Clinical activity of pembrolizumab in refractory MDM2-amplified advanced intimal sarcomas.

Intimal sarcoma (InS) is an ultra-rare and aggressive subtype of soft tissue sarcoma (STS). It usually arises in large mediastinal arteries and the heart. In the advanced setting, sequential cytotoxic chemotherapy is often used, mainly based on retrospective studies and case series but with modest benefit. The use of immune checkpoint inhibitors is a promising strategy for some STS, but identifying biomarkers of response remains challenging due to disease rarity and heterogeneity. A reactive and pro-inflammatory tumor microenvironment (TME) is believed to be associated with better outcomes for patients receiving anti-PD-1-based regimens, generating the rationale to explore this strategy in malignancies with this characteristic, such as InS. We report three cases of advanced InS patients experiencing partial response to pembrolizumab-based therapy despite low tumor mutational burden and absence of mismatch-repair deficiency. We hypothesize that TME-related characteristics such as PD-L1 expression and the presence of tertiary lymphoid structures might explain this phenomenon.

Pembrolizumab in advanced intimal sarcomas Intimal sarcomas are ultra-rare and highly aggressive malignant tumours that most frequently arise in mediastinal arteries or the heart. Besides arising in challenging areas of the thoracic cavity, their rarity directly interferes with the development of new therapies, which negatively impacts patients' prognosis, especially after disease progression on chemotherapy regimens. We reported three cases successfully treated with immunotherapy (represented by pembrolizumab-based regimens), as well as a potential explanation for their outcomes.

Alpha 1-acid glycoprotein is upregulated in severe COVID-19 patients and decreases neutrophil NETs in SARS-CoV-2 infection.

Orosomucoid, or alpha-1 acid glycoprotein (AGP), is a major acute-phase protein expressed in response to systemic injury and inflammation. AGP has been described as an inhibitor of neutrophil migration on sepsis, particularly its immunomodulation effects. AGP's biological functions in coronavirus disease 2019 (COVID-19) are not understood. We sought to investigate the role of AGP in severe COVID-19 infection patients and neutrophils infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Epidemiological data, AGP levels, and other laboratory parameters were measured in blood samples from 56 subjects hospitalized in the ICU with SARS-CoV-2 infection. To evaluate the role of AGP in NETosis in neutrophils, blood samples from health patients were collected, and neutrophils were separated and infected with SARS-CoV-2. Those neutrophils were treated with AGP or vehicle, and NETosis was analyzed by flow cytometry. AGP was upregulated in severe COVID-19 patients (p<0.05). AGP level was positively correlated with IL-6 and C-reactive protein (respectively, p=0.005, p=0.002) and negatively correlated with lactate (p=0.004). AGP treatment downregulated early and late NETosis (respectively, 35.7% and 43.5%) in neutrophils infected with SARS-CoV-2 and up-regulated IL-6 supernatant culture expression (p<0.0001). Our data showed increased AGP in COVID-19 infection and contributed to NETosis regulation and increased IL-6 production, possibly related to the Cytokine storm in COVID-19.

Isolation and primary culture of human abdominal aorta smooth muscle cells from brain-dead donors: an experimental model for vascular diseases.

Primary cell cultures are essential tools for elucidating the physiopathological mechanisms of the cardiovascular system. Therefore, a primary culture growth protocol of cardiovascular smooth muscle cells (VSMCs) obtained from human abdominal aortas was standardized. Ten abdominal aorta samples were obtained from patients diagnosed with brain death who were organ and tissue donors with family consent. After surgical ablation to capture the aorta, the aortic tissue was removed, immersed in a Custodiol® solution, and kept between 2 and 8 °C. In the laboratory, in a sterile environment, the tissue was fragmented and incubated in culture plates containing an enriched culture medium (DMEM/G/10% fetal bovine serum, L-glutamine, antibiotics and antifungals) and kept in an oven at 37 °C and 5% CO2. The aorta was removed after 24 h of incubation, and the culture medium was changed every six days for twenty days. Cell growth was confirmed through morphological analysis using an inverted optical microscope (Nikon®) and immunofluorescence for smooth muscle alpha-actin and nuclei. The development of the VSMCs was observed, and from the twelfth day, differentiation, long cytoplasmic projections, and adjacent cell connections occurred. On the twentieth day, the morphology of the VSMCs was confirmed by actin fiber immunofluorescence, which is a typical characteristic of VSMCs. The standardization allowed VSMC growth and the replicability of the in vitro test, providing a protocol that mimics natural physiological environments for a better understanding of the cardiovascular system. Its use is intended for investigation, tissue bioengineering, and pharmacological treatments.

