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Article ; Online: Does the form of venous thromboembolism prophylaxis following primary total knee arthroplasty alter the rate of early reoperation or revision surgery?

Kerr, David L / Butler, Stephen / Read, Andrew C / Harris, Ian A

2019 Volume 89, Issue 10, Page(s) 1211–1216

Abstract: Background: Currently there is significant variation in the management of venous thromboembolism prophylaxis following total knee arthroplasty (TKA). Excessive wound ooze and bleeding is thought to increase a patient's risk of haematoma formation and ... ...

Abstract	Background: Currently there is significant variation in the management of venous thromboembolism prophylaxis following total knee arthroplasty (TKA). Excessive wound ooze and bleeding is thought to increase a patient's risk of haematoma formation and possible infection. We evaluated the rate of unexpected reoperation in the perioperative period in patients who received aspirin, rivaroxaban or enoxaparin following primary TKA. Method: A systematic literature search was conducted in MEDLINE, CENTRAL and Embase to identify patients who underwent primary TKA. Two researchers independently reviewed the references identified in the literature search. The final 11 studies included for review were published between 1996 and 2016. Results: There was a higher rate of reoperation in patients treated with aspirin following TKA when compared to enoxaparin and rivaroxaban in the perioperative period. Of the 5141 patients treated with enoxaparin, 11 (0.21%) required reoperation; of the 2764 patients treated with rivaroxaban, 12 (0.43%) required reoperation; and of the 228 patients treated with aspirin, seven (3.07%) required reoperation. The average time to follow-up in the 11 studies was 55 days, ranging from 30 to 180 days post-operatively. Conclusion: There was a higher rate of reoperation in patients treated with aspirin following TKA when compared to enoxaparin and rivaroxaban in the perioperative period. While there is extensive data on the safety and efficacy of these medications following joint arthroplasty, improved reporting of surgically relevant outcomes are needed to assist both the surgeon and patient in clinical decision-making.
MeSH term(s)	Arthroplasty, Replacement, Knee/adverse effects ; Aspirin/therapeutic use ; Australia/epidemiology ; Case-Control Studies ; Clinical Decision-Making/methods ; Enoxaparin/therapeutic use ; Factor Xa Inhibitors/therapeutic use ; Heparin, Low-Molecular-Weight/therapeutic use ; Humans ; Perioperative Period/statistics & numerical data ; Platelet Aggregation Inhibitors/therapeutic use ; Postoperative Complications/epidemiology ; Randomized Controlled Trials as Topic ; Reoperation/statistics & numerical data ; Reoperation/trends ; Rivaroxaban/therapeutic use ; Safety ; Treatment Outcome ; Venous Thromboembolism/prevention & control
Chemical Substances	Enoxaparin ; Factor Xa Inhibitors ; Heparin, Low-Molecular-Weight ; Platelet Aggregation Inhibitors ; Rivaroxaban (9NDF7JZ4M3) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2019-06-24
Publishing country	Australia
Document type	Journal Article ; Systematic Review
ZDB-ID	2050749-5
ISSN	1445-2197 ; 1445-1433 ; 0004-8682
ISSN (online)	1445-2197
ISSN	1445-1433 ; 0004-8682
DOI	10.1111/ans.15296
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Zs.A 180: Show issues

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Article ; Online: Peripheral Nerve Block Delays Mobility and Increases Length of Stay in Patients With Geriatric Hip Fracture.

Morriss, Nicholas J / Kerr, David L / Cunningham, Daniel J / Kim, Billy I / MacAlpine, Elle M / LaRose, Micaela A / Wixted, Colleen M / Adu-Kwarteng, Kwabena / DeBaun, Malcolm R / Gage, Mark J

The Journal of the American Academy of Orthopaedic Surgeons

2023 Volume 31, Issue 12, Page(s) 641–649

Abstract: Introduction: Peripheral nerve blocks (PNB) has been increasingly used in the care of patients with geriatric hip fracture to reduce perioperative opiate use and the need for general anesthesia. However, the associated motor palsy may impair patients' ... ...

