Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Conical refraction mode of an optical resonator.

The fundamental mode of a conical refraction resonator, i.e., an optical cavity where light experiences conical refraction (CR) from a biaxial crystal, is experimentally demonstrated in the plano-concave cavity configuration. We have discovered that the fundamental CR mode is characterized by the polarization and intensity structures of CR beams between the plane mirror and CR crystal, and it resembles the fundamental Gaussian mode with homogeneous polarization between the crystal and concave mirror. We theoretically explained this fundamental CR mode using the dual cone model and symmetry of the CR phenomenon and confirmed this explanation by numerical simulations.

Polarization tailored novel vector beams based on conical refraction.

Coherent vector beams with involved states of polarization (SOP) are widespread in the literature, having applications in laser processing, super-resolution imaging and particle trapping. We report novel vector beams obtained by transforming a Gaussian beam passing through a biaxial crystal, by means of the conical refraction phenomenon. We analyze both experimentally and theoretically the SOP of the different vector beams generated and demonstrate that the SOP of the input beam can be used to control both the shape and the SOP of the transformed beam. We also identify polarization singularities of such beams for the first time and demonstrate their control by the SOP of the input beam.

Blue-detuned optical ring trap for Bose-Einstein condensates based on conical refraction.

We present a novel approach for the optical manipulation of neutral atoms in annular light structures produced by the phenomenon of conical refraction occurring in biaxial optical crystals. For a beam focused to a plane behind the crystal, the focal plane exhibits two concentric bright rings enclosing a ring of null intensity called the Poggendorff ring. We demonstrate both theoretically and experimentally that the Poggendorff dark ring of conical refraction is confined in three dimensions by regions of higher intensity. We derive the positions of the confining intensity maxima and minima and discuss the application of the Poggendorff ring for trapping ultra-cold atoms using the repulsive dipole force of blue-detuned light. We give analytical expressions for the trapping frequencies and potential depths along both the radial and the axial directions. Finally, we present realistic numerical simulations of the dynamics of a 87Rb Bose-Einstein condensate trapped inside the Poggendorff ring which are in good agreement with corresponding experimental results.

On the dual-cone nature of the conical refraction phenomenon.

In conical refraction (CR), a focused Gaussian input beam passing through a biaxial crystal and parallel to one of the optic axes is transformed into a pair of concentric bright rings split by a dark (Poggendorff) ring at the focal plane. Here, we show the generation of a CR transverse pattern that does not present the Poggendorff fine splitting at the focal plane, i.e., it forms a single light ring. This light ring is generated from a nonhomogeneously polarized input light beam obtained by using a spatially inhomogeneous polarizer that mimics the characteristic CR polarization distribution. This polarizer allows modulating the relative intensity between the two CR light cones in accordance with the recently proposed dual-cone model of the CR phenomenon. We show that the absence of interfering rings at the focal plane is caused by the selection of one of the two CR cones.

Transformation of vector beams with radial and azimuthal polarizations in biaxial crystals.

We present both experimentally and theoretically the transformation of radially and azimuthally polarized vector beams when they propagate through a biaxial crystal and are transformed by the conical refraction phenomenon. We show that, at the focal plane, the transverse pattern is formed by a ring-like light structure with an azimuthal node, this node being found at diametrically opposite points of the ring for radial/azimuthal polarizations. We also prove that the state of polarization of the transformed beams is conical refraction-like, i.e., that every two diametrically opposite points of the light ring are linearly orthogonally polarized.

Implementation and performance of an in-line incomplete Stokes polarimeter based on a single biaxial crystal.

Due to the increasing interest of polarimetric information in numerous applications, different Stokes polarimeter designs are provided in the literature for the measure of light beam polarization. Recently, the concept of polarimeters based on the conical refraction (CR) phenomenon, occurring in biaxial crystals, was proposed. CR polarimeters are snapshot polarimeters that allow controlling the volume of data redundancy without an increase in the acquisition time. We present the implementation, calibration, and analysis of an incomplete CR-polarimeter optimized for the measure of linear polarizations. A simpler and cheaper experimental configuration is achieved, if compared with other polarimeters proposed in the literature. The suitability of the polarimeter is experimentally demonstrated and some of its benefits, such as its performance in low-intensity conditions, are discussed.

Super-Gaussian conical refraction beam.

We demonstrate the transformation of Gaussian input beams into super-Gaussian beams with a quasi flat-top transverse profile by means of the conical refraction phenomenon by adjusting the ratio between the ring radius and the waist radius of the input beam to 0.445. We discuss the beam propagation of the super-Gaussian beam and show that it has a confocal parameter three times larger than the one that would be obtained from a Gaussian beam. The experiments performed with a KGd(WO4)2 biaxial crystal are in good agreement with the theoretical predictions.

Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.

BACKGROUND: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting. PATIENTS AND METHODS: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers. RESULTS: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003). CONCLUSION: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

Wave-vector and polarization dependence of conical refraction.

