Efficacy of the modified Frailty Index and the modified Charlson Comorbidity Index in predicting complications in patients undergoing operative management of proximal humerus fracture.

BACKGROUND: Comorbidity indices such as the 5-factor modified Frailty Index (mFI-5) and modified Charlson Comorbidity Index (mCCI) are widely used in outcomes research. METHODS: A total of 3893 patients who underwent total shoulder arthroplasty (n=975), hemiarthroplasty (n=495), or open reduction and internal fixation (n=2423) for the treatment of proximal humerus fracture from 2005-2017 were identified from the National Surgical Quality Improvement Program database. Data regarding demographics, comorbidities, American Society of Anesthesiologists class, and postoperative complications were collected, and the mFI-5 and mCCI were calculated for each case. Multivariate logistic regression models and receiver operating characteristic curve analyses were performed. RESULTS: The patient population had a mean age of 68.0 ± 13.2 years, body mass index of 29.1 ± 8.1 and mean operative time of 119.9 ± 55.5 minutes. The most common complications within this cohort were extended length of stay (4 days or more) (1085/3893; 27.87%), transfusion (377/3893; 9.68%), unplanned reoperation (97/3893; 2.49%), urinary tract infection (43/3893; 1.10%), death (42/3893; 1.08%), and deep vein thrombosis (40/3893; 1.03%). After accounting for patient demographics, the mFI-5 (odds ratio [OR] = 1.105, P < .001) and mCCI (OR = 1.063, P < .001) were significantly associated with incidence of any adverse event. Both comorbidity indices had low positive predictive value and high negative predictive value for all adverse events. CONCLUSION: The comorbidity indices mCCI and mFI-5 are both strongly associated with adverse events but have moderate ability to predict complications following surgical treatment of proximal humerus fractures.

Comparison of Outcomes for Elderly Gastric Cancer Patients at Least 80 Years of Age Following Gastrectomy in the United States and China.

OBJECTIVE: The aim of this study was to compare gastric cancer (GC) patients aged 80 years or older undergoing gastrectomy at two high-volume cancer centers in the US and China. METHODS: Patients aged ≥ 80 years who underwent R0 resection at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, USA (n = 159), and Fujian Medical University Union Hospital (FMUUH) in Fujian, China (n = 118) from January 2000 to December 2013 were included. Demographic, surgical, and pathologic variables were compared, and factors associated with survival were determined via multivariate analysis. RESULTS: The number of patients increased annually in the FMUUH cohort but not in the MSKCC cohort. Patients at MSKCC were slightly older (mean age 83.7 vs. 82.7 years), more commonly female (38 vs. 19%), and had higher average body mass index (BMI; 26 vs. 23). Treatment at FMUUH more frequently employed total gastrectomy (59 vs. 20%) and laparoscopic surgery (65 vs. 7%), and less frequently included adjuvant therapy (11 vs. 18%). In addition, FMUUH patients had larger tumors of more advanced T, N, and TNM stage. Morbidity (35 vs. 25%, p = 0.08) and 30-day mortality (2.5 vs. 3.3%, p = 0.67) were similar between the cohorts. For each TNM stage, there was no significant difference between MSKCC and FMUUH patients in 5-year overall survival and disease-specific survival (DSS). TNM stage was the only independent predictor of DSS for both cohorts. CONCLUSIONS: Patients ≥ 80 years of age selected for gastrectomy for GC at MSKCC and FMUUH had acceptable morbidity and mortality, and DSS was primarily dependent on TNM stage.

PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas.

The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)-Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%. Using a human phospho-kinase antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher in tumor tissue compared with normal tissue. Together, these results indicate that the Akt1/2-Nanog pathway is critical for maintenance of sarcoma CSCs and spheroid-forming cells, supporting further exploration of this pathway as a therapeutic target in sarcoma.

Measurement accuracy of 3-Dimensional mapping technologies versus standard goniometry for angle assessment.

BACKGROUND: A specific aspect of the hypospadias phenotype that may contribute to long-term outcomes is the presence of ventral penile curvature and the adequacy of its surgical correction. The current gold standard to assess this angle is intraoperative goniometry of an erect penis. 3-dimensional (3D) mapping technologies may overcome the limitations of these traditional methods through their combination of digital image and geometric replication to produce consistent 3D digital forms of a physical structure. The aim of this study is to evaluate the measurement accuracy and reliability of handheld 3D mapping technologies versus standard goniometry for angle assessment in a laboratory setting. METHODS: Blocks with specified angles (10-45°) were printed using a Zortrax M200 3D printer (±0.2% accuracy). Following the completion of standardized training, blinded participants measured each block angle using a baseline digit goniometer. Additionally, complete digital models of the blocks were created using 3D mapping technologies. Structured light scanning was completed using an Artec Space Spider and Artec Studio 13. Traditional photogrammetry was completed using a Canon Eos Rebel T5i DSLR camera and Agisoft Metashape Pro. Photogrammetry with a 3D camera was completed using the VECTRA H1 and VECTRA Analysis Module. All 3D models were imported into the software Autodesk Inventor in which automated angle measurements through the central plane were obtained. Statistical analysis was performed to determine the accuracy, precision and reliability of each modality using SAS 9.4 software. The reliability of goniometry and each mapping technology was evaluated using two-way random effect models with absolute agreement. RESULTS: Six 3D printed blocks were evaluated. 5 digital models per block were created using each of the 3 mapping technologies. Inter-rater reliability of goniometry was moderate (ICC 0.76, 95% CI 0.46, 0.92), whereas all mapping technologies demonstrated excellent test-retest reliability: structured light scanning (ICC 0.99; 95% CI 0.999, 0.999); traditional photogrammetry (0.99; 0.99, 0.99); 3D camera (0.99; 0.99, 0.99). Mean angle measurements and standard error for each angle and modality are provided in the table. CONCLUSIONS: This study demonstrated excellent accuracy, precision and reliability of off-the-shelf, handheld 3D mapping technologies and moderate reliability for goniometry when applied to measurements of angulation in a laboratory setting. The described methods developed in the laboratory for optimization of angle analysis from 3D models are an important step toward reliable, reproducible phenotypic analysis of congenital genitourinary conditions in future intraoperative and database development applications.

Platelet-derived growth factor receptor-α and -ß promote cancer stem cell phenotypes in sarcomas.

Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and ß (PDGFR-α/ß) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-α/ß in sarcoma CSCs. PDGFR-α/ß activity and the effects of PDGFR-α/ß inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-α/ß activity was significantly higher in cells grown as spheroids (to enrich for CSCs) and in cells sorted for CD133 expression (a marker of sarcoma CSCs). Self-renewal transcription factors Nanog, Oct4, and Slug and epithelial-to-mesenchymal transition (EMT) proteins Snail, Slug, and Zeb1 were also significantly higher in spheroids cells and CD133(+) cells. Spheroid cells and CD133(+) cells demonstrated 2.9- to 4.2-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGFR-α/ß in CSCs using shRNA or pharmacologic inhibitors reduced expression of certain self-renewal and EMT proteins, reduced spheroid formation by 74-82%, reduced migration and invasion by 73-80%, and reversed chemotherapy resistance. In mouse xenograft models, combining PDGFR-α/ß inhibition (using shRNA or imatinib) with doxorubicin had a more-than-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133(+) cells. These results indicate that PDGFR-α/ß activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-α/ß pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.