The Role of Adjuvant Radiotherapy for the Treatment of Resected High-Risk Stage III Cutaneous Melanoma in the Era of Modern Systemic Therapies.

Modern adjuvant systemic therapies (STs) have revolutionized the management of stage III melanoma. Currently, the role of adjuvant radiotherapy (RT) remains unclear. In this single-center retrospective study, patients with clinically detectable stage III melanoma with high-risk features for lymph node basin (LNB) recurrence and whose tumors were fully resected with complete lymphadenectomy (CLD) between 2010 and 2019 were assessed. We determined the cumulative incidence (CIF) of LNB recurrence and any disease recurrence or progression using competing risk analysis. A total of 108 patients were identified; the median age was 59 years (24-92), and 74 (69%) were men. A total of 51 (42%) received adjuvant RT, 22 (20%) received adjuvant ST, and 35 (32%) received no adjuvant therapy. The advent of ST changed clinical practice, with a significant increase in the use of adjuvant ST and a decrease in the use of RT when comparing practice patterns before and after 2015 (p < 0.001). The 3-year CIF of LNB recurrence was similar in patients treated with adjuvant RT (6.3%) and adjuvant ST (9.8%). The 3-year CIF of any disease recurrence or progression was lower in patients receiving adjuvant ST (24%) compared to those receiving adjuvant RT (52%) or no adjuvant therapy (55%, p = 0.06). Three-year overall survival (OS) was not significantly different in patients treated with ST compared to those not treated with any ST (p = 0.118). Despite ST replacing RT as the dominant adjuvant treatment modality, this change in practice has not resulted in increased LNB recurrence for patients at high risk of LNB recurrence following CLD.

Clinico-demographic characteristics and outcomes of radiation-induced sarcomas (RIS): a CanSaRCC study.

Background: Radiation-induced sarcomas (RIS) tend to have aggressive behaviour and because of their rarity, the most appropriate management for these malignancies is uncertain. Objectives: Using the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) database, a national sarcoma registry, we aimed to investigate prognostic factors and outcomes for RIS. Design: Retrospective study of RIS patients treated from 1996 to 2021 at three Canadian centres. Methods: RIS was defined as a sarcoma arising in a previously irradiated field following a 3+ year latency period, whose histology was distinct from the initially irradiated tumour. Clinicopathologic and treatment-related information was extracted from the CanSaRCC database. Overall survival (OS) was defined as the time from RIS diagnosis to death from any cause. Response rate (RR) to neoadjuvant chemotherapy (NACT) was based on physician assessment. Time-to-event analyses were estimated using the Kaplan-Meier method, with Cox regression for multivariate analysis. We considered a two-tailed p-value of <0.05 as statistically significant. Results: One hundred seven tumours met the criteria for RIS and were divided into three subgroups: breast angiosarcoma (BAS, n = 54), osteosarcoma (OST, n = 16), and other soft-tissue sarcomas (STS, n = 37). Patients were mostly female (n = 85, 79%), treated initially for breast carcinomas (n = 54, 50.5%), and diagnosed with high-grade tumours (n = 61/71, 86%). None had evidence of synchronous metastasis. Patients with OST were younger (median age: 48 years, p < 0.001), and BAS had the shortest latency interval (8 versus 18 years for OST/STS, p < 0.001). Most patients underwent surgery, 76% (n = 76/100) R0; 24% (n = 26) received radiation therapy, mostly (n = 15, 57.7%) neoadjuvant. Among those receiving chemotherapy, 30 (75%) underwent NACT; among patients with documented response assessment, the RR was 68% (n = 17/25), being even higher in the BAS population (89.5%, n = 13/17). Median OS was 53 months (95% CI 34-101), with a 5-year OS of 47.6%; larger tumour size, high histologic grade and older age were independent prognostic factors for worse OS. Conclusion: Surgery is standard, and NACT might be useful to downsize large lesions, especially in BAS patients. Raising RIS awareness is fundamental to promoting appropriate management and fostering research through multi-institutional collaborations.