We experimentally address the wave-vector and polarization dependence of the internal conical refraction phenomenon by demonstrating that an input light beam of elliptical transverse profile refracts into two beams after passing along one of the optic axes of a biaxial crystal, i.e. it exhibits double refraction instead of refracting conically. Such double refraction is investigated by the independent rotation of a linear polarizer and a cylindrical lens. Expressions to describe the position and the intensity pattern of the refracted beams are presented and applied to predict the intensity pattern for an axicon beam propagating along the optic axis of a biaxial crystal.

Optical vault: a reconfigurable bottle beam based on conical refraction of light.

We employ conical refraction of light in a biaxial crystal to create an optical bottle for photophoretic trapping and manipulation of particles in gaseous media. We show that by only varying the polarization state of the input light beam the optical bottle can be opened and closed in order to load and unload particles in a highly controllable manner.

Generating a three-dimensional dark focus from a single conically refracted light beam.

We report here the generation of a three-dimensional (3D) dark focus from a single focused monochromatic Gaussian beam that undergoes conical refraction when it propagates along one of the optic axes of a biaxial crystal. We study the resulting ring intensity pattern behind the crystal as a function of the ratio between the ring radius and the beam waist and derive the particular parameter values for which a 3D dark focus with null intensity at the ring center is formed. We have performed experiments with a KGd(WO(4))(2) biaxial crystal, reporting the generation of a bottle beam in full agreement with our theoretical investigations.

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

Therapeutic implications of B-RAF mutations in colorectal cancer.

Colorectal cancers (CRC) with B-RAF mutation carry a particularly poor prognosis. In this context, the value of first-line intensified chemotherapy associated with an anti-VEGF (Vascular endothelial growth factor) to treat metastatic CRC has recently been called into question. In patients with mutated B-RAF, the efficacy of first-line anti-EGFR (Epidermal Growth Factor Receptor) associated with chemotherapy for treatment of metastatic CRC is uncertain while that of anti-VEGF has been shown to be effective. The therapeutic pathways involving inhibition of B-RAF activity, although ineffective as monotherapy, have received marketing authorization when used in association with anti-EGFR for second-line treatment of metastatic CRC. Immunotherapy has provided very encouraging results in a recent phase III study in patients with microsatellite instability, irrespective of their B-RAF status. Finally, new therapies, targeting other RAF proteins and other specific receptors are currently under development. Surgery for liver metastases in patients with the B-RAF mutation should be considered whenever possible, after a complete search for peritoneal carcinomatosis and distant metastases, similarly to workup for patients without the B-RAF mutation.

Super-resolution time-resolved imaging using computational sensor fusion.

Imaging across both the full transverse spatial and temporal dimensions of a scene with high precision in all three coordinates is key to applications ranging from LIDAR to fluorescence lifetime imaging. However, compromises that sacrifice, for example, spatial resolution at the expense of temporal resolution are often required, in particular when the full 3-dimensional data cube is required in short acquisition times. We introduce a sensor fusion approach that combines data having low-spatial resolution but high temporal precision gathered with a single-photon-avalanche-diode (SPAD) array with data that has high spatial but no temporal resolution, such as that acquired with a standard CMOS camera. Our method, based on blurring the image on the SPAD array and computational sensor fusion, reconstructs time-resolved images at significantly higher spatial resolution than the SPAD input, upsampling numerical data by a factor [Formula: see text], and demonstrating up to [Formula: see text] upsampling of experimental data. We demonstrate the technique for both LIDAR applications and FLIM of fluorescent cancer cells. This technique paves the way to high spatial resolution SPAD imaging or, equivalently, FLIM imaging with conventional microscopes at frame rates accelerated by more than an order of magnitude.

A two-stage neural spiking model of visual contrast detection in perimetry.

Perimetry is a commonly used clinical test for visual function, limited by high variability. The sources of this variability need to be better understood. In this paper, we investigate whether noise intrinsic to neural firing could explain the variability in normal subjects. We present the most physiologically accurate model to date for stimulus detection in perimetry combining knowledge of the physiology of components of the visual system with signal detection theory, and show that it requires that detection be mediated by multiple cortical cells in order to give predictions consistent with psychometric functions measured in human observers.

Engineering of orbital angular momentum supermodes in coupled optical waveguides.

In this work we demonstrate the existence of orbital angular momentum (OAM) bright and dark supermodes in a three-evanescently coupled cylindrical waveguides system. Bright and dark supermodes are characterized by their coupling and decoupling from one of the waveguides, respectively. In addition, we demonstrate that complex couplings between modes of different waveguides appear naturally due to the characteristic spiral phase-front of OAM modes in two-dimensional configurations where the waveguides are arranged forming a triangle. Finally, by adding dissipation to the waveguide uncoupled to the dark supermode, we are able to filter this supermode out, allowing for the design of OAM mode cloners and inverters.

Variability components of standard automated perimetry and frequency-doubling technology perimetry.