Abstract	Introduction: Peripheral nerve blocks (PNB) has been increasingly used in the care of patients with geriatric hip fracture to reduce perioperative opiate use and the need for general anesthesia. However, the associated motor palsy may impair patients' ability to mobilize effectively after surgery and subsequently may increase latency to key mobility milestones postoperatively, as well as increase inpatient length of stay (LOS). The aim of this study was to investigate time-to-mobility milestones and length of hospital stay between peripheral, epidural, and general anesthesia. Methods: A retrospective review identified 1,351 patients aged 65 years or older who underwent surgery for hip fracture between 2012 and 2018 at a single academic health system. Patients were excluded if baseline nonambulatory, restricted weight-bearing postoperatively, or sustained concomitant injuries precluding mobilization, with a final cohort of 1,013 patients. Time-to-event analyses for discharge and mobility milestones were assessed using univariate Kaplan-Meier and multivariate Cox proportional hazard regression analyses. Results: PNB was associated with delayed postoperative time to ambulation ( P < 0.001) and time to out-of-bed ( P = 0.029), along with increased LOS ( P < 0.001). Epidural anesthesia was associated with less delay to first out-of-bed ( P = 0.002), less delay to ambulation ( P = 0.001), and overall reduced length of stay ( P < 0.001). Discussion: PNB was associated with slower mobilization and longer hospitalization while epidural anesthesia was associated with quicker mobilization and shorter hospital stays. Epidural anesthesia may be a preferable anesthesia choice in patients with geriatric hip fracture when possible. Level of evidence: Level III.
MeSH term(s)	Humans ; Aged ; Length of Stay ; Hip Fractures/surgery ; Anesthesia, Conduction ; Hospitalization ; Retrospective Studies
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1200524-1
ISSN	1940-5480 ; 1067-151X
ISSN (online)	1940-5480
ISSN	1067-151X
DOI	10.5435/JAAOS-D-22-00277
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Zs.A 4048: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 274: Show issues

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Article ; Online: Soft Tissue Sarcoma of the Extremities: What Is the Value of Treating at High-volume Centers?

Lazarides, Alexander L / Kerr, David L / Nussbaum, Daniel P / Kreulen, R Timothy / Somarelli, Jason A / Blazer, Dan G / Brigman, Brian E / Eward, William C

Clinical orthopaedics and related research

2018 Volume 477, Issue 4, Page(s) 718–727

Abstract: Background: For many cancer types, survival is improved when patients receive management at treatment centers that encounter high numbers of patients annually. This correlation may be more important with less common malignancies such as sarcoma. ... ...

