Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

nteraction between FAK/αB-crystalline is important for viability of the glioblastoma cells

Abstract Glioblastoma multiforme is a tumor of the central nervous system. Focal Adhesion Kinase (FAK) and αB-crystalline are two proteins involved in glioblastoma development. In this study, we investigated whether the FAK/αB-crystalline interaction is important for glioblastoma cells, we aimed to investigate the interaction of these two proteins in the glioblastoma multiforme cell line U87-MG. Two peptides named FP01 peptide (derived from αB-crystalline) and FP02 peptide (derived from FAK) were synthesized for this study. Treatment of U87-MG with the peptides FP01 and FP02 in the concentration at 50 µM reduced the viability cellular to around 41% and 51%, respectively. Morphological alterations in the cells treated with the peptides when compared to the control were observed. This study suggests that the interaction between FAK and αB-crystalline is important for the viability of glioblastoma cells

Aplicação de ferramentas de quimioinformática na comparação da estrutura tridimensional da dihidrofolato redutase expressa em diferentes organismos / Application of cheminformatics tools for comparing dihydrofolate reductase's tridimensional structure expressed by different organisms

A quimioinformática, definida como o emprego de técnicas informáticas na solução de problemas da química, evolui em conjunto com o desenvolvimento de ferramentas computacionais e é de grande relevância para o planejamento racional de fármacos ao otimizar etapas do desenvolvimento de novas moléculas e economizar recursos e tempo. Dentre as técnicas disponíveis destacam-se o planejamento de fármacos baseado na estrutura e no ligante, que quando combinadas auxiliam na identificação e otimização de moléculas ativas frente a alvos farmacológicos. A Dihidrofolato Redutase (DHFR) é uma importante enzima da via dos folatos que catalisa a redução do dihidrofolato em tetrahidrofolato, utilizando NADPH como cofator, reação essencial para a replicação celular, visto que este ciclo resulta na síntese de precursores das bases nitrogenadas que compõem o DNA, consequentemente, inibidores de DHFR são utilizados no tratamento de infecções bacterianas e alguns tipos de câncer. Trypanosoma cruzi, protozoário causador da doença de chagas, é um dos organismos que expressam a DHFR, além do próprio Homo sapiens. Analisaram-se ligantes conhecidos e as estruturas da proteína expressa pelos dois organismos, visando identificar pontos de divergência que possam ser explorados no planejamento de moléculas seletivas para o tratamento da doença de Chagas. Os 6 modelos cristalográficos de T. cruzi e 2 de H. sapiens foram obtidos do banco de dados de proteínas (PDB) após aplicação de filtros de qualidade. Foram analisadas as sequências de aminoácidos dos modelos, com o uso do Cluster Ômega, sua estrutura tridimensional com os programas Pymol e Chimera X, além da análise das cavidades proteicas com o CavityPlus, que também gerou os farmacóforos de ambos alvos. A análise de estrutura primária identificou mutações em três aminoácidos nos cristais do parasita, que podem ser explicados por diferentes caminhos evolutivos de grupos segregados, embora nenhuma mutação observada esteja em regiões de sítio ativo. A análise dos modelos permitiu que fossem identificados os 25 aminoácidos que estão a menos de 5 Å de distância dos ligantes de T. cruzi, sendo 5 aminoácidos responsáveis por interações de hidrogênio com pelo menos um dos ligantes analisados. Destes, 18 se repetem na proteína humana ou são substituídos por outro aminoácido que mantém a mesma interação. Quanto às diferenças observadas, destacam-se a asparagina 44 substituída por uma prolina na proteína humana e a prolina 92, substituída por uma lisina. A análise de cavidades identificou três cavidades em cada proteína, embora somente as cavidades correspondentes ao sítio ativo sejam druggables. A cavidade da proteína humana é maior e mais alongada, além de apresentar o aspecto de um túnel, enquanto a cavidade da proteína parasita é mais aberta, tal abertura permite que ligantes com o anel benzeno meta substituídos explorem uma região existente na cavidade de T. cruzi que é fechada na humana. O farmacóforo de ambas proteínas foi identificado, apresentando diferenças no tamanho e angulação que também podem ser explorados no planejamento de fármacos seletivos

