Development of a core set of outcome measures to be applied toward breast cancer-related lymphedema core outcome domains.

PURPOSE: For breast cancer survivors (BCS) living with breast cancer-related lymphedema (BCRL), what outcome measures (OMs) are recommended to be used to measure standardized outcome domains to fully assess the burden of the disease and efficacy of interventions? An integral component of a standardized core outcome set (COS) are the OMs used to measure the COS. METHODS: A supplemental online survey was linked to a Delphi study investigating a COS for BCRL. OMs were limited to a maximum of 10 options for each outcome domain (OD). There were 14 ODs corresponding to the International Classification of Functioning, Disability, and Health (ICF) framework and respondents rated the OMs with a Likert level of recommendation. The feasibility of the listed OMs was also investigated for most outpatient, inpatient, and research settings. RESULTS: This study identified 27 standardized OMs with a few ODs having 2-3 highly recommended OMs for proper measurement. A few of the recommended OMs have limitations with reliability due to being semi-quantitative measures requiring the interpretation of the rater. CONCLUSION: Narrowing the choices of OMs to 27 highly recommended by BCRL experts may reduce selective reporting, inconsistency in clinical use, and variability of reporting across interdisciplinary healthcare fields which manage or research BCRL. There is a need for valid, reliable, and feasible OMs that measure tissue consistency. Measures of upper extremity activity and motor control need further research in the BCS with BCRL population.

Development of a core outcome set for breast cancer-related lymphedema: a Delphi study.

PURPOSE: For breast cancer survivors (BCS) living with breast cancer-related lymphedema (BCRL), what outcome domains (OD) should be measured to assess the burden of the disease and efficacy of interventions? A Core Outcome Set (COS) that promotes standardized measurement of outcomes within the constraints of time influenced by work environments is essential for patients and the multidisciplinary professionals that manage and research BCRL. METHODS: Using Delphi methodology, a multidisciplinary group of BCRL experts (physical and occupational therapists, physicians, researchers, physical therapist assistants, nurses, and massage therapist) completed two waves of online surveys. BCRL expert respondents that completed the first survey (n = 78) had an average of 26.5 years in practice, whereas, respondents who completed the second survey (n = 33) had an average of 24.9 years. ODs were included in the COS when consensus thresholds, ranging from 70% to 80%, were met. RESULTS: A total of 12 ODs made up the COS. Reaching a minimum consensus of 70%; volume, tissue consistency, pain, patient-reported upper quadrant function, patient-reported health-related quality of life, and upper extremity activity and motor control were recommended at different phases of the BCRL continuum in a time-constrained environment. Joint function, flexibility, strength, sensation, mobility and balance, and fatigue met an 80% consensus to be added when time and resources were not constrained. CONCLUSION: The COS developed in this study thoroughly captures the burden of BCRL. Using this COS may reduce selective reporting, inconsistency in clinical use, and variability of reporting across interdisciplinary healthcare fields, which manage or research BCRL.

A Tissue Dielectric Constant Evaluation of Knee Edema: A Retrospective Intra-rater Reliability and Association Study of Repeated Measures.

BACKGROUND: This research compared the reliability and association of tissue dielectric constant (TDC) measures of knee edema to circumferential measurements of knee girth recorded as part of a physical therapy examination. METHODS: Twenty adults having observable unilateral knee edema were enrolled. A single examiner measured edematous knee swelling with a TDC device and a tape measure across two visits. The presence of edema was recorded as a positive number in reporting side-to-side differences and a positive percentage in documenting change over time. Intra-rater reliability of the measures was assessed with an intra-class correlation coefficient (ICC). Percent change in edema was evaluated independently for both methods using a paired t-test, and the association between measures was assessed by a Pearson's statistic. RESULTS: Both measures were reliable (ICC ≥ 0.81), and both detected a significant percentage decrease (p < 0.05) in edema across visits. The TDC measure changed by 8.3%, an amount nearly four times larger compared to knee girth (2.4%). The subsequent follow-up comparison revealed an inverse relationship (p = 0.049; r = -0.44) between the two percent change measurements of edema. CONCLUSION: The two methods capture different physical attributes of edema. The TDC records the water content of the tissue, while the use of a tape measure records circumferential limb girth. The TDC measurement was reliable and more responsive in detecting a percentage decrease in knee edema in comparison to a circumferential measure of knee girth. The TDC method may have wider use in directly measuring edema in other tissue structures and regions of the body.

