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El linfoma no Hodgkin T/NK nasal es una variante rara y agresiva de linfoma no Hodgkin. Las quimioterapias tipo CHOP son las más frecuentemente utilizadas para el tratamiento. Sin embargo, en los últimos años han aparecido reportes de esquemas diferentes seguidos de trasplante de células progenitoras hematopoyéticas, con resultados promisorios.Reportamos el caso de un paciente con linfoma no Hodgkin T/NK nasal que recibió tratamiento con esquema DDGP seguido de trasplante autólogo de médula ósea.

Normal aging affects the different structures of teeth, in particular, the dentine. These changes are useful in forensic disciplines as a tool for age estimation. Although multiphoton (MP) microscopy has been used to explore dental pieces, a relationship between age and MP response of the human dentine has not been proposed yet. The relationship between MP signals and natural dentine aging is investigated herein. An index of age (INAG) combining two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) images has been used to quantify these changes. The results show that the INAG significantly decreases with age. Moreover, peritubular dentine size and collagen internal properties are also modified with age. This information confirms the usefulness of this technique in forensic age estimation after disasters (natural or manmade) with a lack of comprehensive fingerprint database. Courts and other government authorities might also benefit from this tool when the official age of individuals under special circumstances is required for legal or medical reasons.

The cornea is the optical window to the brain. Its optical and structural properties are responsible for optical transparency and vision. The shape, elasticity, rigidity or stiffness are given by its biomechanical properties, whose stability results in ocular integrity and intraocular pressure dynamics. Here, we report in vivo observation of structural changes and biomechanical alterations of the human cornea induced by acoustic wave pressure within the frequency range of 50-350 Hz and 90 dB of sound pressure level. Central corneal thickness (CCT) and eccentricity (e2) were measured using Scheimpflug imaging and biomechanical properties [corneal hysteresis (CH) and intraocular pressure (IOP] were assessed with air-puff tonometry in 6 young healthy subjects. At the specific 150 Hz acoustic frequency, the variation in CCT and e2 were of 0.058 and 7.33 µm, respectively. Biomechanical alterations were also observed in both IOP (decrease of 3.60 mmHg) and CH that showed an increase of 0.40 mmHg.

Background To evaluate alterations of the choroid in neurodegenerative disease patients versus healthy controls using a custom supervised algorithm based on superpixel segmentation. Methods The prospective study protocol and procedures were approved by the Aragon Research Ethics Committee (CEICA) according to Declaration of Helsinki. Informed consent was obtained from all participants included in the study. Swept-source optical coherence tomography (OCT) B-scan images obtained using a Triton (Topcon, Japan) device were compiled. Images were included from three cohorts: multiple sclerosis (MS) patients and Parkinson disease (PD) patients diagnosed by a neurologist, and healthy subjects. 104 OCT B-scan images were processed using a custom supervised superpixel segmentation (SpS) algorithm to detect boundary limits in the choroidal layer. The algorithm groups pixels with similar structural image properties to generate clusters with similar meaningful properties. SpS automatically selects and groups the superpixels in a segmented choroidal area, computing the choroidal optical image density (COID), the total choroidal area (CA), and choroid density (CD). Results CA and CD were significantly reduced in the two neurodegenerative diseases (higher in PD than in MS) versus healthy subjects (p

The full assessment of the visual system must include the evaluation of the optical quality of the eye and neural visual functions. The objective evaluation of the retinal image quality is often carried out by computing the point spread function (PSF) of the eye. The central part of the PSF is associated with optical aberrations and the peripheral areas with scattering contributions. In that sense, visual acuity and contrast sensitivity function tests can be considered the perceptual neural response to those contributions characterizing the eye’s PSF. However, in natural viewing conditions, visual acuity tests may provide good vision while contrast sensitivity tests can reveal visual impairment in glare vision conditions, such as exposure to bright light sources or night driving conditions. Here we present an optical instrument for the study of disability glare vision under extended Maxwellian illumination to assess the contrast sensitivity function under glare conditions. The limit of the Total Disability Glare threshold, tolerance, and glare adaptation will be investigated as a function of the angular size of the glare source (GA) and the contrast sensitivity function in young adult subjects.

