Seguridad de las drogas biológicas y sintéticas dirigidas utilizadas en pacientes con enfermedades reumáticas inmunomediadas. Datos del registro BIOBADASAR 3.0 / Safety of biological and targeted synthetic drugs in patients with immune-mediated rheumatic diseases. Data from the BIOBADASAR 3.0 registry

Introducción: conocer la seguridad de las drogas actualmente disponibles para el tratamiento de las enfermedades reumáticas es muy importante al momento de tomar decisiones terapéuticas objetivas e individualizadas en la consulta médica diaria. Asimismo, datos de la vida real amplían el conocimiento revelado por los ensayos clínicos. Objetivos: describir los eventos adversos (EA) reportados, estimar su frecuencia e identificar los factores relacionados con su desarrollo. Materiales y métodos: se utilizaron datos BIOBADASAR, un registro voluntario y prospectivo de seguimiento de EA de tratamientos biológicos y sintéticos dirigidos en pacientes con enfermedades reumáticas inmunomediadas. Los pacientes son seguidos hasta la muerte, pérdida de seguimiento o retiro del consentimiento informado. Para este análisis se extrajeron datos recopilados hasta el 31 de enero de 2023. Resultados: se incluyó un total de 6253 pacientes, los cuales aportaron 9533 ciclos de tratamiento, incluyendo 3647 (38,3%) ciclos sin drogas modificadoras de la enfermedad biológicas y sintéticas dirigidas (DME-b/sd) y 5886 (61,7%) con DME-b/sd. Dentro de estos últimos, los más utilizados fueron los inhibidores de TNF y abatacept. Se reportaron 5890 EA en un total de 2701 tratamientos (844 y 1857 sin y con DME-b/sd, respectivamente), con una incidencia de 53,9 eventos cada 1000 pacientes/año (IC 95% 51,9-55,9). La misma fue mayor en los ciclos con DME-b/sd (71,1 eventos cada 1000 pacientes/año, IC 95% 70,7-77,5 versus 33,7, IC 95% 31,5-36,1; p<0,001). Las infecciones, particularmente las de la vía aérea superior, fueron los EA más frecuentes en ambos grupos. El 10,9% fue serio y el 1,1% provocó la muerte del paciente. El 18,7% de los ciclos con DME-b/sd fue discontinuado a causa de un EA significativamente mayor a lo reportado en el otro grupo (11,5%; p<0,001). En el análisis ajustado, las DME-b/sd se asociaron a mayor riesgo de presentar al menos un EA (HR 1,82, IC 95% 1,64-1,96). De igual manera, la mayor edad, el mayor tiempo de evolución, el antecedente de enfermedad pulmonar obstructiva crónica, el diagnóstico de lupus eritematoso sistémico y el uso de corticoides se asociaron a mayor riesgo de EA. Conclusiones: la incidencia de EA fue significativamente superior durante los ciclos de tratamientos que incluían DME-b/sd.

Introduction: knowing the efficacy and safety of the drugs currently available for the treatment of rheumatic diseases is very important when making objective and individualized therapeutic decisions in daily medical consultation. Likewise, real-life data extends the knowledge revealed by clinical trials. Objectives: to describe the reported adverse events (AEs), estimate their frequency and identify factors associated to them. Materials and methods: BIOBADASAR data were used, which is a voluntary, prospective follow-up registry of AEs of biological and synthetic treatments in patients with immune-mediated rheumatic diseases. Patients are followed until death, loss of followup, or withdrawal of informed consent. To carry out this analysis, the data collected up to January 31, 2023 was extracted. Results: a total of 6253 patients were included, who contributed with 9533 treatment periods, including 3647 (38.3%) periods without b/ts-DMARDs and 5886 (61.7%) with b/ts-DMARDs. Among the latter, the most used were TNF inhibitors and abatacept. A total of 5890 AEs were reported in a total of 2701 treatments (844 and 1857 without and with b/ts-DMARDs, respectively), with an incidence of 53.9 events per 1000 patients/ year (95% CI 51.9-55.9). It was higher during the periods with b/ts-DMARDs (71.1 events per 1000 patients/year, 95% CI 70.7-77.5 vs 33.7, 95% CI 31.5-36.1, p<0.001). Infections, particularly those of the upper respiratory tract, were the most frequent AEs in both groups. 10.9% were severe and 1.1% were associated with the death of the patient. 18.7% of the periods with b/ts-DMARDs were discontinued due to an AE, significantly higher than that reported in the other group (11.5%; p<0.001). In the adjusted analysis, b/ts-DMARDs were associated with a higher risk of presenting at least one AE (HR 1.82, 95% CI 1.64-1.96). Similarly, older age, longer evolution time, history of chronic obstructive pulmonary disease, diagnosis of systemic lupus erythematosus, and use of corticosteroids were associated with a higher risk of AE. Conclusions: the incidence of AEs was significantly higher during those treatment periods that included DME-b/sd.

