Trifluridine-tipiracil plus bevacizumab versus trifluridine-tipiracil monotherapy for chemorefractory metastatic colorectal cancer: a systematic review and meta-analysis.

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.

The Potential of the Fibronectin Inhibitor Arg-Gly-Asp-Ser in the Development of Therapies for Glioblastoma.

Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in adults. An important feature that supports GBM aggressiveness is the unique composition of its extracellular matrix (ECM). Particularly, fibronectin plays an important role in cancer cell adhesion, differentiation, proliferation, and chemoresistance. Thus, herein, a hydrogel with mechanical properties compatible with the brain and the ability to disrupt the dynamic and reciprocal interaction between fibronectin and tumor cells was produced. High-molecular-weight hyaluronic acid (HMW-HA) functionalized with the inhibitory fibronectin peptide Arg-Gly-Asp-Ser (RGDS) was used to produce the polymeric matrix. Liposomes encapsulating doxorubicin (DOX) were also included in the hydrogel to kill GBM cells. The resulting hydrogel containing liposomes with therapeutic DOX concentrations presented rheological properties like a healthy brain. In vitro assays demonstrated that unmodified HMW-HA hydrogels only caused GBM cell killing after DOX incorporation. Conversely, RGDS-functionalized hydrogels displayed per se cytotoxicity. As GBM cells produce several proteolytic enzymes capable of disrupting the peptide-HA bond, we selected MMP-2 to illustrate this phenomenon. Therefore, RGDS internalization can induce GBM cell apoptosis. Importantly, RGDS-functionalized hydrogel incorporating DOX efficiently damaged GBM cells without affecting astrocyte viability, proving its safety. Overall, the results demonstrate the potential of the RGDS-functionalized hydrogel to develop safe and effective GBM treatments.

Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

Local therapy in advanced melanoma after immune checkpoint inhibitors aiming to achieve complete response.

Background and Objectives: New scenarios for local therapy have arisen after starting immune checkpoint inhibitors (ICIs) to treat advanced melanoma (AM). The aim of this study is to examine the role of local therapies with curative intention for patients with AM that have been on ICI. Methods: This was a single institution, retrospective analysis of unresectable stage III or IV melanoma patients on treatment with anti-PD1 ± anti-CTLA-4 who underwent local therapy with curative intention with no other remaining sites of disease (NRD). Results: Of the 170 patients treated with ICI, 19 (11.2%) met the criteria of curative intention. The median time on ICI before local therapy was 16.6 months (range: 0.92-43.2). At the time of the local treatment, the disease was controlled in 16 (84.25%) and progressing in 3 patients (15.75%); 14 patients (73.7%) treated a single lesion and 5 (26.3%) treated 2 to 3 lesions. In a median follow-up of 17 months (range: 1.51-38.2) after the local therapy and 9.8 months after the last ICI cycle (range: 0.56-31), only 2 (10.5%) out of 19 patients relapsed. Conclusions: Patients with AM on treatment with ICI were able to achieve NRD after local treatment and may benefit from long-term disease control without systemic treatment.

Guidelines from the Brazilian society of surgical oncology regarding indications and technical aspects of neck dissection in papillary, follicular, and medullary thyroid cancers.

Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians' Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results and conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II-V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; "berry node picking" is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

Early orthognathic surgery with postsurgical bone-anchored retention in unilateral cleft lip and palate: A case report.

We present a case report of early Le Fort I osteotomy with maxillary advancement retained postoperatively by Class III elastics anchored on miniplates in a growing patient with complete unilateral cleft lip and palate (UCLP). A 14-year-old boy who underwent orthognathic surgery at the pubertal growth spurt was presented. During surgery, Bollard miniplates were installed in the posterior region of the maxilla and in the anterior region of the mandible. Class III elastics anchored on miniplates were used at night (8-10 h) starting 60 days after surgery. The force of the elastics progressively increased from 100 g to 250 g. The elastics were replaced daily. The positive overjet remained stable over 15 months of postoperative follow-up. Maxillary advancement was adequately retained using Bollard miniplates and the facial profile remained stable until the end of facial growth.

Anorectal Function and Clinical Characteristics Associated with Faecal Incontinence in Patients with Crohn's Disease.