Background: It is well-known that non-pathological axial myopic eyes present physiological and functional differences in comparison with emmetropic eyes due to altered retinal anatomy. Photostress tests have shown very significant capabilities to discriminate a normal retina from an abnormal retina. Accordingly, the aim of this work was to investigate the differences between myopic and emmetropic eyes in the measured photostress recovery time (PSRT) after retinal light-flashing in a population of young healthy subjects. Methods: A coaxial illumination total disability glare instrument was employed to measure the recovery time after photostress was induced by a 240 milliseconds flash-lighting (535 nm) exposure on 66 myopic and 66 emmetropic eyes. The measurements were carried out for different combinations of glare angles and contrasts of the visual stimuli. Results: In general terms, PSRT in myopic eyes was found at a statistically higher than in emmetropic eyes (Bonferroni correction). For both groups, the measured recovery strongly depends on the contrast of the test object used to measure baseline recovery function and markedly less on the source of glare angles explored. When the PSRTs obtained for different glare angles are averaged, the differences between PSRTs drastically increase with the reduction in the contrast of the stimuli between both groups of study. Conclusions: PSRT is higher for myopic than for young healthy emmetropic eyes (1.2 s and 0.2 s for 5% and 100% contrast test object, respectively). Though seemingly small, the magnitude of this finding can be relevant when flash-lighting happens while driving a car or while performing actions where the reaction time after a visual stimulus can be critical.

Peripheral refraction can lead to the development of myopia. The aim of this study was to compare relative peripheral refraction (RPR) in the same cohort of uncorrected (WCL) and corrected eyes with two different soft contact lenses (CL) designed for myopia control, and to analyze RPR depending on the patient’s refraction. A total of 228 myopic eyes (114 healthy adult subjects) (−0.25 D to −10.00 D) were included. Open-field autorefraction was used to measure on- and off- axis refractions when uncorrected and corrected with the two CLs (dual focus (DF) and extended depth of focus (EDOF)). The RPR was measured every 10° out to 30° in a temporal-nasal orientation and analyzed as a component of the power vector (M). The average RPR for all subjects was hyperopic when WCL and when corrected with EDOF CL design, but changed to a myopic RPR when corrected with DF design. Significant differences were found between RPR curves with both CLs in all the eccentricities (Bonferroni correction p < 0.008, except 10°N). An incremental relationship between relative peripheral refraction at 30 degrees and myopia level was found. It is concluded that the two CLs work differently at the periphery in order to achieve myopia control.

La activación de BIM es esencial para la apoptosis desencadenada por el inhibidor de la tirosina quinasa (TKI) del receptor del factor de crecimiento epidérmico (EGFR) en el cáncer de pulmón de células no pequeñas (CPCNP) con mutación de EGFR. Una deleción en el intrón dos del gen BIM da como resultado la generación de isoformas empalmadas alternativamente que alteran su respuesta apoptótica a los TKI, lo que confiere a las células de NSCLC una resistencia intrínseca a estos medicamentos. Los pacientes con ambas alteraciones tienen mala evolución clínica. El estudio actual tuvo como objetivo investigar la eficacia clínica y la tolerabilidad de EGFR-TKI más bevacizumab (Bev) versus EGFR-TKI solos como tratamiento de primera línea en pacientes con NSCLC avanzado con mutaciones de EGFR y deleciones BIM (BIMdel). MATERIALES Y MÉTODOS Se realizó un análisis retrospectivo. BIMdel se detectó mediante análisis de reacción en cadena de la polimerasa y secuenciación directa de ADN. La expresión de la proteína BIM se investigó mediante inmunohistoquímica y los niveles de ARNm de BIM mediante la reacción en cadena de la polimerasa con transcriptasa inversa. Se compararon las características clínicas, la supervivencia general, la supervivencia libre de progresión (PFS), la tasa de respuesta general (ORR) y los eventos adversos relacionados con el tratamiento entre ambos grupos. RESULTADOS Se incluyeron 33 pacientes; 15 recibieron EGFR-TKI y 18 recibieron EGFR-TKI más Bev. La mediana de edad fue de 63 años, con una mayoría de pacientes mujeres reclutadas. Todos los individuos incluidos tenían una puntuación de rendimiento del Grupo Oncológico Cooperativo del Este de 2 o menos. La adición de Bev resultó en un ORR significativamente más alto (94,4 % versus 40 %, P > 0,001). La mediana de SLP fue más larga con el uso de la terapia combinada (11,12 frente a 7,87 meses; P = 0,001). La mediana de supervivencia general tendió a ser más prolongada en los inhibidores de la tirosina quinasa con EGFR más Bev (30,9 frente a 25,4 meses; P = 0,06), pero no alcanzó significación estadística. La respuesta en términos de PFS parcial y completa, así como en general, se vio afectada favorablemente. CONCLUSIÓN Los EGFR-TKI más Bev confirieron una ORR y una SLP significativamente más altas en pacientes con NSCLC avanzado con mutación de EGFR y BIMdel. Se necesitan más estudios prospectivos para validar estos hallazgos. BIM activation is essential for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions (BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

