Association of PD-L1 expression with driver gene mutations and clinicopathological characteristics in non-small cell lung cancer: A real-world study of 10 441 patients.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression is a well-known predictive biomarker of response to immune checkpoint blockade in non-small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD-L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. METHODS: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD-L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. RESULTS: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD-L1 expression was categorized as PD-L1 negative (45.1%), PD-L1 positive low-expression 1%-49% (32.3%), and PD-L1 positive high-expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD-L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non-adenocarcinoma histology had a significantly higher median PD-L1 expression (p < 0.001). Additionally, PD-L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14-2.25, p < 0.01]). In the multivariate analysis, EGFR-positive tumors were more commonly associated with PD-L1 low expression (OR 0.62 [95% CI: 0.51-0.75], p < 0.01), while ALK-positive tumors had a significant risk of being PD-L1 positive (OR 1.81 [95% CI: 1.30-2.52], p < 0.01). CONCLUSIONS: PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.

Probabilistic Assessment of the Dynamic Viscosity of Self-Compacting Steel-Fiber Reinforced Concrete through a Micromechanical Model.

This article develops a probabilistic approach to a micromechanical model to calculate the dynamic viscosity in self-compacting steel-fiber reinforced concrete (SCSFRC), which implies a paradigm shift in the approach of the deterministic models used. It builds on a previous work by the authors in which Bayesian analysis is applied to rheological micromechanical models in cement paste, self-compacting mortar, and self-compacting concrete. As a consequence of the varied characteristics of the particles in these suspensions (in terms of materials, shapes, size distributions, etc.), as well as their random nature, it seems appropriate to study these systems with probabilistic models. The Bayesian analysis, thorough Markov Chain Monte Carlo and Gibbs Sampling methods, allows the conversion of parametric-deterministic models into parametric-probabilistic models, which results in enrichment in engineering and science. The incorporation of steel fibers requires a new term in the model to account for their effect on the dynamic viscosity of SCSFRC, and this new term is also treated here with the Bayesian approach. The paper uses an extensive collection of experimental data to obtain the probability density functions of the parameters for assessing the dynamic viscosity in SCSFRC. The results obtained with these parameters' distributions are much better than those calculated with the theoretical values of the parameters, which indicates that Bayesian methods are appropriated to respond to questions in complex systems with complex models.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Guía de práctica clínica: tamizaje, diagnóstico y manejo de episodios agudos y profilaxis del angioedema hereditario ­ Parte I: Enfoque diagnóstico / Clinical practice guidelines: screening, diagnosis and management of acute events and prophylaxis of hereditary angioedema ­ Part I: Diagnostic approach

El angioedema hereditario (AEH) es una enfermedad genética rara, con una prevalencia aproximada entre 1 por cada 50.000 habitantes, caracterizada por episodios de edemas a nivel subcutáneo y de mucosas (abdominal, genitourinario, respiratoria), siendo potencialmente mortal cuando hay afectación de la laringe. En Perú se estiman 600 pacientes con AEH. El AEH se puede clasificar del siguiente modo: con deficiencia del inhibidor de C1 (tipos I y II), y sin deficiencia del inhibidor de C1 (denominado anteriormente tipo III). El diagnóstico de laboratorio incluye prueba de complemento C4, prueba cuantitativa y cualitativa para inhibidor de C1 esterasa, y estudios genéticos.

Hereditary angioedema (HAE) is a genetic rare disease with a prevalence of approximately 1 per 50,000 inhabitants, characterized by episodes of edema at the subcutaneous level and mucous membranes (abdominal, genitourinary, respiratory), being potentially fatal when there is involvement of the larynx. In Peru, there are an estimated 600 patients with HAE. HAE can be classified as follows: with C1 inhibitor deficiency (types I and II), and without C1 inhibitor deficiency (previously called type III). Laboratory diagnosis includes C4 complement test, quantitative and qualitative tests for C1 inhibitor esterase, and genetic studies. In this first part of the Clinical Practice Guide, we present the recommendations for the diagnostic approach of HAE.