Advances in Molecular Targeted Ultrasound Contrast Agents / 中国医学科学院学报

In real-time ultrasound,molecular targeted contrast agent is introduced into the blood circulation through peripheral intravenous injection to enhance the imaging signal of target lesions after binding to the corresponding intravascular receptors,which can realize early diagnosis,staging of diseases,assessment of treatment response,and targeted treatment.In addition,molecular targeted ultrasound contrast agents provide a platform for the delivery of drugs and genes via microbubbles,and nanoscale contrast agents can be infiltrated through vascular endothelium into the interstitial space of the lesion for imaging or treatment.The available studies of molecular targeted ultrasound contrast agents mainly focus on the preclinical trials.Some clinical trials have been conducted in humans and preliminarily confirm the safety and feasibility of targeted ultrasound contrast agents.The molecular targeted ultrasound contrast agents enjoy a broad prospect in clinical application.

Clinical practice guideline for stage Ⅳ primary lung cancer in China (2023 edition) / 中华肿瘤杂志

Primary lung cancer is the most common malignant disease and the leading cause of cancer death in China, with an estimated 828 thousand incident cases and 657 thousand deaths in 2016. Due to the absence of effective early screening methods, most patients with lung cancer are in stage Ⅳ when diagnosed. Multi-disciplinary treatment based on systemic therapy is the treatment principle for patients with stage Ⅳ lung cancer, chemotherapy is the cornerstone of stage Ⅳ lung cancer, but its efficacy is unsatisfactory. In recent years, with the rapid development of molecular targeted therapy and immunotherapy, the treatment concept has continuously changed and treatment outcome for patients has also been greatly improved. In order to update the progress in the treatment of stage Ⅳ lung cancer worldwide timely, and further improve the level of standardized diagnosis and treatment of stage Ⅳ lung cancer in China, Chinese Association for Clinical Oncologists and Medical Oncology Branch of Chinese International Exchange and Promotion Association for Medical and Healthcare organized experts to compose "Clinical Practice Guideline for Stage Ⅳ Primary Lung Cancer in China (2023 edition)" .

O Uso do Sequenciamento Total do Exoma no Diagnóstico do Adenocarcinoma Ductal Pancreático / Using Whole Exome Sequencing on Diagnosis of Pancreatic Ductal Adenocarcinoma / El uso de la Secuenciación del Exoma Total en el Diagnóstico del Adenocarcinoma Ductal Pancreático

Introdução: O adenocarcinoma ductal pancreático (PDAC) é uma doença agressiva responsável no Brasil por 2% das neoplasias e 5% das mortes por câncer. A análise do exoma ­ parte do DNA que codifica as proteínas ­ permite identificar as variantes somáticas do tumor e as germinativas do paciente. Essa informação é necessária para implementar a terapia-alvo para o PDAC, pois fornece evidência para selecionar, ou excluir, tratamentos para a doença. Objetivo: Identificar as variantes de interesse clínico e farmacológico presentes no PDAC de quatro pacientes, por meio da técnica de sequenciamento total do exoma(WES). Método: Foram utilizados dados públicos de quatro amostras de pares tumor-normal de PDAC, localizados na cabeça do pâncreas de pacientes caucasianos, estádio T3N1M0, sequenciadas e publicizadas pelo Texas Cancer Research Biobank. Para identificar as variações somáticas e germinativas, utilizou-se o software GATK. As consequências clínicas e farmacológicas dessas variações foram anotadas por meio do software VEP e analisadas mediante o softwareestatístico R. Resultados: Dos quatro tumores, um possui variante estrutural com duplicação do gene AKT2; outro, variantes nos genes da via das ciclinas CDK14 e CDKN2C, o que altera o regime quimioterápico; na linhagem germinativa, um paciente tem variantes no gene XRCC1, que sugere aumento da resposta à platina. Conclusão: Embora a patologia classifique todos os tumores como PDAC, cada paciente ­ bem como o respectivo tumor ­ apresenta especificidades que afetam o diagnóstico e as possibilidades terapêuticas. O WES permite identificá-las a um custo baixo, o que amplia as possibilidades de tratamento do PDAC.