In this paper, we study the synchronization problem in complex dynamic networks of Piece Wise Linear (PWL) systems. PWL systems exhibit multi-scrolls and belong to a special class of Unstable Dissipative Systems (UDS). We consider strongly connected digraphs and linear diffusive couplings. The synchronization regions are computed using the concept of disagreement vectors, generalized algebraic connectivity of the network topology, and Lyapunov functions, which provide lower bounds on the coupling gain of the network. Then, different combinations of linear diffusive coupling are explored by changing the observed and measured variables to illustrate the contribution of our results. The theoretical results are validated by numerical simulations.

Purpose To investigate differences between myopic and emmetropic eyes in the measured recovery time after retinal photobleaching in a population of young healthy subjects. Methods A Maxwellian-illumination total disability glare instrument with controllable glare angular distribution, luminous intensity and contrast of the visual stimuli was employed to measure the recovery time after photo-stress induced vision for a 240 milliseconds exposure time in 66 myopic and 66 emmetropic eyes. The measurements were carried out for different combinations of glare angles and contrast of the visual stimuli. Results Time recovery measured in myopic eyes is significantly higher than emmetropic eyes. The measured recovery depends on both the glare angle and the contrast of the stimuli. In addition, myopic and emmetropic eyes present similar sensitivity to glare in terms of time recovery, however in glare conditions, the differences of measured recovery time drastically increase with the reduction of the contrast of the stimuli between both groups of study. Conclusions A total disability glare instrument has been employed to stablish the differences in the measured recovery time after retinal photobleaching. The versatility and simplicity of the instrument could help to explore those retinal disorders related to photopigment visual function at both central and peripheral retina.

Precision medicine has impacted the field of medical oncology by introducing personalized therapies, improving all measurable outcomes. This field, in turn, has expanded to obtaining and analyzing a vast and ever-increasing amount of genomic information. One technique currently applied is the liquid biopsy, which consists of detecting and isolating DNA and exosomes in cancer patients. Newly developed techniques have made it possible to use the liquid biopsy in a wide range of settings. However, challenges regarding the validation of its clinical utility exist because of a lack of standardization across different techniques and tumor types, confounder genomic information, lack of appropriate clinical trial designs, and a non-measured, and therefore not estimated, economic impact on population health. Nowadays, liquid biopsy is not routinely used, but ongoing research is increasing its popularity, and a new era in oncology is developing. Therefore, it is essential to have an in-depth understanding of the liquid biopsy technique. In this review, we summarize the leading techniques and liquid biopsy applications in cancer.

