Enhancing Urological Cancer Treatment: Leveraging Vasodilator Synergistic Potential with 5-FU for Improved Therapeutic Outcomes.

Backgroud: This study investigates the potential of vasodilator drugs as additive therapy in the treatment of urological cancers, particularly in combination with the antineoplastic agent 5-fluorouracil (5-FU). Methods: The study evaluated the cytotoxic effects of sildenafil, tezosentan and levosimendan alone and in combination with 5-FU on urological cancer cell lines. The assessment included MTT assays, colony formation assays and wound healing assays to determine cell viability, proliferative capacity, and migratory behavior, respectively. Results: Sildenafil and tezosentan showed limited cytotoxic effects, while levosimendan demonstrated moderate anticancer activity. The combination of levosimendan and 5-FU exhibited an additive interaction, enhancing cytotoxicity against cancer cells while sparing normal cells. Levosimendan also inhibited cell migration and proliferation, potentially through mechanisms involving the modulation of cAMP levels and nitric oxide production. Conclusions: The findings suggest that levosimendan can be used in conjunction with 5-FU to reduce the required dose of 5-FU, thereby minimizing side effects without compromising therapeutic efficacy. This study offers a new perspective for enhancing therapeutic outcomes in patients with urological cancers.

Toward Personalized Salbutamol Therapy: Validating Virtual Patient-Derived Population Pharmacokinetic Model with Real-World Data.

Interindividual variability, influenced by patient-specific factors including age, weight, gender, race, and genetics, among others, contributes to variations in therapeutic response. Population pharmacokinetic (popPK) modeling is an essential tool for pinpointing measurable factors affecting dose-concentration relationships and tailoring dosage regimens to individual patients. Herein, we developed a popPK model for salbutamol, a short-acting ß2-agonist (SABA) used in asthma treatment, to identify key patient characteristics that influence treatment response. To do so, synthetic data from physiologically-based pharmacokinetic (PBPK) models was employed, followed by an external validation using real patient data derived from an equivalent study. Thirty-two virtual patients were included in this study. A two-compartment model, with first-order absorption (no delay), and linear elimination best fitted our data, according to diagnostic plots and selection criteria. External validation demonstrated a strong agreement between individual predicted and observed values. The incorporation of covariates into the basic structural model identified a significant impact of age on clearance (Cl) and intercompartmental clearance (Q); gender on Cl and the constant rate of absorption (ka); race on Cl; and weight on Cl in the volume of distribution of the peripheral compartment (V2). This study addresses critical challenges in popPK modeling, particularly data scarcity, incompleteness, and homogeneity, in traditional clinical trials, by leveraging synthetic data from PBPK modeling. Significant associations between individual characteristics and salbutamol's PK parameters, here uncovered, highlight the importance of personalized therapeutic regimens for optimal treatment outcomes.

Macrophage Phenotype Induced by Circulating Small Extracellular Vesicles from Women with Endometriosis.

Evidence suggests that immune system dysfunction and macrophages are involved in the disease establishment and progression of endometriosis. Among the factors involved in this alteration in macrophage activity, Small Extracellular Vesicles (sEVs) have been described to play a role favoring the switch to a specific phenotype with controversial results. This study aims to investigate the potential effect of circulating sEVs in the plasma of well-characterized patients with endometriosis on the polarization of macrophages. sEVs were isolated from the plasma of patients diagnosed with endometriosis confirmed by histopathological analysis. Two groups of patients were recruited: the endometriosis group consisted of patients diagnosed with endometriosis by imaging testing (gynecological ultrasonography and/or magnetic resonance imaging), confirmed by histopathologic study (n = 12), and the control group included patients who underwent laparoscopy for tubal sterilization without presurgical suspicion of endometriosis and without endometriosis or signs of any inflammatory pelvic condition during surgery (n = 12). Human THP1 monocytic cells were differentiated into macrophages, and the effect of sEVs on cell uptake and macrophage polarization was evaluated by fluorescent labeling and measurement of the IL1B, TNF, ARG1, and MRC1 expression, respectively. Although no changes in cell uptake were detected, sEVs from endometriosis induced a polarization of macrophages toward an M2 phenotype, characterized by lower IL1B and TNF expression and a tendency to increase MRC1 and ARG1 levels. When macrophages were stimulated with lipopolysaccharides, less activation was also detected after treatment with endometriosis sEVs. Finally, endometriosis sEVs also induced the expression of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARG); however, treatment with rosiglitazone, a PPARG agonist, had no effect on the change in macrophage phenotype. We conclude that circulating sEVs in women with endometriosis have a certain capacity to shift the activation state of macrophages toward an M2 phenotype, but this does not modify the uptake level or the response to PPARG ligands.

