Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration.

After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain. Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration.

Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration.

After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain . Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration. Highlights: Rapid regeneration of the jaw joint ligament in adult zebrafishDedifferentiation of mature ligamentocytes contributes to regenerationscRNAseq reveals dynamic ECM remodeling and immune activation during regenerationRequirement of Legumain for ECM remodeling and ligament healing.

Self-management goals of cancer survivors with an ostomy.

OBJECTIVES: Ostomies due to cancer surgery impose complex and enduring care challenges that necessitate cancer survivors" self-management. The objective of this analysis is to evaluate ostomates' self- management goals using a qualitative approach. METHODS: A multi-site randomized controlled trial testing the Ostomy Self-Management Training program (OSMT) was delivered via telehealth to a group of cancer survivors with an ostomy randomized to either the OSMT program with goal setting or usual care (UC), without goal setting. Goals were classified by type and frequency according to a modified City of Hope Health-Related Quality of Life framework (physical, psychological, social, spiritual, ostomy-specific, and healthcare quality domains), using a directed and systematic content analysis approach. RESULTS: The 524 self-management goals analyzed by domain frequencies physical (29.4%), ostomy specific (29.0%) and social well-being (25.0%) were predominant. Managing other health issues (7.6%), psychological issues (6.0%), and spiritual well-being issues (3.0%) were next. Common self-management themes were ostomy care independence (87.5%), handling cancer-related issues (62.5%), achieving acceptance (56.2%), resuming physical activity (43.0%), and maintaining fluid/diet balance (43.0%). DISCUSSION/CONCLUSION: Goal-setting offers insights into self-management concerns of cancer survivors with ostomies. Results demonstrate the broad aspects of self-management ostomates face. PRACTICE IMPLICATIONS: Self-management training with patient goal-setting may be used to help ostomates with cancer and their health care providers identify areas for needed education and support.

Adapting to the burdens of care: a telehealth program for cancer survivors with ostomies.

PURPOSE: An ostomy introduces to cancer survivors new demands for self-care and healthcare resource use. A curriculum that teaches ostomates self-management skills may affect survivors' use of resources. METHODS: A prospective randomized trial comparing usual care (UC) with an Ostomy Self-Management Training (OSMT) program delivered by telehealth was conducted in patients with ostomies due to cancer. The intervention occurred over 5 weeks with survey administration at baseline, program completion, and 6 months after completion. Quantitative data were analyzed using a mixed-effects logistic model to predict mean values of resource and service use. Responses to the open-ended question were coded and analyzed with directed content analysis. RESULTS: One hundred and sixty-seven subjects (89 in the OSMT arm and 78 in the UC arm) completed the questionnaire at all time points. The changes in likelihoods of emptying one's ostomy bag > 8 times/week and of incurring any out-of-pocket costs on accessories were 14% greater for the intervention group (p = .029 and p = .063, respectively). Qualitative analysis reveals among the OSMT arm an increase in the proportion of ostomy-specific comments and a decrease in the same metric among the UC arm. Common themes included learning to work with equipment, dealing with gas build-up and finding well-fitting clothing. CONCLUSIONS: There are some indications that participants in this structured telehealth program are more active in ostomy self-care. The reported ostomy self-care activities, healthcare consumables, and healthcare services reported by both groups illustrate the complexity of survivorship care following ostomy surgery. National Clinical Trial Identifier: NCT02974634.

Stoma location and ostomy-related quality of life among cancer survivors with ostomies: A pooled analysis.

INTRODUCTION: We sought to explore how stoma location may affect self-care events and health-related quality of life (HRQOL) in cancer survivors with ostomies. METHODS: A pooled dataset was obtained from three multi-site studies that used the City of Hope Quality of Life-Ostomy questionnaire. Predicted means for HRQOL and individual items were generated adjusting for sex, ostomy type, and body mass index. RESULTS: Among 607 cancer survivors, abdominal quadrant groups were: 138 (23%) upper left, 298 (49%) lower left, 51 (8%) upper right, and 120 (20%) lower right. Survivors with lower right side ostomies more frequently reported weight gain after ostomy surgery (p < 0.001). Stoma on the right side of the abdomen was associated with lower scores for issues with the skin surrounding the ostomy (p = 0.03) and satisfaction with appearance (p = 0.008). DISCUSSION: Stoma location is associated with HRQOL and difficulties adjusting to the ostomy.

