Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Use of roentgenography and magnetic resonance imaging to predict meniscal geometry determined with a three-dimensional coordinate digitizing system.

To evaluate and improve on the procedures used by a tissue bank in selecting donor menisci for transplantation, this study was designed to fulfill four objectives: (a) define and quantify a set of independent parameters for describing the geometry of the medial and lateral menisci, (b) determine how well the sizing protocol of the tissue bank (i.e., two transverse roentgenographic measurements obtained from the injured knee or six transverse magnetic resonance imaging measurements obtained from the contralateral knee) predicts the four standard transverse parameters of the menisci, (c) determine if including one additional transverse roentgenographic measurement for each compartment improves the ability of roentgenograms to predict transverse meniscal parameters, and (d) determine if five magnetic resonance imaging measurements at three different meniscal cross sections of the contralateral knee predict the 15 standard cross-sectional parameters of the meniscus in the injured knee. A laser-based, noncontacting three-dimensional coordinate digitizing system was used to determine surface coordinates from which menisci were reconstructed in a computer. For each reconstructed meniscus, four parameters in the transverse plane and five cross-sectional parameters in each of three regions (i.e., anterior, middle, and posterior) were defined, yielding a set of 19 standard parameters to describe the geometry. Through a correlation analysis, these standard parameters were shown to be largely unrelated to one another, thus confirming that the parameters form an independent set describing the three-dimensional geometry of the menisci. The two roentgenographic measurements were poor predictors of transverse standard meniscal parameters, predicting only one of four standard parameters for the medial meniscus and none of four standard parameters for the lateral meniscus with coefficients of determination greater than or equal to 0.5. Including one additional roentgenographic measurement to the tissue bank protocol increased the number of standard transverse parameters predicted to three of four for the medial meniscus and two of four for the lateral meniscus. Magnetic resonance imaging was better than roentgenography for predicting the three-dimensional meniscal geometry. The transverse measurements from magnetic resonance imaging predicted three of four standard transverse parameters for the medial meniscus and all four for the lateral meniscus. With the addition of the cross-sectional measurements by magnetic resonance imaging, seven of 15 standard cross-sectional parameters were predicted for both the medial and lateral menisci. Assuming that a successful clinical outcome depends on how well an allograft matches the size and shape of the original meniscus, magnetic resonance imaging rather than roentgenography should be used for allograft size-matching by tissue banks.

Cationic liposome mediated transgene expression in the guinea pig cochlea.

Sensorineural hearing loss affects nearly 10% of the American population that is refractory to conventional therapy. Gene therapy represents an intervention with potential therapeutic efficacy. We studied the feasibility of cationic liposome mediated gene transfer within the guinea pig cochlea in vivo following direct microinjection into the cochlea. Transgene expression was persistent up to 14 days in the neurosensory epithelia and surrounding tissue without toxicity and inflammation in the target organ. This study represents the first successful use of cationic liposomes for cochlear gene transfer thus providing a safe and rapid alternative to the use of recombinant viral vectors in gene therapy for inner ear disorders.

The state of tissue hydration determines the strain-rate-sensitive stiffness of human patellar tendon.

The purpose of this study was to investigate the effect of tissue hydration on the structural properties of human patellar tendon. Specimens were subjected to a load relaxation experiment prior to being stretched to failure. The experiments indicated that tendons relaxed faster in hypotonic solutions when compared to hypertonic solutions. At a strain rate of 50% s-1 the structural stiffness was significantly higher while immersed in a hypotonic versus hypertonic solution. No difference in tensile stiffness was documented between baths for 0.5% s-1. Tendons immersed in the hypotonic solution were significantly stiffer for 50% s-1 against 0.5% s-1. The results indicate that the structural properties of human patellar tendon are more sensitive to time when the tissues are fully hydrated.

A high-accuracy three-dimensional coordinate digitizing system for reconstructing the geometry of diarthrodial joints.

This paper describes the design and performance evaluation of a three-dimensional (3-D) coordinate digitizing system (3-DCDS) for measuring both soft and hard biological tissue. The system incorporates a visible semiconducting laser beam and an X-Y positioning table to directly measure 3-D coordinates that define surface points. Experiments conducted to evaluate the performance of the system showed that it delivers an accuracy of 0.1 microm in the Z-direction and 1.4 microm in the X-Y plane, and an overall system root-mean-squared error (RMSE) of 8 microm on surfaces with slopes of less than 45 degrees . This error is lower than that of previously reported measurement techniques. The 3-DCDS measures 3-D coordinates of surface points uniformly separated by 500 microm in the X-Y plane. Because the 3-DCDS is automated, the coordinates are measured efficiently and the accuracy is independent of operator skill. These highly accurate coordinates can be easily incorporated into nodal values for 3-D finite element models (FEM) of diarthrodial joints. To show the use of the 3-DCDS, the 3-D surface coordinates of human menisci were measured from a cadaver specimen.

Mechanosensitivity of bone cells to oscillating fluid flow induced shear stress may be modulated by chemotransport.

Fluid flow has been shown to be a potent physical stimulus in the regulation of bone cell metabolism. In addition to membrane shear stress, loading-induced fluid flow will enhance chemotransport due to convection or mass transport thereby affecting the biochemical environment surrounding the cell. This study investigated the role of oscillating fluid flow induced shear stress and chemotransport in cellular mechanotransduction mechanisms in bone. Intracellular calcium mobilization and prostaglandin E(2) (PGE(2)) production were studied with varying levels of shear stress and chemotransport. In this study MC3T3-E1 cells responded to oscillating fluid flow with both an increase in intracellular calcium concentration ([Ca(2+)](i)) and an increase in PGE(2) production. These fluid flow induced responses were modulated by chemotransport. The percentage of cells responding with an [Ca(2+)](i) oscillation increased with increasing flow rate, as did the production of PGE(2). In addition, depriving the cells of nutrients during fluid flow resulted in an inhibition of both [Ca(2+)](i) mobilization and PGE(2) production. These data suggest that depriving the cells of a yet to be determined biochemical factor in media affects the responsiveness of bone cells even at a constant peak shear stress. Chemotransport alone will not elicit a response, but it appears that sufficient nutrient supply or waste removal is needed for the response to oscillating fluid flow induced shear stress.