Abstract Accelerometry (ACC) shows promise as an easily implemented clinical measure of balance. The purpose of the study was to estimate test–retest reliability of ACC measures and determine the ...relationship between ACC measured at the pelvis and underfoot center of pressure (COP) measures during sensory organization test (SOT) conditions. Eighty-one subjects were recruited from the community with no known orthopedic or vestibular deficits (19–85 years). Subjects completed three consecutive, ninety second trials for each of the six SOT conditions, while wearing the accelerometer. ACC and COP time series were described by calculating the normalized path length, root mean square (RMS), and peak-to-peak values. The test–retest reliability of the three measures within each SOT condition was estimated over three trials using the intraclass correlation coefficient. ACC and COP test–retest reliability were similar, ranging from 0.63 to 0.80 using ACC and 0.42 to 0.81 using COP for the measure of normalized path length. Linear regression between ACC and COP measures showed significant correlation under almost every SOT condition using both single and average measures across trials. The degree of association between COP and ACC was equivalent when using the first trial or the 3-trial average, suggesting that one trial may be sufficient. The use of accelerometry may have value in estimating balance function and minimizing clinical evaluation time.
Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression ...signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.
Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.
Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001. Median survival HR (95% CI) by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.
The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
•A gene expression signature for high-grade serous ovarian cancer prognostic for 2- and 5-year overall survival (OS).•The 101 gene expression signature performs substantially better than age and stage alone.•Median survival by quintile was 9.5, 5.4, 3.8, 3.2 and 2.3 years.•The top five genes associated with OS were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001).
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show ...mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.
Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.
FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).
FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers.
G D Gentzkow ,
S D Iwasaki ,
K S Hershon ,
M Mengel ,
J J Prendergast ,
J J Ricotta ,
D P Steed and
S Lipkin
Advanced Tissue ...Sciences, Inc., La Jolla, CA 92037, USA.
Abstract
OBJECTIVE: To assess the effect of a tissue-engineered human dermis (Dermagraft) in healing diabetic foot ulcers. RESEARCH
DESIGN AND METHODS: This controlled prospective multicenter randomized single-blinded pilot study evaluated healing over a
12-week period in 50 patients with diabetic foot ulcers. These patients were randomized into four groups (three different
dosage regimens of Dermagraft and one control group). All patients received identical care except for the use of Dermagraft
tissue. Ulcer healing was assessed by percentage of wounds achieving complete or 50% closure, time to complete or 50% closure,
and volume and area measurements. RESULTS: Ulcers treated with the highest dosage of Dermagraft, one piece applied weekly
for 8 weeks (group A), healed significantly more often than those treated with conventional wound closure methods; 50% (6
of 12) of the Dermagraft-treated and 8% (1 of 13) of the control ulcers healed completely (P = 0.03). The percentage of wounds
achieving 50% closure was also significantly higher (75 vs. 23%; P = 0.018), and the time to complete or 50% closure was faster
(P = 0.056). The group A regimen was more effective than other treatment regimens. All three were better than the control,
however, and a dose-response was observed. There were no safety concerns. After a mean of 14 months of follow-up (range 11-22
months), there were no recurrences in the Dermagraft-healed ulcers. CONCLUSIONS: Dermagraft was associated with more complete
and rapid healing in diabetic foot ulcers. The recurrence data may indicate an improved quality of wound healing.
PURPOSETo evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian ...high-grade serous carcinoma (HGSC).EXPERIMENTAL DESIGNRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss.RESULTSRB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.CONCLUSIONSCo-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
Structure−activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now ...synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Δ8-THC. Our lead compound, (−)-3-(1-adamantyl)-Δ8-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.
Structures of trans-dichlororuthenium(II) complexes of aminodiphosphines RN(CH2CH2PPh2)2 (1a−d, PNP) and aminophosphines RN(H)CH2CH2PPh2 (2a−d, PNH) ligands are examined. The comparative reactivity ...of these metal complexes in ruthenium-catalyzed transfer hydrogenation reactions is subsequently evaluated.
Enhanced recovery pathways have been shown to reduce length of stay without increasing readmission or complications in numerous areas of surgery. Uptake of gynecologic oncology ERAS guidelines has ...been limited. We describe the effect of ERAS guideline implementation in gynecologic oncology on length of stay, patient outcomes, and economic impact for a province-wide single-payer system.
We compared pre- and post-guideline implementation outcomes in consecutive staging and debulking patients at two centers that provide the majority of surgical gynecologic oncology care in Alberta, Canada between March 2016 and April 2017. Clinical outcomes and compliance were obtained using the ERAS Interactive Audit System. Patients were followed until 30 days after discharge. Negative binomial regression was employed to adjust for patient characteristics.
We assessed 152 pre-ERAS and 367 post-ERAS implementation patients. Mean compliance with ERAS care elements increased from 56% to 77.0% after implementation (p < 0.0001). Median length of stay for all surgeries decreased from 4.0 days to 3.0 days post-ERAS (p < 0.0001), which translated to an adjusted LOS decrease of 31.4% (95% CI = 21.7% - 39.9%, p < 0.0001). In medium/high complexity surgery median LOS was reduced by 2.0 days (p = 0.0005). Complications prior to discharge decreased from 53.3% to 36.2% post-ERAS (p = 0.0003). There was no significant difference in readmission (p = 0.6159), complications up to 30 days (p = 0.6274), or mortality (p = 0.3618) between the cohorts. The net cost savings per patient was $956 (95%CI: $162 to $1636).
Systematic implementation of ERAS gynecologic oncology guidelines across a healthcare system improves patient outcomes and saves resources.
•Implementation of ERAS gynecologic oncology guidelines results in significant clinical improvements and cost savings.•Use of an audit system allows measurement of compliance to the individual ERAS recommendations.•ERAS teams should strive to improve compliance to guidelines as this translates into improved outcomes.
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