ntroduction: The prevalence of pancreatic ductal adenocarcinoma (PDAC) in Brazil is around two percent of all neoplasms. It is an aggressive disease responsible for five percent of all deaths by cancer. The analysis of exome ­ part of the DNA encoding the proteins ­ allows the identification of tumor-specific variants and the patient polymorphism. This information is necessary to implement target therapy for PDAC, as it provides evidence to select, or exclude, PDAC treatments. Objective: Identify the somatic and germinative variants of clinical and pharmacological interest in the PDAC for four patients through the whole-exome sequencing technique (WES). Method: Public sequencing exome data published by Texas Cancer Research Biobank were utilized, from four tumor-normal samples pair of PDAC located in the pancreas head of Caucasian patients, T3N1M0 stage. To identify somatic and germinative variations, the GATK software was adopted. Furthermore, these variants were noted with their clinical and pharmacological information through the VEP software and its consequences were analyzed through the statistical software R. Results: Of the four tumors, one has a structural variant with duplication of the AKT2 gene; another, changes in the pathway of cyclins CDK14 and CDKN2C. Both findings alter the chemotherapy regimen; in the germline, one patient has variants in the XRCC1 gene, which suggests increased response to platinum. Conclusion: Although the pathology classifies all tumours as PDAC, each patient ­ as well as their respective tumor ­ shows specificities that affect the diagnosis and therapeutic possibilities. WES allows to identify them at a low cost, expanding the treatment possibilities of PDAC.

Introducción: El adenocarcinoma ductal pancreático (PDAC) es una enfermedad agresiva que causa en Brasil 5% de las muertes por cáncer. El análisis del exoma ­ parte del ADN que codifica las proteínas ­ permite la identificación de mutaciones específicas del tumor, así como los polimorfismos del paciente. Esta información es necesaria para implementar la terapia dirigida para PDAC. Objetivo: Identificar las variaciones de interés clínico y farmacológico presentes en el PDAC de cuatro pacientes, mediante la técnica secuenciación del exoma completo (WES). Método: Se utilizaron datos públicos de cuatro muestras de pares de tumores normales (T-N) de PDAC, localizados en la cabeza del páncreas de pacientes caucásicos, estadio T3N1M0, secuenciadas y publicadas por Texas Cancer Research Biobank. Para identificar las variaciones somáticas y germinativas, se utilizó el softwareGATK. Se observaron las consecuencias clínicas y farmacológicas de estas variaciones a través del software VEP. Y analizadas sus consecuencias a través del software estadístico R. Resultados: De los cuatro tumores, uno tiene una variante estructural con duplicación del gen AKT2; otro, cambios en la vía de las ciclinas CDK14 y CDKN2C, que altera el régimen de quimioterapia; en el linaje germinal, un paciente tiene variantes en el gen XRCC1, lo que sugiere una mayor respuesta al platino. Conclusión: Aunque la patología clasifica todos los tumores como PDAC, cada paciente ­ así como el tumor respectivo ­ presenta especificidades que afectan el diagnóstico y las posibilidades terapéuticas. WES le permite identificarlos a un bajo costo, lo que amplía las posibilidades de tratamiento de PDAC

Relationship between FAMACHA© scores and zootechnical indicators of a sheep production system / Relação entre os graus FAMACHA© e indicadores zootécnicos de um sistema de produção de ovinos

In Brazil, lamb producers face challenges raising their animals because of high anthelmintic resistance and loss of productivity due to parasites. It is well known that parasitic infections can reduce the performance of sheep. However, until the publication of this work, no research was found that quantified the effects that anemia reflected by FAMACHA© scores can exert on other zootechnical indicators in a lamb production system. The objective of this study was to use the FAMACHA© scores to quantify the impacts of anemia in ewes at breeding and lambing on the productive and reproductive performance of a meat sheep flock. The variables evaluated were i) FAMACHA© score of ewes at breeding and lambing, ii) body condition score of ewes at breeding and at lambing, iii) average daily gain of lambs until weaning, iv) ewe's age, v) birth weights per individual lamb and litter, vi) weaning weight, vii) ewe's weight, viii) litter size and ix) pre-weaning survival. The treatments evaluated corresponded to the FAMACHA© score of the ewes during breeding and lambing. Quantitative responses were submitted to analyses of variance and compared by Duncan's test. In contrast, qualitative or discrete responses were evaluated by the Kruskal & Wallis test and compared to Dunn's test. The Wilcoxon test was performed to compare the FAMACHA©scores of ewes at breeding and lambing. All statistical analyzes were performed using the R-Studio software version 4.2.0 at a 5% significance level. The FAMACHA© score of breeding ewes was related to the body condition score at breeding, ewe weight, pre-weaning survival, ewe age, litter size, and birth weight. Furthermore, the FAMACHA© score of ewes at lambing was related to the body condition score at lambing, ewe weight, pre-weaning survival, birth weight per lamb and litter, pre-weaning average daily gain, weaning weight, and age of the ewe. There was no significant difference between the test times of the FAMACHA© scores of the ewes, indicating that an ewe will present a similar score at both stages. It was concluded that ewes with FAMACHA© scores of 4 and 5 and their offspring showed the worst productive and reproductive performances. Conversely, the ewes with FAMACHA© 1 obtained the opposite result, demonstrating better technical performance.(AU)

