Seasonality of the incidence of bronchiolitis in infants — Brazil, 2016-2022: An interrupted time-series analysis / Sazonalidade da incidência de bronquiolite em lactentes — Brasil, 2016-2022: Uma análise de série temporal interrompida

ABSTRACT Objective: To evaluate the seasonality of acute bronchiolitis in Brazil during the 2020-2022 season and compare it with the previous seasons. Methods: Data from the incidence of hospitalizations due to acute bronchiolitis in infants <1 year of age were obtained from the Department of Informatics of the Brazilian Public Health database for the period between 2016 and 2022. These data were also analyzed by macro-regions of Brazil (North, Northeast, Southeast, South, and Midwest). To describe seasonal and trend characteristics over time, we used the Seasonal Autoregressive Integrated Moving Averages Model. Results: Compared to the pre-COVID-19 period, the incidence of hospitalizations related to acute bronchiolitis decreased by 97% during non-pharmacological interventions (March 2020 - August 2021) but increased by 95% after non-pharmacological interventions relaxation (September 2021 - December 2022), resulting in a 16% overall increase. During the pre-COVID-19 period, hospitalizations for acute bronchiolitis followed a seasonal pattern, which was disrupted in 2020-2021 but recovered in 2022, with a peak occurring in May, approximately 4% higher than the pre-COVID-19 peak. Conclusions: This study underscores the significant influence of COVID-19 interventions on acute bronchiolitis hospitalizations in Brazil. The restoration of a seasonal pattern in 2022 highlights the interplay between public health measures and respiratory illness dynamics in young children.

RESUMO Objetivo: Avaliar a sazonalidade da bronquiolite aguda no Brasil durante a temporada 2020-2022 e compará-la com a das temporadas anteriores. Métodos: Os dados de incidência de internações por bronquiolite aguda em lactentes <1 ano de idade foram obtidos do Departamento de Informática da base de dados da Saúde Pública Brasileira para o período entre 2016 e 2022. Esses dados também foram analisados por macrorregiões do Brasil (Norte, Nordeste, Sudeste, Sul e Centro-Oeste). Para descrever características sazonais e de tendência ao longo do tempo, utilizamos o Modelo de Médias Móveis Integradas Autorregressivas Sazonais. Resultados: Em comparação com o período pré-COVID-19, a incidência de hospitalizações relacionadas com bronquiolite aguda diminuiu 97% durante as intervenções não farmacológicas (março de 2020 - agosto de 2021), mas aumentou 95% após a flexibilização das intervenções não farmacológicas (setembro de 2021 - dezembro de 2022), resultando no aumento geral de 16%. Durante o período pré-COVID-19, as hospitalizações por bronquiolite aguda seguiram um padrão sazonal, que foi interrompido em 2020-2021, mas recuperaram-se em 2022, com um pico ocorrido em maio, aproximadamente 4% superior ao pico pré-COVID-19. Conclusões: Este estudo ressalta a influência significativa das intervenções contra a COVID-19 nas hospitalizações por bronquiolite aguda no Brasil. A restauração de um padrão sazonal em 2022 sublinha a interação entre as medidas de saúde pública e a dinâmica das doenças respiratórias em crianças pequenas.

Mitomycin C as an Anti-Persister Strategy against Klebsiella pneumoniae: Toxicity and Synergy Studies.

The combination of several therapeutic strategies is often seen as a good way to decrease resistance rates, since bacteria can more easily overcome single-drug treatments than multi-drug ones. This strategy is especially attractive when several targets and subpopulations are affected, as it is the case of Klebsiella pneumoniae persister cells, a subpopulation of bacteria able to transiently survive antibiotic exposures. This work aims to evaluate the potential of a repurposed anticancer drug, mitomycin C, combined with the K. pneumoniae lytic phage vB_KpnM-VAC13 in vitro and its safety in an in vivo murine model against two clinical isolates of this pathogen, one of them exhibiting an imipenem-persister phenotype. At the same time, we verified the absence of toxicity of mitomycin C at the concentration using the human chondrocyte cell line T/C28a2. The viability of these human cells was checked using both cytotoxicity assays and flow cytometry.

Short and Long-Term Outcomes of Patients with Pure Membranous Lupus Nephritis Compared to Patients with Proliferative Disease.