Abstract	Background: For many cancer types, survival is improved when patients receive management at treatment centers that encounter high numbers of patients annually. This correlation may be more important with less common malignancies such as sarcoma. Existing evidence, however, is limited and inconclusive as to whether facility volume may be associated with survival in soft tissue sarcoma. Questions/purposes: The purpose of this study was to examine the association between facility volume and overall survival in patients with soft tissue sarcoma of the extremities. In investigating this aim, we sought to (1) examine differences in the treatment characteristics of high- and low-volume facilities; (2) estimate the 5-year survival by facility volume; and (3) examine the association between facility volume and of traveling a further distance to a high-volume center and overall survival when controlling for confounding factors. Methods: The largest sarcoma patient registry to date is contained within the National Cancer Database (NCDB) and captures > 70% of new cancer diagnoses annually. We retrospectively analyzed 25,406 patients with soft tissue sarcoma of the extremities in the NCDB from 1998 through 2012. Patients were stratified based on per-year facility sarcoma volume and we used univariate comparisons and multivariate proportional hazards analyses to correlate survival measures with facility volume and various other patient-, tumor-, and treatment-related factors. First, we evaluated long-term survival for all variables using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multiple patient, tumor, and treatment characteristics were compared between the two facility-volume groups and then included them in the multivariate proportional hazards model. Of the 25,406 patients analyzed, 3310 were treated at high-volume centers (≥ 20 patients annually) and 22,096 were treated at low-volume centers. Patient demographics were generally not different between both patient cohorts, although patients treated at high-volume centers were more likely to have larger and higher grade tumors (64% versus 56% size ≥ 5 cm, 28% versus 14% undifferentiated grade, p < 0.001). Results: When controlling for patient, tumor, and treatment characteristics in a multivariate proportional hazards analysis, patients treated at high-volume facilities had an overall lower risk of mortality than those treated at low-volume centers (hazard ratio, 0.81 [0.75-0.88], p < 0.001). Patients treated at high-volume centers were also less likely to have positive margins (odds ratio [OR], 0.59 [0.52-0.68], p < 0.001) and in patients who received radiation, those treated at high-volume centers were more likely to have radiation before surgery (40.5% versus 21.7%, p < 0.001); there was no difference in the type of surgery performed (resection versus amputation) (OR, 1.01 [0.84-1.23], p = 0.883). Conclusions: With the largest patient cohort to date, this database review suggests that certain patients with soft tissue sarcoma of the extremities, particularly those with large high-grade tumors, may benefit from treatment at high-volume centers. Further investigation is necessary to help improve the referral of appropriate patients to high-volume sarcoma centers and to increase the treatment capacity of and access to such centers. Level of evidence: Level III, therapeutic study.
MeSH term(s)	Female ; Health Services Accessibility ; Hospitals, High-Volume ; Hospitals, Low-Volume ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Referral and Consultation ; Registries ; Retrospective Studies ; Risk Factors ; Sarcoma/mortality ; Sarcoma/pathology ; Sarcoma/surgery ; Soft Tissue Neoplasms/mortality ; Soft Tissue Neoplasms/pathology ; Soft Tissue Neoplasms/surgery ; Time Factors ; Transportation of Patients ; Treatment Outcome ; Tumor Burden ; United States
Language	English
Publishing date	2018-11-28
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	80301-7
ISSN	1528-1132 ; 0009-921X
ISSN (online)	1528-1132
ISSN	0009-921X
DOI	10.1097/01.blo.0000533623.60399.1b
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Uk I Zs.188: Show issues

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Article ; Online: Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Reddy, Gireesh B / Kerr, David L / Spasojevic, Ivan / Tovmasyan, Artak / Hsu, David S / Brigman, Brian E / Somarelli, Jason A / Needham, David / Eward, William C

Molecular cancer therapeutics

2020 Volume 19, Issue 7, Page(s) 1448–1461

Abstract: Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an ... ...

Abstract	Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied
Language	English
Publishing date	2020-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-19-0689
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Zs.A 5750: Show issues

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Article ; Online: Does facility volume influence survival in patients with primary malignant bone tumors of the vertebral column? A comparative cohort study.

Lazarides, Alexander L / Kerr, David L / Dial, Brian L / Steele, John R / Lane, Whitney O / Blazer, Dan G / Brigman, Brian E / Mendoza-Lattes, Sergio / Erickson, Melissa M / Eward, William C

The spine journal : official journal of the North American Spine Society

2020 Volume 20, Issue 7, Page(s) 1106–1113

Abstract: Background context: Facility volume has been correlated with survival in many cancers. This relationship has not been established in primary malignant bone tumors of the vertebral column (BTVC).: Purpose: To investigate whether facility patient ... ...

Abstract	Background context: Facility volume has been correlated with survival in many cancers. This relationship has not been established in primary malignant bone tumors of the vertebral column (BTVC). Purpose: To investigate whether facility patient volume is associated with overall survival in patients with primary malignant BTVCs. Study design: Retrospective comparative cohort. Patient sample: Adult patients with chordomas, chondrosarcomas, or osteosarcomas of the mobile spine. Outcome measures: Five-year survival. Methods: We retrospectively analyzed 733 patients with primary malignant BTVCs in the national cancer database from 2004 through 2015. Univariate and multivariate analyses were used to correlate specific outcome measures with facility volume. Volume was stratified based on cumulative martingale residuals to determine the inflection point of negative to positive impact on survival based on the patient cohort. Long-term survival was compared between patients treated at high and low volume using the Kaplan-Meier method. Only patients with malignant primary tumors were considered eligible for inclusion; patients with incomplete treatment data or benign tumors were excluded. Results: Patients treated at high-volume centers (HVCs) were younger (p=.0003) and more likely to be insured (p<.0001). There were no significant differences in tumor characteristics. Patients treated at high-volume facilities had improved 5-year survival of 71% versus 58% at low-volume centers (p<.0001). Patients treated at HVCs were more likely to receive surgical treatment (91% vs. 80%, p<.0001); if surgery was performed, they were more likely to undergo an en bloc resection (48% vs. 30%, p<.0001). However, there were no differences in margin status or utilization of radiotherapy or chemotherapy between HVCs and low-volume centers. In a multivariate analysis, facility volume was independently associated with improved survival overall (HR 0.75 [0.58-0.97], p=.03). Conclusions: Primary malignant BTVCs are rare, even for HVCs. Despite this, patient survival was significantly improved when treatment was performed at HVCs.
MeSH term(s)	Chordoma ; Cohort Studies ; Humans ; Retrospective Studies ; Spinal Neoplasms/surgery ; Spine ; Treatment Outcome
Language	English
Publishing date	2020-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2037072-6
ISSN	1878-1632 ; 1529-9430
ISSN (online)	1878-1632
ISSN	1529-9430
DOI	10.1016/j.spinee.2020.02.020
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Zs.A 5898: Show issues