No Brasil, produtores de cordeiros enfrentam desafios na criação de seus animais devido à alta resistência anti-helmíntica e perda de produtividade devido a parasitoses. Sabe-se que as infecções parasitárias podem reduzir o desempenho de matrizes ovinas, contudo, até a elaboração desse trabalho não foram encontradas pesquisas que mensuraram os efeitos que a anemia refletida pelos graus FAMACHA© podem exercer sobre outros indicadores zootécnicos em um sistema de produção de cordeiros. Sendo assim, o objetivo desse estudo foi quantificar os impactos das verminoses em matrizes ovinas, representadas pelo grau FAMACHA©, durante a estação de monta e a parição, no desempenho produtivo e reprodutivo de um rebanho ovino de corte. As variáveis avaliadas foram: i) grau FAMACHA© das matrizes à monta e ao parto, ii) escore de condição corporal das matrizes à monta e ao parto, iii) ganho médio diário até o desmame, iv) idade da matriz, v) pesos dos cordeiros ao nascer individual e por parto, vi) peso ao desmame, vii) peso da matriz, viii) prolificidade e ix) sobrevivência pré-desmame. Os tratamentos avaliados corresponderam ao grau FAMACHA© das matrizes durante a monta e parto. As respostas quantitativas foram submetidas à análise de variância e comparadas pelo teste de Duncan, já as respostas qualitativas ou discretas foram avaliadas pelo teste de Kruskal & Wallis e comparadas pelo teste de Dunn. Realizou-se o teste de Wilcoxon para comparar os graus FAMACHA© das matrizes nos momentos de monta e parto. Todas as análises estatísticas foram realizadas no software R-Studio versão 4.2.0 ao nível de 5% de significância. O grau FAMACHA© das matrizes à monta foi relativo ao escore de condição corporal à monta, peso da matriz, sobrevivência pré-desmame, idade da matriz, prolificidade e peso ao nascer coletivo por parto. Já o grau FAMACHA© das matrizes ao parto foi relativo ao escore de condição corporal ao parto, peso da matriz, sobrevivência pré-desmame, pesos ao nascer individual e coletivo por parto, ganho médio diário pré-desmame, peso ao desmame e idade da matriz. Não houve diferença significativa entre os momentos dos graus FAMACHA© das matrizes, indicando que uma ovelha manterá um grau FAMACHA© similar em ambas as fases. Conclui-se que ovelhas com graus FAMACHA© 4 e 5, assim como suas crias, apresentaram os piores desempenhos produtivos e reprodutivos. Em contrapartida, as matrizes com FAMACHA©1 obtiveram o resultado oposto, mostrando indicadores zootécnicos com valores mais eficientes ao sistema de produção.(AU)

Discussion on the Focus of On-site Inspection of Clinical Trials of Lung Cancer Targeted Therapy and Immunotherapy Drugs / 中国肺癌杂志

As lung cancer targeted therapy and immunotherapy drugs are the current hot spot in the research and development area of new anti-tumor drugs, the amount of clinical trial in this area is increasing year by year. On the basis of combing the on-site inspections of drug registration clinical trials from 2019 to 2021, combined with the characteristics of lung cancer targeted therapy and immunotherapy drugs, this paper discusses the focus of on-site inspection of clinical trials of such drugs, and puts forward suggestions for the compliant implementation of lung cancer clinical trials.
.