BACKGROUND AND AIMS: Faecal incontinence is an important complaint reported by patients with Crohn's disease [CD] and it is associated with several disease-related mechanisms, including anorectal functional disorders. This study aimed to assess the anorectal function and clinical characteristics to identify parameters associated with faecal incontinence in CD patients. METHODS: This is a cross-sectional study of 104 patients with CD, aged 18 years or older, from a referral centre between August 2019 and May 2021. Patients responded to a specific questionnaire, and underwent medical record review, proctological examination and anorectal functional assessment with anorectal manometry. RESULTS: Of the 104 patients, 49% were incontinent. Patients with incontinence had a lower mean resting pressure [43.5 vs 53.1 mmHg; p = 0.038], lower mean squeeze pressure [62.1 vs 94.1 mmHg; p = 0.036] and lower maximum rectal capacity [140 vs 180 mL; p < 0.001]. Faecal incontinence was also associated with disease activity [p < 0.001], loose stools [p = 0.02], perianal disease [p = 0.006], previous anoperineal surgery [p = 0.048] and number of anorectal surgeries [p = 0.036]. CONCLUSIONS: This is the largest reported study describing manometric findings of Crohn's disease patients with and without faecal incontinence. Our results identified an association between faecal incontinence and functional disorders, in addition to clinical features in these patients. Functional assessment with anorectal manometry may help choose the best treatment for faecal incontinence in patients with CD.

Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A.

The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RETC634R ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention.

Aprendizaje de competencias no técnicas en las urgencias prehospitalarias: perspectiva de los estudiantes de Medicina / Learning non-technical skills in pre-hospital emergency services: medical students' perspective

RESUMEN Introducción: para garantizar una atención de calidad en las urgencias, la formación médica debe incluir aspectos no técnicos, como la comunicación, el liderazgo, la capacidad de decisión y la interacción del equipo. Objetivo: analizar la percepción de los estudiantes de Medicina sobre el aprendizaje de competencias no técnicas, a través de simulaciones en situaciones de urgencia prehospitalaria. Materiales y métodos: estudio de enfoque cualitativo, con 50 estudiantes matriculados en el curso de Medicina de la universidad pública del sur de Minas Gerais, Brasil, seleccionados por conveniencia. Para la recolección de datos se utilizaron entrevistas semiestructuradas, y para el análisis de los mismos se utilizó el Análisis Temático. Resultados: se elaboraron dos temas: "La simulación como instrumento de construcción de conocimiento y desarrollo personal", y "Además de los procedimientos, las competencias no técnicas son fundamentales para el ejercicio de la medicina de urgencia", con el subtema: "Diferentes personas, diferentes trayectorias para el desarrollo de competencias no técnicas". La simulación se percibe como un recurso que permite experimentar el rol de un médico en el ambiente prehospitalario, de manera similar a la vida real, y despierta la necesidad de desarrollar competencias no técnicas. Este proceso no está desconectado del autoconocimiento. Conclusión: la simulación se percibe como una estrategia favorable para la construcción de conocimientos y la movilización del desarrollo de competencias no técnicas, fundamentales para el ejercicio de la medicina de urgencia. Se recomienda su inserción temprana en la graduación médica.

ABSTRACT Introduction: to ensure quality of care in emergencies, medical training must include non-technical aspects such as communication, leadership, decision-making and team interaction. Objective: to analyze the perception of medical students about learning non-technical skills, through simulations in pre-hospital emergency situations. Materials and methods: qualitative study with 50 students enrolled in the medical course at the public university in Southern Minas Gerais, selected by convenience. For data collection, semi-structured interviews were used, and thematic analysis was used to analyze them. Results: two themes were elaborated: "Simulation as an instrument for the construction of knowledge and personal development" and "Beyond the procedures, non-technical skills are basic for the practice of medicine in emergency", with the sub-theme "Different people, different ways for the development of non-technical skills". Conclusion: simulation is perceived as a recourse which allows experiencing the role of a physician in the pre-hospital environment, in a way similar to real life, and promotes the need of developing non-technical skills. This process is not disconnected from self-knowledge. Its early insertion in medical graduation is recommended.

Cancer risk-reducing surgery: Brazilian Society of Surgical Oncology Guideline Part 2 (Gastrointestinal and thyroid).

BACKGROUND: Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population. OBJECTIVES: The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations. METHODS: The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Eleven questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations. RESULTS: For all questions including risk-reducing colectomy, gastrectomy, and thyroidectomy, a major agreement was achieved by the participants, always using accessible alternatives. CONCLUSION: This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO and it should serve as an important reference for the management of families with cancer predisposition.