Cancer survivors' greatest challenges of living with an ostomy: findings from the Ostomy Self-Management Telehealth (OSMT) randomized trial.

OBJECTIVES: An ostomy results in lifelong quality of life changes for a cancer survivor. We describe the greatest challenges reported from a randomized trial of cancer survivors with stomas (ostomies). METHODS: Cancer survivors with ostomies participating in a multi-site randomized prospective trial of an Ostomy Self-Management Telehealth (OSMT) program versus usual care (UC) were surveyed at six months post accrual. An open-ended question requested greatest challenges after ostomy surgery. Quantitative descriptive and qualitative analyses were used to examine greatest challenges reported. RESULTS: A total of 118 trial participants identified greatest challenges with 55 in the OSMT and 63 in the UC. Six conceptual domains were used to code comments-physical, psychological, social, and spiritual quality of life; ostomy-specific issues, and healthcare issues. The OSMT contributed 187 comments, and UC contributed 235 comments. Ostomy specific issues and social well-being had the most comments overall with UC contributing more comments in all domains except physical well-being. Word Clouds revealed post-operative and treatment-related issues and going out in public as the most common challenges in both groups. Word Clouds compared types of ostomies revealing bowel function challenges (colostomy group), difficulties going out in public (ileostomy group), and positive support (urostomy group). CONCLUSIONS: Fewer challenges submitted by the OSMT group provide the beginning evidence of the OSMT program impact. Dominant challenges across both groups were social well-being and ostomy care. Challenges varied by type of ostomy. Findings support long-term care and support for all cancer survivors with ostomies. TRIAL REGISTRATION: NCT02974634.

Programmatic Costs of the Telehealth Ostomy Self-Management Training: An Application of Time-Driven Activity-Based Costing.

OBJECTIVES: Programmatic cost assessment of novel clinical interventions can inform their widespread dissemination and implementation. This study aimed to determine the programmatic costs of a telehealth Ostomy Self-Management Training (OSMT) intervention for cancer survivors using Time-Driven Activity-Based Costing (TDABC) methodology. METHODS: We demonstrated a step-by-step application of TDABC based on a process map with core OSMT intervention activities and associated procedures and determined resource use and costs, per unit procedure. We also assessed per-patient costs from a payer perspective and provided estimates of total hours and costs by personnel, activity, and procedure. RESULTS: The per-patient cost of the OSMT was $1758. Personnel time accounted for 91% of the total cost. Site supervisor and information technology technician time were the most expensive personnel resources. Telehealth technical and communication equipment accounted for 8% of the total cost. Intervention coordination and monitoring efforts represented most of the total time cost (62%), followed by the intervention delivery (35%). The procedures with the highest cost were communication via phone or virtual meetings (24%), email exchanges (18%), and telehealth session delivery (18%). CONCLUSIONS: Future efforts to replicate, disseminate, and implement the OSMT intervention should anticipate funding for nonclinical components of the intervention, including coordination and monitoring, and consider how these activities can be performed most efficiently. For institutions without established telemedicine programs, selection of videoconferencing platforms and adequate staffing for participant technical support should be considered. Our step-by-step application of TDABC serves as a case study demonstrating how interventionists can gather data on resource use and costs of intervention activities concurrently with their collection of trial data.

Association of Fatigue and Outcomes in Advanced Cancer: An Analysis of Four SWOG Treatment Trials.