Two Case Reports of Type 2 Diabetes Induced by Immune Checkpoint Inhibitors Combined with Chemotherapy / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) have become an important means of cancer treatment, and their application in the clinic is becoming more and more widespread. The adverse reactions caused by ICIs are gradually recognized. Among them, immunotherapy-related diabetes is a rare adverse reaction and type 1 diabetes mellitusis common. With the wide application of ICIs combined with chemotherapy in lung cancer patients, patients with type 2 diabetes mellitus have gradually been discovered during the treatment. However, the effect of continued use of ICIs maintenance therapy on blood glucose and ICIs treatment process in these patients is still unclear. This article reports two cases of type 2 diabetes mellitus induced by immune checkpoint inhibitor combined with chemotherapy, one of whom converted to type 1 diabetes mellitus, in order to increase the understanding of immunotherapy-related diabetes.
.

Anti-angiogenesis in Lung Cancer: Current Situation, Progress and Confusion / 中国肺癌杂志

Lung cancer is a highly vascular tumors, over the past ten years, anti-angiogenes is has been proved to be an effective and highly promising combinational treatment. The data of the combination of anti-angiogenesis with chemotherapy, targeted therapy, immunotherapy has been constantly updating. Advanced lung cancer patients, no matter different groups or different stages of the disease, are benefited from anti-angiogenes. In this paper, based on the clinical status and unsolved problems, combined with the latest clinical and translational research data, we reviewed the current anti-angiogenesis treatment of lung cancer.
.

Research Progress of Immunotherapy for Non-small Cell Lung Cancer with Drive Gene Mutation / 中国肺癌杂志

Lung cancer is the most lethal malignancy around the world and non-small cell lung cancer (NSCLC) accounts for 80% of all cases. Most of the NSCLC patients has "driver gene mutations" and targeted therapy achieved a relatively good efficacy, but some patients progressed or relapsed after treatment. Previous studies demonstrated that immune checkpoint inhibitor could improve the prognosis of advanced-stage NSCLC and prolong the survival time. However, the efficacy of immune therapy varies in NSCLC patients with different immune and molecular features. The efficacy of immune therapy was controversial in NSCLC patients with driver gene mutation. The present review will summarize the immune characteristics of NSCLC patients with driver mutation and the directions of immunotherapy for patients with driver mutation.
.

Tumores del estroma gastrointestinal en un Hospital de México / Gastrointestinal stroma tumor in a hospital of Mexico

Introducción: Los tumores del estroma gastrointestinal son neoplasias de comportamiento benigno o maligno. Se originan de las células intersticiales de Cajal del tubo digestivo. Objetivo: Describir dos formas distintas de presentación clínica de los tumores del estroma gastrointestinal. Casos clínicos: El caso 1, paciente femenina de 65 años de edad que acudió por síntomas compresivos del tubo digestivo superior a causa de un gastrointestinal gástrico. El caso 2, paciente masculino de 56 años de edad que acudió por sangrado de tubo digestivo medio ocasionado por un gastrointestinal intestinal. Conclusiones: Los tumores del estroma gastrointestinal tienen distinta presentación clínica. Su tratamiento es esencialmente quirúrgico y en algunos casos complementados con terapia molecular dirigida(AU)

Introduction: Gastrointestinal stromal tumors are neoplasms of benign or malignant behavior. They originate from the interstitial cells of Cajal in the digestive tract. Objective: The objective of this work is to describe two different forms of clinical presentation. Case report: case 1: 65-year-old female patient who presented for compression symptoms of the upper digestive tract due to gastric GIST; case 2: 56-year-old male who presented with bleeding from the middle digestive tract caused by intestinal GIST. Conclusions: GISTs have different clinical presentation. Its treatment is essentially surgical and in some cases supplemented with targeted molecular therapy(AU)

CDK4/6 signaling pathway and its targeted therapeutic agents in cancer therapy: a review / 生物工程学报

The development and progression of most cancers have been well recognized as the result of highly activated cell cycle. Cyclin dependent kinase 4/6 plays important roles not only in mitosis, but also in multiple biological processes that contribute to cancer development, such as aging, apoptosis and histone modification. Three FDA approved CDK4/6 inhibitors, Palbociclib, Ribociclib and Abemaciclib, have been used as targeted cancer therapeutic agents to benefit patients with endocrine therapy-resistant breast cancer and other types of cancer, prolonging their survival. However, the clinical application of these inhibitors also leads to acquired drug resistance and other problems. This paper reviews the regulatory roles of CDK4/6, the application of CDK4/6 inhibitors in cancer and the challenge of drug resistance.

