Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

A semiconductor laser used for direct measurement of the blood perfusion of tissue.

An instrument consisting merely of a semiconductor laser in its own housing was used to measure the blood perfusion in tissue. Use is made of the feedback of Doppler-scattered light to the photodiode in the laser housing. A recording perfusion of a finger under occlusion of blood flow in the arm is shown.

Condensed Monte Carlo simulations for the description of light transport.

A novel method, condensed Monte Carlo simulation, is presented that applies the results of a single Monte Carlo simulation for a given albedo micro(s)/(micro(alpha) & micro(s)) to obtaining results for other albedos; micro(s) and micro(alpha), are the scattering and absorption coefficients, respectively. The method requires only the storage of the number of interactions of each photon with the medium. The reflectance and transmittance of turbid slabs can thus be found from a limited number of condensed Monte Carlo simulations. We can use an inversion procedure to obtain the absorption and scattering coefficients from the total reflectance and total transmittance of slabs. Remitted photon densities from a semi-infinite medium as a function of the distance between the light source and the detector for all albedos can be found even from the results of a single condensed Monte Carlo simulation. The application of similarity rules may reduce further the number of Monte Carlo simulations that are needed to describe the influence of the distribution of scattering angles on the results.

Optical properties of human dermis in vitro and in vivo.

Condensed Monte Carlo simulation results have been used for calculating absorption and reduced scattering coefficients from the literature data on the measured total transmittance and total reflectance of samples of the human skin in vitro. The results of several measuring methods have been compared. We have also estimated the range for absorption coefficients and reduced scattering coefficients at 660 and 940 nm from measured intensities at the skin surface as a function of the distance from the location where the light enters the skin by using condensed Monte Carlo simulations for a homogeneous semi-infinite medium. The in vivo values for the absorption coefficients and the reduced scattering coefficients appear to be much smaller than the values from the in vitro measurements, that have been assumed until now. The discrepancies have been discussed in detail. Our in vivo results are in agreement with other in vivo measurements that are available in the literature.

A monitoring device for pressurised-air-driven diaphragm-based artificial heart assist devices.

A non-invasive device has been developed to monitor the diaphragm position and the blood flow in artificial heart assist devices equipped with a pressurised-air-driven diaphragm. Light scattering from the diaphragm is used as a mechanism for measuring. Information about the position of several points of the diaphragm can be obtained. The completely empty or filled situation can be detected and used for control purposes. Flow data can be extracted and bending characteristics of the diaphragm during operation can be studied.

Laser Doppler blood flowmetry using two wavelengths: Monte Carlo simulations and measurements.

A new laser Doppler blood flowmeter for measuring skin perfusion is presented. The flowmeter consists of a probe that uses two different wavelengths and is able to measure at different depths. It may be used to distinguish the superficial microcirculation of the skin providing nutritional flow and the flow in deeper situated blood vessels (thermoregulatory flow). Measurements and Monte Carlo simulations of the Doppler signals for human skin are shown.

Analytical calculations and Monte Carlo simulations of laser Doppler flowmetry using a cubic lattice model.

In addition to the static cubic lattice model for photon migration in turbid biological media by Bonner et al. [J. Opt. Soc. Am. A 4, 423-432 (1987)], a dynamic method is presented to calculate the average absolute Doppler shift as a function of the distance between the point of injection of photons into the medium and the point of detection. At every lattice point a moving particle is assumed with a constant velocity in random directions. The velocity direction fluctuates randomly in time. When a photon is scattered at a lattice point it has a finite probability to be Dopper shifted, since in reality not every scattering event occurs with a moving particle. Calculated average absolute Doppler shifts are verified with Monte Carlo simulations. We verified the applicability of the derived formulas for continuous isotropic and continuous anisotropic media. Good agreement is found between the calculated and simulated average absolute Doppler shifts. Small differences between calculated and simulated average abso ute Doppler shifts can be explained by the assumptions made in the theory. Furthermore the calculations of the average absolute Doppler shift confirm the theory of Bonner et al. that the first moment ?omega? of a spectrum S(omega) measured with a blood perfusion meter is linearly proportional to the average number m of scattering events with a moving particle in case of m < 1 and linearly proportional to the square root of m in the case of m > 1. It is confirmed that the average absolute Doppler shift depends on the average number of scattering events at the position of the detection. This effect is, apart from the size and position of the probe volume, essential for the interpretation of the signal measured with a laser Doppler perfusion meter.

