Electrostatic hindrance to diffusion in flexible crosslinked gels: A coarse-grained simulation study.

In this work, we study how electrostatic forces slow down the diffusion of solute in flexible gels through coarse-grained simulations. The model used explicitly considers the movement of solute particles and polyelectrolyte chains. These movements are performed by following a Brownian dynamics algorithm. The effect of three electrostatic parameters characterizing the system (solute charge, polyelectrolyte chain charge, and ionic strength) is analyzed. Our results show that the behavior of both the diffusion coefficient and the anomalous diffusion exponent changes upon the reversal of the electric charge of one of the species. In addition, the diffusion coefficient in flexible gels differs significantly from that in rigid gels if the ionic strength is low enough. However, the effect of chain flexibility on the exponent of anomalous diffusion is significant even at high ionic strength (100 mM). Our simulations also prove that varying the polyelectrolyte chain charge does not have exactly the same effect as varying the solute particle charge.

Impact of Targeted Therapy on the Survival of Patients With Advanced-Stage Non-small Cell Lung Cancer in Oncosalud - AUNA.

BACKGROUND: Lung cancer is still a prevalent and fatal neoplasm in developing countries. In the last decades, chemotherapy (CHT) maintenance occupied an important role in the treatment, as well as targeted therapies. We aimed to evaluate the survival impact of targeted therapy in advanced lung cancer at a private Peruvian institution (Oncosalud - AUNA). METHODS: We reviewed retrospectively medical records of patients with advanced-stage non-small cell lung cancer (NSCLS) (clinical stage III-IV) who received CHT and maintenance treatment with target therapy (TT) or CHT. The impact was assessed by progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method, and comparisons of survival curves were performed using log-rank or Breslow test and Cox model. RESULTS: The median age of the patients was 65 years. Clinical characteristics, as well as the treatment type, showed no significant difference between the two groups. The maintenance schedule in those receiving CHT was generally pemetrexed (70%) and in those receiving TT was erlotinib (60.7%). In patients receiving TT, the median PFS was 13 months compared to 7 months in those receiving CHT; likewise, the median OS was 45 and 17 months, respectively. The PFS and OS curves showed significant differences (P < .05), achieving a better survival in subjects treated with TT. CONCLUSION: Progression-Free Survival and OS were superior in patients who received targeted therapy than those treated only with CHT, the 2 years rate of PFS and OS was nearly double to those who received only CHT-based treatments.

The impact of telemedicine on cancer care: real-world experience from a Peruvian institute during the COVID-19 pandemic.

Background: The COVID-19 pandemic caused discontinuities in cancer care (CC) in most countries. Here, the authors describe the real-world impacts of implementing a contingency plan employing telemedicine for CC. Methods: A retrospective study of patients who received CC through telemedicine at the Instituto Nacional de Enfermedades Neoplasicas, Peru, from March 2020 to February 2021 was conducted. Impacts were measured by comparing the amount of CC administered during the pandemic versus the prior year. Results: A total of 16,456 telemedicine visits were carried out. An annual comparative analysis showed a gap of 23% and telemedicine accounted for 27.6% of the total CC administered during the pandemic. A high (4.50/5) level of patient satisfaction with telemedicine was reported. Conclusion: Telemedicine is an important tool to facilitate the continuity of CC.

Coarse-grained Monte Carlo simulations of nanogel-polyelectrolyte complexes: electrostatic effects.

Coarse-grained Monte-Carlo simulations of nanogel-polyelectrolyte complexes have been carried out. The results presented here capture two phenomena reported in experiments with real complexes: (i) the reduction in size after absorbing just a few chains and (ii) the charge inversion detected through electrophoretic mobility data. Our simulations reveal that charge inversion occurs if the polyelectrolyte charge is large enough. In addition, the distribution of chains inside the nanogel strongly depends on whether charge inversion takes place. It should also be stressed that the chain topology has little influence on most of the properties studied here.

Lung Cancer in the Young.