Immune Checkpoint Inhibitors in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience from a Canadian Comprehensive Cancer Centre.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4-NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4-NE). Immune-compromised patients, ECOG performance 2-3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study.

Toxicity and outcomes of melanoma brain metastases treated with stereotactic radiosurgery: the risk of subsequent symptomatic intralesional hemorrhage exceeds that of radiation necrosis.

PURPOSE: We aimed to assess the outcomes and patterns of toxicity in patients with melanoma brain metastases (MBM) treated with stereotactic radiosurgery (SRS) with or without immunotherapy (IO). METHODS: From a prospective registry, we reviewed MBM patients treated with single fraction Gamma Knife SRS between 2008 and 2021 at our center. We recorded all systemic therapies (chemotherapy, targeted therapy, or immunotherapy) administered before, during, or after SRS. Patients with prior brain surgery were excluded. We captured adverse events following SRS, including intralesional hemorrhage (IH), radiation necrosis (RN) and local failure (LF), as well as extracranial disease status. Distant brain failure (DBF), extracranial progression-free survival (PFS) and overall survival (OS) were determined using a cumulative Incidence function and the Kaplan-Meier method. RESULTS: Our analysis included 165 patients with 570 SRS-treated MBM. Median OS for patients who received IO was 1.41 years versus 0.79 years in patients who did not (p = 0.04). Ipilimumab monotherapy was the most frequent IO regimen (30%). In the absence of IO, the cumulative incidence of symptomatic (grade 2 +) RN was 3% at 24 months and remained unchanged with respect to the type or timing of IO. The incidence of post-SRS g2 + IH in patients who did not receive systemic therapy was 19% at 1- and 2 years compared to 7% at 1- and 2 years among patients who did (HR: 0.33, 95% CI 0.11-0.98; p = 0.046). Overall, neither timing nor type of IO correlated to rates of DBF, OS, or LF. Among patients treated with IO, the median time to extracranial PFS was 5.4 months (95% IC 3.2 - 9.1). CONCLUSION: The risk of g2 + IH exceeds that of g2 + RN in MBM patients undergoing SRS, with or without IO. IH should be considered a critical adverse event following MBM treatments.

Adequacy of venous thromboembolism risk stratification and prophylaxis in a tertiary university hospital.

Background: Venous thromboembolism is the third most common cardiovascular disease and the main cause of preventable death in hospitalized patients. Prophylaxis is still underused, despite well-established guidelines in the literature. Studies show a worldwide prophylaxis adequacy rate close to 50%. Objectives: To assess the adequacy of risk stratification and prophylactic measures for venous thromboembolism in a tertiary university hospital. Methods: A cross-sectional observational study was carried out, collecting data from medical records. Adult patients hospitalized by different specialties were enrolled and divided into surgical and clinical groups. The risk stratification of venous thromboembolism performed by the attending physicians was compared with stratification based on recent guidelines performed by the research physicians. Prophylaxis measures prescribed by the attending physicians were compared with guideline recommendations, thus obtaining the prophylaxis adequacy rate. Results: 400 patients were analyzed, 169 (42.3%) surgical and 231 (57.7%) clinical. The overall stratification adequacy rate was 50.8%. Adequacy rates were 39.1% and 59.3% in the surgical and clinical groups respectively (P < 0.0001). The overall prophylaxis adequacy rate was 71.5%, with 78.1% in the surgical group and 66.7% in the clinical group (P=0.0137). Conclusions: Risk stratification adequacy is low, demonstrating a low awareness among prescribing physicians of the need for adequate stratification for prescription of prophylaxis. However, the prophylaxis prescription adequacy rates are higher than those in global data.