Advancing Precision Medicine: A Review of Innovative In Silico Approaches for Drug Development, Clinical Pharmacology and Personalized Healthcare.

The landscape of medical treatments is undergoing a transformative shift. Precision medicine has ushered in a revolutionary era in healthcare by individualizing diagnostics and treatments according to each patient's uniquely evolving health status. This groundbreaking method of tailoring disease prevention and treatment considers individual variations in genes, environments, and lifestyles. The goal of precision medicine is to target the "five rights": the right patient, the right drug, the right time, the right dose, and the right route. In this pursuit, in silico techniques have emerged as an anchor, driving precision medicine forward and making this a realistic and promising avenue for personalized therapies. With the advancements in high-throughput DNA sequencing technologies, genomic data, including genetic variants and their interactions with each other and the environment, can be incorporated into clinical decision-making. Pharmacometrics, gathering pharmacokinetic (PK) and pharmacodynamic (PD) data, and mathematical models further contribute to drug optimization, drug behavior prediction, and drug-drug interaction identification. Digital health, wearables, and computational tools offer continuous monitoring and real-time data collection, enabling treatment adjustments. Furthermore, the incorporation of extensive datasets in computational tools, such as electronic health records (EHRs) and omics data, is also another pathway to acquire meaningful information in this field. Although they are fairly new, machine learning (ML) algorithms and artificial intelligence (AI) techniques are also resources researchers use to analyze big data and develop predictive models. This review explores the interplay of these multiple in silico approaches in advancing precision medicine and fostering individual healthcare. Despite intrinsic challenges, such as ethical considerations, data protection, and the need for more comprehensive research, this marks a new era of patient-centered healthcare. Innovative in silico techniques hold the potential to reshape the future of medicine for generations to come.

Exploring the Role of Drug Repurposing in Bridging the Hypoxia-Depression Connection.

High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood-brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1.

The elusive Luminal B breast cancer and the mysterious chemokines.

PURPOSE: Invasive ductal breast cancer (IDC) is heterogeneous. Staging and immunohistochemistry (IH) allow for effective therapy but are not yet ideal. Women with Luminal B tumors show an erratic response to treatment. This prospective study with 81 women with breast cancer aims to improve the prognostic stratification of Luminal B patients. METHODS: This is a prospective translational study with 81 women with infiltrating ductal carcinoma, grouped by TNM staging and immunohistochemistry, for survival analysis, and their correlations with the chemokines. Serum measurements of 13 chemokines were performed, including 7 CC chemokines [CCL2(MCP1), CCL3(MIP1α), CCL4(MIP1ß), CCL5(Rantes), CCL11(Eotaxin), CCL17(TARC), CCL20(MIP3α)], 6 CXC chemokines [CXCL1(GroAlpha), CXCL5(ENA78), CCXCL8(IL-8), CXCL9(MIG), CXCL10(IP10), CXCL11(ITAC)]. RESULTS: Overall survival was significantly dependent on tumor staging and subtypes by immunohistochemistry, with a median follow-up time the 32.87 months (3.67-65.63 months). There were age correlations with IP10/CXCL10 chemokines (r = 0.4360; p = 0.0079) and TARC/CCL17 (Spearman + 0.2648; p = 0.0360). An inverse correlation was found between body weight and the chemokines Rantes/CCL5 (r = - 0.3098; p = 0.0169) and Eotaxin/CCL11 (r = - 0.2575; p = 0.0470). Smokers had a higher concentration of MIP3α/CCL20 (Spearman + 0.3344; p = 0.0267). Luminal B subtype patients who expressed lower concentrations of ENA78/CXCL5 (≤ 254.83 pg/ml) (Log-Rank p = 0.016) and higher expression of MIP1ß/CCL4 (> 34.84 pg/ml) (Log-Rank p = 0.014) had a higher risk of metastases. CONCLUSION: Patients with Luminal B breast tumors can be better stratified by serum chemokine expression, suggesting that prognosis is dependent on biomarkers other than TNM and IH.

Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine.

Drug-drug interactions (DDIs) represent a significant concern in healthcare, particularly for patients undergoing polytherapy. DDIs can lead to a range of outcomes, from decreased therapeutic effectiveness to adverse effects. Salbutamol, a bronchodilator recommended for the treatment of respiratory diseases, is metabolized by cytochrome P450 (CYP) enzymes, which can be inhibited or induced by co-administered drugs. Studying DDIs involving salbutamol is crucial for optimizing drug therapy and preventing adverse outcomes. Here, we aimed to investigate CYP-mediated DDIs between salbutamol and fluvoxamine through in silico approaches. The physiologically based pharmacokinetic (PBPK) model of salbutamol was developed and validated using available clinical PK data, whereas the PBPK model of fluvoxamine was previously verified by GastroPlus. Salbutamol-fluvoxamine interaction was simulated according to different regimens and patient's characteristics (age and physiological status). The results demonstrated that co-administering salbutamol with fluvoxamine enhanced salbutamol exposure in certain situations, especially when fluvoxamine dosage increased. To sum up, this study demonstrated the utility of PBPK modeling in predicting CYP-mediated DDIs, making it a pioneer in PK DDI research. Furthermore, this study provided insights into the relevance of regular monitoring of patients taking multiple medications, regardless of their characteristics, to prevent adverse outcomes and for the optimization of the therapeutic regimen, in cases where the therapeutic benefit is no longer experienced.

The Involvement of Hypoxia in the Response of Neuroblastoma Cells to the Exposure of Atorvastatin.

Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment. Atorvastatin is a type of statin with several potentialities as an anti-cancer agent, supported by several studies. Our study aimed to explore the effect of this drug in SH-SY5Y human neuroblastoma cells. Additionally, we also aimed to understand how this drug acts under hypoxia and the inhibition of hypoxia-inducible factor-1 (HIF-1). For that purpose, we assessed cellular viability/morphology after exposure to different concentrations of atorvastatin, with or without chemically induced hypoxia with chloride cobalt (CoCl2) and with or without echinomycin (HIF-1α inhibitor). Our results supported the cytotoxic effects of atorvastatin. Additionally, we also revealed that besides these effects, under hypoxia, this drug induced proliferation of the neuroblastoma cells, supporting the importance of different stimuli and environment on the effect of drugs on cancer cells.

The Effects of Chitosan on the Healing Process of Oral Mucosa: An Observational Cohort Feasibility Split-Mouth Study.

The healing process is a dynamic process accompanied by some classical symptoms of inflammation such as redness, swelling, pain, and loss of function. Chitosan is a natural polymer with properties that contribute to tissue healing, with properties that could be applied in periodontal therapy, such as the wound healing of oral mucosa. This experimental split-mouth study aims to assess the possibilities of chitosan influencing the healing process of oral mucosa in eight patients, where the studied group was subjected to two oral surgeries: one with chitosan hydrogel into the socket and other without the biomaterial. A semi-quantitative analysis of the data was performed. Some classic signs of inflammation in a short period of time were observed where chitosan acted, compared to the control. An absence of bleeding was observed in the chitosan cases. According to the literature, chitosan recruits and activates neutrophils and macrophages and stimulates angiogenesis. Hemostatic and antimicrobial activity of chitosan also play an important role in wound healing. Chitosan seems to improve the postoperative quality of patients, allowing rapid wound healing with less complications.

Salbutamol in the Management of Asthma: A Review.

Asthma is a common inflammatory disease of the lungs. The prevalence of asthma is increasing worldwide, and the tendency indicates that the number of asthma sufferers will soar in the coming years for several reasons, in particular, the lifestyles we have adopted that expose us to risk factors. Salbutamol is the first selective short-acting ß2-agonist (SABA) used as an alternative reliever in the treatment of asthma. Its therapeutic effect is based on its potent smooth muscle relaxant properties, which allow the inhibition of bronchial smooth muscle contraction and subsequent bronchodilation. Salbutamol can be administered orally, intravenously (IV), intramuscularly (IM), subcutaneously, or by inhalation. For this reason, the pharmacokinetic (PK) parameters-absorption, distribution, metabolism, and elimination-are highly diverse and, consequently, the efficacy and adverse effects also differ between each formulation. Here, we review the pharmacological profile of different salbutamol formulations, focusing on their efficacy and adverse effects for its original application, asthma.