Laser Doppler velocimetry and Monte Carlo simulations on models for blood perfusion in tissue.

Laser Doppler flow measurements and Monte Carlo simulations on small blood perfusion flow models at 780 nm are presented and compared. The dimensions of the optical sample volume are investigated as functions of the distance of the laser to the detector and as functions of the angle of penetration of the laser into the sample. The effects of homodyne and heterodyne scattering are investigated.

Reflectance pulse oximetry in fetal lambs.

Transmission pulse oximetry is used for monitoring in many clinical settings. However, for fetal monitoring during labor and in situations with poor peripheral perfusion, transmission pulse oximetry cannot be used. Therefore, we developed a reflectance pulse oximeter, which uses the relative intensity changes of the reflected red and infrared light (red/infrared ratio) to measure the arterial oxygen saturation. The performance of the reflectance pulse oximeter was studied in acute experiments in fetal lambs. By stepwise reduction of the inspired oxygen concentration of the ewe, measurements were done at the fetal scalp at various arterial oxygen saturation levels (17-82%). Reflectance pulse oximeter readings were averaged over periods of 15 s and compared with simultaneously taken fetal arterial blood samples. A calibration curve for the relationship between red/infrared ratio and arterial oxygen saturation was obtained from 53 measurements in four fetal lambs, by linear regression analysis [red/infrared = 4.088-(0.038.SaO2), r = 0.96]. In these experiments, the pulse oximeter showed a precision of 4.7% oxygen saturation around the calibration curve, with a 95% confidence interval of +/- 9.4%.

Fiber-coupled self-mixing diode-laser Doppler velocimeter: technical aspects and flow velocity profile disturbances in water and blood flows.

The effects of disturbances of the flow pattern in front of the fiber facet of a fiber-coupled self-mixing diode-laser Doppler velocimeter system are investigated. This was done by comparing measurements and calculations of the Doppler frequency spectrum with the expected values. The calculated Doppler spectrum was obtained from the calculation of light scattered (with or without Doppler shift) by the moving particles in front of the fiber facet. The velocity profile of the particles was calculated with a finite-element method. Measurements were done with water (with polystyrene spheres) and whole blood as the samples. Good agreement between measurements and calculations were obtained. The velocimeter was modeled as a five-mirror setup. The reflectivity of the fiber facet closest to the laser turns out to have the most influence on the sensitivity and stability of the laser. Direct reflection of unwanted light back into the laser cavity was avoided by placing a glass plate in front of the fiber. Design consi ations are presented.

Reduced light-scattering properties for mixtures of spherical particles: a simple approximation derived from Mie calculations.

The reduced scattering cross section per unit of volume Sigma'(s) identical withSigma(s)(1 - g) is an important parameter to describe light propagation in media with scattering and absorption. Mie calculations of the asymmetry factor g for nonabsorbing spheres and Q(sca), the ratio of the scattering cross section Sigma(s) and the particle cross section, show that Q(sca)(1 - g) = 3.28x(0.37)(m - 1)(2.09) is true to within a few percent, when the Mie parameters for relative refractive index m and size x are in the ranges of 1 < m

Laser Doppler velocimeter based on the self-mixing effect in a fiber-coupled semiconductor laser: theory.

A laser Doppler velocimeter that consists of a semiconductor laser coupled to a fiber and that uses the self-mixing effect is presented. The velocimeter can be used for solids and fluids. A theoretical model is developed to describe the self-mixing signals as a function of the amount of feedback into the laser and the distance from the laser to the moving object. Good agreement is found between this theory and measurements.

Self-mixing laser-Doppler velocimetry of liquid flow and of blood perfusion in tissue.

The velocimetry method of self-mixing, i.e., the feedback of Doppler-scattered light into the laser cavity, is used for the measurement of liquid flow and of blood perfusion in human tissue. The method is elucidated by the registration of the blood perfusion of a finger under repeated occlusion of the veins in the upper arm and with the velocity measurement of a liquid flow containing scattering particles.