INTRODUCTION: Median age at diagnosis of lung cancer is 70 years. Its presentation in patients 40 or younger is uncommon and it has been proposed that maybe it is a different disease due to its clinical characteristics and genetic makeup. There are a limited number of studies in this population and they report different clinic-pathological characteristics in comparison with older patients. METHODS: We described the incidence of lung cancer patients diagnosed at age 40 or younger at the Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima-Peru; from 2009 to 2017 and evaluated the characteristic of NSCLC. Epidemiologic and clinic-pathological data was collected from clinical files. Analysis was carried out using SPSSvs19 software. RESULTS: We identified 3823 patients with lung cancer seen at INEN during the study period. Among these, 166 (4.3%) patients were 40 years or younger, and 137/166 (82.5%) were NSCLC. Median age at diagnosis was 36 years (range 14-40 years) and 59.1% of patients were female. A smoking history was present in 14.4% of patients. Frequent symptoms at diagnosis were cough (62.0%), chest pain (51.8%) and dyspnea (40.9%). Adenocarcinoma was the most common histological type (63.3%). Most patients had advanced disease at diagnosis (84.7%). The median overall survival was 8.2 months. CONCLUSIONS: The proportion of young patients with lung cancer in our population is higher than that reported in the most recent literature. Lung cancer in the young is mostly sporadic, more frequent in women, usually adenocarcinoma type and it presents with advanced disease, resulting in a very poor survival.

[Reduction of dysfunctional self-injurious and self-stimulatory behaviors in autism disorders spectrum through occupational therapy]. / Reducción de las conductas autolesivas y autoestimulatorias disfuncionales en los trastornos del espectro del autismo a través de la terapia ocupacional.

Self-stimulatory and self-injurious behaviors are very frequent in neurodevelopmental disorders, being a source of anxiety and suffering for persons who have that behavior and their families. Sometimes these behaviors are so intense and frequent that it becomes a selfintegrity risk. A bibliographic review was conducted on the different approaches that have been developed until today; in addition, this article explains the methodology applied in our clinic, with a data collection on the effect of therapy on self-injurious and self-stimulatory behaviors in 20 cases, as a starting point for future research. The sensory integration model that complements pharmacological and behavioral cognitive treatment is highlighted, since it considers sensory needs relevant and trains the capacity for functional self-regulation.

Las conductas auto estimulatorias y auto lesivas son muy frecuentes en los trastornos del neurodesarrollo, siendo una fuente de ansiedad y sufrimiento importante tanto para las personas que las presentan como para sus familias. En ocasiones estas conductas son tan intensas y frecuentes que llegan a ser un peligro para la salud del sujeto. Se realiza una revisión bibliográfica sobre las diferentes vías de atención de estas conductas desarrolladas hasta el momento, y se expone la metodología aplicada en nuestra clínica, presentando datos recopilados sobre el efecto de la terapia sobre las conductas auto lesivas y auto estimulatorias en 20 casos, como punto de partida para próximas investigaciones. Se destaca el modelo de integración sensorial que complementa el tratamiento farmacológico y el cognitivo conductual, ya que considera relevante las necesidades sensoriales y entrena la capacidad de auto regulación funcional.

Maximizing the absorption of small cosolutes inside neutral hydrogels: steric exclusion versus hydrophobic adhesion.

In this work the equilibrium absorption of nanometric cosolutes (which could represent drugs, reactants, small globular proteins and other kind of biomacromolecules) inside neutral hydrogels is studied. We specially focus on exploring, for different swelling states, the competition between the steric exclusion induced by the cross-linked polymer network constituting the hydrogel, and the solvent-induced short-range hydrophobic attraction between the polymer chains and the cosolute particle. For this purpose, the cosolute partition coefficient is calculated by means of coarse-grained grand canonical Monte Carlo simulations, and the results are compared to theoretical predictions based on the calculation of the excluded and binding volume around the polymer chains. For small hydrophobic attractions or large cosolute sizes, the steric repulsion dominates, and the partition coefficient decreases monotonically with the polymer volume fraction, ϕm. However, for large enough hydrophobic attraction strength, the interplay between hydrophobic adhesion and the steric exclusion leads to a maximum in the partition coefficient at certain intermediate polymer density. Good qualitative and quantitative agreement is achieved between simulation results and theoretical predictions in the limit of small ϕm, pointing out the importance of geometrical aspects of the cross-linked polymer network, even for hydrogels in the swollen state. In addition, the theory is able to predict analytically the onset of the maximum formation in terms of the details of the cosolute-monomer pair interaction, in good agreement with simulations too. Finally, the effect of the many-body attractions between the cosolute and multiple polymer chains is quantified. The results clearly show that these many-body attractions play a very relevant role determining the cosolute binding, enhancing its absorption in more than one order of magnitude.