Radiation-induced sarcomas following childhood cancer - A Canadian Sarcoma Research and Clinical Collaboration Study (CanSaRCC).

BACKGROUND: Radiation-induced sarcoma (RIS) is a late toxicity of radiation therapy (RT) usually associated with poor prognosis. Due to ongoing improvements in childhood cancer treatment and patient outcomes, RIS may become more prevalent notwithstanding evolving indications for RT. Due to limited reported studies, we sought to review our experience with RIS in survivors of pediatric cancer. METHODOLOGY: Data were collected on RIS patients following treatment for childhood cancer (initial diagnosis <18 years) identified in the CanSaRCC database. Additionally, details on the protocol guidance at time of treatment were compared with current guidelines for the same disease. RESULTS: Among 12 RIS identified, median age at initial diagnosis was 3.5 years (range 0.16-14) and the latency from RT to RIS diagnosis was 24.5 (range 5.4-46.2) years. Initial diagnoses included neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, retinoblastoma and Hodgkin's Lymphoma. RIS histologies included osteosarcoma and soft tissue sarcomas. In comparison to protocols followed at time of diagnosis to current ones (2022), 7/12 (58%) patients would have required RT. RIS treatment included chemotherapy, radiation and surgery in 3/11 (27%), 10/11 (90%), and 7/11 (63%) patients, respectively. With a median follow-up time of 4.7 years from diagnosis of RIS, 8 (66%) patients were alive and 4 (33%) had died of progressive RIS. CONCLUSION: RIS is a serious late effect of radiotherapy in childhood cancer; however, radiation remains an integral component of primary tumor management and requires participation from a specialized multi-disciplinary team, aiming to mitigate RIS and other potential late effects.

Periquiteira (Cochlospermum orinocense): A Promising Amazon Fiber for Application in Composite Materials.

Natural lignocellulosic fibers (NLFs) have in recent decades appeared as sustainable reinforcement alternatives to replace synthetic fibers in polymer composite material applications. In this work, for the first time, the periquiteira (Cochlospermum orinocense), a lesser known NLF from the Amazon region, was analyzed for its density and, by X-ray diffraction (XRD), to calculate the crystallinity index as well as the microfibrillar angle (MFA), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), scanning electron analysis (SEM) and tensile strength. The apparent density found for the periquiteira fiber was 0.43 g/cm3, one of the NLF's lowest. XRD analysis indicated a crystallinity index of 70.49% and MFA of 7.32°. The TGA disclosed thermal stability up to 250 °C. The FTIR analysis indicated the presence of functional groups characteristic of NLFs. The SEM morphological analysis revealed that the periquiteira fiber presents fine bundles of fibrils and a rough surface throughout its entire length. The average strength value of the periquiteira fiber was found as 178 MPa. These preliminary results indicate that the periquiteira fiber has the potential to be used as a reinforcing agent in polymeric matrices and can generate a lightweight composite with excellent mechanical properties that can be used in various industrial sectors.

Real-world treatment outcomes in HR+ HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice. METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A). OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR). RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%). CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.