Patterns of disease relapse and posttreatment follow-up of patients with resected pancreatic adenocarcinoma: A single-center analysis.

BACKGROUND AND OBJECTIVES: To describe the patterns of disease relapse and follow-up of patients with resected pancreatic adenocarcinoma. Additionally, we looked at patients' characteristics at relapse and survival. METHODS: We included patients with potentially resectable pancreatic adenocarcinoma diagnosed from 2008 to 2018 who were submitted to resection with clear macroscopic margins and started posttreatment surveillance. RESULTS: The study population consists of 73 patients. The median interval between imaging studies was 3.2 months during the first 2 years of follow-up and 5.1 months thereafter. Forty-eight patients (65.8%) experienced disease relapse. The most frequent single site of relapse was locoregional (N = 21; 43.8%). At relapse, 31 patients (64.6%) were symptomatic and forty-two patients (87.6%) had Eastern Cooperative Oncology Group performance status 0 or 1. Most patients were able to undergo additional anticancer therapy (N = 41; 85.4%). Patients with asymptomatic relapses experienced longer median postrelapse survival (25.4 vs. 11.3 months; p = 0.015). CONCLUSIONS: A follow-up protocol that included imaging studies every 3 months in the first 2 years and every 6 months thereafter is able to diagnose disease relapse when patients have adequate performance status and are still able to undergo additional anticancer treatment.

COVID-19 pandemic on health professionals in a third level hospital in Spain: job changes during the first wave, mental health at 4 months, and follow-up at 9 months.

OBJECTIVE: To determine the impact that the COVID-19 pandemic has had on health professionals, in terms of work changes and mental health. METHOD: 1) Cross-sectional study and 2) longitudinal prospective study on health professionals who worked directly with patients affected by COVID-19 pandemic during the period between March-June 2020 in a tertiary hospital in Barcelona. Baseline (July-November 2020) and follow-up (November 2020-March 2021) data were collected. Data related to the job and toxic habits were collected with ad hoc questionnaires, and data related to perceived stress, post-traumatic stress, depression, and anxiety using validated questionnaires. RESULTS: In the baseline group (cross-sectional study), 90 professionals participated, 76% nurses. More than a third were on sick leave or took drugs to manage stress. Half of smokers increased tobacco use, and one in 5 increased alcohol consumption. Habitual shift change is significantly associated with depression, professional profile with anxiety, and perceived stress with age. In the longitudinal prospective study, the follow-up group (n = 64) shows high levels of stress and anxiety, which are maintained or even significantly increased over time. CONCLUSIONS: The structural changes that occurred in the hospital during the first wave of the COVID-19 pandemic had a strong impact on professionals, many of them presenting an increase in toxic habits, as well as impaired mental health that is maintained over time.

An Integrative Approach to Characterize the Early Phases of Dimethylhydrazine-Induced Colorectal Carcinogenesis in the Rat.

This study aimed to characterize an animal model of colorectal cancer (CRC) in the early stages of disease development. Twenty-nine male Wistar rats were divided into two control groups (CTRL1 and CTRL2), receiving EDTA-saline injections and two induced groups (CRC1 and CRC2), receiving 1,2-dimethylhydrazine (DMH) injections for seven consecutive weeks. CRC1 and CTRL1 were euthanized at the 11th week, while CRC2 and CTRL2 were euthanized at the 17th week. DMH treatment decreased microhematocrit values and IL-6, ghrelin, and myostatin serum levels. Histopathological analysis of intestinal sections showed that DMH-treated rats were characterized by moderate to severe epithelial dysplasia. An adenoma was observed in one animal (CRC2 group), and the presence of inflammatory infiltrate at the intestinal level was primarily observed in DMH-treated animals. DMH also induced Ki-67 immunoexpression. The gut microbiota analysis showed a higher abundance of Firmicutes, Clostridia, Clostridiales, Peptostreptococcaceae, Blautia, Romboutsia, and Clostridium sensu stricto in CRC than CTRL rats, whereas Prevotellaceae, Prevotella, Akkermansia, and Lactobacillus levels were more prevalent in CTRL animals. Our results suggest that this model could be helpful to investigate chemoprevention in the early stages of CRC.