Background Thymomas are a group of rare neoplasms of the anterior mediastinum. The objective of this study was to describe the demographics, clinical characteristics and treatment approaches in Latin America. Methods This was a retrospective multicenter cohort study including patients with histologically proven thymomas diagnosed between 1997 and 2018. Demographics, clinicopathological characteristics and therapeutic outcomes were collected locally and analyzed in a centralized manner. Results A total of 135 patients were included. Median age at diagnosis was 53 years old (19–84), 53.3% (n = 72) of patients were female and 87.4% had an ECOG performance score ranging from 0–1. A total of 47 patients (34.8%) had metastatic disease at diagnosis. Concurrent myasthenia gravis occurred in 21.5% of patients. Surgery was performed in 74 patients (54.8%), comprising 27 (20%) tumorectomies and 47 (34.8%) thymectomies. According to the Masaoka‐Koga system, overall survival (OS) at five‐years was 73.4%, 63.8% and 51%, at stages I–II, III–IVA and IVB, respectively (p = 0.005). Furthermore, patients with low lactate dehydrogenase (LDH) (≤373 IU/L) at baseline and myasthenia gravis concurrence showed significantly better OS (p = 0.001 and p = 0.008, respectively). In multivariate analysis, high LDH levels (HR 2.8 [95% confidence interval [CI]: 1.1–7.8]; p = 0.036) at baseline and not performing a surgical resection (HR 4.1 [95% CI: 1.3–12.7]; p = 0.016) were significantly associated with increased risk of death. Conclusions Our data provides the largest insight into the clinical characteristics and outcomes of patients with thymomas in Latin America. Survival in patients with thymomas continues to be very favorable, especially when subjected to adequate local control., Here, we report the largest analysis of clinical characteristics of thymomas and outcomes in Latin American patients. Out of 135 patients included in the study, 21.5% (n = 29) concurrently presented myasthenia gravis. Relapse‐free survival rates at five‐years were 58.5% for stage I–II, and 35.4% for stage III. Five‐year overall survival rates were 73.4%, 63.8% and 51%, at stages I–II, III–IVA and IVB, respectively.

Toric intraocular lenses (T-IOLs) may lose their optical quality if they are not correctly positioned inside the capsular bag once implanted. In this work, T-IOLs with cylinder powers of +1.50, +4.50 and +7.50 D and differing degrees of spherical aberration have been designed, manufactured and tested in vitro using a commercial optical bench that complies with the requirements of standard ISO 11979-2. Moreover, the effect of tilt and rotation on optical quality was assessed by means of numerical ray tracing on an astigmatic eye model, while the effect of decentration was evaluated numerically and experimentally.

Glaucoma disease is the second leading cause of blindness in the world. This progressive ocular neuropathy is mainly caused by uncontrolled high intraocular pressure. Although there is still no cure, early detection and appropriate treatment can stop the disease progression to low vision and blindness. In the clinical practice, the gold standard used by ophthalmologists for glaucoma diagnosis is fundus retinal imaging, in particular optic nerve head (ONH) subjective/manual examination. In this work, we propose an unsupervised superpixel-based method for the optic nerve head (ONH) segmentation. An automatic algorithm based on linear iterative clustering is used to compute an ellipse fitting for the automatic detection of the ONH contour. The tool has been tested using a public retinal fundus images dataset with medical expert ground truths of the ONH contour and validated with a classified (control vs. glaucoma eyes) database. Results showed that the automatic segmentation method provides similar results in ellipse fitting of the ONH that those obtained from the ground truth experts within the statistical range of inter-observation variability. Our method is a user-friendly available program that provides fast and reliable results for clinicians working on glaucoma screening using retinal fundus images.

Purpose The aim of this work is to determinate the effects in the physical parameters in terms of intraocular pressure (IOP) and central corneal thickness (CCT) and corneal biomechanics in terms of corneal resistance factor (CRF) and corneal hysteresis (CH) of wearing silicone-hydrogel soft contact lenses (SiH-CLs) in young adult subjects during a short-term follow-up. Methods 40 eyes of 20 healthy patients with a mean age of 22.87 ± 4.14 were involved in this study. Subjects with corneal diseases, dry eye, irregular astigmatism or who have been previous contact lens wearers were excluded. The ocular response analyzer (Reichert Ophthalmic Instruments) was used to measure CH, CRF and IOP and Scheimpflug imaging (the GALILEI™ Dual Scheimpflug camera analyzer, Ziemer) was used to measure CCT before and 10 days (Group 1) and 20 days (Group 2) after wearing the SiH-CLs. Results IOP was significantly decreased 10 days after using the SiH-CLs (p = 0.009). Within the 20 days' period, Group 2 revealed an even more pronounced decrease in IOP (p = 0.003) while CH increased significantly (p = 0.04). CCT and CRF did not show a significant change during the period of SiH-CLs use. Our finding allowed obtaining an empirical expression that relates IOP, CCT, CRF and CH within a biomechanical compensation experimental model. Conclusions Corneal biomechanical parameters and physical properties of the cornea may be altered due to SiH-CLs use. Our findings could have an impact on the management of glaucoma progression and ocular hypertension.

