher UT was associated with greater physician age (p = .01) and years in practice (p = 0.015), but not sex or race. Higher UT was associated with greater SDM self-efficacy (p < 0.001), but not patient-reported SDM. CONCLUSION: Greater age and practice experience predict greater physician UT, suggesting that UT might be improved through training, while UT is associated with greater confidence in SDM, suggesting that improving UT might improve SDM. However, UT was unassociated with patient-reported SDM, raising the need for further studies of these relationships. PRACTICE IMPLICATIONS: Developing and implementing training interventions aimed at increasing physician UT may be a promising way to promote SDM in clinical care.
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Toma de Decisiones Conjunta , Médicos de Atención Primaria , Humanos , Lactante , Incertidumbre , Toma de Decisiones , Participación del Paciente , Relaciones Médico-PacienteRESUMEN
OBJECTIVE: Identify if primary care physicians (PCPs) accurately understand patient preferences for colorectal cancer (CRC) testing, whether shared decision making (SDM) training improves understanding of patient preferences, and whether time spent discussing CRC testing improves understanding of patient preferences. METHODS: Secondary analysis of a trial comparing SDM training plus a reminder arm to a reminder alone arm. PCPs and their patients completed surveys after visits assessing whether they discussed CRC testing, patient testing preference, and time spent discussing CRC testing. We compared patient and PCP responses, calculating concordance between patient-physician dyads. Multilevel models tested for differences in preference concordance by arm or time discussing CRC. RESULTS: 382 PCP and patient survey dyads were identified. Most dyads agreed on whether CRC testing was discussed (82%). Only 52% of dyads agreed on the patient's preference. SDM training did not impact accuracy of PCPs preference diagnoses (55%v.48%,p = 0.22). PCPs were more likely to accurately diagnose patient's preferences when discussions occurred, regardless of length. CONCLUSION: Only half of PCPs accurately identified patient testing preferences. Training did not impact accuracy. Visits where CRC testing was discussed resulted in PCPs better understanding patient preferences. PRACTICE IMPLICATIONS: PCPs should take time to discuss testing and elicit patient preferences.
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Neoplasias del Colon , Neoplasias Colorrectales , Médicos , Humanos , Neoplasias del Colon/diagnóstico , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Prioridad del PacienteRESUMEN
BACKGROUND: For adults aged 76-85, guidelines recommend individualizing decision-making about whether to continue colorectal cancer (CRC) testing. These conversations can be challenging as they need to consider a patient's CRC risk, life expectancy, and preferences. OBJECTIVE: To promote shared decision-making (SDM) for CRC testing decisions for older adults. DESIGN: Two-arm, multi-site cluster randomized trial, assigning physicians to Intervention and Comparator arms. Patients were surveyed shortly after the visit to assess outcomes. Analyses were intention-to-treat. PARTICIPANTS AND SETTING: Primary care physicians affiliated with 5 academic and community hospital networks and their patients aged 76-85 who were due for CRC testing and had a visit during the study period. INTERVENTIONS: Intervention arm physicians completed a 2-h online course in SDM communication skills and received an electronic reminder of patients eligible for CRC testing shortly before the visit. Comparator arm received reminders only. MAIN MEASURES: The primary outcome was patient-reported SDM Process score (range 0-4 with higher scores indicating more SDM); secondary outcomes included patient-reported discussion of CRC screening, knowledge, intention, and satisfaction with the visit. KEY RESULTS: Sixty-seven physicians (Intervention n=34 and Comparator n=33) enrolled. Patient participants (n=466) were on average 79 years old, 50% with excellent or very good self-rated overall health, and 66% had one or more prior colonoscopies. Patients in the Intervention arm had higher SDM Process scores (adjusted mean difference 0.36 (95%CI (0.08, 0.64), p=0.01) than in the Comparator arm. More patients in the Intervention arm reported discussing CRC screening during the visit (72% vs. 60%, p=0.03) and had higher intention to follow through with their preferred approach (58.0% vs. 47.1, p=0.03). Knowledge scores and visit satisfaction did not differ significantly between arms. CONCLUSION: Physician training plus reminders were effective in increasing SDM and frequency of CRC testing discussions in an age group where SDM is essential. TRIAL REGISTRATION: The trial is registered on clinicaltrials.gov (NCT03959696).
