Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study.

OBJECTIVE: Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. METHODS: This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. RESULTS: A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. CONCLUSIONS: PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Investigation on the mancozeb toxicity in adult zebrafish (Danio rerio).

Agriculture has gained increasing importance in response to the continuous growth of the world population and constant need for food. To avoid production losses, farmers commonly use pesticides. Mancozeb is a fungicide used in agriculture as this compound is effective in combating fungi that harm crops. However, this fungicide may also produce damage to non-target organisms present in soil and water. Therefore, this study aimed to investigate the influence of exposure to mancozeb on survival rate, locomotor activity, behavior, and oxidative status utilizing adult zebrafish (Danio rerio) as a model following exposure to environmentally relevant concentrations of this pesticide. The experimental groups were negative control, positive control, and mancozeb (0.3; 1.02; 3.47; 11.8 or 40 µg/L). Zebrafish were exposed to the respective treatments for 96 hr. Exposure to mancozeb did not markedly alter survival rate and oxidative status of Danio rerio. At a concentration of 11.8 µg/L, the fungicide initiated changes in locomotor pattern of the animals. The results obtained suggest that the presence of mancozeb in the environment might produce locomotor alterations in adult zebrafish, which subsequently disrupt the animals' innate defense mechanisms. In nature, this effect attributed to mancozeb on non-target organisms might result in adverse population impacts and ecological imbalance.

Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study

ABSTRACT Objective Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. Methods This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. Results A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. Conclusions PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Epidemiological profile, temporal analysis, and future projections of suicide cases in rural cities in the extreme south of Brazil.

The present study aimed to verify the time series (2000-2017) of death rates by suicide and its associated factors in 4 municipalities in the extreme south of Brazil. Data were obtained through the analysis of medical reports and police report bulletins at the Instituto Médico Legal, in the city of Rio Grande. The suicide rate in the Rio Grande region varied from 4 to 11 suicides per 100,000 inhabitants and it is estimated that by 2030 this rate could reach 16.5 suicides per 100,000 inhabitants. The rural cities of Santa Vitória do Palmar and Chuí present even higher suicide averages when compared to Rio Grande, the most populous city of the four. The death rate from suicide increased gradually in the period analyzed, with the prevalence rising among the youngest and the elderly population. A more comprehensive understanding of the influences of environmental issues on suicidal decisions constitutes an important action that needs to be taken, both because of regional vulnerabilities and the target population identified. Evidence indicates that knowledge of factors affecting individuals residing in this Brazilian region where increased suicide rates are recorded needs to be recognized as a priority.

Beneficial effects of mate-herb, Ilex paraguariensis St. Hil. against potassium dichromate-induced oxidative stress and nephrotoxicity.

Chimarrão is a typical beverage made from the infusion of dried and ground leaves and stems of Ilex paraguariensis (popularly known as Yerba mate or mate herb) which is widely consumed in parts of South America. The aim of this study was to examine the effects of the chimarrão against nephrotoxicity and oxidative stress induced by the potassium dichromate (PD) salt in male Wistar rats. The experiment lasted 17 days, and in the first 15 days animals ingested a chimarrão infusion or control drinking water and then submitted to an intraperitoneal injection (15 mg/kg) of PD (or saline solution) and euthanized after 48 hr at which time animals still received infusion or drinking water. Blood plasma and 24 hr-urine samples were collected to measure creatinine levels as an estimate of glomerular filtration rate (GFR). Concomitantly oxidative stress was determined in the kidneys as evidenced by levels of carbonyl groups, malondialdehyde (MDA) and antioxidant capacity against peroxyl radicals. Potassium dichromate induced oxidative stress in the kidneys and reduced GFR. Treatment with chimarrão during the 15 days prior to PD injection reduced PD salt-mediated oxidative stress. Further, treatment with post-injection chimarrão to PD-administered rats improved the GFR. Our findings support that the use of the chimarrão beverage may be considered as an important nephroprotective substance.