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Article: Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study.

Catanzano, Anthony A / Kerr, David L / Lazarides, Alexander L / Dial, Brian L / Lane, Whitney O / Blazer, Dan G / Larrier, Nicole A / Kirsch, David G / Brigman, Brian E / Eward, William C

Sarcoma

2019 Volume 2019, Page(s) 4878512

Abstract: Background: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we ... ...

Abstract	Background: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies. Methods: We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan-Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival. Results: Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76-1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58-1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38-0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52-1.06 and HR 0.93, 95% CI 0.71-1.21, respectively). Conclusions: Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.
Language	English
Publishing date	2019-10-13
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	1338527-6
ISSN	1357-714X
ISSN	1357-714X
DOI	10.1155/2019/4878512
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Zs.A 5073: Show issues

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Article ; Online: Epidemiologic and survival trends in adult primary bone tumors of the spine.

Kerr, David L / Dial, Brian L / Lazarides, Alexander L / Catanzano, Anthony A / Lane, Whitney O / Blazer, Dan G / Brigman, Brian E / Mendoza-Lattes, Sergio / Eward, William C / Erickson, Melissa E

The spine journal : official journal of the North American Spine Society

2019 Volume 19, Issue 12, Page(s) 1941–1949

Abstract: Background context: Malignant primary spinal tumors are rare making it difficult to perform large studies comparing epidemiologic, survival, and treatment trends. We investigated the largest registry of primary bone tumors, the National Cancer Database ( ...

Abstract	Background context: Malignant primary spinal tumors are rare making it difficult to perform large studies comparing epidemiologic, survival, and treatment trends. We investigated the largest registry of primary bone tumors, the National Cancer Database (NCDB), to compare epidemiologic and survival trends among these tumors. Purpose: To use the NCDB to describe current epidemiologic trends, treatment modalities, and overall survival rates in patients with chordomas, osteosarcomas, chondrosarcomas, and Ewing sarcomas of the mobile spine. The secondary objective was to determine prognostic factors that impact overall survival rates. Study design: Retrospective study. Patient sample: A total of 1,011 patients with primary bone tumors of the spine (377 chordomas, 223 chondrosarcomas, 278 Ewing sarcomas, and 133 osteosarcomas). Outcome measures: Five-year survival. Methods: We reviewed the records of 1,011 patients in the NCDB from 2004 through 2015 with histologically confirmed primary osteosarcoma, chondrosarcoma, Ewing sarcoma, or chordoma of the spine. Demographic, clinical, and outcomes data were compiled and compared using chi-squared tests and ANOVA. Long-term survival was compared using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multivariate analysis was performed to determine survival determinants. Results: Surgical resection was the primary mode of treatment for chondrosarcoma (90%), chordoma (84%), and osteosarcoma (80%). The treatment for Ewing sarcoma was multimodal involving chemotherapy, radiation therapy, and surgical resection. Five-year survival rates varied significantly with chordomas and chondrosarcomas having the greatest survival (70% and 69%), osteosarcomas having the worse survival (38%), and Ewing having intermediate 5-year survival at 62% (overall log-rank p<.0001). Multivariate analysis demonstrated significantly improved 5-year survival rates with younger age at diagnosis, private insurance status, lower comorbidity score, lower tumor grade, smaller tumor size, surgical resection, and negative surgical margin. Radiation therapy only improved survival for Ewing sarcoma. Conclusions: This study provides the most comprehensive description of the epidemiologic, treatment, and survival trends of primary bone tumors of the mobile spine. Second, patient and tumor characteristics associated with improved 5-year survival were identified using a multivariate model.
MeSH term(s)	Adolescent ; Adult ; Aged ; Chondrosarcoma/epidemiology ; Chondrosarcoma/surgery ; Chordoma/epidemiology ; Chordoma/surgery ; Female ; Humans ; Male ; Middle Aged ; Neurosurgical Procedures/statistics & numerical data ; Sarcoma, Ewing/epidemiology ; Sarcoma, Ewing/surgery ; Spinal Neoplasms/epidemiology ; Spinal Neoplasms/surgery ; Survival Rate
Language	English
Publishing date	2019-07-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2037072-6
ISSN	1878-1632 ; 1529-9430
ISSN (online)	1878-1632
ISSN	1529-9430
DOI	10.1016/j.spinee.2019.07.003
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Zs.A 5898: Show issues