PURPOSE: To evaluate and compare intra- and intertest variability components for both standard automated perimetry (SAP) and frequency-doubling technology (FDT) perimetry in a small group of normal individuals and patients with glaucoma. METHODS: The method of constant stimuli (MOCS) was used to examine matched test locations with both SAP and FDT perimetry stimuli in a group of eight normal individuals and seven patients with glaucoma. Subjects were tested weekly at three predetermined visual field loci for 5 consecutive weeks. Frequency-of-seeing (FOS) curves were generated and used to quantify threshold sensitivity (50% seen on FOS, in decibels), intratest variability (FOS interquartile range, in decibels), and intertest variability (interquartile range of weekly repeated threshold determinations, in decibels). RESULTS: In patients with glaucoma, SAP intra- and intertest variabilities were found to increase with sensitivity reductions, as previously reported. FDT perimetry revealed that both intra- and intertest variability components did not appreciably change with reductions in sensitivity. With the measurement scales used in this investigation, both intra- and intertest variability components were significantly greater for SAP than for FDT perimetry (P < 0.001 and P = 0.003, respectively). Intratest variability exceeded intertest variability for both SAP (P = 0.001) and FDT perimetry (P < 0.001). CONCLUSIONS: For both SAP and FDT perimetry, variability occurring within a single test session contributed more to total variability than between-session variability. When the measurement scales available on commercial instrumentation were used, FDT perimetry exhibited significantly less variability than SAP, especially within regions of visual field sensitivity loss. FDT perimetry therefore shows promise as an effective test for detecting progressive glaucomatous visual field loss, although prospective longitudinal validation is still required to determine sensitivity to change.

Computerized method of visual acuity testing: adaptation of the amblyopia treatment study visual acuity testing protocol.

PURPOSE: To report a computerized method for determining visual acuity in children using the Amblyopia Treatment Study visual acuity testing protocol. METHODS: A computerized visual acuity tester was developed that uses a programmed handheld device that uses the Palm operating system (Palm, Inc, Santa Clara, California). The handheld device communicates with a personal computer running a Linux operating system and 17-inch monitor. At a test distance of 3 m, single letters can be displayed from 20/800 to 20/12. A C program on the handheld device runs the Amblyopia Treatment Study visual acuity testing protocol. Using this method, visual acuity was tested in both the right and left eyes, and then the testing was repeated in 156 children age 3 to 7 years at four clinical sites. RESULTS: Test-retest reliability was high (r =.92 and 0.95 for and right and left eyes, respectively), with 88% of right eye retests and 94% of left eye retests within 0.1 logarithm of minimal angle of resolution (logMAR) units of the initial test. The 95% confidence interval for an acuity score was calculated to be the score +/- 0.13 logMAR units. For a change between two acuity scores, the 95% confidence interval was the difference +/- 0.19 logMAR units. CONCLUSIONS: We have developed a computerized method for measurement of visual acuity. Automation of the Amblyopia Treatment Study visual acuity testing protocol is an effective method of testing visual acuity in children 3 to 7 years of age.

Measurement error of visual field tests in glaucoma.

AIM: Psychophysical strategies designed for clinical visual field testing produce rapid estimates of threshold with relatively few stimulus presentations and so represent a trade-off between test quality and efficiency. The aim of this study was to determine the measurement error of a staircase algorithm similar to full threshold with standard automated perimetry (SAP) and frequency doubling perimetry (FDP) in glaucoma patients. METHODS: Seven patients with early open angle glaucoma (OAG) were prospectively recruited. All were experienced in laboratory based psychophysics. Three matched test locations were examined with SAP (externally driven Humphrey field analyser) and FDP (CRT) in a single arbitrarily selected eye of each subject. Each location was tested twice with a 4-2-2 dB staircase strategy, similar to full threshold, and then with the method of constant stimuli (MOCS). Accuracy (threshold estimation error) was quantified by determination of differences between "true" threshold measurements made by MOCS and single staircase threshold estimates. Precision (repeatability) was quantified by the differences between repeated staircase threshold estimates. RESULTS: Precision was relatively high for both tests, although higher for FDP than SAP at depressed sensitivity levels. The staircase strategy significantly underestimated threshold sensitivity for both test types, with the mean difference (95% CI) between staircase and MOCS thresholds being 4.48 dB (2.35 to 7.32) and 1.35 dB (0.56 to 1.73) for SAP and FDP respectively. Agreement levels (weighted kappa) between MOCS and staircase thresholds were found to be 0.48 for SAP and 0.85 for FDP. Although this "bias" appeared constant for FDP across all sensitivity levels, this was not the case for SAP where accuracy decreased at lower sensitivity levels. CONCLUSION: Estimations of threshold sensitivity made using staircase strategies common to clinical visual field test instrumentation are associated with varying degrees of measurement error according to visual field test type and sensitivity. In particular, SAP significantly overestimates the "true" level of sensitivity, particularly in damaged areas of the visual field, suggesting that clinical data of this type should be interpreted with caution.