OBJECTIVES: Membranous lupus nephritis (MLN) is thought to have a more benign course than proliferative lupus nephritis (PLN). We aimed to determine the differences in short and long-term outcomes between patients with MLN and PLN. METHODS: We included patients with first biopsy-proven MLN and PLN. Short-term outcomes included complete proteinuria recovery (CPR), complete renal response (CRR), and primary efficacy renal response (PERR). Long-term outcomes included a sustained ≥40% reduction in baseline estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular (CV) events, ≥2 increase in SDI, and death. Univariable and multivariable Cox proportional hazard models were used to examine the effect of baseline characteristics on long-term outcomes. RESULTS: Of 215 patients, 51 had pure MLN, and 164 had PLN. We found no significant differences between the two groups in achieving CPR, CRR, and PERR at 1 and 2 years. Median time to outcomes was slightly, but insignificantly, longer in the MLN group.For long-term outcomes, PLN was associated with worse renal and non-renal outcomes, but this was not statistically significant.In the multivariable Cox proportional hazard models, ESKD was associated with the following baseline variables: younger age (HR 0.92, 95% CI 0.87-0.97), higher creatinine (HR 1.01, 95% CI 1.01-1.02), low complement (HR 4.0, 95% CI 1.04-11.10), and higher chronicity index (HR 1.28, 95% CI 1.08-1.51). CONCLUSION: The resolution of proteinuria in LN is slow. MLN is not a benign disease and may be associated with deterioration of renal function, ESKD, damage, CV events, and death.

The SLICE-3D dataset: 400,000 skin lesion image crops extracted from 3D TBP for skin cancer detection.

AI image classification algorithms have shown promising results when applied to skin cancer detection. Most public skin cancer image datasets are comprised of dermoscopic photos and are limited by selection bias, lack of standardization, and lend themselves to development of algorithms that can only be used by skilled clinicians. The SLICE-3D ("Skin Lesion Image Crops Extracted from 3D TBP") dataset described here addresses those concerns and contains images of over 400,000 distinct skin lesions from seven dermatologic centers from around the world. De-identified images were systematically extracted from sensitive 3D Total Body Photographs and are comparable in optical resolution to smartphone images. Algorithms trained on lower quality images could improve clinical workflows and detect skin cancers earlier if deployed in primary care or non-clinical settings, where photos are captured by non-expert physicians or patients. Such a tool could prompt individuals to visit a specialized dermatologist. This dataset circumvents many inherent limitations of prior datasets and may be used to build upon previous applications of skin imaging for cancer detection.

Cost-effectiveness of blinatumomab for the treatment of B­precursor acute lymphoblastic leukemia pediatric patients with high­risk first­relapse in Mexico.

BACKGROUND: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective. METHODS: A decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs. RESULTS: Blinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99 % of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico. LIMITATIONS: Health-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained. CONCLUSIONS: Blinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.

Impact of inflammation on cognitive function in patients with highly inflammatory rheumatoid arthritis.

OBJECTIVE: To evaluate cognitive function in patients with rheumatoid arthritis (RA) and inflammatory activity. PATIENTS AND METHODS: We performed a cross-sectional study of a cohort of patients with RA initiating their first biological treatment due to moderate-to-high inflammation and a healthy control group (no inflammatory diseases) matched for age, sex and educational level. All participants underwent a comprehensive neuropsychological assessment, with cognitive impairment defined as a Montreal Cognitive Assessment (MoCA) score<26. Additional assessments included various cognitive tests (STROOP, forward and backward digit spans), anxiety and depression scales (Hospital Anxiety and Depression Scale), quality of life measures (Quality of Life-Rheumatoid Arthritis) and average inflammatory activity according to the 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) into high activity (DAS28≥3.2) and low activity (DAS28<3.2) groups, also CRP levels and interleukin 6 (IL-6) levels were measured using an ELISA. RESULTS: The study population comprised 140 participants, 70 patients with RA and 70 controls. Patients more frequently experienced cognitive impairment than controls (60% vs 40%; p=0.019) and had lower mean (SD) values in the MoCA (23.6 (3.9) vs 25.1 (3.4); p=0.019. As for subtests of the MoCA, involvement was more marked in patients than in controls for the visuospatial-executive (p=0.030), memory (p=0.026) and abstraction (p=0.039) domains. Additionally, patients scored lower on executive function, as assessed by the backward digit span test (4.0 (1.7) vs 4.7 (1.9); p=0.039). Cognitive impairment is associated with age and a lower educational level in the general population, and among patients with RA with educational level, obesity and average inflammatory activity (DAS28, CRP, and IL-6). CONCLUSIONS: Patients with RA with high inflammatory activity are more susceptible to cognitive impairment, which specifically affects the domains of visuospatial, memory, abstraction and executive function.

