Preoperative comprehensive geriatric assessment and multidisciplinary team input in older people undergoing elective orthopaedic surgery: A feasibility trial.

OBJECTIVE: To determine the feasibility of preoperative comprehensive geriatric assessment (CGA) and multidisciplinary team (MDT) input for older people undergoing elective orthopaedic surgery in a tertiary New Zealand setting. METHODS: This single-centre retrospective study included elective orthopaedic patients older than 65 years (and Maori/Pasifika aged greater than 55 years) with hyperpolypharmacy, frailty, neurocognitive disorders and poor functional status. Patients attended a preoperative clinic where they had a geriatrician-led CGA along with MDT input. The feasibility of this preoperative model was assessed using outcomes of acceptability, accessibility and adherence. A qualitative description of patient demographics along with clinic assessment and interventions further describes this pilot experience. RESULTS: Sixty patients met inclusion criteria. This group were vulnerable older people (median age 77 years), with a high incidence of hyperpolypharmacy (85%), frailty (80%) and neurocognitive disorders (30%). Acceptability was high (97%), along with CGA accessibility (100%); however, MDT accessibility varied (53-90%). Adherence to MDT intervention was low; with only 26% of patients completing physiotherapy sessions and only 29% adhering to dietary advice. Accurate recall was a significant factor contributing to poor adherence. Comprehensive geriatric assessment was demonstrated to be a broad and flexible intervention. CONCLUSIONS: CGA with MDT input is an acceptable and accessible intervention to be utilised as part of improved preoperative care for the older person undergoing elective orthopaedic surgery. Further consideration around methods to increase adherence in this patient group should be explored. Future research should focus on refining the intervention, and quantifying impact on patient outcomes.

A randomised controlled pilot trial of two interventions to manage dry mouth in pre-operative elective surgical patients.

BACKGROUND: Dry mouth is a common perioperative patient complaint. There are a number of treatments used for dry mouth in other settings which are effective. None have been tested previously in the perioperative setting. Interventions to Manage Dry mouth (IM DRY) compared the effect of water and a saliva substitute on mouth dryness. The primary objective was to demonstrate the feasibility of conducting a large randomised controlled trial and secondary scientific aims were to assess treatment potential efficacy. METHODS: Single blind, pilot randomised controlled trial (RCT) of 101 pre-operative elective surgical patients who were randomised to water or saliva substitute (Biotene oral rinse, GlaxoSmithKline, Australia) at a tertiary, university hospital. Dry mouth was assessed by 100 mm visual analogue scale (VAS) and 5-point Likert score. RESULTS: One hundred participants completed follow-up and comprised the analysis dataset. All feasibility outcomes were achieved (recruitment rate > 5 participants a week, >95% completeness of the dataset, study protocol acceptability to staff, acceptability to participants > 66% and adherence to time limits within the protocol). Mean recruitment rate was 6 participants per week. These data were 99% complete. There were no adverse side effects or complications noted. There were no concerns raised by staff regarding acceptability. Overall, there was a mean of 30 min (± SD 5 min) between delivery of the intervention and the assessment, 30 min being the target time. The difference in VAS post intervention was - 11.2 mm (95% CI - 17.3 to - 5.1 mm) for water and - 12.7 mm (95% CI - 18.7 to - 6.7 mm) for saliva substitute. The proportion of patients who had improved dry mouth increased from 52% for water to 62% for saliva substitute. CONCLUSIONS: IM DRY successfully achieved its primary feasibility aims: recruitment rate, completeness of these, acceptability and protocol adherence. Saliva substitutes, used in the perioperative management of dry mouth, may be a simple, inexpensive, and low risk solution to help alleviate this common complaint. A large randomised controlled trial is feasible and is currently recruiting (ANZCTR 12619000132145). ETHICS AND TRIAL REGISTRATION: Northern A New Zealand Health and Disability Ethics Committee (reference 17/NTA/152). Australian New Zealand Clinical Trials Registry (Number: 12618001270202). Registered retrospectively 18 October 2018.

Multicellular Spheroids as a Model for Hypoxia-induced EMT.