Chemoinformatic, defined as the use of informatic techniques to solve chemical problems, has evolved together with new computational tools and it is quite important for rational drug designing, by optimizing different steps on the development pipeline of new molecules, saving resources and time. From all the available tools, structure and ligand based drug design shall be highlighted, when combined, they support the identification and optimization of active molecules from pharmaceutical targets. Dihydrofolate reductase (DHFR) is an important enzyme of the folate pathway that catalyzes the reduction of dihydrofolate to tetrahydrofolate, by using NADPH as cofactor. This reaction is essential for cell replication, as this pathway results in the synthesis of nucleobases that build the DNA. That's the reason why DHFR inhibitors are used for treating bacterial infections and some types of cancer. Trypanosoma cruzi, a protozoa that causes Chagas disease, is one of the organisms that express DHFR, besides Homo sapiens itself. This work analyzed known ligands and the structure of the protein expressed by both organisms, aiming to identify divergence points that could be explored for designing selective drugs for Chagas disease treatment. The 6 proteins crystallographic models from T. cruzi and 2 from H. sapiens were obtained from protein data bank (PDB) after the application of quality filters. The amino acid sequence of each model was analyzed by Clustal Omega, its tridimensional structure by Pymol and Chimera X and the cavity analysis by CavityPlus, that also generated the pharmacophore from both targets. The primary structure analysis identified mutations on three amino acids on the parasite christal, which may be explained by different evolutive paths from segregated groups, although none of the observed mutations are on the active site region. The model's analysis allowed the identification of 24 amino acids that are closer than 5 Å from the T. cruzi ligands, 5 of them responsible for hydrogen interactions on at least one of the ligands analyzed. 18 of them are repeated on the human protein or are replaced by another amino acid that preserves the same interaction. As by the differences observed that shall be highlighted, asparagine 44 is replaced by a proline on the human protein, and proline 92 by a lysin. The cavity analysis identified three cavities on each protein, although only the cavities of the active site are druggables. The human protein cavity is bigger and longer, besides it looks like its a tunnel, when the parasite protein is open, that opening allows ligands with benzene ring meta substituted to explore the existing regions of the T. cruzi protein that is closed on the human protein. Lastly, the pharmacophore from both proteins was identified, it shows differences on size and angulation that also could be explored in the designing of selective drugs

Absenteísmo e suas causas no contexto da saúde dos trabalhadores em oncologia: revisão integrativa / Absenteeism and it's causes in the context of oncology workers health: integrative review / Ausentismo y sus causas en el contexto de la salud de los trabajadores en oncología: revisión integradora

O ritmo elevado de trabalho, somado às demandas físicas e psicológicas, levam ao estresse nos contextos pessoal e laboral, o que faz com que as pessoas se afastem de seus ambientes de trabalho como um dos motivos apontados para a incapacidade para o trabalho. Essa realidade tem sido amplamente observada no ambiente hospitalar, possivelmente associada a problemas relacionados à fadiga da compaixão, geralmente em serviços de oncologia. Dessa forma, a motivação deste estudo foi compreender os motivos do absenteísmo em oncologia, e se esse episódio ocorre devido ao processo de trabalho. Objetivo:Investigar as causas do absenteísmo entre profissionais expostos a riscos ambientais e biopsicossociais em hospitais oncológicos. Metodologia:Trata-se de uma revisaointegrativa sobre o tema do absenteísmo, o que indica novos rumos para futuras investigações. Foi realizada uma revisão da literatura com base em três pilares: 1) O processo de trabalho multidisciplinar em oncologia e o risco de adoecimento; 2) O absentismo dos profissionais de saúde em oncologia; 3) O problema da pandemia de COVID-19 para os trabalhadores da saúde. Posteriormente, foram escolhidos os descritores e a partir deles foram realizadas buscas nas bases de dados eletrônicas PUBMED, LILACS e SCOPUS. Resultados:Obteve-se um resultado de dez estudos. Constatou-se que os principais transtornos, que levam à incapacidade para o trabalho e, por sua vez, ao absenteísmo, foram de origem psíquica (depressão e Síndrome de Burnout) e de origem musculoesquelética. Conclusões:A dupla jornada de trabalho foi citada como fator facilitador para o aparecimento desses transtornos, onde tais cenários não incapacitam o trabalhador para o desenvolvimento de suas atividades, que podem ser temporárias ou permanentes (AU).

The high pace of work, added to the physical and psychological demands, lead to stress in personal and work contexts, which causes people to withdraw from their work environments as one of the reasons mentioned for incapacitation for work. This reality hasbeen widely observed in the hospital setting, possibly associated with problems related to compassion fatigue, usually in oncology services. The motivation of this study was to understand the reasons for absenteeism in oncology, and if this episode occursdue to the work process. Objective:Investigating the causes of absenteeism among professionals exposed to environmental and biopsychosocial risks in cancer hospitals. Methodology:This is a integrative review on the theme of absenteeism, which indicates new directions for future investigations. A literature review was carried out based on three pillars: 1) The multidisciplinary work process in oncology and the risk of illness; 2) The absenteeism of health professionals in oncology; 3) The problem of the COVID-19 pandemic for health workers. Subsequently, the descriptors were chosen and based on them, searches were carried out in the electronic databases PUBMED, LILACS and SCOPUS. Results:A result of ten studies was obtained. It was found that the main disorders, which lead to incapacity for work and, in turn, absenteeism, were of psychic origin (depression and Burnout Syndrome) and of musculoskeletal origin. Conclusions: Texto das conclusões em inglêsThe double work shift was cited as a facilitating factorfor the appearance of these disorders, where such scenarios do not incapacitate the worker to develop their activities, which may be temporary or permanent (AU).