Guía de práctica clínica: tamizaje, diagnóstico y manejo de episodios agudos y profilaxis del angioedema hereditario ­ Parte II: Manejo y tratamiento / Clinical practice guidelines: screening, diagnosis and management of acute events and prophylaxis of hereditary angioedema ­ Part II: Management and treatment

El angioedema hereditario (AEH) es una enfermedad genética rara, con una prevalencia aproximada entre 1 por cada 50.000 habitantes, caracterizada por episodios de edemas a nivel subcutáneo y de mucosas (abdominal, genitourinario, respiratoria), siendo potencialmente mortal cuando hay afectación de la laringe. En Perú se estiman 600 pacientes con AEH. El AEH se puede clasificar del siguiente modo: con deficiencia del inhibidor de C1 (tipos I y II), y sin deficiencia del inhibidor de C1 (denominado anteriormente tipo III). El diagnóstico de laboratorio incluye prueba de complemento C4, prueba cuantitativa y cualitativa para inhibidor de C1 esterasa, y estudios genéticos. Existen tratamientos específicos a nivel mundial para crisis agudas y profilaxis en AEH. Sin embargo, en Perú el único tratamiento registrado actualmente es el ecallantide, útil en crisis agudas; además, podemos utilizar tratamientos alternativos como el ácido tranexámico y el danazol. En esta segunda parte de la Guía de Práctica Clínica, presentamos las recomendaciones para el manejo y el tratamiento del AEH.

Hereditary angioedema (HAE) is a genetic rare disease with a prevalence of approximately 1 per 50,000 inhabitants, characterized by episodes of edema at the subcutaneous level and mucous membranes (abdominal, genitourinary, respiratory), being potentially fatal when there is involvement of the larynx. In Peru, there are an estimated 600 patients with HAE. HAE can be classified as follows: with C1 inhibitor deficiency (types I and II), and without C1 inhibitor deficiency (previously called type III). Laboratory diagnosis includes C4 complement test, quantitative and qualitative test for C1 inhibitor esterase, and genetic studies. There are specific treatments worldwide for acute crises and prophylaxis in HAE; in Peru the only currently registered treatment is ecallantide, useful in acute crises; we can also use alternative treatments such as tranexamic acid and danazol. In this second part of the Clinical Practice Guide, we present the recommendations for the management and treatment of HAE.

Propagation Speed of Dynamic Mode-I Cracks in Self-Compacting Steel Fiber-Reinforced Concrete.

The objective of this study is to measure the crack propagation speed in three types of self-compacting concrete reinforced with steel fibers loaded under four different loading rates. Central-notched prismatic beams with two types of fibers (13 mm and 30 mm in length), three fiber volume ratios, 0.51%, 0.77% and 1.23%, were fabricated. Four strain gages were glued on one side of the specimen notch to measure the crack propagation velocity, a fifth one at the notch tip to estimate the strain rates upon the initiation of a cohesive crack and the stress-free crack. A servo-hydraulic testing machine and a drop-weight impact device were employed to conduct three-point bending tests at four loading-point displacement rates, the former to perform tests at 2.2 µm/s, 22 mm/s and the latter for those at 1.77 m/s, 2.66 m/s, respectively. With lower fiber contents, smooth mode-I cracks were formed, the crack speed reached the order of 1 mm/s and 20 m/s. However, crack velocities up to 1417 m/s were obtained for the concrete with high content of fibers under impact loading. This value is fairly close to the theoretically predicted terminal crack velocity of 1600-1700 m/s. Numerical simulations based on cohesive theories of fracture and preliminary results based on the technique of Digital Image Correlation are also presented to complement those obtained from the strain gages. In addition, the toughness indices are calculated under all four loading rates. Strain hardening (softening) behavior accounting from the initiation of the first crack is observed for all three types of concrete at low (high) loading rates. Significant enhancement in the energy absorption capacity is observed with increased fiber content.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

Dynamic Fracture Behavior of Steel Fiber Reinforced Self-Compacting Concretes (SFRSCCs).

