Masticatory performance in oral function assessment: Alternative methods.

BACKGROUND: Masticatory function declines with age or disease, implicating a poor chewing efficiency and an often-unconscious change for a less healthy, yet easy to chew diet. Timely screening of masticatory function may foster an early-onset diagnosis and potential treatment. The aim of this study was to compare alternative diagnostic tools for masticatory function to a Jelly-scan test. MATERIALS AND METHODS: Patients aged 70 years and older who were hospitalised for rehabilitation were recruited for this study. A total of four different tests for masticatory function were administered. The Japanese Society of Gerodontology glucose extraction test (Jelly-scan) was used as reference to compare a colour-changing gum test (Gum1-colour) as well as a mixing ability test with a visual (Gum2-visual) and opto-electronical (Gum2-digital) analyses. Receiver operating characteristic (ROC) curves were used to establish the discriminative value, kappa-values were used to estimate individual agreements and correlations were verified using Spearman's tests. RESULTS: Sixty-one patients (Men n = 23, Women n = 38) aged 82.4 ± 6.8 years participated in the experiments. The average number of natural teeth was 16.5 ± 10.5, 34.4% of the participants wore removable dentures. For all tests, the sum of sensitivity and specificity was >150%. All test correlated with Jelly-scan (absolute Rho >0.5). With Jelly-scan 51 participants (83.6%) were diagnosed with "masticatory hypofunction". After reducing the cut-off value of the test from 100 mg/dL to 65 mg/dL, only 33 participants (54%) fulfilled the diagnosis. This post-hoc analysis increased the sensitivity of the Gum2-tests and the agreement to kappa >0.5 for all three tests. CONCLUSION: All three tests can be considered useful screening alternatives. In its original version, Jelly-scan may tend to over-diagnose masticatory hypofunction, hence a novel cut-off with better agreement between tests is suggested.

Oral function and nutritional status in non-acute hospitalised elders.

INTRODUCTION: Malnutrition and risk of malnutrition continues to be a common finding in elders, yet its association with oral function in hospitalised patients remains unclear. MATERIAL AND METHODS: Patients aged 70 years or over who had been hospitalised for non-acute rehabilitation were recruited. Nutritional risk was screened using the Mini-Nutritional Assessment Short Form (MNA-SF) and Nutritional Risk Screening (NRS) scores. Malnutrition was assessed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. All participants underwent the oral hypofunction test battery, evaluating oral hygiene, oral dryness, occlusal force, tongue-lip motor function, tongue pressure, masticatory and swallowing function. Statistical analyses comprised Mann-Whitney or Kruskal-Wallis tests. Bivariate associations between categorical variables were tested using the Pearson chi-square test; for continuous variables, the Spearman correlation was calculated. A P-value < .05 was considered statistically significant. RESULTS: Sixty patients aged a mean 82.5 ± 7.0 years participated. Some 88.3% were diagnosed with oral hypofunction, and this was more common in older patients (P = .020). Analysing the 7 oral hypofunction tests as an interval variable (NiOF) revealed additional correlations with number of teeth (ρ = 0.477) as well as the nutritional risk, evaluated by the MNA-SF (ρ = -0.284) and NRS (ρ = 0.317) scores. NiOF scores were higher among denture wearers (P = .003). GLIM did not confirm the correlation with NiOF. Biomarkers such as serum albumin and CRP were not associated with the NiOF score. CONCLUSION: In this sample, the association between oral function and nutritional state is more obvious in nutritional risk scores than in the malnutrition diagnosis by GLIM.

Validation of a novel diagnostic tool for decreased tongue pressure.

INTRODUCTION: Reduced tongue pressure may render eating and swallowing difficult. The purpose of this study was to investigate whether the tongue training device can also be used as a diagnostic device and whether its sensitivity and specificity are equal to the numerical tongue pressure measuring device. MATERIAL AND METHODS: The target group is patients aged 70 years and over who are hospitalised for rehabilitation. Tongue pressure was measured by both, a tongue pressure measuring instrument and a tongue training tool. The diagnosis of the reduced tongue pressure was made with the tongue pressure measuring instrument and set the verified with the novel tongue training tool. RESULTS: Sixty-two participants were included in the study. Forty-five were classified by the tongue pressure measuring device and 53 by the tongue training device as 'low tongue pressure'. Spearman correlation confirmed a positive correlation between the tongue pressure measuring device and the tongue training device rs  = 0.800, p = 0.01 level (2-tailed). The tongue training device test identified sensitivity was 100%, and its specificity was 52.9%. The AUC of the ROC curve is 0.901. CONCLUSION: The tongue training device seems a simple, safe and readily available alternative to the tongue pressure measuring device for the diagnosis of low tongue pressure, with an excellent sensitivity and very good specificity.

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial.

BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.

The PACOVAR-trial: a phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer.

BACKGROUND: The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. METHODS/DESIGN: This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). DISCUSSION: The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer.

Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in the pathogenesis of inflammatory disorders such as infection, sepsis, and autoimmune disease. MIF exists preformed in cytoplasmic pools and exhibits an intrinsic tautomerase and oxidoreductase activity. MIF levels are elevated in the serum of animals and patients with infection or different inflammatory disorders. To elucidate how MIF actions are controlled, we searched for endogenous MIF-interacting proteins with the potential to interfere with key MIF functions. Using in vivo biotin-tagging and endogenous co-immunoprecipitation, the ribosomal protein S19 (RPS19) was identified as a novel MIF binding partner. Surface plasmon resonance and pulldown experiments with wild type and mutant MIF revealed a direct physical interaction of the two proteins (K(D) = 1.3 x 10(-6) m). As RPS19 is released in inflammatory lesions by apoptotic cells, we explored whether it affects MIF function and inhibits its binding to receptors CD74 and CXCR2. Low doses of RPS19 were found to strongly inhibit MIF-CD74 interaction. Furthermore, RPS19 significantly compromised CXCR2-dependent MIF-triggered adhesion of monocytes to endothelial cells under flow conditions. We, therefore, propose that RPS19 acts as an extracellular negative regulator of MIF.

Influence of macrophage migration inhibitory factor (MIF) on the zinc content and redox state of protein-bound sulphydryl groups in rat sperm: indications for a new role of MIF in sperm maturation.

The function of macrophage migration inhibitory factor (MIF) in sperm maturation was studied by investigating its role in the biochemical maturation of the outer dense fibres. Rat sperm obtained from the caput and cauda epididymis were stimulated overnight with either recombinant MIF or MIF-containing vesicles originating from epididymal fluid at various concentrations. The zinc content of both the sperm and the medium was determined by means of atomic absorption spectrometry. Incubation in both recombinant MIF and vesicular MIF resulted in a statistically significant decrease of the zinc content in stimulated caput sperm of approximately 50%. In parallel, the conditioned media showed a clear increase in the concentration of this trace metal. The effect of MIF was less marked in cauda sperm. In addition, we demonstrated a statistically significant increase of detectable free thiol groups in the sperm mid- and principle piece in isolated rat sperm after stimulation with MIF at concentrations of 25 and 50 ng/ml. Our data suggest that MIF plays an important role in the maturation process of rat sperm during epididymal transit by inducing the elimination of zinc and affecting the amount of free sulphydryl groups in the sperm flagella.