El alto ritmo de trabajo, sumado a las exigencias físicas y psicológicas, genera estrés en el contexto personal y laboral, lo que provoca que las personas se alejen de sus ambientes laborales como una de las razones esgrimidas para la incapacidad detrabajar. Esta realidad ha sido ampliamente observada en el ambiente hospitalario, posiblemente asociada a problemas relacionados con la fatiga por compasión, generalmente en los servicios de oncología. Así, la motivación de este estudio fue comprender las razones del ausentismo en oncología y si este episodio ocurre debido al proceso de trabajo. Objetivo:Investigar las causas del ausentismo entre profesionales expuestos a riesgos ambientales y biopsicosociales en hospitales oncológicos. Metodología:Se trata deuna revisión integradorasobre el tema del ausentismo, que indica nuevos rumbos para futuras investigaciones. Se realizó una revisión de la literatura basada en tres pilares: 1) El proceso de trabajo multidisciplinario en oncología y el riesgo de enfermedad; 2) El ausentismo de los profesionales de la salud en oncología; 3) El problema de la pandemia de COVID-19 para los trabajadores de la salud. Posteriormente se eligieron los descriptores y a partir de ellos se realizaron búsquedas en las bases de datos electrónicas PUBMED, LILACS y SCOPUS. Resultados:Se obtuvo un resultado de diez estudios. Se encontró que los principales trastornos que conducen a la incapacidad para trabajar y, a su vez, al ausentismo, fueron de origen psíquico (depresión y síndrome deBurnout) y de origen músculoesquelético. Conclusiones:La doble jornada laboral fue citada como un factor facilitador para la aparición de estos trastornos, dondedichos escenarios no incapacitan al trabajador para el desarrollo de sus actividades, las cuales pueden ser temporales o permanentes (AU).

Actualización de informe de tocilizumab en el tratamiento de pacientes oncológicos con COVID-19: (21 de agosto del 2023) / Update on tocilizumab in the treatment of cancer patients with COVID-19: (August 21, 2023)