Oral cancer is aggressive and invasive. The 5-year survival rate is around 50% and has not improved in over 50 years. One-third of oral cancer patients develop local and/or regional tumor recurrence following treatment. We continue to use our multicellular spheroid (MCS) model to better understand how the extracellular matrix contributes to epithelial to mesenchymal transition and how hypoxia contributes to the progression of oral squamous cell carcinoma (SCC).

Differential diagnosis and management of oral ulcers.

The diagnosis and treatment of oral lesions is often challenging due to the clinician's limited exposure to the conditions that may cause the lesions and their similar appearances. While many oral ulcers are the result of chronic trauma, some may indicate an underlying systemic condition such as a gastrointestinal dysfunction, malignancy, immunologic abnormality, or cutaneous disease. Correctly establishing a definitive diagnosis is of major importance to clinicians who manage patients with oral mucosal disease. Some of these diseases are infectious; however, most are chronic, symptomatic, and desquamative. Treatment and management requires an understanding of the immunopathologic nature of the lesion. This review will address how to differentiate and diagnose varying types of oral ulcers and provide a treatment strategy.

Differential spheroid formation by oral cancer cells.

Squamous cell carcinomas (SCC) make up 96% of all oral cancers. Most laboratory SCC studies grow cells as a monolayer, which does not accurately represent the disease in vivo. We used a more relevant multicellular spheroid (MCS) model to study this disease. The SCC9ß6KDFyn cell line, which expresses full-length ß6 and a kinase dead Fyn formed the largest MCS. Cell adhesive properties are dynamic and N-cadherin was increased in the largest MCS. c-Raf mediates the survival of tumor cells and was consistently expressed both in monolayers and in the MCS by SCC9ß6D1 cells which lack the ß6 cytoplasmic tail and, do not activate Fyn. SCC9ß6KDFyn cells also express high levels of c-Raf when grown as spheroids in which Fyn suppression stimulates MCS formation. Tumor microenvironment and growth patterns modulate cell behavior and suppression of Fyn kinase may promote MCS growth.

The cytoplasmic extension of the integrin ß6 subunit regulates epithelial-to-mesenchymal transition.

Prognosis for oral cancer patients has not improved in over 60 years due to invasion and recurrence. To understand the invasive behavior of this tumor, we evaluated the role of the αvß6 integrin. Invasive oral SCC cells express the αvß6 integrin, which contains an 11-amino-acid extension on its ß-subunit unique to the integrin family. We determined that this ß6 cytoplasmic extension regulates the composition of the intermediate filament network and the organization of signaling structures called focal contacts. The auto-phosphorylation of FAK, which is localized to focal contacts, was also regulated by the ß6-cytoplasmic tail, as were the transcription factors Notch and STAT3. Lastly, we also determined that activation of MAPK required the full-length ß6 integrin. Together these results indicate that the signaling critical to epithelial-to-mesenchymal transition (EMT) is regulated by the ß6 integrin cytoplasmic domain.

Expression of EMMPRIN modulates mediators of tumor invasion in oral squamous cell carcinoma.

Squamous cell carcinoma (SCC) accounts for 96 percent of all intraoral malignancies. The five-year survival rate is 50 percent and has not improved in 60 years. During SCC progression, subsets of SCC cells undergo an epithelial-to-mesenchymal transition (EMT) to become highly invasive. The extracellular matrix metalloproteinase inducer (EMMPRIN) contributes to EMT by activating local matrix metalloproteinases (MMPs). In this study, we found that EMMPRIN modulates the invasive phenotype and may be a potential therapeutic target.

Revisiting epithelial-to-mesenchymal transition through adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) has a 5-year survival rate of 90%. The 15-year survival rate drops to 10% due to recurrence and invasion. ACC has three subtypes: cribriform, tubular, and solid. The cribriform subtype has the best prognosis and the solid subtype has the worst prognosis. By immunohistochemistry of tissue sections, we showed that the solid form expresses αvß6 integrin and tenascin-C, which are known promoters of epithelial-to-mesenchymal transition (EMT). We also defined two ACC cell lines with the characteristics of the cribriform and solid subtype. The SACC83 cells grow in basaloid-like clusters and express high levels of E-cadherin. In contrast, the ACCh cells are more myoepithelial-like and express high levels of vimentin and of αvß6 integrin. The ACCh cells are highly invasive and this behavior is dependent upon the αvß6 integrin function. Our results suggest that the transition from the cribriform to solid form may occur through EMT.