Functional and psychosocial quality of life in gynecologic Cancer survivors with and without lymphedema symptoms.

OBJECTIVE: The goal of this study was to compare function, quality of life, body image and distress levels between gynecologic cancer survivors with and without lymphedema symptoms as well as to determine how many individuals received rehabilitation treatment following treatment for gynecological malignancy. METHODS: This prospective longitudinal cohort study sought to examine long-term physical and psychosocial outcomes among gynecologic cancer survivors. RESULTS: Participants in the symptomatic group reported lower quality of life, lower function scores, and greater cancer-related, with greater rates of clinically significant levels of distress. These results remained largely consistent in multivariable models. CONCLUSIONS: We found lower extremity lymphedema to be associated with lower quality of life, lower limb function, greater distress, and negative body image.

Shoulder Kinematics of Axillary Web Syndrome in Women Treated for Breast Cancer.

OBJECTIVE: To better understand how the shoulder moves in breast cancer survivors with axillary web syndrome (AWS), we compared 3-dimensional (3D) shoulder kinematics during shoulder elevation among breast cancer survivors with and without AWS 5 years postoperatively. Although research consistently shows decreased shoulder range of motion with AWS, we do not understand the underlying biomechanics. DESIGN: Nested case control study. SETTING: University Academic Breast Center. PARTICIPANTS: Twenty-five women who had surgery 5 years previously for unilateral breast cancer with the removal of at least 1 lymph node participated in this study (N=25). Twelve participants had AWS; 13 women did not have AWS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Three-dimensional shoulder kinematic data during shoulder forward flexion, scapular plane abduction, and coronal plane abduction were collected using 3D electromagnetic motion tracking. Kinematic data were extracted at 30°, 60°, 90°, and 120° of arm elevation for scapular upward rotation, internal rotation, and posterior tilt as well as for glenohumeral external rotation. RESULTS: Women with AWS demonstrated 15.2° less scapular upward rotation at 120° humerothoracic elevation (95% confidence interval [-25.2, -5.2], P=.005), regardless of plane. No significant between-group differences were found for any other angle of scapular upward rotation, nor for scapular internal rotation, scapular posterior tilt, or glenohumeral axial rotation at any angle. CONCLUSIONS: Five years after surgery for breast cancer, women diagnosed with AWS have altered scapulohumeral kinematics that may place them at an increased risk of shoulder pain based on existing kinematic literature in healthy cohorts. This information can help guide rehabilitation programs for breast cancer survivors to facilitate pain-free upper extremity function after treatment.

Five-Year Cumulative Incidence of Axillary Web Syndrome and Comparison in Upper Extremity Movement, Function, Pain, and Lymphedema in Survivors of Breast Cancer With and Without Axillary Web Syndrome.

OBJECTIVE: To determine the cumulative incidence and natural history of axillary web syndrome (AWS) and its related postoperative risk for physical impairments in a cohort of women followed for 5 years post breast cancer surgery. DESIGN: Prospective, longitudinal study. SETTING: Academic health center. PARTICIPANTS: Women (N=36) with and without AWS after breast cancer surgery with sentinel node biopsy or axillary lymph node dissection. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were assessed for AWS, shoulder goniometric flexion and abduction range of motion, function (Disability of the Arm, Shoulder, and Hand), lymphedema (bioimpedance spectroscopy, girth measures, tissue dielectric constant), and pain (visual analog scale) at 2, 4, 12, and 78 weeks and 5 years after breast cancer surgery. Analysis of variance compared range of motion, function, lymphedema, and pain in women identified with AWS with those without AWS across visits. Univariate logistic regression assessed if AWS was a risk factor for physical impairment at 5 years. RESULTS: The cumulative incidence of AWS was 57%. Fifty percent (14/28) of the women who completed all study visits had signs of AWS at 5 years. Abduction active range of motion was significantly lower in women with AWS at 2 and 4 weeks post surgery. AWS was identified as a risk factor for reduced shoulder motion at 5 years. Regardless of AWS, 75% of the women experienced 1 or more upper extremity physical impairments at 5 years, which is an increase from 66% at 78 weeks in the same cohort. CONCLUSIONS: AWS is associated with reduced shoulder range of motion in the early postoperative time period, can persist for 5 years after breast cancer surgery, and increases the risk of long-term reduced shoulder range of motion. Long-term physical issues are apparent after breast cancer surgery regardless of AWS.