Adequação da estratificação de risco e da profilaxia do tromboembolismo venoso em hospital universitário terciário / Adequacy of venous thromboembolism risk stratification and prophylaxis in a tertiary university hospital

Resumo Contexto O tromboembolismo venoso (TEV) é a terceira doença cardiovascular mais comum e a principal causa de óbito evitável em pacientes internados. Apesar de diretrizes bem estabelecidos na literatura, a profilaxia dessa afecção ainda é subutilizada. Estudos apontam taxa de adequação da profilaxia próxima de 50% mundialmente. Objetivos Avaliar a adequação da estratificação de risco e da prescrição de medidas de profilaxia do TEV em um hospital universitário terciário. Métodos Estudo transversal observacional realizado através da coleta de dados de prontuário. Foram incluídos pacientes adultos internados em diferentes especialidades e divididos em grupos cirúrgico e clínico. A estratificação de risco de TEV realizada pelos médicos assistentes foi comparada com a realizada pelos médicos pesquisadores, com base nas diretrizes recentes. A prescrição de medidas de profilaxia realizadas pelos médicos assistentes foi comparada com as recomendações das diretrizes, obtendo assim a taxa de adequação da profilaxia. Resultados Foram avaliados 400 pacientes, sendo 169 (42,3%) cirúrgicos e 231 (57,7%) clínicos. A taxa geral de adequação da estratificação foi de 50,8%. Nos grupos cirúrgico e clínico, as taxas de adequação foram respectivamente 39,1% e 59,3% (p < 0,0001). A taxa geral de adequação da profilaxia foi de 71,5%, enquanto no grupo cirúrgico foi de 78,1% e no grupo clínico de 66,7% (p = 0,0137). Conclusões A adequação da estratificação de risco para TEV foi baixa, demonstrando a pouca conscientização dos médicos assistentes sobre esse problema. No entanto, as taxas de adequação da prescrição de medidas de profilaxia estão superiores às de dados globais.

Abstract Background Venous thromboembolism is the third most common cardiovascular disease and the main cause of preventable death in hospitalized patients. Prophylaxis is still underused, despite well-established guidelines in the literature. Studies show a worldwide prophylaxis adequacy rate close to 50%. Objectives To assess the adequacy of risk stratification and prophylactic measures for venous thromboembolism in a tertiary university hospital. Methods A cross-sectional observational study was carried out, collecting data from medical records. Adult patients hospitalized by different specialties were enrolled and divided into surgical and clinical groups. The risk stratification of venous thromboembolism performed by the attending physicians was compared with stratification based on recent guidelines performed by the research physicians. Prophylaxis measures prescribed by the attending physicians were compared with guideline recommendations, thus obtaining the prophylaxis adequacy rate. Results 400 patients were analyzed, 169 (42.3%) surgical and 231 (57.7%) clinical. The overall stratification adequacy rate was 50.8%. Adequacy rates were 39.1% and 59.3% in the surgical and clinical groups respectively (P < 0.0001). The overall prophylaxis adequacy rate was 71.5%, with 78.1% in the surgical group and 66.7% in the clinical group (P=0.0137). Conclusions Risk stratification adequacy is low, demonstrating a low awareness among prescribing physicians of the need for adequate stratification for prescription of prophylaxis. However, the prophylaxis prescription adequacy rates are higher than those in global data.