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Article ; Online: The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database.

Dial, Brian L / Kerr, David L / Lazarides, Alexander L / Catanzano, Anthony A / Green, Cindy L / Risoli, Thomas / Blazer, Dan G / Goodwin, Rory C / Brigman, Brian E / Eward, William C / Larrier, Nicole A / Kirsch, David G / Mendoza-Lattes, Sergio A

Spine

2020 Volume 45, Issue 12, Page(s) E742–E751

Abstract: Study design: Retrospective review.: Objective: To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas.: Summary of background data: The role of RT for the treatment of chordomas ... ...

Abstract	Study design: Retrospective review. Objective: To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas. Summary of background data: The role of RT for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve OS, but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas following surgical resection. Methods: Patients were stratified based on surgical margin status (positive vs. negative). Utilizing the Kaplan-Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic RT). OS was subsequently compared between patients treated with palliative dose (<40 Gy), low dose (40-65 Gy), and high dose (>65 Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality. Results: One thousand four hundred seventy eight chordoma patients were identified; skull base (n = 567), sacral (n = 551), and mobile spine (n = 360). Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82% vs. 71%, P = 0.03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared with palliative and low dose RT (P < 0.001). Advanced RT techniques and SRS were associated with improved OS compared with EBRT. In the multivariate analysis high dose advanced RT (>65 Gy) was superior to EBRT. Conclusion: Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and cumulative dose more than 65 Gy. Level of evidence: 4.
MeSH term(s)	Adult ; Aged ; Chordoma/radiotherapy ; Chordoma/surgery ; Databases, Factual ; Female ; Humans ; Male ; Middle Aged ; Proton Therapy ; Radiotherapy Dosage ; Radiotherapy, Adjuvant ; Radiotherapy, Intensity-Modulated ; Retrospective Studies ; Sacrum ; Skull Base
Language	English
Publishing date	2020-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	752024-4
ISSN	1528-1159 ; 0362-2436
ISSN (online)	1528-1159
ISSN	0362-2436
DOI	10.1097/BRS.0000000000003406
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Zs.A 1305: Show issues

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Article ; Online: E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms.

Molecular cancer research : MCR

2019 Volume 17, Issue 6, Page(s) 1391–1402

Abstract: CDH1 (also known as E-cadherin), an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a ... ...

Abstract	CDH1 (also known as E-cadherin), an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth. IMPLICATIONS: We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.
MeSH term(s)	Antigens, CD/metabolism ; Cadherins/metabolism ; Cell Line, Tumor ; Cell Proliferation/physiology ; Down-Regulation/physiology ; Epithelial-Mesenchymal Transition/physiology ; Humans ; Prognosis ; Sarcoma/metabolism ; Signal Transduction/physiology ; Up-Regulation/physiology
Chemical Substances	Antigens, CD ; CDH1 protein, human ; Cadherins
Language	English
Publishing date	2019-03-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-18-0763
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Zs.A 5744: Show issues

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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