Structural insights into the modulation of PDGF/PDGFR-ß complexation by hyaluronan derivatives.

Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-ß by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-ß. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-ß. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-ß can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-ß signaling system in angiogenesis and related disease conditions.

Hyaluronan/Collagen Hydrogels with Sulfated Glycosaminoglycans Maintain VEGF165 Activity and Fine-Tune Endothelial Cell Response.

In order to restore the regeneration capacity of large-size vascularized tissue defects, innovative biomaterial concepts are required. Vascular endothelial growth factor (VEGF165) is a key factor of angiogenesis interacting with sulfated glycosaminoglycans (sGAG) within the extracellular matrix. As this interplay mainly controls and directs the biological activity of VEGF165, we used chemically modified sGAG derivatives to evaluate the structural requirements of sGAG for controlling and tuning VEGF165 function and to translate these findings into the design of biomaterials. The in-depth analysis of this interaction by surface plasmon resonance and ELISA studies in combination with molecular modeling stressed the relevance of the substitution position, degree of sulfation, and carbohydrate backbone of GAG. Acrylated hyaluronan (HA-AC)/collagen (coll)-based hydrogels containing cross-linked acrylated, sulfated hyaluronan (sHA-AC) derivatives with different substitution patterns or an acrylated chondroitin sulfate (CS-AC) derivative function as multivalent carbohydrate-based scaffolds for VEGF165 delivery with multiple tuning capacities. Depending on the substitution pattern of sGAG, the release of biologically active VEGF165 was retarded in a defined manner compared to pure HA/coll gels, which further controlled the VEGF165-induced stimulation of endothelial cell proliferation and extended morphology of cells. This indicates that sGAG can act as modulators of protein interaction profiles of HA/coll hydrogels. In addition, sHA-AC-containing gels with and even without VEGF165 strongly stimulate endothelial cell proliferation compared to gels containing only CS-AC or HA-AC. Thus, HA/coll-based hydrogels containing cross-linked sHA-AC are biomimetic materials able to directly influence endothelial cells in vitro, which might translate into an improved healing of injured vascularized tissues.

Tissue Dielectric Constant Measures in Women With and Without Clinical Trunk Lymphedema Following Breast Cancer Surgery: A 78-Week Longitudinal Study.

OBJECTIVE: Following breast cancer surgery with lymph node removal, women are at risk of developing lymphedema in the upper extremity or trunk. Currently, trunk lymphedema diagnosis relies on a clinical assessment because no quantifiable standard method exists. Tissue dielectric constant (TDC) values are quantifiable measures of localized skin tissue water and may be able to detect trunk lymphedema. The goal of this study was to (1) compare parameters derived from TDC measurements with those derived from clinically accepted criteria for trunk lymphedema in women following breast cancer surgery and (2) explore the potential utility of TDC to detect trunk lymphedema early in its progression. METHODS: This prospective longitudinal study, a secondary analysis from a larger study, observed women with and without clinically determined truncal lymphedema following breast cancer surgery. TDC was measured on the lateral trunk wall at post-surgery weeks 2, 4, 12, and 78 in women who had surgical breast cancer treatment with lymph node removal. Clinical assessment for trunk lymphedema was determined at 78 weeks by a lymphedema expert. Comparison of TDC measurements in women with and without clinical trunk lymphedema was analyzed. RESULTS: Clinical assessment identified trunk lymphedema in 15 out of 32 women at 78 weeks. These women had TDC ratios statistically higher than women without truncal lymphedema. CONCLUSION: The overall findings indicate that TDC has the ability to quantify trunk lymphedema and might be valuable in early detection. IMPACT: TDC may be a beneficial tool in the early detection of breast cancer-related trunk lymphedema, which could trigger intervention. LAY SUMMARY: A new device may help recognize trunk lymphedema in patients with breast cancer so they could receive appropriate treatment.

Dual Action of Sulfated Hyaluronan on Angiogenic Processes in Relation to Vascular Endothelial Growth Factor-A.