PURPOSE: Patient-reported outcomes may be associated with cancer outcomes. We evaluated clinically significant fatigue (CSF), overall survival, adverse events (AEs), and quality of life (QOL) during cancer treatment. METHODS: We compared outcomes in four phase II or III chemotherapy trials, two advanced non-small-cell lung cancer and two advanced hormone-refractory prostate cancer, with or without baseline CSF. CSF was defined as a rating of two or greater on the Functional Assessment of Cancer Therapy fatigue question or a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 fatigue symptom score of 50% or greater. Survival was compared according to CSF using Kaplan-Meier estimates and Cox regression models. Differences in AE rates by CSF were assessed via chi-squared tests, and QOL changes from baseline to 3 months via linear regression. RESULTS: Of 1,994 participants, 1,907 (median age 69 years, range: 32-91) had complete baseline QOL survey data, with 52% reporting CSF at baseline. For the two hormone-refractory prostate cancer studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios of (95% CI, P value) 1.32 (1.13 to 1.55, P < .001) and 1.31 (1.02 to 1.67, P = .03) and with increased incidence of grade 3-5 constitutional (16.5% v 9.4%, P = .002; 13.9% v 6.3%, P = .002) and neurologic (11.7% v 6.1%, P = .006; 9.0% v 3.9%, P = .01) AEs, respectively. Baseline CSF was associated with a higher mortality rate in one non-small-cell lung cancer study: hazard ratio 1.44 and 1.04 to 2.00, P = .03. CONCLUSION: Oncology trial participants with baseline CSF had poorer survival and experienced more AEs than participants without CSF. This indicates fatigue as an important baseline prognostic factor in oncology treatment trials.

Srsf3 mediates alternative RNA splicing downstream of PDGFRα signaling in the facial mesenchyme.

Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) is crucial for mammalian craniofacial development, although the mechanisms by which the activity of downstream intracellular effectors is regulated to mediate gene expression changes have not been defined. We find that the RNA-binding protein Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRα signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. We further demonstrate that ablation of Srsf3 in the mouse neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Finally, we show that Srsf3 regulates the alternative RNA splicing of transcripts encoding protein kinases in the mouse facial process mesenchyme to regulate PDGFRα-dependent intracellular signaling. Collectively, our findings reveal that alternative RNA splicing is an important mechanism of gene expression regulation downstream of PI3K/Akt-mediated PDGFRα signaling in the facial mesenchyme and identify Srsf3 as a critical regulator of craniofacial development.

An Ostomy Self-management Telehealth Intervention for Cancer Survivors: Technology-Related Findings From a Randomized Controlled Trial.

BACKGROUND: An Ostomy Self-management Telehealth (OSMT) intervention by nurse educators and peer ostomates can equip new ostomates with critical knowledge regarding ostomy care. A telehealth technology assessment aim was to measure telehealth engineer support requirements for telehealth technology-related (TTR) incidents encountered during OSMT intervention sessions held via a secure cloud-based videoconferencing service, Zoom for Healthcare. OBJECTIVE: This paper examines technology-related challenges, issues, and opportunities encountered in the use of telehealth in a randomized controlled trial intervention for cancer survivors living with a permanent ostomy. METHODS: The Arizona Telemedicine Program provided telehealth engineering support for 105 OSMT sessions, scheduled for 90 to 120 minutes each, over a 2-year period. The OSMT groups included up to 15 participants, comprising 4-6 ostomates, 4-6 peer ostomates, 2 nurse educators, and 1 telehealth engineer. OSMT-session TTR incidents were recorded contemporaneously in detailed notes by the research staff. TTR incidents were categorized and tallied. RESULTS: A total of 97.1% (102/105) OSMT sessions were completed as scheduled. In total, 3 OSMT sessions were not held owing to non-technology-related reasons. Of the 93 ostomates who participated in OSMT sessions, 80 (86%) completed their OSMT curriculum. TTR incidents occurred in 36.3% (37/102) of the completed sessions with varying disruptive impacts. No sessions were canceled or rescheduled because of TTR incidents. Disruptions from TTR incidents were minimized by following the TTR incident prevention and incident response plans. CONCLUSIONS: Telehealth videoconferencing technology can enable ostomates to participate in ostomy self-management education by incorporating dedicated telehealth engineering support. Potentially, OSMT greatly expands the availability of ostomy self-management education for new ostomates. TRIAL REGISTRATION: ClinicalTrials.gov NCT02974634; https://clinicaltrials.gov/ct2/show/NCT02974634.

Healthy behaviors are associated with positive outcomes for cancer survivors with ostomies: a cross-sectional study.