Highlights • The identification of the KRAS G12C mutation in non-small cell lung cancer is relevant with new molecules being introduced for treatment. • The variation of mutation prevalence among different regions indicate that certain populations are more prone to develop KRAS G12C mutations among lung cancer than others. • Using genomic markers traditionally employed for the identification of individuals we managed to construct a model that was predictive for KRAS G12C mutational incidence, further indicating that appearance of KRAS G12C follows population substructures., Background The KRAS exon 2 p. G12C mutation in patients with lung adenocarcinoma has been increasing in relevance due to the development and effectiveness of new treatment medications. Studies around different populations indicate that regional variability between ethnic groups and ancestries could play an essential role in developing this molecular alteration within lung cancer. Methods In a prospective and retrospective cohort study on samples from lung adenocarcinoma from 1000 patients from different administrative regions in Colombia were tested for the KRAS p.G12C mutation. An analysis of STR populations markers was conducted to identify substructure contributions to mutation prevalence. Results Included were 979 patients with a national mean frequency for the KRAS exon 2 p.G12C mutation of 7.97% (95%CI 6.27–9.66%). Variation between regions was also identified with Antioquia reaching a positivity value of 12.7% (95%CI 9.1–16.3%) in contrast to other regions such as Bogota DC (Capital region) with 5.4% (2.7–8.2%) and Bolivar with 2.4% (95%CI 0–7.2%) (p-value = 0.00262). Furthermore, Short tandem repeat population substructures were found for eight markers that strongly yielded association with KRAS exon 2 p.G12C frequency reaching an adjusted R2 of 0.945 and a p-value of < 0.0001. Conclusions Widespread identification of KRAS exon 2 p.G12C mutations, especially in cases where NGS is not easily achieved is feasible at a population based level that can characterize regional and national patterns of mutation status. Furthermore, this type of mutation prevalence follows a population substructure pattern that can be easily determined by population and ancestral markers such as STR.

Disability glare is defined as the loss of contrast sensitivity of the retinal image due to intraocular straylight originated from the presence of an intense and broad bright light in the field of vision. This loss of vision can range between vision loss at high spatial frequencies or total temporal blindness. If the extreme case occurs, the recovery time is crucial in night driving conditions or those professional activities in which maximum visual acuity is required at any moment. The recovery time depends mainly on the intensity and glare angle of the light source, ocular straylight, and the photoreceptor response at the retina. The recovery time can also be affected by ocular pathologies, aging, or physiological factors that increase ocular straylight. The aim of this work is to develop a new optical instrument based on psychophysical methodology as well as to investigate the recovery time from total disability glare (photobleaching) as a function of the contrast of the visual target and the glare angle of the source in healthy volunteers. Results showed significant exponential correlation between recovery time and contrast of the visual target and linear correlation between contrast sensitivity and the glare angle. Those findings allowed to obtain an empirical expression to compute the recovery time required to restore contrast sensitivity baseline vision after photobleaching. Finally, a statistical dependence of recovery time with age was found for short glare angles that disappear as the glare angle increases.

The structural integrity of the cornea and transparency are critical for normal vision. Corneal evaluation in ophthalmology and clinical research requires fast and user-friendly techniques allowing accurate diagnoses and follow-up of pathologies, injuries or surgery. Macroscopic irregularities in the anterior corneal surface are the main cause of irregular refractive vision problems. The microscopic and nanoscopic irregularities within the three-dimensional architecture of cornea are the cause of loss of optical transparency and scattering. In this review, the state of the art of the different corneal imaging techniques with three-dimensional capabilities will be detailed and discussed according to the descriptive level of analysis: macroscopic, microscopic and nanoscopic scales.