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Neoplasias Colorrectales , Médicos , Humanos , Anciano , Detección Precoz del Cáncer , Neoplasias Colorrectales/diagnóstico , Participación del Paciente , Toma de DecisionesRESUMEN
Thousands of colonoscopies were canceled during the initial surge of the COVID-19 pandemic. As facilities resumed services, some patients were hesitant to reschedule. The purpose of this study was to determine whether a decision aid plus telephone coaching would increase colorectal cancer (CRC) screening and improve patient reports of shared decision making (SDM). A randomized controlled trial assigned adults aged 45-75 without prior history of CRC who had a colonoscopy canceled from March to May 2020 to intervention (n = 400) or usual care control (n = 400) arms. The intervention arm received three-page decision aid and call from decision coach from September 2020 through November 2020. Screening rates were collected at 6 months. A subset (n = 250) in each arm was surveyed 8 weeks after randomization to assess SDM (scores range 0-4, higher scores indicating more SDM), decisional conflict, and screening preference. The sample was on average, 60 years old, 53% female, 74% White, non-Hispanic, and 11% Spanish speaking. More intervention arm patients were screened within 6 months (35% intervention vs 23% control, p < 0.001). The intervention respondents reported higher SDM scores (mean difference 0.7 [0.4, 0.9], p < 0.001) and less decisional conflict than controls (-21% [-35%, -7%], p = 0.003). The majority in both arms preferred screening versus delaying (68% intervention vs. 65% control, p = 0.75). An SDM approach that offered alternatives and incorporated patients' preferences resulted in higher screening rates. Patients who are overdue for CRC screening may benefit from proactive outreach with SDM support.
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COVID-19 , Neoplasias Colorrectales , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Toma de Decisiones Conjunta , Pandemias , Detección Precoz del Cáncer/métodos , Neoplasias Colorrectales/diagnóstico , Toma de DecisionesRESUMEN
Background. Early in the COVID-19 pandemic colonoscopies for colorectal cancer (CRC) screening were canceled. Patient perceptions of the benefits and risks of routine screening relative to health concerns associated with the COVID-19 pandemic were unknown. Purpose. Assess patient anxiety, worry, and interest in CRC screening during the COVID-19 pandemic. Methods. A random sample of 200 patients aged 45 to 75 y with colonoscopy cancellation due to COVID-19 in March to May 2020 were surveyed. Anxiety, COVID-19 and CRC risk perceptions, COVID-19 and CRC worry, likelihood of following through with colonoscopy in the next month, and interest in alternatives to colonoscopy were assessed. Subsequent screening was tracked for 12 mo. Results. Respondents (N = 127/200, 63.5%) were on average 60 y old, female (59%), college educated (62% college degree or more), and White (91%). A substantial portion of patients (46%) stated they may not follow through with a colonoscopy in the next month. There was greater interest in stool-based testing than in delaying screening (48% v. 26%). Women, older patients, and patients indicating tolerance of uncertainty due to complexity reported they were less likely to follow through with colonoscopy in the next month. Greater interest in stool-based testing was related to lower perceptions of CRC risk. Greater interest in delaying screening was related to less worry about CRC and less tolerance of risk. Over 12 mo, 60% of participants completed screening. Patients who stated they were more likely to screen in the next month were more likely to complete CRC screening (P = 0.01). Conclusions. Respondents who had a colonoscopy canceled during the COVID-19 pandemic varied in interest in rescheduling the procedure. A shared decision-making approach may help patients address varying concerns and select the best approach to screening for them. Highlights: In the wake of the first wave of the COVID-19 pandemic, almost half of patients stated they were not likely to follow through with a colonoscopy in the short term, about half were interested in screening with a stool-based test, and only one-quarter were interested in delaying screening until next year.Patients who perceived themselves at higher risk of colorectal cancer were less interested in stool-based testing, and patients who were more worried about colorectal cancer were less interested in delaying screening.A shared decision-making approach may be necessary to tailor screening discussions for patients during subsequent waves of the pandemic, other occasions where resources are limited and patient preferences vary, or where patients hold conflicting views of screening.