[COVID-19 pandemic on health professionals in a third level hospital in Spain: job changes during the first wave, mental health at 4 months, and follow-up at 9 months]. / Pandemia COVID-19 sobre profesionales sanitarios en un hospital de tercer nivel en España: cambios laborales durante la primera ola, salud mental a los 4 meses y seguimiento a los 9 meses.

Objective: To determine the impact that the COVID-19 pandemic has had on health professionals, in terms of work changes and mental health. Method: 1) Cross-sectional study and 2) longitudinal prospective study on health professionals who worked directly with patients affected by COVID-19 pandemic during the period between March-June 2020 in a tertiary hospital in Barcelona. Baseline (July-November 2020) and follow-up (November 2020-March 2021) data were collected. Data related to the job and toxic habits were collected with ad hoc questionnaires, and data related to perceived stress, post-traumatic stress, depression, and anxiety using validated questionnaires. Results: In the baseline group (cross-sectional study), 90 professionals participated, 76% nurses. More than a third were on sick leave or took drugs to manage stress. Half of smokers increased tobacco use, and one in 5 increased alcohol consumption. Habitual shift change is significantly associated with depression, professional profile with anxiety, and perceived stress with age. In the longitudinal prospective study, the follow-up group (n = 64) shows high levels of stress and anxiety, which are maintained or even significantly increased over time. Conclusions: The structural changes that occurred in the hospital during the first wave of the COVID-19 pandemic had a strong impact on professionals, many of them presenting an increase in toxic habits, as well as impaired mental health that is maintained over time.

Brazilian society of surgical oncology: Guidelines for the surgical treatment of mid-low rectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer in North America, Western Europe, and Brazil, and represents an important public health problem. It is estimated that approximately 30% of all the CRC cases correspond to tumors located in the rectum, requiring complex multidisciplinary treatment. In an effort to provide surgeons who treat rectal cancer with the most current information based on the best evidence in the literature, the Brazilian Society of Surgical Oncology (SBCO) has produced the present guidelines for rectal cancer treatment that is focused on the main topics related to daily clinical practice. OBJECTIVES: The SBCO developed the present guidelines to provide recommendations on the main topics related to the treatment of mid-low rectal cancer based on current scientific evidence. METHODS: Between May and June 2021, 11 experts in CRC surgery met to develop the guidelines for the treatment of mid-low rectal cancer. A total of 22 relevant topics were disseminated among the participants. The methodological quality of a final list with 221 sources was evaluated, all the evidence was examined and revised, and the treatment guideline was formulated by the 11-expert committee. To reach a final consensus, all the topics were reviewed via a videoconference meeting that was attended by all 11 of the experts. RESULTS: The prepared guidelines contained 22 topics considered to be highly relevant in the treatment of mid-low rectal cancer, covering subjects related to the tests required for staging, surgical technique-related aspects, recommended measures to reduce surgical complications, neoadjuvant strategies, and nonoperative treatments. In addition, a checklist was proposed to summarize the important information and offer an updated tool to assist surgeons who treat rectal cancer provide the best care to their patients. CONCLUSION: These guidelines summarize concisely the recommendations based on the most current scientific evidence on the most relevant aspects of the treatment of mid-low rectal cancer and are a practical guide that can help surgeons who treat rectal cancer make the best therapeutic decision.

Profile of Crohn's disease patients who underwent anorectal examination under anesthesia

Introduction: Crohn's disease (CD) is an inflammatory bowel disease, and in ~ 30% of cases it is associated with perianalmanifestations. To identify the extent of the damage and to implement an appropriate treatment, anorectal examination under anesthesia (EUA) is fundamental. Objective: To describe the profile of patients who underwent anorectal EUA in university and private hospitals in the state of Bahia, Brazil. Methodology: A retrospective, descriptive study with 46 patients who underwent anorectal EUA between March, 2016 and November, 2019. Results: A total of 62 anorectal EUAs were performed in 46 patients. With an average age of 36.8 years, the female gender was predominant (52.2%) among these patients. Anal fistulas were the most frequent findings (83.8%), and in most cases they were treated with a seton placement (69.4%). The main recommended surgical indication was a proper evaluation and identification of perianal disease, followed by drainage of the abscess and therefore immunobiological therapy (59.6%). Conclusion: In the present study, the profile of CD patients was similar to those found in the literature, with a high rate of complex anal fistulas. Additional studies are still necessary to further comprehend and treat this particular and debilitating manifestation of the disease. (AU)