Pathological healing characterized by abnormal angiogenesis presents a serious burden to patients' quality of life requiring innovative treatment strategies. Glycosaminoglycans (GAG) are important regulators of angiogenic processes. This experimental and computational study revealed how sulfated GAG derivatives (sGAG) influence the interplay of vascular endothelial growth factor (VEGF)165 and its heparin-binding domain (HBD) with the signaling receptor VEGFR-2 up to atomic detail. There was profound evidence for a HBD-GAG-HBD stacking configuration. Here, the sGAG act as a "molecular glue" leading to recognition modes in which sGAG interact with two VEGF165-HBDs. A 3D angiogenesis model demonstrated the dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells. While GAG alone promote sprouting, they downregulate VEGF165-mediated signaling and, thereby, elicit VEGF165-independent and -dependent effects. These findings provide novel insights into the modulatory potential of sGAG derivatives on angiogenic processes and point towards their prospective application in treating abnormal angiogenesis.

Upper extremity disability and quality of life after breast cancer treatment in the Greater Plains Collaborative clinical research network.

PURPOSE: Chronic upper extremity disability (UED) is common after breast cancer treatment but under-identified and under-treated. Although UED has been linked to quality of life (QoL), the role of UED as mediator between contemporary treatment practices and QoL has not been quantified. This investigation describes UED in a contemporary sample of breast cancer patients and examines its relationship with personal and treatment factors and QoL. METHODS: Eight hundred and thirty-three women diagnosed at eight medical institutions during 2013-2014 with microscopically confirmed ductal carcinoma in situ or invasive stage I-III breast cancer were surveyed an average of 22 months after diagnosis. UED was measured with a modified QuickDASH and QoL with the FACT-B. The questionnaire also collected treatments, sociodemographic information, comorbidity, body mass index, and a 3-item health literacy screener. RESULTS: Women who received post-mastectomy radiation and chemotherapy experienced significantly worse UED and QoL. Women who had lower income, lower health literacy and prior diabetes, arthritis or shoulder diagnoses had worse UED. Patients with worse UED reported significantly worse QoL. Income and health literacy were independently associated with QoL after adjustment for UED but treatment and prior conditions were not, indicating mediation by UED. UED mediated 52-79% of the effect of mastectomy-based treatments on QoL as compared with unilateral mastectomy without radiation. UED and QoL did not differ by type of axillary surgery or post-mastectomy reconstruction. CONCLUSIONS: A large portion of treatment effect on QoL is mediated by UED. Rehabilitation practices that prevent and alleviate UED are likely to improve QoL for breast cancer survivors.

Spatial and Temporal Variability of Upper Extremity Edema Measures After Breast Cancer Surgery.

Background: Tissue dielectric constant (TDC), as an index of local tissue water, and girth measurements are quantitative methods to measure and characterize lymphedema. Objective: To describe the spatial and temporal variability in arm girth and TDC values in women surgically treated for breast cancer and to describe the relationship between these measures. Methods and Results: This was a prospective longitudinal study that observed 36 women for 78 weeks after breast cancer surgery with lymph node removal. Arm circumferences and TDC values, as indices of local tissue water, were measured on both arms at multiple sites at postsurgery weeks 2, 4, 12, and 78 in women undergoing surgical breast cancer treatment with one or more axillary lymph nodes removed. TDC and girth values remained relatively uniform from visit-to-visit for both at-risk and contralateral control arms with no overall statistically significant difference in values (p > 0.05). There was a strong inverse correlation between arm girth and the TDC value in both the at-risk and control arms (p < 0.001). Overall, there was no statistically significant difference in TDC interarm ratios among visits or anatomical sites. TDC values for at-risk and control arms tended to significantly decrease with increasing distance from the wrist (p < 0.001). Conclusion: TDC arm values and girth measures remained relatively uniform in women after breast cancer surgery. The fact that TDC values are higher distally than proximally provides new information from which TDC measurements may be interpreted and also provides a better understanding of arm spatial variability in relation to girth measures.

Sulfation degree not origin of chondroitin sulfate derivatives modulates keratinocyte response.

Chondroitin sulfate (CS) sulfation-dependently binds transforming growth factor-ß1 (TGF-ß1) and chronic wounds often accompany with epidermal hyperproliferation due to downregulated TGF-ß signaling. However, the impact of CS on keratinocytes is unknown. Especially biotechnological-chemical strategies are promising to replace animal-derived CS. Thus, this study aims to evaluate the effects of CS derivatives on the interaction with vascular endothelial growth factor-A (VEGF-A) and on keratinocyte response. Over-sulfated CS (sCS3) interacts stronger with VEGF-A than CS. Furthermore, collagen coatings with CS variants are prepared by in vitro fibrillogenesis. Stability analyses demonstrate that collagen is firmly integrated, while the fibril diameters decrease with increasing sulfation degree. CS variants sulfation-dependently decelerate keratinocyte (HaCaT) migration and proliferation in a scratch assay. HaCaT cultured on sCS3-containing coatings produced increased amounts of solute active TGF-ß1 which could be translated into biomaterials able to decrease epidermal hyperproliferation in chronic wounds. Overall, semi-synthetic and natural CS yield to comparable responses.