The implementation of the Plan Esperanza and response to the imPACT Review.

Following the implementation of the National Cancer Prevention and Control Results-based Budget Programme (PpR Cancer-024) in 2011, the Peruvian Government approved the Plan Esperanza-a population-based national cancer control plan-in 2012. Legislation that ensured full government-supported funding for people who were otherwise unable to access or afford care and treatment accompanied the Plan. In 2013, the Ministry of Health requested an integrated mission of the Programme of Action for Cancer Therapy (imPACT) report to strengthen cancer control in Peru. The imPACT Review, which was executed in 2014, assessed Peru's achievements in cancer control, and areas for improvement, including cancer control planning, further development of population-based cancer registration, increased prevention, early diagnosis, treatment and palliative care, and the engagement and participation of civil society in the health-care system. This Series paper gives a brief history of the development of the Plan Esperanza, describes the innovative funding model that supports it, and summarises how funds are disseminated on the basis of disease, geography, and demographics. An overview of the imPACT Review, and the government's response in the context of the Plan Esperanza, is provided. The development and execution of the Plan Esperanza and the execution of and response to the imPACT Review demonstrates the Peruvian Government's commitment to fighting cancer across the country, including in remote and urban areas.

[Methodology in the diagnosis of Attention Deficit Hyperactivity Disorder (ADHD)]. / Metodología en el diagnóstico del Trastorno por Déficit de Atención e Hiperactividad (TDAH).

INTRODUCTION: The aim of the study is to demonstrate the need to apply an assessment methodology in Attention Deficit Hyperactivity Disorder (ADHD) due to the lack of agreement between parents and teachers on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). METHODS: This is a retrospective descriptive study of three years and ten months. The sample was drawn from 640 subjects assessed and diagnosed with ADHD, aged between 8 and 16 years, and with a Total Intellectual Quotient (TQ) between 80 and 120. Subjects underwent a neuropsychological assessment. Certain scales of the questionnaires: Child and Adolescent Assessment System (SENA) and Behavioural Assessment of Executive Function-2 (BRIEF-2), both completed by parents, and the DSM-5 criteria answered by parents and teachers were taken into account. RESULTS: As a result, a low concordance was observed between the observations obtained from the DSM-5 between parents and teachers.

Introducción: El objetivo del trabajo es evidenciar la necesidad de aplicar una metodología de evaluación en el Trastorno por Déficit de Atención e Hiperactividad (TDAH) por la falta de acuerdo entre padres y profesores en los criterios del Manual diagnóstico y estadístico de los trastornos mentales, quinta edición (DSM-5). Métodos: Se trata de un estudio descriptivo retrospectivo de tres años y diez meses. La muestra se extrajo de 640 sujetos evaluados y diagnosticados de TDAH, con edades comprendidas entre 8 y 16 años, y un Cociente Intelectual Total (CIT) entre 80 y 120. A los sujetos se les aplicó una evaluación neuropsicológica. Se tuvieron en cuenta determinadas escalas de los cuestionarios: Sistema de Evaluación de Niños y Adolescentes (SENA) y Evaluación Conductual de la Función Ejecutiva-2 (BRIEF-2), ambos cumplimentados por padres, y los criterios del DSM-5 contestados por padres y profesores. Resultados: Como resultado se observa una baja concordancia entre las observaciones obtenidas del DSM-5 entre padres y profesores.

Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC.