Oxidative damage in the Vesper mouse (Calomys laucha) exposed to a simulated oil spill-a multi-organ study.

Small wild mammals have been used to measure the damage caused by exposure to oil-contaminated soil, including deer mice. However, the study of toxic effects of crude oil using oxidative damage biomarkers in the wild rodent Calomys laucha (Vesper mouse) is absent. This investigation aimed to evaluate the effects of acute exposure to contaminated soil with different concentrations of crude oil (0, 1, 2, 4 and 8% w/w), simulating an accidental spill, using oxidative stress biomarkers in the liver, kidneys, lungs, testes, paw muscle, and lymphocytes of C. laucha. Animals exposed to the contaminated soil showed increases in lipid peroxidation and protein carbonylation at the highest exposure concentrations in most organ homogenates analyzed and also in blood cells, but responses to total antioxidant capacity were tissue-dependent. These results showed that acute exposure to oil-contaminated soil caused oxidative damage in C. laucha and indicate these small mammals may be susceptible to suffer the impacts of such contamination in its occurrence region, threatening the species' survival.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report.

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

2030 Agenda: discussion on Brazilian priorities facing air pollution and climate change challenges.

The advance of human activities in a disorderly way has accelerated in recent decades, intensifying the environmental impacts directly linked to these practices. The atmosphere, essential for the maintenance of life, is increasingly saturated with pollutants, offering risks to practically all the inhabitants of the planet, a process that, in addition to causing illness and early mortality, is related to serious financial losses (including in the production of goods), dangerous temperature increase and severe natural disasters. Although this perception is not recent, the global initiative to control the different mechanisms that trigger the commitment of biodiversity and irreversible climate changes arising from pollution is still very incipient, given that global initiatives on the subject emerged just over 50 years ago. Brazil is a territory that centralizes many of these discussions, as it still faces both political and economic obstacles in achieving a sustainable growth model as it was agreed through the United Nations 2030 Agenda. Even though there is little time left for the completion of these goals, much remains to be done, and despite the fulfillment of this deadline, the works will certainly need to be extended for much longer until an effective reorientation of consciousness occurs. Scientific researches and discussions are fundamental tools to the understanding of issues still little explored in this field.

Better understanding the behavior of air pollutants at shutdown times - results of a short full lockdown.

Numerous studies have evaluated the effects of lockdowns during the COVID-19 pandemic, but most of them have concerned large cities and regions. This study aimed to evaluate the dynamics of air pollutants during and after the implementation of a short lockdown in the medium-sized city of Pelotas, Brazil, using hourly measurements of pollutants. The evaluation period included in this study was between August 9th and 12th, 2020. A machine learning model was used to investigate the expected behavior against what was observed during the study period. All pollutants presented a gradual reduction until a dynamic plateau established 48 hours after the start of the lockdown: NO2 (↓4%), O3 (↓34%), SO2 (↓24%), CO (↓48%), PM10 (↓82%) and PM2.5 (↓82%). At the end of the restriction measures, the PM10 and PM2.5 levels continued to decline beyond expectations. Our findings show that these measures can positively affect the air quality in medium-sized cities.

"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

Clinical Course, Genetic, and Immunohistochemical Characterization of Solid Pseudopapillary Tumor of the Pancreas (Frantz Tumors) in a Brazilian Cohort.

Frantz tumors or solid pseudopapillary pancreatic neoplasm (SPN) are rare exocrine neoplasms that carry a favorable prognosis; they represent up to 3% of all tumors located in the region of the pancreas and have specific age and gender predispositions. In recent years, the rising curve of diagnosis is entitled to the evolution and access of diagnostic imaging. In this paper, we have retrospectively reviewed and described the clinical course of 40 patients with SPN from three institutions in Brazil, who had their diagnosis between 2005 and 2020, and analyzed the clinicopathological, genetic, and surgical aspects of these individuals. In accordance with the literature, most patients were women, 60% with unspecified symptoms at diagnosis, with tumors mainly located in the body and tail of the pancreas, of whom 70% underwent a distal pancreatectomy with sparing splenectomy as a standard procedure, and none of the cases have experienced recurrence to date. Surgery still remains the mainstay of treatment given the low metastatic potential, but more conservative approaches as observed in this cohort are evolving to become the standard of care. Herein, we present an in-depth analysis of cases focusing on the latest literature and report some of the smallest tumor cases in the literature. To our knowledge, this is the first report evaluating germline genetic testing and presenting a case of detected Li-Fraumeni syndrome.