Fast-track adaptive laboratory evolution of Cupriavidus necator H16 with divalent metal cations.

Microbial strain improvement through adaptive laboratory evolution (ALE) has been a key strategy in biotechnology for enhancing desired phenotypic traits. In this Biotech Method paper, we present an accelerated ALE (aALE) workflow and its successful implementation in evolving Cupriavidus necator H16 for enhanced tolerance toward elevated glycerol concentrations. The method involves the deliberate induction of genetic diversity through controlled exposure to divalent metal cations, enabling the rapid identification of improved variants. Through this approach, we observed the emergence of robust variants capable of growing in high glycerol concentration environments, demonstrating the efficacy of our aALE workflow. When cultivated in 10% v/v glycerol, the adapted variant Mn-C2-B11, selected through aALE, achieved a final OD600 value of 56.0 and a dry cell weight of 15.2 g L-1, compared to the wild type (WT) strain's final OD600 of 39.1 and dry cell weight of 8.4 g L-1. At an even higher glycerol concentration of 15% v/v, Mn-C2-B11 reached a final OD600 of 48.9 and a dry cell weight of 12.7 g L-1, in contrast to the WT strain's final OD600 of 9.0 and dry cell weight of 3.1 g L-1. Higher glycerol consumption by Mn-C2-B11 was also confirmed by high-performance liquid chromatography (HPLC) analysis. This adapted variant consumed 34.5 times more glycerol compared to the WT strain at 10% v/v glycerol. Our method offers several advantages over other reported ALE approaches, including its independence from genetically modified strains, specialized genetic tools, and potentially carcinogenic DNA-modifying agents. By utilizing divalent metal cations as mutagens, we offer a safer, more efficient, and cost-effective alternative for expansion of genetic diversity. With its ability to foster rapid microbial evolution, aALE serves as a valuable addition to the ALE toolbox, holding significant promise for the advancement of microbial strain engineering and bioprocess optimization.

Bilateral Lung Injury with Delayed Pneumothorax following Preoperative Cryoanalgesia for Pectus Excavatum Repair in a 13-year-old Boy.

A 13-year-old male patient with marfanoid features and pectus excavatum with Haller index 4 and correction index of 38% underwent the Nuss procedure with cryoanalgesia 9 days prior, which transpired uneventfully. Preoperative spirometry was normal, and echocardiogram showed light aortic valve dilation. A month later, during a routine outpatient checkup, he referred middle abdominal pain, denying respiratory symptoms nor thoracic pain. He presented bilateral apical and right basal hypophonesis. Chest X-ray revealed bilateral pneumothorax and right pleural effusion. Consequently, the patient was admitted to the emergency room, and a chest computed tomography was ordered, reporting right apical blebs. Bilateral thoracoscopy was performed, and apexes were checked for pulmonary blebs to rule out primary pneumothorax. In the right chest, a wedge resection of a distorted area on the apex and pleuroabrasion were done. Four air leaking eschars were found when performing lung expansion under water as leaking test, corresponding to cryoanalgesia intercostal eschars, and subsequently closed by primary suture. In the left chest, there were no blebs. However, another four pleural lesions with intact pleura in the left lower lobe were also found. Postoperative course was uneventful and chest drains were removed 48 hours after surgery. He remains asymptomatic 21 months after discharge. Cryoanalgesia in pectus excavatum is spreading due to the improvement in postoperative pain control. However, some complications may occur.

Benzbromarone as adjuvant therapy for cystic fibrosis lung disease: a pilot clinical trial.

OBJECTIVE: Cystic fibrosis (CF) affects multiple organs, the most severe consequences being observed in the lungs. Despite significant progress in developing CF transmembrane conductance regulator-specific treatments for CF lung disease, exploring alternative CF-targeted medications seems reasonable. We sought to evaluate the potential beneficial effects of oral benzbromarone as an adjuvant therapy in CF patients with reduced lung function. METHODS: This was a prospective open-label pilot study of oral benzbromarone (100 mg/day) administered once daily for 90 days. Patients were followed at a tertiary referral center in southern Brazil. Safety was assessed by the number of reported adverse events. Secondary objectives included percent predicted FEV1 (FEV1%) and pulmonary exacerbations. RESULTS: Ten patients were enrolled. Benzbromarone was found to be safe, with no serious drug-related adverse events. Eight patients completed the study; the median relative change in FEV1% tended to increase during the treatment, showing an 8% increase from baseline at the final visit. However, a nonparametric test showed that the change was not significant (p = 0.06). Of a total of ten patients, only one experienced at least one pulmonary exacerbation during the study. CONCLUSIONS: Oral benzbromarone appears to be safe, and improved FEV1% has been observed in patients with CF. Further assessment in larger trials is warranted to elucidate whether oral benzbromarone can be a potential adjuvant therapy for CF.