Function, Shoulder Motion, Pain, and Lymphedema in Breast Cancer With and Without Axillary Web Syndrome: An 18-Month Follow-Up.

Background: Axillary web syndrome (AWS) can develop following breast cancer surgery and presents as a tight band of tissue in the axilla with shoulder abduction. Objective: The objectives were to determine the prevalence and natural history of AWS and the association between AWS and function, range of motion, pain, lymphedema, and body mass index (BMI). Design: This study was a longitudinal prospective cohort study utilizing a repeated measures design. Methods: Axillary web syndrome, function, shoulder range of motion, pain, and lymphedema (using circumference, bioimpedance spectroscopy, tissue dielectric constant) were assessed in women at 2, 4, and 12 weeks and 18 months following breast cancer surgery. Prevalence of AWS and the association with the measured outcomes were analyzed. Results: Thirty-six women agreed to participate in the study. The cumulative prevalence of AWS was 50% (18/36) at 18 months following breast cancer surgery. AWS was identified as a risk factor for reduced function. Women with AWS had statistically reduced range of motion, lower BMI, and higher number of lymph nodes removed compared to the non-AWS group. Forty-one percent (13/32) of women had AWS at 18 months. AWS reoccurred in 6 women following resolution, and a new case developed beyond the early postoperative period. The overall prevalence of physical impairments ranged from 66% to 97% within the first 18 months following surgery regardless of AWS. Limitations: Limitations include a small sample size and potential treatment effect. Conclusion: AWS occurs in approximately 50% of women following breast cancer surgery. It can persist for 18 months and potentially longer, develop beyond the early postoperative time period, and reoccur after resolution. Clinicians need to be aware of the chronicity of AWS and its association with reduced range of motion and function.

Sulfated Hyaluronan Derivatives Modulate TGF-ß1:Receptor Complex Formation: Possible Consequences for TGF-ß1 Signaling.

Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-ß1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-ß1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-ß1 to its TGF-ß receptor-I (TßR-I) and -II (TßR-II). However, sequential addition of sHA3 to the TßR-II/TGF-ß1 complex led to a significantly stronger recruitment of TßR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TßR-I when added sequentially. For the first time bioactivity of TGF-ß1 in conjunction with sHA was investigated at the receptor level. TßR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-ß1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-ß1-driven skin fibrosis.

Movement, Function, Pain, and Postoperative Edema in Axillary Web Syndrome.

BACKGROUND: Axillary web syndrome (AWS) is a condition that may develop following breast cancer surgery and that presents as a palpable axillary cord of tissue. OBJECTIVE: The purposes of this study were: (1) to determine the clinical characteristics of AWS related to movement, function, pain, and postoperative edema and (2) to define the incidence of and risk factors for AWS within the first 3 months following breast cancer surgery. DESIGN: This was a prospective cohort study with a repeated-measures design. METHODS: Women who underwent breast cancer surgery with sentinel node biopsy or axillary lymph node dissection (N=36) were assessed for AWS, shoulder range of motion, function, pain, and postoperative edema (using girth measurements, bioimpedance, and tissue dielectric constant) at 2, 4, and 12 weeks. Demographic characteristics were used for risk analysis. RESULTS: Seventeen women (47.2%) developed AWS, and AWS persisted in 10 participants (27.8%) at 12 weeks. Abduction range of motion was significantly lower in the AWS group compared with the non-AWS group at 2 and 4 weeks. There were no differences between groups in measurements of function, pain, or edema at any time point. Trunk edema measured by dielectric constant was present in both groups, with an incidence of 55%. Multivariate analysis determined lower body mass index as being significantly associated with AWS (odds ratio=0.86; 95% confidence interval=0.74, 1.00). LIMITATIONS: Limitations included a short follow-up time and a small sample size. CONCLUSION: Axillary web syndrome is prevalent following breast/axilla surgery for early-stage breast cancer and may persist beyond 12 weeks. The early consequences include movement restriction, but the long-term effects of persistent AWS cords are yet unknown. Low body mass index is considered a risk factor for AWS.