Background: To assess retinal and optical changes associated with near vision reading for different lighting conditions in electronic screens. Methods: Twenty-four young healthy subjects participated in the study; an iPad and an Ebook were chosen as stimuli for 5 min of reading task with different lighting conditions. Central and peripheral retinal thicknesses in the macular ETDRS areas by optical coherence tomography were analyzed. Results: Significant differences were found between basal retinal thickness and retinal thickness after reading with iPad and high illumination, in the N6 (p = 0.021) and I6 (p = 0.049) areas, and low illumination (S3: p = 0.008, N3: p = 0.018, I3: p = 0.021, N6: p = 0.018 and I6: p = 0.020), being thinner after reading. The same trend was observed after reading with an Ebook and high lighting in the N3 (p = 0.037) and N6 (p = 0.028). For low lighting conditions, only retinal thinning was observed. After reading, retinal shape analysis revealed significant changes from computed basal eccentricity for high lighting conditions only. At the periphery, those differences in eccentricity values were statistically significant for both lighting conditions. Conclusions: Young people can recover visual quality after 5 min of reading tasks at different lighting levels on electronic devices, while peripheral retinal expansion remains altered, especially at low lighting levels.

Cognitive manufacturing, as a paradigm for providing intelligence to manufacturing systems and enabling interaction with operators presents limitations. Manufacturing system requires to be adaptive to machine tools, manufacturing environments and operators. In this line, the enactive approach to cognitive science provides a paradigm for the design of new biologically inspired cognitive architectures. Likewise, the advantages of Key Enabling Technologies and the concept of Industry 4.0 reveal new opportunities for increasing industrial innovation and developing sustainable industrial environments. These technologies are appropriated to overcome the limitations of cognitive manufacturing, because they can achieve the integration of physical and digital systems focused on cyber-physical systems. In this work, an architecture for the sustainable development of enactive manufacturing systems based on holonic paradigm is proposed and its main associated informational model is described.

In this paper, a Second-Harmonic-Generation (SHG) microscope was used to study the relationship between collagen structural arrangement, image quality and polarization sensitivity in human corneas with different organizations. The degree of order (or alternatively, the Structural Dispersion, SD) was quantified using the structure tensor method. SHG image quality was evaluated with different objective metrics. Dependence with polarization was quantified by means of a parameter defined as polarimetric modulation, which employs polarimetric SHG images acquired with four independent polarization states. There is a significant exponential relationship between the quality of the SHG images and the SD of the samples. Moreover, polarization sensitivity strongly depends on collagen arrangement. For quasi- or partially organized specimens, there is a polarization state that noticeably improves the image quality, providing additional information often not seen in other SHG images. This does not occur in non-organized samples. This fact is closely related to polarimetric modulation, which linearly decreases with the SD. Understanding in more detail the relationships that take place between collagen distribution, image quality and polarization sensitivity brings the potential to enable the development of optimized SHG image acquisition protocols and novel objective strategies for the analysis and detection of pathologies related to corneal collagen disorders, as well as surgery follow-ups.

Background: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer (NSCLC). Methods: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial NGS panel in liquid biopsy.Results: There were ten males (66.7%), and the median patient’s age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival (OS) of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate (ORR) was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.Conclusions: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

espanolEste articulo de revision resume las principales aportaciones de la Tesis Doctoral “Polarizacion y microscopia multifotonica para el analisis de estructuras oculares” realizada en el Laboratorio de Optica de la Universidad de Murcia. En ella se han desarrollado metodos matematicos para analizar y clasificar la estructura externa o micrometrica de los tejidos oculares formados por colageno tipo I. Por otra parte, se ha desarrollado un modelo teorico para analizar la dependencia con la polarizacion de la senal de segundo armonico y obtener una expresion analitica para el calculo de la organizacion interna o molecular del colageno. Asi mismo se ha establecido la relacion experimental entre orden externo e interno usando un microscopio multifotonico polarimetrico. Finalmente se ha aplicado el formalismo Stokes-Mueller para el calculo de las propiedades de polarizacion del colageno asi como la mejora de visualizacion de estructuras locales. Los metodos desarrollados se han propuesto como herramienta diferencial de diagnostico en la enfermedad ocular conocida como queratocono EnglishThis review article summarizes the main contributions of the PhD Thesis titled “Polarization and multiphoton microsocopy for the analysis of ocular structures” carried out at the Laboratorio de Optica of the University of Murcia. This work presents mathematical methods developed to both analyze and classify the external or micrometric scale of type I collagen-based ocular tissues. On the one hand, a theoretical model has been developed to explore the polarization dependence of second harmonic generation signal. This allowed obtaining an analytical expression to calculate the internal or molecular collagen organization. On the other hand, an experimental relationship between external and internal collagen organization has been stablished. Finally, the Stokes-Mueller formalism has been applied to compute the polarization properties of type-I fibrillar collagen and to improve the visualization of local structures. These methods have been proposed as a differential clinical tool for the diagnosis of corneal keratoconus