Severe Food Protein-Induced Enterocolitis Syndrome After Hematopoietic Stem Cell Transplantation: Pediatric Case Report.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. In the last few years, after the publication of the consensus guidelines, with refined diagnostic criteria and improved awareness, FPIES is diagnosed with increased frequency. However, despite having a background of immune dysregulation, this complication has just been described once in the posttransplant setting, in an adult patient. To the best of our knowledge, there are no reports of pediatric patients developing FPIES after a hematopoietic stem cell transplant (HCT). METHODS: Retrospective review of a pediatric patient who developed severe FPIEs after a HCT. RESULTS: In this case report, the clinical presentation and diagnosis challenges of a pediatric patient who developed severe FPIES after HCT are described. The patient developed severe vomiting, diarrhea, lethargy, and shock and required admission to the pediatric intensive care unit in three occasions before the diagnosis was made. CONCLUSIONS: To the best of our knowledge, this is the first report of severe FPIES post-HCT in a pediatric patient. Physicians who are looking after pediatric patients in the post-HCT setting need to be aware of this possibility and include this entity in the differential diagnosis in order to reduce its associated morbidity.

Congenital LMNA-Related Muscular Dystrophy in Paediatrics: Cardiac Management in Monozygotic Twins.

Pathogenic variants in LMNA have been associated with a wide spectrum of muscular conditions: the laminopathies. LMNA-related congenital muscular dystrophy is a laminopathy characterised by the early onset of symptoms and often leads to a fatal outcome at young ages. Children face a heightened risk of malignant arrhythmias. No established paediatric protocols for managing this condition are available. We review published cases and provide insights into disease progression in two twin sisters with LMNA-related muscular dystrophy. Our objective is to propose a cardiac surveillance and management plan tailored specifically for paediatric patients. We present a family of five members, including two twin sisters with LMNA-related muscular dystrophy. A comprehensive neuromuscular and cardiac work-up was performed in all family members. Genetic analysis using massive sequencing technology was performed in both twins. Clinical assessment showed that only the twins showed diagnoses of LMNA-related muscular dystrophy. Follow-up showed an early onset of symptoms and life-threatening arrhythmias, with differing disease progressions despite both twins passing away. Genetic analysis identified a de novo rare missense deleterious variant in the LMNA gene. Other additional rare variants were identified in genes associated with myasthenic syndrome. Early-onset neuromuscular symptoms could be related to a prognosis of worse life-threatening arrhythmias in LMNA related muscular dystrophy. Being a carrier of other rare variants may be a modifying factor in the progression of the phenotype, although further studies are needed. There is a pressing need for specific cardiac recommendations tailored to the paediatric population to mitigate the risk of malignant arrhythmias.

Fixed-Seat Rowing versus Sliding-Seat Rowing: Effects on Physical Fitness in Breast Cancer Survivors.

This study aimed to analyze the effects of a team rowing-based training program on physical fitness and anthropometric parameters in female breast cancer survivors (n = 40; 56.78 ± 6.38 years). The participants were divided into two groups: one rowed in fixed-seat rowing (FSR) boats (n = 20; 56.35 ± 4.89 years), and the other rowed in sliding-seat rowing (SSR) boats (n = 20; 57.20 ± 7.7 years). Both groups engaged in two 75 min sessions per week for 24 weeks. Significant improvements were observed in both groups in terms of weight (FSR: -1.93 kg, SSR: -1.75 kg), body mass index (FSR: -0.73 kg/m2, SSR: -0.67 kg/m2), waist circumference (FSR: -2.83 cm, SSR: -3.66 cm), and hip circumference (FSR: -2.02 cm, SSR: -2.88 cm). Muscle strength improved in the lower extremities (jump test: FSR: 2.99 cm, SSR: 3.11 cm) and upper extremities (dominant: FSR: 4.13 kgf, SSR: 4.34 kgf; non-dominant: FSR: 3.67 kgf, SSR: 3.32 kgf). Aerobic capacity also improved, with the SSR group showing a greater increase (FSR: 63.05 m, SSR: 93.65 m). Flexibility tests revealed better results in the SSR group for both dominant (SSR: 1.75 cm vs. FSR: -5.55 cm) and non-dominant limbs (SSR: 1.72 cm vs. FSR: -3.81 cm). These findings suggest that the type of rowing modality can influence physical fitness outcomes, with the SSR group showing superior improvements compared to the FSR group.