Therapeutic Options for Chlamydia trachomatis Infection: Present and Future.

Sexually transmitted infections (STIs), such as Chlamydia trachomatis (Ct) infection, have serious consequences for sexual and reproductive health worldwide. Ct is one of the most common sexually transmitted bacterial infections in the world, with approximately 129 million new cases per year. C. trachomatis is an obligate intracellular Gram-negative bacterium. The infection is usually asymptomatic, notwithstanding, it could also be associated with severe sequels and complications, such as chronic pain, infertility, and gynecologic cancers, and thus there is an urgent need to adequately treat these cases in a timely manner. Consequently, beyond its individual effects, the infection also impacts the economy of the countries where it is prevalent, generating a need to consider the hypothesis of implementing Chlamydia Screening Programs, a decision that, although it is expensive to execute, is a necessary investment that unequivocally will bring financial and social long-term advantages worldwide. To detect Ct infection, there are different methodologies available. Nucleic acid amplification tests, with their high sensitivity and specificity, are currently the first-line tests for the detection of Ct. When replaced by other detection methods, there are more false negative tests, leading to underreported cases and a subsequent underestimation of Ct infection's prevalence. Ct treatment is based on antibiotic prescription, which is highly associated with drug resistance. Therefore, currently, there have been efforts in line with the development of alternative strategies to effectively treat this infection, using a drug repurposing method, as well as a natural treatment approach. In addition, researchers have also made some progress in the Ct vaccine development over the years, despite the fact that it also necessitates more studies in order to finally establish a vaccination plan. In this review, we have focused on the therapeutic options for treating Ct infection, expert recommendations, and major difficulties, while also exploring the possible avenues through which to face this issue, with novel approaches beyond those proposed by the guidelines of Health Organizations.

The effect of delayed treatment in breast cancer patients: How much is too late? An experience of a single-center study effect of surgery delay in survival.

BACKGROUND AND OBJECTIVES: Proper treatment is critical for control and curative intent in breast cancer. Delays in receiving treatment can influence patients' prognoses. METHODS: Retrospective, observational, single-center study based on data from medical records of 747 patients with non-metastatic invasive ductal breast carcinoma (I-III) in the initial analysis, comprising 554 patients undergoing adjuvant and 193 neoadjuvant treatment. Kaplan-Meier, Cox regression and time-dependent Cox regression were performed to obtain the predictive value of time to surgery and time to first treatment. Immortal time bias was managed and only 721 patients were included in the multivariable analysis. RESULTS: During a median observation of 64.4 months, there were 140 death events and 177 disease progression events. Time to surgery (TTS) and time from completion of neoadjuvant chemotherapy to surgery (TNS) showed a significant impact on overall survival, associated with a 6% increased chance of death [HR: 1.06 (1.03-1.09), p < 0.001] and 4% [HR: 1.04 (1.00-1.09), p = 0.048] with a one-month increment, respectively. By multivariable analysis, continuous TTS had a different weight as a prognostic factor in stage IIIA/IIIB [adjusted HR: 1.249 (1.072-1.454), p = 0.004] compared to stage I/II [adjusted HR: 1.093 (1.048-1.141), p < 0.0005]. Likewise, TNS was significant after adjusting for other factors [adjusted HR: 1.092 (1.038-1.148), p = 0.001]. CONCLUSION: Delay in receiving surgery with curative intent impairs the survival of patients with breast cancer.

Epidermal growth factor receptor (EGFR) expression in the serum of patients with triple-negative breast carcinoma: prognostic value of this biomarker.