INTRODUCTION: ALK tyrosine kinase inhibitors have exhibited promising activity against advanced ALK-rearranged NSCLC. However, co-occurring genetic alterations, such as CDKN2A/B or TP53, may negatively affect the efficacy of targeted therapies. METHODS: From December 2017 to December 2022, this study cohort analyzed next-generation sequencing data of 116 patients with metastatic ALK-rearranged NSCLC from five Latin American cancer centers. Clinicopathologic and molecular features were associated with clinical outcomes and risk of brain metastasis (BrM) in patients with and without concurrent somatic alterations. RESULTS: All patients (N = 116) received a second-generation ALK tyrosine kinase inhibitor, and alectinib was selected in 87.2% of cases. Coalterations occurred in 62% of the cases; the most frequent were TP53 mutations (27%) and CDKN2A/B loss (18%). The loss of CDKN2A/B was associated with an increased risk of BrM, with a cumulative incidence of 33.3% versus 7.4% in the non-coaltered subgroup. Compared with patients without coalterations, patients with concurrent CDKN2A/B loss (n = 21) had a shorter median progression-free survival (10.2 versus 34.2 mo, p < 0.001) and overall survival (26.2 versus 80.7 mo, p < 0.001). In the multivariate analysis, co-occurring CDKN2A/B loss was associated with poorer progression-free survival and OS despite the presence of other somatic coalterations, TP53 mutations, BrM, and Eastern Cooperative Oncology Group Performance Status. CONCLUSIONS: This study confirmed the worse prognostic value, which depicted co-occurring alterations in patients with ALK rearrangement. CDKN2A/B loss was substantially associated with worse outcomes and a higher risk of brain metastases. The evidence presented in our study may help select patients with ALK-positive tumors suitable for treatment escalation and closer brain follow-up.

Voltammetric behaviour of free DNA bases, methylcytosine and oligonucleotides at disposable screen printed graphite electrode platforms.

Improvements in analytical methods for the determination and quantification of methylcytosine in DNA are vital since it has the potential to be used as a biomarker to detect different diseases in the first stage such as in the case of carcinomas and sterility. In this work we utilized screen printed graphite electrodes (SPGE) for studying the electrochemical response of all free DNA bases, methylcytosine and short oligonucleotides by cyclic voltammetry (CV) and square wave voltammetry (SWV). CV and SWV responses of free DNA bases and methylcytosine have been investigated by using SPGE platforms and the feasibility of detecting and quantifying cytosine and methylcytosine as free DNA moieties has been evaluated as a function of pH, concentration and the presence of the other free DNA bases in solution simultaneously. Repeatability of using SWV has been performed for the electrochemical behavior of both 250 µM cytosine and 250 µM methylcytosine in the presence of 25 µM guanine, with coefficient of variations of 6.9% and 2.6% respectively based upon peak current (N = 5). Six-mer oligonucleotides with a sequence 5'-XXXCGC-3', where the XXX motif corresponds to TTT, TTA, TAA and AAA have been performed using SWV in 0.1 M acetate buffer pH 5.0 to explore how the DNA base position effects the electrooxidation of guanine and cytosine into the oligonucleotide. Furthermore SWV comparisons of the electrooxidation of the oligonucleotides 5'-CGCGCG-3' and its methylated 5'-mCGmCGmCG-3' have been performed with concentrations in acetate buffer solutions, and the interaction of both oligonucleotides with the graphitic surface of the SPGE has been demonstrated by fitting well-known adsorption models such as Freundlich and Langmuir kinetics according to the SWV current response of guanine, cytosine and methylcytosine into the oligonucleotide.

Real-world outcomes of anti-EGFR therapy in advanced non-small cell lung cancer EGFR mutated in Peru.