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

Opposing effects of the purinergic P2X7 receptor on seizures in neurons and microglia in male mice.

BACKGROUND: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. METHODS: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. RESULTS: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome. CONCLUSIONS: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.

Use of Eculizumab in Pediatric Patients with High-Risk Transplantation-Associated Thrombotic Microangiopathy: Outcomes and Risk Factors Associated with Response and Survival. A Retrospective Study on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Transplantation-associated thrombotic microangiopathy (TA-TMA) is associated with high morbidity and mortality. Although survival has improved significantly with the introduction of eculizumab, the need for improvement remains, especially in high-risk patients. This study aimed to describe the results obtained with eculizumab in a pediatric cohort with the attempt to define which risk factors could determine the response to treatment. We designed a national multicenter retrospective study of children treated with eculizumab for high-risk TA-TMA. The study cohort comprised 29 patients who had undergone a first (n = 28) or second (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for malignant (n = 17) or nonmalignant (n = 12) disease. The median time from HSCT to TA-TMA diagnosis was 154 days (interquartile range [IQR], 103 to 263 days). Eleven patients (38%) who were initially diagnosed with low- to intermediate-risk TA-TMA progressed to high-risk TA-TMA (hrTA-TMA), within a median time of 4 days (IQR, 1 to 33 days). SC5b-9 was increased in 90% of 20 patients in whom it was measured. Renal (n = 12), pulmonary (n = 1), and intestinal (n = 1) biopsy confirmed the diagnosis in 12 of 14 patients (85%). Seventeen patients (58%) had extrarenal involvement with serositis (n = 13; 44,8%), pulmonary (n = 12; 41,4%), gastrointestinal (n = 8; 27.6%), cardiovascular (n = 7; 24.1%), or central nervous system (CNS) (n = 2; 6.9%) involvement. The median time from hrTA-TMA diagnosis to the initiation of eculizumab was 7 days (IQR, 1 to 8 days). Overall, 19 patients (65.5%) responded to eculizumab, of whom 17 (58.6%) achieved a complete response and 2 (6.9%) achieved a partial response. The remaining 10 patients (34.5%) did not show any of response. The overall response rate to eculizumab for TA-TMA was 27.59% (95% confidence interval [CI], 14.87% to 47.66%) at 1 month, 55.17% (95% CI, 38.43% to 73.48%) at 3 months, and 62.07% (95% CI, 45.10% to 79.13%) at 6 months after eculizumab initiation. In multivariate analysis, the pulmonary involvement decreased the probability of response (hazard ratio [HR], .18; P = .0298). The 1-year overall survival (OS) was 55.2% (95% CI, 35.6% to 71.0%) for the whole cohort and 83.3% (95% CI, 56.7% to 94.3%) for patients who responded to eculizumab. Pulmonary involvement (HR, 14.93; P = .0043) and CNS involvement (HR, 8.63; P = .0497) were associated with a statistically significant decrease in survival. We found that patients diagnosed with hrTA-TMA with pulmonary involvement had a poor response to eculizumab, and that patients with pulmonary and CNS involvement had significantly decreased survival. Given these results, we hypothesize that providing eculizumab therapy at an early stage of the disease before organ damage is established might significantly improve the response and, consequently, survival.

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.

BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

Ten-Year Results of Accelerated Partial-Breast Irradiation with Interstitial Multicatheter Brachytherapy after Breast-Conserving Surgery for Low-Risk Early Breast Cancer.

Patients with an early carcinoma of the breast are commonly treated by breast-conserving surgery (BCS) and postoperative radiotherapy. Partial-breast irradiation has gained acceptance in the last few years. Between December 2008 and December 2017, 182 low-risk breast cancer patients treated by BCS in the four university hospitals of the province of Las Palmas and treated with APBI using interstitial multicatheter brachytherapy were included in this study. After a mean follow-up for survivors of 10 years, the treatment was shown to be safe, as no severe acute/late toxicity (grade ≥ 3) was observed. The 10-year IBTR was 1.7% (95%CI: 0.7-2.7%), and the cause-specific survival was 94.9% (95%CI: 93.2-96.6%). We suggest that multicatheter brachytherapy after BCS is safe and effective in early breast cancer patients.