Background: Epidermal growth factor receptor (EGFR) overexpression has been considered a poor prognostic factor in breast cancer. Methodology: A prospective study of 206 women with breast cancer analysed by stages (I, II, III and IV) and by immunohistochemical subtype (Luminal A, Luminal B, HER2+ and triple-negative (TN)); 89 healthy controls with normal recent mammography were included. The EGFR measured in the serum (sEGFR) was detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method (R&D Systems kit DY231) collected by blood before any treatment in patients. Kaplan-Meier method and Cox regression were carried out to obtain the prognostic value, considering significance if p < 0.05. Results: With a median follow-up of 36.6 months, 47 deaths occurred. Multivariable Cox regression showed difference of overall survival (OS) associated with sEGFR levels (sEGFR ≤ or > 47.8 ng/mL) in patients with TN cancers, but not of Luminal A, Luminal B or HER2+ subtypes; adjusted by stage, the death risk increased by approximately 415% [hazard ratio (HR): 5.149 (1.900-13.955), p = 0.001] for patients with sEGFR > 47.8 ng/mL compared to patients with a lower sEGFR value. There was no significant correlation of sEGFR with staging, histological tumour grade (G1/G2/G3), Ki67 (< or ≥14%) or body mass index. Conclusions: Increased sEGFR expression in patients with TN tumours is a significant predictor of lower OS and its quantification is inexpensive and straightforward.

New Data for Nebivolol after In Silico PK Study: Focus on Young Patients and Dosage Regimen.

Nebivolol (NEB) is a highly selective ß1 receptor antagonist with a distinct pharmacological profile. This drug is approved for the treatment of hypertension in the US, and hypertension and heart failure in Europe. Here, we review observations based on age dependence and explore new drug regimens with in-silico studies, to achieve better efficacy and safety. The clinical data were obtained from six published literature reports. Then the data were used for model building, evaluation, and simulation. A two-compartment model with first-order absorption, lag time, linear elimination, and the following covariates: age and genotype were the ones best describing our population. Simulation of different dose regimens resulted in an increase chance of efficacy and safety when the dose regimen was altered to 6 mg every 36 h. It is worth noting that our population in this study constituted of young and healthy individuals. Studies regarding the effects of NEB according to age are scarce; however, they are needed to further improve efficacy and safety, and reduce adverse effects.

A hierarchical approach to combine histological grade and immunohistochemical factors to identify high-risk luminal breast cancers.

Background: The luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions. Methods: A retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I-III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan-Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors. Results: During a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316-0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286-0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415-1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403-1.088), p = 0.104). Conclusion: The semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.

Prognosis value of lymphovascular invasion in patients with invasive ductal breast carcinoma according to lymph node metastasis status.

Background: Tumour lymphovascular invasion is not routinely assessed in all pathology services, and whether reporting it quantitatively or qualitatively is the main factor associated with the loss of this prognostic event. This study aimed to analyse the prognostic value of qualitatively reported lymphovascular invasion in patients with invasive breast ductal carcinoma. Methods: This was a retrospective, single-center study, enrolling a total of 426 patients with invasive ductal carcinoma of the breast with a report of lymphovascular invasion, with a median follow-up of approximately 4.5 years. Kaplan-Meier and Cox regression was performed to obtain the predictive value of lymphovascular invasion. Propensity score matching was performed to reduce bias by standardising factors with significant differential distribution of lymphovascular invasion status. Results: Lymphovascular invasion was present in 197 (49.2%) patients. Multivariate Cox regression showed that lymphovascular invasion independently increases the risk of death by almost two times (adjusted hazard ratio (HR): 2.045 (1.226-3.406), p = 0.006) and the risk of distant metastasis by more than two times (adjusted HR: 2.373 (1.404-4.010), p = 0.001). Subgroup analysis after matching by propensity score in adjuvant-only patients showed that the lymphovascular invasion is a factor of increased death in N- patients (adjusted HR: 12.597 (1.624-97.728), p = 0.015) and of distant metastasis-free survival in N+ patients (adjusted HR: 4.862 (1.649-14.335), p = 0.004) and almost for N- patients (adjusted HR 7.905 (0.969-64.509), p = 0.004). Conclusion: The presence of lymphovascular invasion is a predictor of worse prognosis in patients with invasive ductal carcinoma of the breast, even with metastatic lymph node disease (N1-N3).

Inanimate Surfaces and Air Contamination with Multidrug Resistant Species of Staphylococcus in the Neonatal Intensive Care Unit Environment.