ANTECEDENTES: Según la REVISIÓN RÁPIDA N°01-2020 realizado el 16 de Setiembre del 2020, por solicitud del Equipo Funcional de Infectología, se realiza una revisión rápida con el fin de realizar una búsqueda y análisis de Ia mejor evidencia científica disponible sobre la intervención farmacológica tocilizumab en el manejo de pacientes con COVID-19. La Unidad Funcional de Evaluación de Tecnologías Sanitarias de INEN se creó el 15 de enero del 2020 mediante R.J. 020-2020-J/INEN y dentro de sus funciones están el "Evaluar aquellas tecnologías sanitarias requeridas por órganos usuarios, que sean nuevas para la entidad y/o no cuenten con cobertura financiera para la/s IAFAS". Definiendo tecnologías sanitarias a "cualquier intervención que pueda ser utilizada en la promoción de la salud, prevención, diagnóstico o tratamiento de una enfermedad, rehabilitación o cuidados prolongados. Se incluyen los medicamentos, los dispositivos, los procedimientos médicos y quirúrgicos, así como los sistemas organizativos dentro de los cuales se proporciona dicha atención sanitária. Dentro de las funciones de UFETS-INEN es re-evaluar tecnologías que fueron evaluadas previamente con alguna recomendación en contra o una aprobación que requiera evaluación. METODOLOGÍA: PARA ACTUALIZACIÓN En el presente documento se hace una actualización a la metodología usada en el primer informe, actualización de resultados de la búsqueda científica y de estudios. No se cambiará la pregunta PICO. ACERCA DE LA TECNOLOGÍA: Los marcadores inflamatorios marcadamente elevados (p. ej., dímero D, ferritina) y las citocinas proinflamatorias elevadas (incluida la interleucina [IL]-6) se asocian con la COVID-19 crítica y fatal, y el bloqueo de la vía inflamatoria puede prevenir la progresión de la enfermedad2 . Se han evaluado varios agentes que se dirigen a la vía de la IL-6 en ensayos aleatorios para el tratamiento de la COVID-19; estos incluyen los bloqueadores del receptor de IL-6 tocilizumab y sarilumab y el inhibidor directo de IL-6 siltuximab. Diferentes estudios, guías y normas incluyen el uso de Tocilizumab para el tratamiento de pacientes con COVID-19 severo. INDICACIÓN E INTERVENCIÓN (TECNOLOGÍA SANITARIA) A UTILIZAR: Anteriormente (fecha del informe 16 septiembre del 2020) sumarios como UpToDate, cuya ultimo actualización fue el 09 de septiembre del 2020, no incluyen tocilizumab como una medida estándar de tratamiento dentro del manejo de los pacientes con enfermedad severa. Refieren que los datos publicados se limitan a estudios observacionales o series de casos para Inhibidores de la vía de la IL-6, dentro de los cuales se encuentra tocilizumab, sin embargo, hasta esa fecha no había una certeza clara sobre su beneficio. En un estudio de 544 pacientes con COVID-19 grave, el tratamiento con tocilizumab (n = 179) se asoció con una disminución del riesgo de ventilación mecánica invasiva o muerte (HR ajustado 0,61). Sin embargo, en su última actualización incluyen al tocilizumab dentro de sus sugerencias, con una indicación de tocilizumab (8 mg/kg como dosis única intravenosa) como una opción para las personas que requieren oxígeno de alto flujo o soporte respiratorio más intensivo. Sin embargo, hacen hincapié en el uso de esta, pues solo se usará tocilizumab en pacientes que también están tomando dexametasona (u otro glucocorticoide) y generalmente se limita a una dosis única. METODOLOGÍA: Primero se realizó una revisión de los documentos que fueron enviados a la unidad y se actualizó la estrategia de búsqueda del Instituto Nacional de Enfermedades Neoplásicas (INEN). Se elaboró la pregunta PICO. La segunda parte estuvo enfocada en un análisis de la revisión de la literatura para respaldar la decisión basada en evidencia científica. (22 de julio del 2023). La segunda parte estuvo enfocada en un análisis de la revisión de la literatura para respaldar la decisión basada en evidencia científica. (22 de julio del 2023). Además, se adiciona un estudio peruano, que por recomendación de experto se coloca en el análisis de los resultados de estudio (este estudio se encuentra en la base de datos de Scielo-Perú). ANÁLISIS: El estudio RECOVERY presentó un estudio del uso de tocilizumab5 , un ensayo clínico aleatorizado, controlado y abierto que evaluó los efectos de tocilizumab en pacientes adultos hospitalizados con COVID-19 con hipoxia y evidencia de inflamación sistémica. Los participantes del ensayo con hipoxia fueron elegibles para la asignación aleatoria en una proporción de 1:1 al estándar de atención habitual solo versus el estándar de atención habitual más tocilizumab a una dosis de 400 mg-800 mg (dependiendo del peso) administrada por vía intravenosa. El estudio no menciona el porcentaje de pacientes. con cáncer. En cuanto a los resultados más importantes, el estudio encontró que tocilizumab mejoró la supervivencia y otros resultados clínicos en pacientes hospitalizados con COVID-19 con hipoxia y evidencia de inflamación sistémica. El 621 (31%) de los 2022 pacientes asignados a tocilizumab y 729 (35%) de los 2094 pacientes asignados a la atención habitual murieron dentro de los 28 días (HR 0,85; IC del 95%: 0,76-0,94; p = 0,0028). CONCLUSIONES: En base a las funciones de UFETS-INEN se actualizó la REVISIÓN RÁPIDA N°01-2020 realizado el 16 de Setiembre del 2020. No se ha tenido experiencia con el empleo de tocilizumab en nuestra institución. Se siguieron las recomendaciones de nuestro informe previo. En el proceso actual post-pandemia, la vacunación de SARS-CoV-2 ha logrado disminuir la mortalidad e ingreso a UCI, por lo que el efecto absoluto del tocilizumab puede ser mínimo en pacientes vacunados, implicando que la intervención no sea costo-efectiva en este grupo. Debido a todo lo anterior, no recomendamos el uso de tocilizumab en pacientes con COVID-19 severo y cáncer, a menos que sea parte de algún ensayo clínico controlado y/o se obtenga evidencia sólida sobre la eficacia y seguridad de tocilizumab. Se recomienda enviar a la oficina de seguros este informe para su evaluación.

Relationship between actinic keratosis and malignant skin lesions on the eyelid / Relação entre ceratose actínica e lesões cutâneas malignas na pálpebra

ABSTRACT Purpose: To evaluate the variables possibly related to actinic keratosis and malignant skin lesions on the eyelid. Methods: A prospective study of patients with suspected eyelid malignancy was conducted. The participants underwent a 2-mm punch biopsy at two opposite sites of the lesion for diagnosis, and the results were compared with those of the histopathological study of the surgical excised specimen. The patients with an actinic keratosis component were divided into two groups (actinic keratosis-associated malignancy and actinic keratosis alone), which were compared for the following variables: age, disease duration, largest diameter, tumor area, Fitzpatrick classification, sex, tumor site and margin involvement. A cluster analysis was also performed. Results: We analyzed 174 lesions, of which 50 had an actinic keratosis component. Actinic keratosis was associated with squamous cell carcinoma in 22% of the cases and to basal cell carcinoma in 38%, which shows that both neoplasms may have contiguous actinic keratosis. Statistical analysis revealed no significant difference among the variables. In a cluster analysis, four groups were identified with malignant lesions in the medial canthus with the largest mean diameter and area. All margin involvements on the lower eyelid were related to malignancy, which means that all cases with margin involvement had an almost 100% risk of malignancy. Conclusions: Larger actinic keratosis lesions in the medial canthus and lesions with margin involvement on the lower eyelid have a greater probability of malignant association.