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BACKGROUND: Clinical guidelines recommend engaging patients in shared decision making for common orthopedic procedures; however, limited work has assessed what is occurring in practice. This study assessed the quality of shared decision making for elective hip and knee replacement and spine surgery at four network-affiliated hospitals. METHODS: A cross-sectional sample of 875 adult patients undergoing total hip or knee joint replacement (TJR) for osteoarthritis or spine surgery for lumbar herniated disc or lumbar spinal stenosis was selected. Patients were mailed a survey including measures of Shared Decision Making (SDMP scale) and Informed, Patient-Centered (IPC) decisions. We examined decision-making across sites, surgeons, and conditions, and whether the decision-making measures were associated with better health outcomes. Analyses were adjusted for clustering of patients within surgeons. RESULTS: Six hundred forty-six surveys (74% response rate) were returned with sufficient responses for analysis. Patients who had TJR reported lower SDMP scores than patients who had spine surgery (2.2 vs. 2.8; p < 0.001). Patients who had TJR were more likely to make IPC decisions (OA = 70%, Spine = 41%; p < 0.001). SDMP and IPC scores varied widely across surgeons, but the site was not predictive of SDMP scores or IPC decisions (all p > 0.09). Higher SDMP scores and IPC decisions were associated with larger improvements in global health outcomes for patients who had TJR, but not patients who had spine surgery. CONCLUSIONS: Measures of shared decision making and decision quality varied among patients undergoing common elective orthopedic procedures. Routine measurement of shared decision making provides insight into areas of strength across these different orthopedic conditions as well as areas in need of improvement.
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Toma de Decisiones Conjunta , Procedimientos Ortopédicos , Adulto , Estudios Transversales , Toma de Decisiones , Atención a la Salud , HumanosRESUMEN
BACKGROUND: Determining the primary indication of a surgical procedure can be useful in identifying patients undergoing elective surgery where shared decision-making is recommended. The purpose of this study was to develop and validate an algorithm to identify patients receiving the following combinations of surgical procedure and primary indication as part of a study to promote shared decision-making: (1) knee arthroplasty to treat knee osteoarthritis (KOA); (2) hip arthroplasty to treat hip osteoarthritis (HOA); (3) spinal surgery to treat lumbar spinal stenosis (SpS); and (4) spinal surgery to treat lumbar herniated disc (HD). METHODS: Consecutive surgical procedures performed by participating spine, hip, and knee surgeons at four sites within an integrated care network were included. Study staff reviewed electronic medical records to ascertain a "gold standard" determination of the procedure and primary indication status. Electronic algorithms consisting of ICD-10 and CPT codes for each combination of procedure and indication were then applied to records for each case. The primary measures of validity for the algorithms were the sensitivity and specificity relative to the gold standard review. RESULTS: Participating surgeons performed 790 procedures included in this study. The sensitivity of the algorithms in determining whether a surgical case represented one of the combinations of procedure and primary indication ranged from 0.70 (HD) to 0.92 (KOA). The specificity ranged from 0.94 (SpS) to 0.99 (HOA, KOA). CONCLUSION: The electronic algorithm was able to identify all four procedure/primary indication combinations of interest with high specificity. Additionally, the sensitivity for the KOA cases was reasonably high. For HOA and the spine conditions, additional work is needed to improve the sensitivity of the algorithm to identify the primary indication for each case.