Producción Científica, Corneal cross-linking (CXL) is a surgical procedure able to modify corneal biomechanics and stabilize keratoconus progression. Although it is known that CXL produces changes in corneal collagen distribution, these are still a topic of discussion. Here we quantitatively compare the corneal stroma architecture between two animal models four weeks after in vivo conventional CXL treatment, with second harmonic generation (SHG) imaging microscopy and the structure tensor (ST). The healing stage and the stroma recovery were also analyzed by means of histological sections. Results show that the CXL effects depend on the initial arrangement of the corneal collagen. While the treatment increases the order in corneas with a low level of initial organization, corneas presenting a fairly regular pattern are hardly affected. Histological samples showed active keratocytes in anterior and middle stroma, what means that the recovery is still in progress. The combination of SHG imaging and the ST is able to objectively discriminate the changes suffered by the collagen arrangement after the CXL treatment, whose effectiveness depends on the initial organization of the collagen fibers within the corneal stroma., Sociedad Española para la Investigación de las Diferencias Individuales (grant FIS2016-76163-R), Fundación Séneca (grant 19897/GERM/15)

The optical quality of an image depends on both the optical properties of the imaging system and the physical properties of the medium in which the light travels from the object to the final imaging sensor. The analysis of the point spread function of the optical system is an objective way to quantify the image degradation. In retinal imaging, the presence of corneal or cristalline lens opacifications spread the light at wide angular distributions. If the mathematical operator that degrades the image is known, the image can be restored through deconvolution methods. In the particular case of retinal imaging, this operator may be unknown (or partially) due to the presence of cataracts, corneal edema, or vitreous opacification. In those cases, blind deconvolution theory provides useful results to restore important spatial information of the image. In this work, a new semi-blind deconvolution method has been developed by training an iterative process with the Glare Spread Function kernel based on the Richardson-Lucy deconvolution algorithm to compensate a veiling glare effect in retinal images due to intraocular straylight. The method was first tested with simulated retinal images generated from a straylight eye model and applied to a real retinal image dataset composed of healthy subjects and patients with glaucoma and diabetic retinopathy. Results showed the capacity of the algorithm to detect and compensate the veiling glare degradation and improving the image sharpness up to 1000% in the case of healthy subjects and up to 700% in the pathological retinal images. This image quality improvement allows performing image segmentation processing with restored hidden spatial information after deconvolution.

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Additional file 4. Table S1

Producción Científica, The organization of the corneal stoma is modified due to different factors, including pathology, surgery or external damage. Here the changes in the organization of the corneal collagen fibers during natural healing after chemical burn are investigated using second harmonic generation (SHG) imaging. Moreover, the structure tensor (ST) was used as an objective tool for morphological analyses at different time points after burn (up to 6 months). Unlike control corneas that showed a regular distribution, the collagen pattern at 1 month of burn presented a non-organized arrangement. SHG signal levels noticeably decreased and individual fibers were hardly visible. Over time, the healing process led to a progressive re-organization of the fibers that could be quantified through the ST. At 6 months, the stroma distribution reached values similar to those of control eyes and a dominant direction of the fibers re-appeared. The present results show that SHG microscopy imaging combined with the ST method is able to objectively monitor the temporal regeneration of the corneal organization after chemical burn. Future implementations of this approach into clinically adapted devices would help to diagnose and quantify corneal changes, not only due to chemical damages, but also as a result of disease or surgical procedures., © 2021 Optical Society of America. Users may use, reuse, and build upon the article, or use the article for text or data mining, so long as such uses are for non-commercial purposes and appropriate attribution is maintained. All other rights are reserved., Ministerio de Sanidad. Instituto de Salud Carlos III (PI15/01906), Fundación Séneca (19897/GERM/15)