RESUMO Objetivo: Avaliar as possíveis variáveis relacionadas à ceratose actínica e lesões malignas cutâneas nas pálpebras. Métodos: Estudo prospectivo de pacientes com lesões palpebrais suspeitas de malignidade. Os participantes foram submetidos à biopsia por trépano (punch) de 2-mm em dois pontos opostos da lesão como método diagnóstico e os resultados foram comparados com o estudo histopatológico da peça excisada cirurgicamente. Aqueles que apresentaram ceratose actínica como resultado foram divididos em dois grupos (ceratose actínica associada com malignidade e ceratose actínica isolada) e foram comparados de acordo com as variáveis: idade, tempo de doença, maior diâmetro, área do tumor, classificação de Fitzpatrick, gênero, localização e acometimento da margem palpebral. A análise de cluster também foi realizada. Resultados: Foram analisadas 174 lesões e 50 delas tinham ceratose actínica como componente do tumor. Ceratose actínica esteve associada ao Carcinoma Espinocelular em 22% dos casos e ao Carcinoma Basocelular em 38%, mostrando que ambos podem ter ceratose actínica adjacente. A análise estatística não encontrou diferença entre as variáveis. A análise de cluster identificou quatro grupos e mostrou que lesões malignas no canto medial tinham maiores diâmetro e área. Acometimento da margem na pálpebra inferior relacionou-se em 100% com malignidade, enquanto a ausência de acometimento da margem mostrou menor chance de malignidade. Conclusões: Lesões maiores de ceratose actínica no canto medial e lesões com acometimento da margem palpebral inferior têm maiores chances de associação com malignidade.

Effects of radiation therapy on tumor microenvironment: an updated review / 中华医学杂志(英文版)

Cancer is a major threat to human health and causes death worldwide. Research on the role of radiotherapy (RT) in the treatment of cancer is progressing; however, RT not only causes fatal DNA damage to tumor cells, but also affects the interactions between tumor cells and different components of the tumor microenvironment (TME), including immune cells, fibroblasts, macrophages, extracellular matrix, and some soluble products. Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME. Currently, the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood. This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.

Advances in Predictive Research of Immune Checkpoint Inhibitors-related Adverse Events / 中国肺癌杂志

The era of tumor treatment has been revolutionized by the advent of immune checkpoint inhibitors. However, while immunotherapy benefits patients, it can also lead to immune-related adverse events that may affect multiple organs and systems throughout the body, potentially even posing a life-threatening risk. The diverse clinical manifestations and onset times of these adverse events further complicate their prediction and diagnosis. The purpose of this paper is to review the clinical characteristics and predicted biomarkers of adverse events related to inhibitors at immune checkpoints, in order to help clinicians evaluate drug risks and early warn adverse events.
.

Application and Effectiveness of Chinese Medicine in Regulating Immune Checkpoint Pathways / 中国结合医学杂志

Immunotherapy targeting immune checkpoint molecules has emerged as a key approach in cancer treatment, representing the forefront of antitumor research. However, studies on immune checkpoint molecules have mainly focused on targeted therapies. Chinese medicine (CM) research as a complementary medicine has revealed that immune checkpoint molecules also undergo disease-specific changes in the context of autoimmune diseases. This review article presents a comprehensive analysis of CM studies on immune checkpoint molecules in the last 5 years, with a focus on their role in different diseases and treatment modalities. CM research predominantly utilizes oral administration of herbal plant extracts or acupuncture techniques, which stimulate the immune system by activating specific acupoints through temperature and needling. In this study, we analyzed the modulation and mechanisms of immune checkpoint molecules associated with different coinhibitory and costimulatory molecules, and reviewed the immune functions of related molecules and CM studies in treating autoimmune diseases and tumors. By summarizing the characteristics and research value of CM in regulating immune checkpoint molecules, this review aims to provide a useful reference for future studies in this field.