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Algoritmos , Toma de Decisiones , Desplazamiento del Disco Intervertebral/cirugía , Procedimientos Ortopédicos/normas , Osteoartritis de la Cadera/cirugía , Osteoartritis de la Rodilla/cirugía , Estenosis Espinal/cirugía , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Electrónica , Humanos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Decision aids (DAs) have been shown to increase decision quality in randomized controlled trials. This study compared the effectiveness of two different decision aids with different modes of delivery. PARTICIPANTS AND METHODS: Patients with angiogram-proven coronary artery disease (CAD) were eligible to participate and randomly assigned to either a booklet/DVD DA or an online DA. Participants completed a survey after viewing the material that assessed patients' knowledge, treatment preferences, use of and satisfaction with the tool, and open-ended reflections on the treatment decision-making process. RESULTS: Of the 62 patients screened, 34 agreed to participate and were randomly assigned to a group. Of those, 28 (15/17 booklet/DVD and 13/17 online) participants completed the survey. Patients were more likely to report reviewing all of the booklet/DVD DA compared with the online DA (60 vs. 31%, P=0.15). Knowledge scores were significantly higher in the booklet/DVD DA group than the online DA group (67 vs. 47%, P=0.018). Participants in both arms felt it was very or extremely important that doctors give patients materials like these before a catheterization (93% for booklet/DVD DA and 85% for online, P=0.54). Patients' qualitative feedback highlighted significant gaps in knowledge about treatment options, as well as a strong desire to have educational materials in advance of diagnostic catheterizations. CONCLUSION: The pilot study suggests that both decision aids are highly valued by patients with CAD. The booklet/DVD DA was associated with higher rates of complete review and improved knowledge about the management of stable coronary disease.
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Toma de Decisiones Clínicas/métodos , Información de Salud al Consumidor/métodos , Enfermedad de la Arteria Coronaria , Técnicas de Apoyo para la Decisión , Anciano , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/psicología , Enfermedad de la Arteria Coronaria/terapia , Sistemas de Apoyo a Decisiones Clínicas , Femenino , Alfabetización en Salud , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Prioridad del Paciente , Proyectos PilotoRESUMEN
OBJECTIVE: To integrate patient decision aid (DA) delivery to promote shared decision-making and provide more patient-centred care within an orthopaedic surgery department for treatment of hip and knee osteoarthritis, lumbar herniated disc and lumbar spinal stenosis. METHODS: Different strategies were used across three distinct phases to promote DA delivery. First, we used a quality improvement bonus to generate awareness and interest in the DAs among specialists. Second, we adapted the electronic referral management system to enable DA orders at referral to a specialist. Third, we engaged clinic staff and specialists to design workflows that promoted DA delivery. We tracked the number of patients who received a DA, who ordered the DA, and collected usage data from a subset of patients. Our target was to reach 60% of patients with DAs. RESULTS: In phase 1, 28% (43/155) of spine patients and 37% (114/308) of hip/knee patients received a DA. In phase 2, 54% (64/118) of spine referrals and 58% (189/324) of hip/knee referrals included a request to send a patient a DA. In phase 3, 56% (90/162) of spine patients and 69% (213/307) of hip/knee patients received a DA, significantly more than in phase 1 (P<0.0001). In phase 3, both more DAs were ordered by clinic staff compared with specialists (56% phase 3 vs 34% phase 1, P<0.001) and sent before the visit (74% phase 3 vs 17% phase 1, P<0.001). Patients were more likely to report reviewing the DA when delivered before the visit (63% before vs 50% after, P=0.005). CONCLUSION: DA implementation into clinic workflow is possible and facilitated by engagement of the entire care team and the support of health information technology.