BACKGROUND: Despite the advances in the management of advanced non-small cell lung cancer (NSCLC), the access to genetic profiling and target therapies remains a challenge in Latin America, even in countries with a higher rate of targetable mutations. The aim of this study is to evaluate the clinical outcomes of anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) treatment in a Peruvian real-world setting. METHODS: This is a retrospective study of recurrent or advanced NSCLC EGFR mutated patients diagnosed and treated with anti-EGFR TKI at Instituto Nacional de Enfermedades Neoplásicas (INEN) between January 1, 2015 to December 31, 2020. The outcomes were objective response rate (ORR), progression free survival (PFS), and overall survival (OS). RESULTS: We identify 613 stage IV or recurrent NSCLC patients who were tested for EGFR mutations and found a pathogenic mutation in 39.5% of patients. Only 51.2% of them received anti-EGFR TKI as institutional treatment. ORR was 58%, after median follow-up of 32 months, the estimated median PFS was 13.9 months (11.1-16.7 months), and the estimated median OS was 21.7 months (18.5-24.9 months). No differences were found in PFS according to line of treatment or brain metastases at diagnosis (p = 0.46 and p = 0.07, respectively), respect to OS there were no differences line of treatment (p = 0.12), significant difference were found in presence of brain metastases (p = 0.006). CONCLUSION: Our study demonstrates that erlotinib for advanced NSCLC harboring EGFR-activating mutations is effective even in patients usually excluded from clinical trial, like those previously exposed to one or more lines of chemotherapy or with brain metastases.

Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices.

The introduction of immunotherapy has brought about a paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). It has not only significantly improved the prognosis of patients but has also become a cornerstone of treatment, particularly in those without oncogenic driver mutations. Immune checkpoint inhibitors (ICIs) play a crucial role in the treatment of lung cancer and can be classified into two main groups: Anti-cytotoxic T lymphocyte antigen-4 (Anti-CTLA-4) and anti-T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti-PD-L1). Certainly, the landscape of approved first line immunotherapeutic approaches has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The complexity of decision-making in this realm arises due to the absence of direct prospective comparisons. However, a thorough analysis of the long-term efficacy and safety data derived from pivotal clinical trials can offer valuable insights into optimizing treatment for different patient subsets. Moreover, ongoing research is investigating emerging biomarkers and innovative therapeutic strategies that could potentially refine the current treatment approach even further. In this comprehensive review, our aim is to highlight the latest advances in immunotherapy for advanced NSCLC, including the mechanisms of action, efficacy, safety profiles, and clinical significance of ICI.

[Perception of anxiety and learning difficulties according to the criteria of the family and teachers of children with Attention Deficit Hyperactivity Disorder]. / Percepción de la ansiedad y de las dificultades de aprendizaje según los criterios de la familia y de los profesores de niños con trastorno por déficit de atención e hiperactividad.

Both Attention Deficit Hyperactivity Disorder (ADHD) and anxiety are two of the disorders that are most evident in the infant-juvenile population and there is a correlation between the two, as shown in numerous studies. The combination of both disorders affects the child's teaching-learning processes, causing learning difficulties (LD). The aims of the present study were based on assessing the criteria evidenced by parents and teachers in children with ADHD to characterize the degree of adequacy of perception and to evaluate whether this is in line with reality or insufficient, whether there are differences in this perception between parents and teachers, and to analyze their awareness of the possible AD they may present, in order to provide appropriate guidelines for favourable intervention and evolution. The sample consisted of 137 subjects aged between 9 and 15 years with a Total IQ (TIQ) between 80 and 120. The instruments used were: the Wechsler Intelligence Scale for Children-V (WISCV), the State-Trait Anxiety Questionnaire for Children (STAI-C), the Child and Adolescent Assessment System (SENA) and the Inventory of Problems at School (IPE). As a result, it is observed that the anxiety perceived by these children is not related to the anxiety perceived by parents and teachers, although the latter do coincide in their assessment.