Rare tumors: a blue ocean of investigation / 医学前沿

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors / 中华肿瘤杂志

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors / 中华肿瘤杂志

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

Immunometabolism: a new dimension in immunotherapy resistance / 医学前沿

Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

Focal adhesion kinase inhibition decreases cell viability and induces apoptosis of JAK2 V617F positive cells

Abstract Focal Adhesion Kinase (FAK) protein participates in proliferation, migration, cell survival, and apoptosis process. It has been described as overexpressed in several neoplasms being a promising target for therapy. BCR-ABL negative chronic Myeloproliferative Neoplasms (MPN) are clonal disorders characterized by the excess of proliferation and apoptosis resistance. The identification of the acquired JAK2 V617F mutation in MPN patients allowed a better understanding of pathogenesis. However, there is still no pharmacological treatment that leads all patients to molecular remission, justifying new studies. The present study aimed to evaluate FAK involvement in the viability and apoptosis of HEL and SET-2 cells, both JAK2 V617F positive cell lines. The FAK inhibitor PF 562,271 was used. Cell viability was determined using MTT assay and apoptosis verified by cleaved PARP, cleaved Caspase 3 and Annexin-V/PI staining detection. FAK inhibition significantly reduced HEL and SET-2 cells viability and induced apoptosis. Considering the role of JAK/STAT pathway in MPN, further investigation of FAK participation in the MPN cells proliferation and apoptosis resistance, as well as possible crosstalk between JAK and FAK and downstream pathways may contribute to the knowledge of MPN pathophysiology, the discovery of new molecular targets, and JAK inhibitors resistance mechanisms.

Potencial quimiopreventivo de lipídios estruturados obtidos da Tributirina e Tricaprilina na fase de promoção da hepatocarcinogênese experimental / Chemopreventive potential of structured lipids obtained from Tributyrin and Tricaprylin in the promotion phase of experimental hepatocarcinogenesis

A quimioprevenção do câncer refere-se ao uso de compostos naturais ou sintéticos para prevenir o desenvolvimento das neoplasias antes do estabelecimento da malignidade. O ácido butirico (AB) atua como um potente quimiopreventivo na hepatocarcinogênese, reduzindo o número e o tamanho de lesões pré neoplásicas persistentes (pLPN), induzindo a apoptose e modulando mecanismos epigenéticos. Já o ácido caprílico (AC), além da sua atuação como potencializador de absorção, vem sendo investigado na área da prevenção do câncer. Neste cenário, o objetivo do trabalho visa avaliar a atividade quimiopreventiva de lipídios estruturados (EST) obtidos por interesterificação enzimática da tributirina com a tricaprilina, na fase de promoção da hepatocarcinogênese experimental. Após o processo de interesterificação, o produto final apresentou novos triacilgliceróis com composição de duas moléculas de ácido butírico para uma de ácido caprilíco. Ratos machos isogênicos da linhagem Fischer 344 foram submetidos ao modelo do hepatócito resistente, sendo distribuídos em dois grupos e tratados diariamente por via intragástrica com lipídios estruturados (EST) ou com o seu controle isocalórico, a maltodextrina (MD), durante a fase de promoção. Como esperado, não houve diferença estatística (p>0,05) em relação ao peso inicial e final dos animais dos grupos MD e EST, o que indica ausência de toxicidade dos compostos administrados. Na análise macroscópica do fígado, foi observada uma redução de 33,3% no grupo EST em relação ao número médio de nódulos macroscópicos em comparação ao grupo MD, porém essa redução não atingiu diferença estatística (p>0,05). Para a avaliação das lesões pré neoplásicas (LPN) foi utilizada a marcação imunoistoquímica para glutationa-S-transferase (GST-P). O grupo EST apresentou uma redução no número de lesões em remodelação e total GSTP-P+, quando comparado com o grupo MD (p<0,05). Quando avaliada a % de corpúsculos apoptóticos e índice de proliferação celular, não houve diferença estatística entre os grupos (p>0,05). Animais tratados com lipídios estruturados apresentaram maiores (p<0,05) concentrações de AC e AB por grama de tecido hepático em relação ao tratamento com maltodextrina. Em relação aos danos no DNA, o grupo EST resultou em cometas de comprimentos menores (p<0,05), menores níveis de γ-H2AX (p<0,05) e maiores concentrações de p53 nuclear, quando comparados aos animais que receberam maltodextrina, sugerindo uma proteção contra danos no DNA no grupo tratado com EST. Os resultados mostraram que o tratamento com EST resultou em ações efetivas na fase de promoção da hepatocarcinogênese experimental

