Comparative Craniofacial Bone Regeneration Capacities of Mesenchymal Stem Cells Derived from Human Neural Crest Stem Cells and Bone Marrow

Most craniofacial bones are derived from the ectodermal germ layer via neural crest stem cells, which are distinct from mesoderm-derived long bones. However, current craniofacial bone tissue engineering approaches do not account for this difference and utilize mesoderm-derived bone marrow mesenchymal stem cells (BM-MSCs) as a paradigm cell source. The effect of the embryonic origin (ontogeny) of an MSC population on its osteogenic differentiation potential and regenerative ability still remains unresolved. To clarify the effects of MSC ontogeny on bone regenerative ability, we directly compared the craniofacial bone regenerative abilities of an ecto-mesenchymal stem cell (eMSC) population, which is derived from human embryonic stem cells via a neural crest intermediate, with mesodermal adult BM-MSCs. eMSCs showed comparable osteogenic and chondrogenic ability to BM-MSCs in 2-D in vitro culture, but lower adipogenic ability. They exhibited greater proliferation than BM-MSCs and comparable construct mineralization in a well-established 3-D polycaprolactone-tricalcium phosphate (PCL-TCP) scaffold system in vitro. eMSC-derived 3D osteogenic constructs were maintained for longer in a proliferative osteoblast state and exhibited differential levels of genes related to fibroblast growth factor (FGF) signaling compared to BM-MSCs. Although both eMSC and BM-MSC-seeded scaffold constructs could promote bone regeneration in a rat calvarial defect model, eMSC-derived osseous constructs had significantly higher cellularity due to increased number of proliferative (Ki67+) cells than those seeded with BM-MSCs, and exhibited enhanced new bone formation in the defect area as compared to untreated controls. Overall, our study demonstrates the potential of human eMSCs for future clinical use in craniofacial regeneration applications and indicates the importance of considering MSC origin when selecting an MSC source for regenerative applications. </p

Comparative Craniofacial Bone Regeneration Capacities of Mesenchymal Stem Cells Derived from Human Neural Crest Stem Cells and Bone Marrow

Most craniofacial bones are derived from the ectodermal germ layer via neural crest stem cells, which are distinct from mesoderm-derived long bones. However, current craniofacial bone tissue engineering approaches do not account for this difference and utilize mesoderm-derived bone marrow mesenchymal stem cells (BM-MSCs) as a paradigm cell source. The effect of the embryonic origin (ontogeny) of an MSC population on its osteogenic differentiation potential and regenerative ability still remains unresolved. To clarify the effects of MSC ontogeny on bone regenerative ability, we directly compared the craniofacial bone regenerative abilities of an ecto-mesenchymal stem cell (eMSC) population, which is derived from human embryonic stem cells via a neural crest intermediate, with mesodermal adult BM-MSCs. eMSCs showed comparable osteogenic and chondrogenic ability to BM-MSCs in 2-D in vitro culture, but lower adipogenic ability. They exhibited greater proliferation than BM-MSCs and comparable construct mineralization in a well-established 3-D polycaprolactone-tricalcium phosphate (PCL-TCP) scaffold system in vitro. eMSC-derived 3D osteogenic constructs were maintained for longer in a proliferative osteoblast state and exhibited differential levels of genes related to fibroblast growth factor (FGF) signaling compared to BM-MSCs. Although both eMSC and BM-MSC-seeded scaffold constructs could promote bone regeneration in a rat calvarial defect model, eMSC-derived osseous constructs had significantly higher cellularity due to increased number of proliferative (Ki67+) cells than those seeded with BM-MSCs, and exhibited enhanced new bone formation in the defect area as compared to untreated controls. Overall, our study demonstrates the potential of human eMSCs for future clinical use in craniofacial regeneration applications and indicates the importance of considering MSC origin when selecting an MSC source for regenerative applications. </p

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research