Gestational and Neonatal Outcomes in Cities in the Largest Coal Mining Region in Brazil.

Brazil has one of the largest mineral coal reserves in the world. More than 40% of this ore is in the Candiota Mine, in the extreme south of Brazil, which was previously identified as a hotspot of environmental pollution. In addition, an important part of Brazil's population suffers from socioeconomic vulnerability. Since there is no information on unfavorable gestational and neonatal outcomes associated with these problems, we conducted a cross-sectional study with 1950 mother-child binomials, aiming to evaluate the association between these outcomes and air pollution as well as socioeconomic, demographic and health variables in seven cities in the region. Of the total births, 11.6% were preterm and 9.5% of neonates had low birth weight (<2500 g). These conditions were also associated with skin color, previous abortions, birth type and prenatal care, as well as exposure to higher levels of coarse particulate matter (PM10) during the first trimester of pregnancy. Regarding air pollutants, although the daily limits for PM10 were exceeded on less than 5% of days, the annual average overtook the values proposed by WHO. Thus, we concluded that prematurity and low birth weight in this region are related to air pollution, and to socioeconomic variables and health care.

Neoadjuvant chemotherapy or upfront surgery in localized pancreatic cancer: a contemporary analysis.

Neoadjuvant chemotherapy is considered a new treatment option for potentially resectable pancreatic cancer. However, data are not well established on overall survival and delaying surgery in resectable pancreatic cancer, as well as on those patients that ultimately cannot undergo surgery. We analyzed pancreatic cancer patients treated in a tertiary hospital from January 2016 to December 2020. Patients with resectable stage I and II pancreatic cancer were evaluated regarding surgery, neoadjuvant treatment, and other clinical demographics. The survival function was estimated using the Kaplan-Meier method, and the relationship between the variables of interest and the overall survival (OS) was assessed by adopting the proportional regression Cox models. A total of 216 patients were evaluated. 81 of them with resectable/borderline resectable disease and 135 with unresectable /metastatic disease at diagnosis. Median OS for stage I and II disease were 36 and 28 months, respectively. For resectable pancreatic cancer median OS was 28 months, for borderline resectable pancreatic cancer median OS was 11 months. Median OS for stage III (locally advanced) and stage IV (metastatic) were 10 and 7 months, respectively (p < 0.0001). Median OS of 9 months were obtained for patients with stage I and II that did not undergo surgery compared to 25 months in patients that underwent surgery in any time (p < 0.001). Comparing patients with localized disease, median OS for patients treated with upfront surgery was 28 months, compared to 15 months in patients treated with neoadjuvant approach (p = 0.04). Most patients that did not undergo surgery have decline of performance status or disease progression on neoadjuvant treatment. On multivariable analysis in pancreatic cancer stages I and II, including age, sex, borderline or resectable disease, CA 19-9, positive lymph nodes and neoadjuvant treatment, the surgery was the only factor associated with improved overall survival (p = 0.04). Upfront surgery should still be considered a standard of care approach for resectable pancreatic cancer. Biomarker driven studies and randomized trials with combination therapies are necessary to address neoadjuvant chemotherapy and delaying surgery in purely resectable pancreatic cancer.

EGFR-RAD51 fusion in lung adenocarcinoma with systemic and intracranial response to osimertinib: A case report and review of the literature.