24-hour Holter as a method for correlating symptoms and arrhythmic events

INTRODUCTION: Complaints of palpitations are widespread in clinical practice and, in most cases, require 24-hour Holter or prolonged monitoring. When the symptom is due to an arrhythmia, the possibility of obtaining an electrocardiographic record of the moment of the complaint is very useful and can help direct therapy. OBJECTIVE: To evaluate the relationship between symptoms and arrhythmic events in a large 24-hour Holter sample. METHODS: 6,585 24-hour Holters were selected in a tertiary cardiology hospital in 2018. Of these, 483 (7.33%) were excluded. They did not contain information about symptoms in the report, and 363 (5.5%) because they did not have data from the event diary. The remaining 5,739 exams were analyzed for the relationship between symptoms (data provided by the patient) and electrocardiographic changes. Results: Of the 5,739 Holters and event diaries analyzed, 46% were from male individuals. The average age was 58.2 years. Of the total sample, 93.18% (5348 patients) did not report symptoms in the event diary. However, 68.6% (3668 patients) of the exams contained significant changes. The main changes were frequent extrasystoles (>30/h) and non-sustained tachycardias. Frequent atrial ectopy and frequent ventricular ectopy occurred in 913 and 1412 patients, respectively. Ventricular tachycardia and supraventricular tachycardia occurred in 1,879 and 1,166 patients. Symptoms were reported by 391 patients (6.81%). The sensitivity for positive clinical ECG correlation was 24.8%. Men reported fewer symptoms (31% of reports), with a lower rate of positive clinical correlation (33% among men). In women, the clinical correlation was 66%. CONCLUSION: 1) Although sensitive for detecting asymptomatic arrhythmic events, the traditional 24-hour Holter has significant limitations, even in populations with known arrhythmias, correlating symptoms with electrocardiographic changes. The high rate of altered exams without reporting symptoms may reflect the limitation of applying the event diary used. 2) More accessible and practical monitoring methods could reduce the discrepancy between arrhythmic events and symptoms, facilitating doctors' understanding of the factors that motivate patients to seek health services.

Silk Fibroin Hydrogels Incorporated with the Antioxidant Extract of Stryphnodendron adstringens Bark.

Barbatimão (Stryphnodendron adstringens) is a Brazilian medicinal plant known for its pharmacological properties, including healing activity related to its phenolic composition, which is chiefly given by tannins. In order to preserve its stability and bioactivity, barbatimão extracts can be incorporated into (bio-)polymeric matrixes, of which silk fibroin stands out due to its versatility and tunable properties. This work aimed to obtain barbatimão bark extract rich in phenolic compounds and evaluate its incorporation in fibroin hydrogels. From the extraction process, it was observed that the PG (propylene glycol) extract presented a higher global yield (X0) and phenolic compounds (TPC) than the ET (ethanol) extract. Furthermore, the antioxidant activity (ORAC and FRAP) was similar between both extracts. Regarding the hydrogels, morphological, chemical, thermal, and mechanical characterizations were performed to understand the influence of the barbatimão extract and the solvent on the fibroin hydrogel properties. As a result, the hydrogels containing the barbatimão PG extract (BT/PG hydrogels) showed the better physical-chemical and structural performance. Therefore, these hydrogels should be further investigated regarding their potential in medical and pharmaceutical applications, especially in wound healing.

Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.

The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.

Unique SLC12A2-ROS1 fusion is associated with marked response to crizotinib in lung adenocarcinoma.

Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) gene define a subset of non-small cell lung cancers highly sensitive to small-molecule tyrosine kinase inhibitors. However, little is known about the impact of different fusion partners on tyrosine kinase inhibitor efficacy. We herein describe a case of a 26-year-old never-smoker patient from southern Africa with metastatic lung adenocarcinoma driven by SLC12A2-ROS1 fusion, who had a pronounced and durable response to crizotinib. The present case underscores the importance of pursuing actionable alterations in patients with similar clinical and epidemiological characteristics. In addition, provides the second report of crizotinib activity against lung malignancies harboring the unique SLC12A2-ROS1 fusion and highlights the importance of a deeper understanding of molecular alterations in underrepresented subgroups of patients to tailor the decision-making in daily practice.

Inpatient consultations with the vascular and endovascular surgery team at an academic tertiary hospital.