Three-point bending tests on notched beams of three types of steel fiber-reinforced self-compacting concrete (SFRSCC) have been performed by using both a servo-hydraulic machine and a drop-weight impact instrument. The lo ading rates had a range of six orders of magnitude from 2.20 × 10-3 mm/s (quasi-static) to 2.66 × 10³ mm/s. These SFRSCCs had the same matrix, but various types of steel fiber (straight and hooked-end) and contents (volume ratios), 0.51%, 0.77% and 1.23%, respectively. The results demonstrate that the fracture energy and the flexural strength increase as the loading rate increases. Moreover, such tendency is relatively moderate at low rates. However, at high rates it is accentuated. For the 0.51% fiber content, the dynamic increase factors of the flexural strength and the fracture energy are approximately 6 and 3, while for the 1.23% fiber content, they are around 4 and 2, respectively. Thus, the higher the fiber content the less rate sensitivity there is.

Temperature and relative humidity estimation and prediction in the tobacco drying process using Artificial Neural Networks.

This paper presents a system based on an Artificial Neural Network (ANN) for estimating and predicting environmental variables related to tobacco drying processes. This system has been validated with temperature and relative humidity data obtained from a real tobacco dryer with a Wireless Sensor Network (WSN). A fitting ANN was used to estimate temperature and relative humidity in different locations inside the tobacco dryer and to predict them with different time horizons. An error under 2% can be achieved when estimating temperature as a function of temperature and relative humidity in other locations. Moreover, an error around 1.5 times lower than that obtained with an interpolation method can be achieved when predicting the temperature inside the tobacco mass as a function of its present and past values with time horizons over 150 minutes. These results show that the tobacco drying process can be improved taking into account the predicted future value of the monitored variables and the estimated actual value of other variables using a fitting ANN as proposed.

Effect of sulphate concentration and sulphide desorption on the combined removal of organic matter and sulphate from wastewaters using expanded granular sludge bed (EGSB) reactors

During the application of anaerobic processes to high sulphate concentration wastewaters, operational problems are expected due to the occurrence of sulphate reduction. Sulphide production reduces effluent quality and may produce inhibition. The application of Expanded Granular Sludge Bed (EGSB) reactors for the combined removal of organic matter and sulphate was studied at different COD/sulphate and 3 values of pH. During the EGSB reactor operation, most of the sulphide remains in the liquid phase reducing effluent quality. The inclusion of a desorption column in the recirculation of the EGSB reactor promotes mass transfer to the gas phase, reducing the sulphide concentration in the liquid phase, significantly decreasing the chemical oxygen demand of the effluent.

Colecistectomía laparoscópica: experiencia de 851 casos / Laparoscopic cholecystectomy: experience with 851 cases

Se practicaron 851 colecistectomía laparoscópica desde Enero de 1991 hasta Febrero de 1996. Se convirtieron 25 casos (2.9 por ciento) a cirugía abierta: 17(2 por ciento) debido a anatomía compleja, 4 debido a hemorragia, 3 por lesión de duodeno. Se presentaron 146 casos de colecistitis aguda (17.2 por ciento) y 705 de colecistitis crónicas (82.8 por ciento). Se llevaron a cabo 20 colangiografías operatorias selectivas (2.3 por ciento), de las cuales 5 resultaron positivas (2 casos manejados con colangiopancreatografía retrógada endoscópica [CPRE] post operatoria, en dos casos se extrajeron los cálculos per operatoriamente con cesta de Dormia y en un caso se avanzó instrumentalmente al duodeno. Treinta y ocho pacientes desarrollaron complicaciones (4.5 por ciento): 8 operatorias (0.9 por ciento), 3 post operatorias mayores (0.3 por ciento) y 27 post operatorias menores (3.1 por ciento). La complicación más frecuente fue la infección umbilical (n=27,3.1 por ciento). No se presentaron muertes en este estudio