Tanto el Trastorno por Déficit de Atención e Hiperactividad (TDAH) como la ansiedad son dos de los trastornos que más se evidencian en la población infanto-juvenil existiendo una correlación entre ambos tal y como se recoge en numerosos estudios. La combinación de ambos trastornos afecta a los procesos de enseñanza-aprendizaje del niño provocando dificultades de aprendizaje (DA) en el mismo. Los objetivos del presente trabajo se basaron en valorar los criterios que evidencian padres y profesores en niños con TDAH para caracterizar el grado de adecuación de la percepción y evaluar si esta se ajusta a la realidad o es insuficiente, si existen diferencias en dicha percepción entre padres y docentes; analizar la conciencia que tienen sobre las posibles DA que puedan presentar, para así aportar orientaciones adecuadas que permitan una favorable intervención y evolución. La muestra se compone de 137 sujetos con edades comprendidas entre 9 y 15 años con un Coeficiente Intelectual Total (CIT) de entre 80 y 120. Los instrumentos que se utilizaron fueron: la escala de inteligencia de Wechsler para niños-V (WISC-V), el Cuestionario de Ansiedad Estado-Rasgo en Niños(STAI-C), el Sistema de Evaluación de Niños y Adolescentes(SENA) y el Inventario de Problemas en la Escuela (IPE). Como resultado se observa que la ansiedad percibida por estos niños no está relacionada con la que aprecian padres y profesores, sin embargo, estos últimos sí que coinciden en su apreciación.

Improving the Antibacterial Properties of Dental Bonding Materials Loaded with Silver Compounds.

Biofilm accumulation, the appearance of white spot lesions and the development of secondary caries are the main complications in orthodontic patients. A promising approach to fight this situation is the development of adhesive cements with improved antibacterial properties. The aim of the present study was to evaluate the possibility of improving the antibacterial properties of glass ionomer cements by incorporating different types of antimicrobial compounds without altering their physical and mechanical properties. Different concentrations of silver carbonate (SC) and an inorganic glass with encapsulated silver were added to the glass ionomer cement, as well as chitosan, to achieve synergistic antibacterial activity. Variations in the antibacterial capacity were evaluated using the agar diffusion test; the potential alteration of the physical and mechanical properties of the material was analyzed by the shear bond strength test. SEM characterization and colorimetric evaluation were also conducted. Samples of SC up to 1% and inorganic glass with encapsulated silver up to 5% showed significant improvement in their antibacterial ability without compromising shear strength. The highest antimicrobial activity was observed for Lactobacillus acidophilus, with inhibition zones of 3.8 and 3.1 mm for SC and inorganic glass, respectively. The characterization of the samples did not detect any major structural changes between the different samples. The only group that underwent a noticeable color change was the group with SC. The results show that the incorporation of silver carbonate and inorganic glass with encapsulated silver provided the glass ionomer cement with an antibacterial capacity without compromising the bond strength and without modifying the structure of the material.

Breast cancer subtype and clinical characteristics in women from Peru.

Introduction: Breast cancer is a heterogeneous disease, and the distribution of the different subtypes varies by race/ethnic category in the United States and by country. Established breast cancer-associated factors impact subtype-specific risk; however, these included limited or no representation of Latin American diversity. To address this gap in knowledge, we report a description of demographic, reproductive, and lifestyle breast cancer-associated factors by age at diagnosis and disease subtype for The Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study. Methods: The PEGEN-BC study is a hospital-based breast cancer cohort that includes 1943 patients diagnosed at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. Demographic and reproductive information, as well as lifestyle exposures, were collected with a questionnaire. Clinical data, including tumor Hormone Receptor (HR) status and Human Epidermal Growth Factor Receptor 2 (HER2) status, were abstracted from electronic medical records. Differences in proportions and mean values were tested using Chi-squared and one-way ANOVA tests, respectively. Multinomial logistic regression models were used for multivariate association analyses. Results: The distribution of subtypes was 52% HR+HER2-, 19% HR+HER2+, 16% HR-HER2-, and 13% HR-HER2+. Indigenous American (IA) genetic ancestry was higher, and height was lower among individuals with the HR-HER2+ subtype (80% IA vs. 76% overall, p=0.007; 152 cm vs. 153 cm overall, p=0.032, respectively). In multivariate models, IA ancestry was associated with HR-HER2+ subtype (OR=1.38,95%CI=1.06-1.79, p=0.017) and parous women showed increased risk for HR-HER2+ (OR=2.7,95%CI=1.5-4.8, p<0.001) and HR-HER2- tumors (OR=2.4,95%CI=1.5-4.0, p<0.001) compared to nulliparous women. Multiple patient and tumor characteristics differed by age at diagnosis (<50 vs. >=50), including ancestry, region of residence, family history, height, BMI, breastfeeding, parity, and stage at diagnosis (p<0.02 for all variables). Discussion: The characteristics of the PEGEN-BC study participants do not suggest heterogeneity by tumor subtype except for IA genetic ancestry proportion, which has been previously reported. Differences by age at diagnosis were apparent and concordant with what is known about pre- and post-menopausal-specific disease risk factors. Additional studies in Peru should be developed to further understand the main contributors to the specific age of onset and molecular disease subtypes in this population and develop population-appropriate predictive models for prevention.