BACKGROUND: Contamination of the hospital environment with multi-resistant (MDR) Staphylococcus increases the risk of infection. The aim of this study is to identify the MDR species of Staphylococcus on inanimate surfaces, in air, and in clinical samples, and analyze the risk factors that correlate with the occurrence of infections in a Neonatal Intensive Care Unit. METHODS: Samples of inanimate surfaces and air were taken using a premoistened swab (0.9% sodium chloride) and spontaneous air sedimentation, respectively. The clinical isolates were recovered from infected neonates. The isolates (environmental and clinical) were identified by matrix-assisted laser desorption ionization-time of flight and the resistance profile was calculated using the disk diffusion agar technique. RESULTS: In total, 181 isolates were obtained, 93 from (surfaces), 18 from the air, and 70 clinical samples. S. epidermidis was the most frequent species (66.8%), and the failure rate in air cleaning was 100%. More than 60% of the isolates were MDR, and the majority of clinical isolates (60.4%) had a resistance profile identical to that of the environmental isolates. CONCLUSION: Staphylococcus spp. were found in most of the analyzed samples, with a high frequency of MDR isolates, demonstrating the importance of the hospital environment as a reservoir, and the need for infection control measures, and rational use of antimicrobials.

The benefits of trastuzumab in the treatment of HER2+ breast cancer as a function of exposure time.

BACKGROUND: Breast cancer is a heterogeneous disease with overexpression of several receptors, such as human epidermal receptor 2 (HER2), which is a prognostic and predictive biomarker for treatment with the anti-HER2 monoclonal antibody trastuzumab. This study aimed to test the contribution of this regimen in patients with overexpression/amplification of HER2 for periods shorter than the 1-year treatment recommendation. METHODS: A retrospective single-centre study involving 155 patients with non-metastatic (stages I-III) invasive ductal HER2+ breast carcinoma, with a median follow-up of 48.9 months after completion of adjuvant therapy, except endocrine therapy. RESULTS: About 60% of patients received trastuzumab therapy for a median time of 365 days. Although the use of trastuzumab for a short period has provided some benefit, analyses of survival with a continuous dependent variable have revealed a minimum time for improved survival. In the multivariate analysis by Cox regression, trastuzumab use duration exceeding 9 weeks resulted in protection against distant metastasis (adjusted HR: 0.307 (0.139-0.678), p = 0.004), disease progression (adjusted hazard ratio (HR) 0.353 (0.175-0.714), p = 0.004) and death (adjusted HR: 0.267 (0.105-0.678), p = 0.005), being superior to multimodal systemic therapy with chemotherapy and to endocrine therapy without trastuzumab, but inferior to almost 1 year of administration of this monoclonal antibody, especially regarding overall survival (adjusted HR: 0.203 (0.069-0.596), p = 0.004). CONCLUSION: Despite showing some benefits, the protective effect derived from a suboptimal time of trastuzumab exposure is inferior to the standard course of 1 year.

The effectiveness of radiotherapy in preventing disease recurrence after breast cancer surgery.

BACKGROUND AND OBJECTIVES: The locoregional management of breast cancer has a critical impact on prognosis. This study aimed to analyze the effectiveness of radiotherapy against the deleterious effect of positive surgical margins on disease outcomes. METHODS: Retrospective, single-center study enrolled 721 breast cancer patients with a median follow-up of approximately 64.50 months (3.67-247.40). Analyses were performed considering the end of adjuvant therapy, except endocrine therapy. Kaplan-Meier and Cox regression were performed to obtain the predictive value of treatments. RESULTS: The minimally adequate radiotherapy (≥45 cGy) was associated with improved outcomes in breast cancer patients compared to inadequate radiotherapy (<45 cGy/no) by controlling locoregional relapses and distant metastasis. In patients with positive surgical margins (n = 53), radiotherapy was associated with an approximate decrease of 90% in locoregional relapse risk [adjusted HR: 0.108 (0.012-0.932), p = 0.043]. Radiotherapy did not alter the adverse effect of positive surgical margins, especially in patients with a higher risk of poorly differentiated tumors (n = 146), presence of lymphovascular invasion (n = 163), and triple-negative subtype (n = 113). Notwithstanding, radiotherapy was associated with respective decreases of distant metastasis risk of 75.2% [adjusted HR: 0.248 (0.081-0.762), p = 0.015] and 67.8% [adjusted HR: 0.322 (0.101-1.029), p = 0.056] in patients with triple-negative tumors or with lymphovascular invasion. CONCLUSION: Adequate radiotherapy is associated with better outcomes in breast cancer. Despite improving locoregional relapse-free survival, radiotherapy does not ablate positive surgical margins, a factor of poorer prognosis that prevails mainly in patients with factors of higher relapse risk.