Cancer chemoprevention refers to the use of natural or synthetic compounds to prevent the development of neoplasms before the establishment of malignancy. Butyric acid (AB) acts as a potent chemopreventive in hepatocarcinogenesis, reducing the number and size of persistent preneoplastic lesions (pLPN), inducing apoptosis and modulating epigenetic mechanisms. Caprylic acid (CA), in addition to its role as an absorption enhancer, has been investigated in the area of cancer prevention. In this scenario, the objective of this work was to evaluate the chemopreventive activity of structured lipids (EST) obtained by enzymatic interesterification of tributyrin with tricaprylin, in the phase of promotion experimental hepatocarcinogenesis. After the interesterification process, the final product presented new triacylglycerols with a composition of two molecules of butyric acid to one of caprylic acid. Isogenic male Fischer 344 rats were submitted to the resistant hepatocyte model, divided into two groups and treated daily intragastrically with structured lipids (EST) or with its isocaloric control, maltodextrin (MD), during the promotion phase. As expected, there was no statistical difference (p>0.05) in relation to the initial and final weight of the animals in the MD and EST groups, which indicates the absence of toxicity of the administered compounds. In the macroscopic analysis of the liver, a reduction of 33.3% was observed in the EST group in relation to the mean number of macroscopic nodules compared to the MD group, but this reduction did not reach a statistical difference (p>0.05). For the evaluation of pre-neoplastic lesions (PNL) immunohistochemical staining for glutathione-Stransferase (GST-P) was used. The EST group showed a reduction in the number of remodeling lesions and total GSTP-P+, when compared to the MD group (p<0.05). Animals treated with structured lipids had higher (p<0.05) concentrations of AC and AB per gram of liver tissue compared to treatment with maltodextrin. Regarding DNA damage, the EST group resulted in comets of shorter lengths (p<0.05), lower levels of γ-H2AX (p<0.05) and high concentration of nuclear p53, when compared to animals that received maltodextrin, suggesting protection against DNA damage in the EST treated group. The results showed that EST treatment resulted in effective actions in the promotion phase of experimental hepatocarcinogenesis

Unraveling the complex link between vitamin D levels and cancer: A crucial understanding for designing future supplementation approaches

Abstract Numerous studies have underscored the essential role of sunlight in vitamin D synthesis, while other studies have examined the association between dietary supplementation and vitamin D levels in different oncologic indications. In certain oncologic types, low levels of vitamin D correlate with a higher risk of cancer progression or poorer outcomes. On the contrary, the protective role of vitamin D remains ambiguous for some cancers. Given that the majority of cancer patients exhibit vitamin D deficiency or insufficiency, there have been suggestions to adopt supplementation strategies. However, vitamin D modulates and interacts with several molecular pathways. Therefore, it is crucial to contextualize the level and circumstances in which the action of vitamin D is observed. Distinct outcomes may emerge based on factors such as the method of assessing vitamin D levels, the size of the study populations, their genetic background, and the specific cancer type under investigation. In this article, we summarize some of the relevant studies examining the relationship between vitamin D levels and cancer. We further briefly outline the process of vitamin D synthesis and its effects on specific cellular pathways involved in cancer progression, highlighting essential considerations for future vitamin D assessments and supplementation approaches.

Selective photodynamic effects on cervical adenocarcinoma cells provided by F127 Pluronic®-based micelles modulating hypericin delivery

Abstract Cervical cancer is a leading cause of death among women. The endocervical adenocarcinoma (ECA) represents an aggressive and metastatic type of cancer with no effective treatment options currently available. We evaluated the antitumoral and anti-migratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against a human cell line derived from invasive cervical adenocarcinoma (HeLa) compared to a human epithelial cell line (HaCaT). The phototoxicity and cytotoxicity of F127/HYP were evaluated by the following assays: colorimetric assay, MTT, cellular morphological changes by microscopy and long-term cytotoxicity by clonogenic assay. In addition, we performed fluorescence microscopy to analyze cell uptake and subcellular distribution of F127/HYP, cell death pathway and reactive oxygen species (ROS) production. The PDT mechanism was determined with sodium azide and D-mannitol and cell migration by wound-healing assay. The treatment with F127/HYP promoted a phototoxic result in the HeLa cells in a dose-dependent and selective form. Internalization of F127/HYP was observed mainly in the mitochondria, causing cell death by necrosis and ROS production especially by the type II PDT mechanism. Furthermore, F127/HYP reduced the long-term proliferation and migration capacity of HeLa cells. Overall, our results indicate a potentially application of F127/HYP micelles as a novel approach for PDT with HYP delivery to more specifically treat ECA.

Pyroligneous extracts with therapeutic action: A technological prospect

Abstract The Pyroligneous extract is a product from the combustion of plant biomass with applications in the fields of health, industrial chemistry, and agriculture. The discovery of new molecules with therapeutic potential and of natural origin continues to be one of the great challenges for research centres around the world. The following work aims to analyze, through a technological prospection, the use of pyroligneous extracts for therapeutic purposes. To carry out the study, searches were carried out in documents deposited in Brazil, Europe, and the United States and searched on platforms specialized in patents. The number of inventions using pyroligneous extract with therapeutic applications is still quite small, however, innovations have been observed for the treatment of diseases of great clinical relevance such as cancer and hypertension. The systematic mapping of innovations is of great importance for the development of new technologies.