Stem cell markers as predictors of oral cancer invasion.

We previously showed that within primary tumors there exist subpopulations of cells expressing stem cell markers. Using immunofluorescence and western blotting, we examined the expression of stem cell markers tumor-rejection antigen 1-60 (TRA1-60) and octamer-binding transcription factor 3/ 4 (OCT3/4) to determine their relationship with cell invasiveness. Six human oral cancer cell lines were examined and a direct correlation was found between expression of these stem cell markers and invasion. Poor expression of E-cadherin and increased expression of N-cadherin was also found in TRA1-60- and OCT3/4- expressing cells. Phosphorylation of the major signaling molecule mitogen activated protein kinase (MAPK) was greatest in the TRA1-60- and OCT3/4- expressing cells. These results suggest that expression of specific stem cell markers in tumors may help guide a clinician's choice of treatment.

Alphavbeta3 suppresses the RhoA-LIMK1 pathway in K1735 melanoma.

Mucocutaneous melanoma has a five-year survival rate of less than 10 percent. The alphavbeta3 integrin promotes invasion, which requires actin reorganization by cofilin. The authors previously showed that cofilin and alphavbeta3 promote invasion. K1735 melanoma has several clones, each with different levels of alphavbeta3. The authors found that expression of alphavbeta3 suppresses activation of RhoA thus inhibiting LIMK1 phosphorylation of cofilin. This indicates that alphavbeta3 integrin suppresses the RhoA/ ROCK/LIMK1 pathway.

Prevalent dietary supplement use in older New Zealand men.

AIMS: Because of a lack of recent data from New Zealand older men, we examined dietary supplement use in this demographic. METHODS: We surveyed men aged $gt;40 years who were participating in a trial of calcium supplementation on bone and cardiovascular outcomes. RESULTS: Forty-seven percent reported using at least one supplement and 30% of users took more than two different supplements. Amongst users, median monthly expenditure on these products was NZ$20 (interquartile range: $10-$45). The most common supplements used were vitamins or minerals (49%), followed by nutritional oils (22%) (including fish oils, 13%) and glucosamine/chondroitin preparations (13%). Supplements were mainly taken for reasons of non-specific prophylaxis or health maintenance (58% of reasons), although 21% of reasons cited treatment or symptom alleviation for a medical condition. Daily requirements for vitamins A, D and E were exceeded, from supplement intake alone, by 12%, 10% and 40% of supplement users respectively. CONCLUSIONS: Many older New Zealand men spend substantial amounts of money on dietary supplements despite uncertain health benefits. Health professionals should remain alert to supplement use by their patients, including males.

Evaluation of the FRAX and Garvan fracture risk calculators in older women.

Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5-year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T-score -1.3) were used to estimate fracture risk during follow-up using the FRAX and Garvan calculators. The FRAX-New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67-0.70; osteoporotic fracture 0.62-0.64; any fracture 0.60-0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use.

Expression of Fyn kinase modulates EMT in oral cancer cells.

Oral squamous cell carcinoma (SCC) is an aggressive tumor with a poor 5-year survival rate. Oral SCC can undergo epithelial to mesenchymal transition (EMT). We previously showed that the epithelial integrin alphavbeta6 complexes with Fyn kinase in oral SCC to promote EMT. Using immunofluorescence microscopy and Western blotting, we evaluated whether the expression of specific markers of EMT were influenced by modulating serum concentration (ie. growth factors). The SCC cultures were grown under contrasting levels of serum. In low serum (1%), Fyn promoted EMT; whereas suppression of Fyn kinase promoted the epithelial phenotype. However, when the SCC cells were grown in 10% serum, activation of Fyn had the reverse effect. Lastly, cell migration was evaluated under low serum conditions (1% FBS). Activation of Fyn promoted SCC cell migration and its suppression thwarted SCC migration toward FN. These results indicate that the activation of Fyn kinase as well as local growth factor concentration modulate EMT in oral SCC.