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Técnicas de Apoyo para la Decisión , Conocimientos, Actitudes y Práctica en Salud , Ortopedia/organización & administración , Participación del Paciente/métodos , Mejoramiento de la Calidad/organización & administración , Centros Médicos Académicos , Anciano , Toma de Decisiones , Registros Electrónicos de Salud/organización & administración , Femenino , Humanos , Desplazamiento del Disco Intervertebral/cirugía , Masculino , Persona de Mediana Edad , Osteoartritis/cirugía , Grupo de Atención al Paciente , Derivación y Consulta/organización & administración , Factores Socioeconómicos , Estenosis Espinal/cirugía , Flujo de TrabajoRESUMEN
PROBLEM: Physicians must be competent in several different kinds of communication skills in order to implement shared decision making; however, these skills are not part of routine medical student education, nor are they formally taught during residency training. INTERVENTION: We developed a 1- and 2-hour workshop curriculum for internal medicine residents to promote shared decision making in treatment decisions for four common chronic conditions: diabetes, depression, hypertension, and hyperlipidemia. The workshops included a written case exercise, a short didactic presentation on shared decision-making concepts and strategies for risk communication, and two role-playing exercises focused on decision making for depression and hyperlipidemia treatment. CONTEXT: We delivered the workshop as a required component of the resident curriculum in ambulatory medicine. To evaluate the impact of the workshop, we used written course evaluations, tracked the use of the newly introduced Decision Worksheets, and asked preceptors to perform direct observation of treatment decision conversations. OUTCOME: Residents were involved in the development of the workshop and helped identify key content, suggested framing for difficult topics, and confirmed the need for the skills workshop. One hundred thirty internal medicine and medicine-pediatrics residents attended 8 workshops over a 4-month period. In written cases completed before the workshop, the majority of residents indicated that they would discuss medications, but few mentioned other treatment options or documented patients' goals and preferences in a sample encounter note with a patient with new depression symptoms. Overall, most participants (89.7%) rated the workshop as excellent or very good, and 93.5% said that they would change their practice based on what they learned. Decision Worksheets addressing diabetes, depression, hyperlipidemia, and hypertension were available on a primary care-focused intranet site and were downloaded almost 1,200 times in the first 8 months following the workshops. Preceptors were able to observe only one consult during which one of the four topics was discussed. LESSONS LEARNED: Internal medicine residents had considerable gaps in shared decision-making skills as measured in a baseline written exercise. Residents provided valuable contributions to the development of a Decision Worksheet to be used at the point of care. Participants rated the skills workshop highly, though interns rated the exercise more useful than PGY-2 and PGY-3 residents did. The Decision Worksheets were accessed often following the sessions; however, observing the Decision Worksheets in use in real time was a challenge in the resident-faculty clinic. Additional studies are warranted to examine whether the workshop was successful in increasing residents' ability to implement skills in practice.
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Competencia Clínica , Curriculum , Toma de Decisiones , Educación de Postgrado en Medicina/métodos , Medicina Interna/educación , Pediatría/educación , Grupos Focales , Humanos , Internado y Residencia , Desarrollo de Programa , Evaluación de Programas y Proyectos de SaludRESUMEN
PURPOSE: To determine the efficacy of combining radiation (XRT) with a dual epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. METHODS AND MATERIALS: Immunoblotting was performed for EGFR, phosphorylated-EGFR, and phosphorylated-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3, and human umbilical vein endothelial cells treated with XRT +/- AEE788. Tumor xenografts were established for DU145 and PC-3 on hind limbs of athymic nude mice assigned to four treatment groups: (1) control, (2) AEE788, (3) XRT, and (4) AEE788 + XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging. RESULTS: AEE788 effectively decreased phosphorylated-EGFR and phosphorylated-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 + XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed a radiosensitization effect in human umbilical vein endothelial cells and increased apoptosis susceptibility. Concurrent AEE788 + XRT compared with either alone led to significant tumor growth delay in DU145 tumors. Conversely, PC-3 tumors derived no added benefit from combined-modality therapy. In DU145 tumors, a significant decrease in tumor blood flow with combination therapy was shown by using power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. Maldi-spectrometry (MS) imaging showed that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. CONCLUSIONS: AEE788 + XRT showed efficacy in vitro/in vivo with DU145-based cell models, whereas PC-3-based models were adequately treated with XRT alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and showed effects on both tumor cell proliferation and vascular destruction.