Background: Inpatient consultations are a fundamental component of practice in tertiary care centers. However, such consultations demand resources, generating a significant workload. Objectives: To investigate the profile of inpatient consultations requested by other specialties and provided by the Vascular and Endovascular Surgery team at an academic tertiary hospital. Methods: Prospective observational study. Results: From May 2017 to May 2018, 223 consultations were provided, representing 2.2% of the workload. Most consultations were requested by Oncology (16.6%), Hematology (9.9%), Nephrology (9.0%), and Cardiology (6.3%). The leading reasons for inpatient consultation were: need for vascular access (51.1%) and requests to evaluate a vascular disease (48.9%). Acute venous diseases accounted for 19.3% of consultations, chronic arterial diseases for 14.8%, acute arterial diseases for 7.2%, diabetic feet for 5.4%, and chronic venous diseases accounted for 2.2%. Surgical treatment was performed in 57.0%, either conventional (43.9%) or endovascular (13.0%). Almost all (98.2%) patients' issues were resolved. Conclusions: Inpatient consultations with the Vascular and Endovascular Surgery team in a tertiary academic hospital accounted for 2.2% of the team's entire workload. Most patients were elective and underwent low-complexity elective surgical procedures. There may be an opportunity to improve healthcare, redirecting these patients to the outpatient flow.

Introdução: Interconsultas são um componente fundamental da prática clínica em centros de atendimento terciários. No entanto, esse tipo de consulta requer recursos, resultando em uma alta carga de trabalho. Objetivo: Investigar o perfil das interconsultas solicitadas por outros departamentos e realizadas pela equipe de Cirurgia Vascular e Endovascular em um hospital universitário terciário. Métodos: Estudo observacional prospectivo. Resultados: De maio de 2017 a maio de 2018, foram realizadas 223 consultas, correspondendo a 2,2% da carga de trabalho. A maioria das consultas foram solicitadas pelos departamentos de Oncologia (16,6%), Hematologia (9,9%), Nefrologia (9,0%) e Cardiologia (6,3%). As principais razões das interconsultas foram a necessidade de acesso vascular (51,1%) e de avaliação de doenças vasculares (48,9%). As doenças venosas agudas corresponderam a 19,3% das avaliações; as doenças arteriais crônicas, a 14,8%; as doenças arteriais agudas, a 7,2%; o pé diabético, a 5,4%; e as doenças venosas crônicas corresponderam a 2,2%. Foi realizado tratamento cirúrgico em 57,0% dos casos, tanto convencional (43,9%) quanto endovascular (13,0%). Foram resolvidos os problemas de quase todos os pacientes (98,2%). Conclusão: As interconsultas realizadas pela equipe de Cirurgia Vascular e Endovascular em um hospital universitário terciário corresponderam a 2,2% da carga de trabalho total. A maioria dos pacientes eram eletivos e foram submetidos a procedimentos cirúrgicos eletivos de baixa complexidade. O redirecionamento desses pacientes para o atendimento ambulatorial poderia auxiliar na melhoria dos serviços de saúde.

Short-Term Outcomes of Transfemoral Carotid Artery Stenting and Carotid Endarterectomy in Symptomatic Patients: Data from a Multicentric Prospective Registry in Brazil.

BACKGROUND: Transfemoral carotid artery stenting (TF-CAS) and carotid endarterectomy (CEA) are alternative strategies for stroke prevention in patients with atherosclerotic carotid disease. Because their main objective is to prevent future ischemic events, regular reassessment of the outcomes is mandatory for providing the best therapy. The purpose of this study was to describe the practice and the outcomes of TF-CAS and CEA in symptomatic patients in public university hospitals in Brazil, using data from a prospective multicentric registry. METHODS: A prospective 8-year observational study of patients with symptomatic carotid artery atherosclerotic disease that underwent TF-CAS and CEA in 5 public university hospitals affiliated with the RHEUNI (Registry Project of Vascular Disease in the Public University Hospitals of São Paulo). All consecutive procedures were included. The indications for the procedures were determined by each surgeon's individual discretion, in accordance with a preoperative risk evaluation. The outcome measures were any 30-day follow-up death, stroke, myocardial infarction (MI), and their combined outcome (major adverse cardiovascular events [MACE]). The registration of the study was made at clinicaltrials.gov NCT02538276. RESULTS: From January 2012 through December 2019, 376 consecutive and symptomatic patients were included in the study records. There were 152 TF-CAS procedures (40.4%) and 224 CEA procedures (59.5%). All completed the 30-day follow-up period. Occurrence of death (TF-CAS: 0.66% × CEA: 0.66%, P = 0.99), stroke (TF-CAS: 4.61% × CEA: 4.46%, P = 0.99), and MI (TF-CAS: 0.66% × CEA: 0%, P = 0.403) were similar in both groups, without statistically significant differences. MACE rate did not differ in both groups (TF-CAS: 5.92% × CEA: 4.46%, P = 0.633). CONCLUSIONS: Data from a prospective registry of 5 Brazilian university hospitals showed that TF-CAS and CEA in symptomatic patients had similar 30-day perioperative rates of death, stroke, and MI and their combination.