The retinal and the choroidal thickness were measured at four locations along the horizontal direction (foveola, one nasal to the fovea and two temporal) in a group of 43 young adults (mean age: 27.1 ± 3.9 years), with ocular refraction ranging from emmetropia to high myopia (0 to −10D). Thickness values were obtained from OCT images centered at the foveal depression. The retinal thickness exhibited a correlation with refraction at all eccentricities but not at the fovea. When different subgroups of refraction were considered, the analysis of such correlations indicated that only the retinal thickness in the group of high myopia (refraction ≤ −6D) was statistically different from the other two groups (emmetropes: [−0.5, 0] D, and myopes: (−6, −0.5) D). No significant differences were found between emmetropic and myopic groups. In contrast to the retina, the choroidal thickness exhibited a significant correlation with refraction at the fovea, although such dependency only stood for high myopes (the choroid of myopes and emmetropes exhibited similar thickness). Correlation with refraction was also found at the nasal location, arising between emmetropic and high myopia groups. Other choroidal locations among groups did not exhibit relationship with the refraction. It is concluded that the differences in the choroid and retina thickness along the horizontal meridian as a function of refraction do not characterize the onset and progression of myopia at early stages, since they only manifest in the group of high myopia.

Purpose To numerically evaluate and compare the tolerance to misalignment and tilt of aspheric intraocular lenses (IOLs) designed for three eyes: with standard cornea and with simulated corneas after myopic and hyperopic laser ablation surgery. Methods Three aspheric IOLs of +20.00 diopter (D) with different spherical aberration (SA) (Z40) values have been designed using a theoretical model eye. Drastic changes on the theoretical eye anterior corneal asphericity have been performed to simulate myopic and hyperopic refractive surgeries. The effect of IOL misalignment and tilt on the image quality has been evaluated using a commercial optical software design for the three eye models. Image quality was assessed from the modulation transfer function (MTF), root mean square (RMS) values of defocus, astigmatism, coma and spherical aberration (Z40), and retinal images obtained from a visual simulator using an aleatory optotype of 0.00 LogMar visual acuity (VA). Results IOL misalignment and tilt reduced MTF values in general, and increased wavefront aberrations errors. Aberration-free IOLs maintained best the MTF values when misalignments were applied, together with good on-axis optical quality. IOLs with negative SA (Z40) correction decreased the MTF value under 0.43 for misalignments values higher than 0.50 mm with the three corneas. The effect of misalignment on RMS astigmatism and coma was correlated with the IOL SA (Z40) and with the three corneas. Conclusions This theoretical study shows that the largest degradation in image quality arises for the IOL with the highest amount of spherical aberration (Z40). Moreover, it has been found that the aspherical design has a more influential role in misalignment tolerance than in tilt tolerance.

Papillary carcinoma is the most prevalent type of thyroid cancer. Its diagnosis requires accurate and subjective analyses from expert pathologists. Here we propose a method based on the Hough transform (HT) to detect and objectively quantify local structural differences in collagen thyroid nodule capsules. Second harmonic generation (SHG) microscopy images were acquired on non-stained histological sections of capsule fragments surrounding the healthy thyroid gland and benign and tumoral/malignant nodules. The HT was applied to each SHG image to extract numerical information on the organization of the collagen architecture in the tissues under analysis. Results show that control thyroid capsule samples present a non-organized structure composed of wavy collagen distribution with local orientations. On the opposite, in capsules surrounding malignant nodules, a remodeling of the collagen network takes place and local undulations disappear, resulting in an aligned pattern with a global preferential orientation. The HT procedure was able to quantitatively differentiate thyroid capsules from capsules surrounding papillary thyroid carcinoma (PTC) nodules. Moreover, the algorithm also reveals that the collagen arrangement of the capsules surrounding benign nodules significantly differs from both the thyroid control and PTC nodule capsules. Combining SHG imaging with the HT results thus in an automatic and objective tool to discriminate between the pathological modifications that affect the capsules of thyroid nodules across the progressions of PTC, with potential to be used in clinical settings to complement current state-of-the-art diagnostic methods.