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Receptores ErbB/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Purinas/uso terapéutico , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Terapia Combinada/métodos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/efectos de la radiación , Receptores ErbB/antagonistas & inhibidores , Humanos , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/metabolismo , Purinas/farmacocinética , Tolerancia a Radiación/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Trasplante HeterólogoRESUMEN
OBJECTIVE: Stereotactic radiotherapy (ablative radiation) is a modality that holds considerable promise for effective treatment of intracranial and extracranial malignancies. Although tumor vasculature is relatively resistant to small fractionated doses of ionizing radiation, large ablative doses of ionizing radiation lead to effective demise of the tumor vasculature. The purpose of this study was (1) to noninvasively monitor and compare tumor physiologic parameters in response to ablative radiation treatments and (2) to use these noninvasive parameters to optimize the schedule of administration of radiation therapy. METHODS: Lewis lung carcinoma tumors were implanted into C57BL/6 mice and treated with ablative radiation. The kinetics of change in physiologic parameters of a response to single-dose 20-Gy treatments was measured. Parameters studied included tumor blood flow, apoptosis, and proliferation rates. Serial tumor sections were stained to correlate noninvasive Doppler assessment of tumor blood flow with microvasculature histologic findings. RESULTS: A single administration of 20 Gy led to an incomplete tumor vascular response, with subsequent recovery of tumor blood flow within 4 days after treatment. Sustained reduction of tumor blood flow by administering the successive ablative radiation treatment before tumor blood flow recovery led to a 3-fold tumor growth delay. The difference in tumor volumes at each measurement time point (every 2 days) was statistically significant (P=.016). CONCLUSIONS: This study suggests a rational design of schedule optimization for radiation-mediated, vasculature-directed treatments guided by noninvasive assessment of tumor blood flow levels to ultimately improve the tumor response.
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Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/cirugía , Radiocirugia , Animales , Apoptosis , Carcinoma Pulmonar de Lewis/diagnóstico por imagen , Carcinoma Pulmonar de Lewis/patología , Ratones , Ratones Endogámicos C57BL , Radiocirugia/métodos , Técnica de Ventana Cutánea , UltrasonografíaRESUMEN
PURPOSE: Integrins alpha v beta 3 and alpha v beta 5 are important in tumor growth and angiogenesis and have been recently explored as targets for cancer therapy. Radiotherapy also inhibits tumor growth and affects vasculature. We explored the combination of integrin antagonist Cilengitide (EMD 121974) and ionizing radiation. METHODS AND MATERIALS: Levels of alpha v beta 3 were determined for human umbilical vein endothelial cells (HUVEC), as well as H157 and H460 human non-small-cell lung cancer cells, using FACS analysis and immunofluorescence imaging. Clonogenic assays, Western immunoblots probed for cleaved caspase 3, and Annexin-V probing were used to evaluate cell survival and apoptosis. A cell detachment assay and matrigel assay were used to further examine the effects of treatment. RESULTS: Human umbilical vein endothelial cells had the highest alpha v beta 3 level, followed by H157, and H460. Interestingly, we found that 5 Gy irradiation induced expression of alpha v beta 3 in all cell lines. Clonogenic assays showed a radiosensitizing effect with Cilengitide, and calculation of the dose enhancement ratio showed that the effect was highest in HUVECs (1.38), followed by H157 (1.19), and H460 (1.10), corresponding to the levels of target expression. There was an increase in apoptotic cells after combination treatment with Cilengitide and radiation, and there was an increase in detached cells after treatment with Cilengitide. Additionally, there was decreased endothelial tubule formation after combination treatment. CONCLUSIONS: We conclude that radiation induces expression of alpha v beta 3 integrin in endothelial and non-small-cell lung cancer models, and that integrin antagonist Cilengitide is a radiosensitizer in proportion to the levels of target integrin expression.