Comparison of Young's Modulus of Continuous and Aligned Lignocellulosic Jute and Mallow Fibers Reinforced Polyester Composites Determined Both Experimentally and from Theoretical Prediction Models.

Mechanical properties of composites reinforced with lignocellulosic fibers have been researched in recent decades. Jute and mallow fibers are reinforcement alternatives, as they can contribute to increase the mechanical strength of composite materials. The present work aims to predict the Young's modulus with application of continuous and aligned lignocellulosic fibers to be applied as reinforcement in polyester matrix. Fibers were manually separated and then arranged and aligned in the polyester matrix. Composites with addition 5, 15, and 25 vol% jute and mallow fibers were produced by vacuum-assisted hand lay-up/vaccum-bagging procedure. Samples were tested in tensile and the tensile strength, elasticity modulus, and deformation were determined. Results showed that the intrinsic Young's modulus of the fibers was set at values around 17.95 and 11.72 GPa for jute and mallow fibers, respectively. Statistical analysis showed that composites reinforced with 15 and 25 vol% jute and mallow presented the highest values of tensile strength and Young's modulus. The incorporation of 25 vol% of jute and mallow fibers increased the matrix Young's modulus by 534% and 353%, respectively, effectively stiffening the composite material. Prediction models presented similar values for the Young's modulus, showing that jute and mallow fibers might be used as potential reinforcement of polymeric matrices.

Prospective Assessment of a Protocol Using Neuromonitoring, Early Limb Reperfusion, and Selective Temporary Aneurysm Sac Perfusion to Prevent Spinal Cord Injury During Fenestrated-branched Endovascular Aortic Repair.

OBJECTIVE: The aim of this study was to analyze the outcomes of a standardized protocol using routine CSFD, neuromonitoring, LL reperfusion, and selective TASP to prevent SCI during F-BEVAR. BACKGROUND: SCI is to be the most devastating complication for the patient, family, and surgeon, with impact on patient's quality of life and long-term prognosis. An optimal standardized protocol may be used to improve outcomes. METHODS: Patients enrolled in a prospective, nonrandomized single-center study between 2013 and 2018. A SCI prevention protocol was used for TAAAS or complex abdominal aneurysms with ≥5-cm supraceliac coverage including CSFD, neuromonitoring, LL reperfusion, and selective TASP. Endpoints included mortality and rates of SCI. RESULTS: SCI prevention protocol was used in 170 of 232 patients (73%) treated by F-BEVAR. Ninety-one patients (55%) had changes in neuromonitoring, which improved with maneuvers in all except for 9 patients (10%) who had TASP. There was one 30-day or in-hospital mortality (0.4%). Ten patients (4%) developed SCIs including in 1% (1/79) of patients with normal neuromonitoring and 10% (9/91) of those who had decline in neuromonitoring ( P = 0.02). Permanent paraplegia occurred in 2 patients (1%). Factors associated with SCI included total operating time (odds ratio 1.5, 95% confidence interval 1.1-2.2, P = 0.02) and persistent changes in neuromonitoring requiring TASP (odds ratio 15.7, 95% confidence interval 2.9-86.2, P = 0.001). CONCLUSION: This prospective nonrandomized study using a standardized strategy to prevent SCI was associated with low incidence of the SCI during F-BEVAR. Permanent paraplegia occurred in 1%.