BACKGROUND: Cancer survivors (CS) with ostomies may face challenges in sustaining physical activity (PA) levels and maintaining healthy diets. This analysis describes lifestyle behaviors and their relationships with health-related quality of life (HRQOL) in CS with ostomies. METHODS: This is a cross-sectional, secondary analysis of a multisite randomized self-management education trial for CS with ostomies. The baseline self-reported measures were queried on aerobic PA and diet using the City of Hope Quality of Life Ostomy measure, and the Self-Efficacy to Perform Self-Management Behaviors questionnaire (SE). PA was compared against the American Cancer Society PA guidelines for CS. Relationships between PA and HRQOL were evaluated using multiple linear regression, stratified by BMI. RESULTS: Among 200 responders, fewer than 20% met or exceeded the PA guideline for cancer survivors; overall, confidence in the ability to perform gentle or aerobic PA was moderate (6/10 on the SE). Overall HRQOL (p = 0.038), psychological well-being (p = 0.017), and physical strength (p = 0.025) were associated with increased PA. Almost half (48.7%) of CS reported a special diet. CS with urostomies were less likely to report diet adjustments after their ostomy surgeries (OR: 0.16, 95% CI [0.08-0.38]) than CS with fecal ostomies. CONCLUSIONS: Better HRQOL is associated with PA guideline achievement among CS with ostomies. Additionally, diet adjustments were reported more frequently in CS with fecal ostomies. Our findings bear clinical relevance for designing ostomy self-management and lifestyle recommendations for CS with ostomies. IMPLICATIONS FOR CANCER SURVIVORS: The evaluation of lifestyle behaviors may be an especially important focus for CS with ostomies.

Pdgfra and Pdgfrb Genetically Interact in the Murine Neural Crest Cell Lineage to Regulate Migration and Proliferation.

Cranial neural crest cells (cNCCs) are migratory, multipotent cells that originate from the forebrain to the hindbrain and eventually give rise to the cartilage and bone of the frontonasal skeleton, among other derivatives. Signaling through the two members of the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases, alpha and beta, plays critical roles in the cNCC lineage to regulate craniofacial development during murine embryogenesis. Further, the PDGFRs have been shown to genetically interact during murine craniofacial development at mid-to-late gestation. Here, we examined the effect of ablating both Pdgfra and Pdgfrb in the murine NCC lineage on earlier craniofacial development and determined the cellular mechanisms by which the observed phenotypes arose. Our results confirm a genetic interaction between the two receptors in this lineage, as phenotypes observed in an allelic series of mutant embryos often worsened with the addition of conditional alleles. The defects observed here appear to stem from aberrant cNCC migration, as well as decreased proliferation of the facial mesenchyme upon combined decreases in PDGFRα and PDGFRß signaling. Importantly, we found that PDGFRα plays a predominant role in cNCC migration whereas PDGFRß primarily contributes to proliferation of the facial mesenchyme past mid-gestation. Our findings provide insight into the distinct mechanisms by which PDGFRα and PDGFRß signaling regulate cNCC activity and subsequent craniofacial development in the mouse embryo.

Does multicenter care impact the outcomes of surgical patients with gastrointestinal malignancies requiring complex multimodality therapy?

BACKGROUND: Regionalization of oncologic care has increased, but less is known whether patient outcomes are influenced by receipt of multimodality care through multicenter care (MCC) or single-center care (SCC). METHODS: Patients from 2004 to 2015 National Cancer Data Base diagnosed with stage II-III esophageal (EA), stage II-III pancreatic (PA), and stage II-IV rectal (RA) adenocarcinoma who underwent resection at a high volume center (HVC) and required radiation and/or chemotherapy were included. MCC (care at 2+ facilities) and SCC patients were propensity-score matched 1:2 and Cox proportional hazards regression used to analyze survival. RESULTS: On multivariable regression analysis, MCC in RA patients (N = 325/2097, 15.5%) was more associated with residing ≥40 miles from the HVC (odds ratio [OR] = 2.37; P = .044) and receipt of neoadjuvant chemotherapy (1.42, P = .040). In PA patients (N = 75/380, 19.7%), residing ≥40 miles from the HVC (OR = 3.22; P = .001), and in EA patients (N = 88/534, 16.5%), younger patients (<50 years: OR = 2.96; P = .011) were associated with MCC. Following propensity score matching, EA (N = 147), PA (N = 133), and RA (N = 661) patients had no difference in 1-year and 3-year overall survival when comparing MCC to SCC. CONCLUSIONS: The use of MCC appears safe without a difference in survival and may offer significant advantages in convenience to patients as they undergo their complex oncologic care.