Comprehensive next-generation sequencing panels are leading to detection of rare gene fusion events. EFGR-RAD51 fusion is a rare oncogenic finding and clinical data for management of this condition is scarce. We report a widely metastatic non-small cell lung cancer in a never-smoker young male patient with sustained near-complete systemic and intracranial response to osimertinib, a third-generation EGFR tyrosine-kinase inhibitor (TKI). We also review the available data of other TKIs in this scenario and underscore the role of comprehensive molecular testing for NSCLC.

Anatomical atlas of the upper part of the human head for electroencephalography and bioimpedance applications.

Objective.The objective of this work is to develop a 4D (3D+T) statistical anatomical atlas of the electrical properties of the upper part of the human head for cerebral electrophysiology and bioimpedance applications.Approach.The atlas was constructed based on 3D magnetic resonance images (MRI) of 107 human individuals and comprises the electrical properties of the main internal structures and can be adjusted for specific electrical frequencies. T1w+T2w MRI images were used to segment the main structures of the head while angiography MRI was used to segment the main arteries. The proposed atlas also comprises a time-varying model of arterial brain circulation, based on the solution of the Navier-Stokes equation in the main arteries and their vascular territories.Main results.High-resolution, multi-frequency and time-varying anatomical atlases of resistivity, conductivity and relative permittivity were created and evaluated using a forward problem solver for EIT. The atlas was successfully used to simulate electrical impedance tomography measurements indicating the necessity of signal-to-noise between 100 and 125 dB to identify vascular changes due to the cardiac cycle, corroborating previous studies. The source code of the atlas and solver are freely available to download.Significance.Volume conductor problems in cerebral electrophysiology and bioimpedance do not have analytical solutions for nontrivial geometries and require a 3D model of the head and its electrical properties for solving the associated PDEs numerically. Ideally, the model should be made with patient-specific information. In clinical practice, this is not always the case and an average head model is often used. Also, the electrical properties of the tissues might not be completely known due to natural variability. Anatomical atlases are important tools forin silicostudies on cerebral circulation and electrophysiology that require statistically consistent data, e.g. machine learning, sensitivity analyses, and as a benchmark to test inverse problem solvers.

CAAos platform: an integrated platform for analysis of cerebral hemodynamics data.

Objective.The purpose of this article is to introduce readers to the concept and structure of the CAAos (CerebralAutoregulationAssessmentOpenSource) platform, and provide evidence of its functionality.Approach.The CAAos platform is a new open-source software research tool, developed in Python 3 language, that combines existing and novel methods for interactive visual inspection, batch processing and analysis of multichannel records. The platform is scalable, allowing for the customization and inclusion of new tools.Main results.Currently, the CAAos platform is composed of two main modules, preprocessing (containing artefact removal, filtering and signal beat to beat extraction tools) and cerebral autoregulation (CA) analysis modules. Two methods for assessing CA have been implemented into the CAAos platform: transfer function analysis (TFA) and the autoregulation index (ARI). In order to provide validation of the TFA and ARI estimates derived from the CAAos platform, the results were compared with those derived from two other algorithms. Validation was performed using data from 28 participants, corresponding to 13 acute ischemic stroke patients and 13 age- and sex-matched control subjects. Agreement between estimates was assessed by intraclass correlation coefficient and Bland-Altman analysis. No significant statistical difference between the algorithms was found. Moreover, there was an excellent correspondence between the curves of all parameters analysed, with the intraclass correlation coefficient ranging from 0.98 (95%CI 0.976-0.999) to 1.00 (95%CI 1 -1). The mean differences revealed a very small magnitude bias indicating an excellent agreement between the estimates.Significance.As open-source software, the source code for the software is freely available for noncommercial use, reducing barriers to performing CA analysis, allowing inspection of the inner-workings of the algorithms, and facilitating networked activities with common standards. The CAAos platform is a tailored software solution for the scientific community in the cerebral hemodynamic field and contributes to the increasing use and reproducibility of CA assessment.