¿Cuándo el patólogo debe solicitar inmunomarcación con B-Catenina?: una revisión de la literatura a propósito de dos casos / When should the pathologist request immunostaining with B-catenin?: a review of the literature on two cases

For more than 20 years, immunohistochemistry has represented an auxiliary test of great relevance to support pathological work, however, it should be noted that the pillar of diagnosis continues and will continue to be the classic morphological description based on hematoxylin eosin and the trained eye of the specialist. In neoplastic pathologies, whether benign or malignant, it is becoming increasingly necessary to incorporate new tissue biomarkers that help objectify or confirm the diagnosis of each patient, in order to provide better treatment or a more precise diagnosis about the biological nature of their illness. In this line, there has been intense research in relation to the participation of the Wnt/ß-catenin pathway in the development of various types of tumors, including colon adenocarcinoma, some pancreatic neoplasms and even some tumors of mesenchymal origin, as will be seen. in this work. In this context and based on two clinical cases of special interest, we have prepared a brief review of the literature considering the biological aspects of ß-catenin, tumors where there is currently a true relative consensus that its immunolabeling offers a real contribution to the confirmation of the entity and finally a limited exposition regarding the future of this biomarker in the pathology discipline.

Desde hace más de 20 años la inmunohistoquímica ha representado una prueba auxiliar de gran relevancia para apoyar el trabajo anatomopatológico, no obstante, cabe señalar que, aún el pilar del diagnóstico sigue y seguirá siendo la descripción morfológica clásica basada en hematoxilina eosina y el ojo entrenado del especialista. En las patologías neoplásicas, ya sea benignas, como malignas, se hace cada vez más necesario la incorporación de nuevos biomarcadores tisulares que ayuden a objetivar o confirmar el diagnóstico de cada paciente, con objeto de entregar un mejor tratamiento o un diagnóstico más preciso de la naturaleza biológica de su enfermedad. En esta línea, ha habido intensa investigación en relación con la participación de la vía Wnt/ß-catenina en el desarrollo de varios tipos de cáncer, entre ellos el adenocarcinoma de colon, algunas neoplasias pancreáticas e incluso algunos tumores de origen mesenquimal como se verá en este trabajo. En este contexto y partir de dos casos clínicos de especial interés, hemos preparado una breve revisión de la literatura considerando los aspectos biológicos de la ß-catenina, los tumores donde en la actualidad existe verdadero consenso de que su inmunomarcación ofrece un aporte real a la confirmación de la entidad y finalmente una exposición acotada respecto al futuro de este biomarcador en la disciplina de la anatomía patológica.

The morphological challenge in determining nuclear size and shape in anatomopathological neoplasia analysis / El desafío morfológico en la determinación del tamaño y forma nuclear en el análisis anatomopatológico de neoplasias

SUMMARY: From 1984 stereology was added to unbiased methods and procedures, i.e., counts became more reliable studying morphological images in a random and uniform isotropic way. Therefore, the orientation and sectioning methods adapted to stereological quantification are essential. A critical quantitative subject in practical pathology concerns diagnosing and classifying neoplasias. Pathologists evaluated different types of tumors by determining the nuclear roundness factor (NRF). NRF is calculated by the ratio between the nuclear radius obtained from the area and the perimeter. However, NRF is biased data because it depends on the sectioning orientation, nuclei shape, and section thickness. The stereology proposed an unbiased alternative to assess the nucleus from tumor cells, counteracting NRF quantitatively. Therefore, the volume-weighted mean nuclear volume has been used to prognostic tumors in several organs. In urology, this was used, for example, to study primary carcinoma of the bladder, renal and prostatic carcinomas.

RESUMEN: A partir de 1984 se agregó la estereología a los métodos y procedimientos sin distorción, es decir, los conteos se volvieron más confiables al estudiar imágenes morfológicas de forma aleatoria e isotrópica uniforme. Por tanto, los métodos de orientación y seccionamiento adaptados a la cuantificación estereológica son fundamentales. Un tema cuantitativo crítico en la patología práctica se refiere al diagnóstico y clasificación de las neoplasias. Los patólogos evaluaron diferentes tipos de tumores determinando el factor de redondez nuclear (NRF). NRF se calcula por la relación entre el radio nuclear obtenido del área y el perímetro. Sin embargo, NRF son datos distorsionados debido a que dependen de la orientación de la sección, la forma de los núcleos y el grosor de la sección. La estereología propuso una alternativa imparcial para evaluar el núcleo de las células tumorales, contrarrestando cuantitativamente el NRF. Por lo tanto, el volumen nuclear medio ponderado se ha utilizado para pronosticar tumores en varios órganos. En urología, esto se utilizó, por ejemplo, para estudiar el carcinoma primario de vejiga, carcinomas renales y prostáticos.