Genomic landscape of lung cancer in the young.

Background: Lung cancer in the young is a rare entity of great interest due to the high frequency of targetable mutations. In this study, we explored the genomic landscape of non-small cell lung cancer (NSCLC) in young patients and compared it with genetic alterations in older patients. Methods: Comparative study of the genomic profile of NSCLC young (≤40 years old) vs older patients (>40 years old) from Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Archival paraffin-embedded tumor samples were profiled with FoundationOne CDx assay to identify short variants alterations (insertions and deletions), copy number variations (CNV), tumor mutational burden and microsatellite instability in 324 driver genes and rearrangements in 28 commonly rearranged genes. A targetable alteration was defined as any alteration in a driver oncogene for which an FDA approved therapy existed at the time of study enrollment. Results: Overall, 62 tumors were profiled, 32 from young and 30 from older patients. All clinicopathological features (smoking status, clinical stage, and histology) were similar between groups, except for gender (65.6% of females in the younger group vs 40% in the older group, P=0.043). At least one actionable mutation was present in 84.4% and 83.3% in younger and older patients, respectively. Alteration rates in the main genes were: BRAF, 3.1%(n=1) vs 0%; EGFR, 46.9% (n=15) vs 43.3% (n=13); ERBB2, 12.5% (n=4) vs 16.7% (n=5); KRAS, 15.6% (n=5) vs 16.7% (n=5); ALK, 6.3% (n=2) vs 3.3% (n=1); RET, 0.0% vs 3.3% (n=1); ROS1, 3.1% (n=1) vs 3.3% (n=1); NTRK1, 0.0% vs 3.3% (n=1) and MET, 3.1% (n=1) vs 13.3% (n=4). Mean TMB was 4.04 Mut/Mb (SD ± 3.98) for young vs 8.06 Mut/Mb (SD ± 9.84) for older patients (P=0.016). There were not significant differences in CNV, frequency of gene rearrangements, or microsatellites instability. Conclusion: NSCLC in the young in our cohort was characterized by a high frequency of actionable genetic aberrations and a low TMB, which was also true for our older patients. The enrichment of actionable mutations in young patients described in other reports might be attributed to differences in the etiology and clinicopathological characteristics between younger and older patients and therefore not be applicable to all populations.

Coarse-Grained Simulations of Release of Drugs Housed in Flexible Nanogels: New Insights into Kinetic Parameters.

The diffusion-controlled release of drugs housed in flexible nanogels has been simulated with the help of a coarse-grained model that explicitly considers polymer chains. In these in silico experiments, the effect of its flexibility is assessed by comparing it with data obtained for a rigid nanogel with the same volume fraction and topology. Our results show that the initial distribution of the drug can exert a great influence on the release kinetics. This work also reveals that certain surface phenomena driven by steric interactions can lead to apparently counterintuitive behaviors. Such phenomena are not usually included in many theoretical treatments used for the analysis of experimental release kinetics. Therefore, one should be very careful in drawing conclusions from these formalisms. In fact, our results suggest that the interpretation of drug release curves in terms of kinetic exponents (obtained from the Ritger-Peppas Equation) is a tricky question. However, such curves can provide a first estimate of the drug diffusion coefficient.

A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population.

BACKGROUND: Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC. METHODS: A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes. RESULTS: EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1-2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79-15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92-15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55-5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7-15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18-3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49-5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22-4.80) p = 0.011 respectively]. CONCLUSION: EGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy.

p.G12C KRAS mutation prevalence in non-small cell lung cancer: Contribution from interregional variability and population substructures among Hispanics.

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.