Clinical practice guideline for stage Ⅳ primary lung cancer in China(2021 version) / 中华肿瘤杂志

Primary lung cancer is the most common malignancy and the leading cause of cancer death in China, with an estimated 787 thousands incident cases and 631 thousands deaths in 2015. Due to its aggressive behavior and the absence of effective early screening methods, most patients with lung cancer in China are in stage Ⅳ when diagnosed. Chemotherapy is the cornerstone of stage Ⅳ lung cancer, but its efficacy is unsatisfactory. In recent years, with the rapid development of molecular targeted therapy and immunotherapy, the treatment concept has continuously changed and survival for patients has also been greatly improved. In order to update the progress in the treatment of stage Ⅳ lung cancer worldwide timely, and further improve the level of standardized diagnosis and treatment of stage Ⅳ lung cancer in China, Chinese Association for Clinical Oncologists and Medical Oncology Branch of Chinese International Exchange and Promotion Association for Medical and Healthcare organized experts to formulate "Clinical Practice Guideline for Stage Ⅳ Primary Lung Cancer in China(2021 version)" .

Progress in systemic therapy for triple-negative breast cancer / 医学前沿

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.

Paniculitis secundaria a terapia target en paciente con melanoma, lo que el dermatólogo debe saber: reporte de un caso / Panniculitis in association with target therapy in melanoma patient, what the dermatologist should know: a case report

Las terapias target constituyen hoy en día una alternativa terapéutica cada vez más utilizada para el manejo de pacientes con melanoma metastásico. Sin embargo, se han descrito múltiples efectos farmacológicos adversos asociados a su uso, siendo los cutáneos los de mayor prevalencia. Se presenta el caso de un hombre de 55 años con diagnóstico de melanoma cutáneo metastásico etapa IV, BRAFV600E mutado, en tratamiento con dabrafenib/trametinib que consultó por desarrollo de lesiones nodulares eritematosas sensibles en extremidades superiores e inferiores, asociadas a sensación febril durante el curso del tratamiento. Se descartó alguna infección sobreagregada. Se realizó una biopsia de las lesiones cutáneas, con confirmación diagnóstica histopatológica de una paniculitis mixta de predominio septal, granulomatosa y con vasculitis leucocitoclástica. La paniculitis asociada a esta terapia ha sido descrita en la literatura y se ha considerado un efecto farmacológico inmunomediado adverso, relacionándose a un mejor pronóstico para el melanoma metastásico en tratamiento. Por lo tanto, así como en el caso presentado, se evita la suspensión del fármaco y se asocia terapia sintomática en caso de mayores molestias del paciente. Es de alta relevancia para el dermatólogo conocer e interpretar adecuadamente este efecto adverso farmacológico, y así indicar el manejo más adecuado para el paciente.

Target therapies are currently a therapeutic option increasingly used for the management of patients with metastatic melanoma. However, there are multiple adverse pharmacological effects associated with their use that have been described. Cutaneous adverse reactions are the most frequent. We report the case of a 55-year-old man with a diagnosis of stage IV BRAFV600E-mutated metastatic cutaneous melanoma undergoing treatment with dabrafenib/trametinib, who consulted due to the development of erythematous nodular lesions in the upper and lower limbs associated with febrile sensation during the course of treatment. Infection was ruled out and a biopsy of the skin lesions was done, which provided the histopathological confirmation of a predominantly septal, granulomatous with leukocytoclastic vasculitis, mixed panniculitis. Panniculitis associated with this therapy has been described in the literature and has been considered an immune-mediated pharmacological adverse effect. It is considered to be related to a better prognosis in the treatment of metastatic melanoma. Consequently, as shown in this case report, target therapy should not be discontinued and symptomatic medication should be given to alleviate patient discomfort. The dermatologist should know and properly interpret this adverse effect and prescribe the most appropriate management for the patient.

Clinical response and safety of apatinib monotherapy in recurrent, metastatic cervical cancer after failure of chemotherapy: a retrospective study / 부인종양

Potential life years not saved due to lack of access to anti-EGFR tyrosine kinase inhibitors for lung cancer treatment in the Brazilian public healthcare system: Budget impact and strategies to improve access. A pharmacoeconomic study

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.

MicroRNAs: new biomarkers and promising therapeutic targets for diabetic kidney disease / MicroRNAs: novos biomarcadores e alvos terapêuticos promissores da doença renal do diabetes

Abstract Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus associated with significant morbidity and mortality regarded as a global health issue. MicroRNAs - small RNA molecules responsible for the post-transcriptional regulation of gene expression by degradation of messenger RNA or translational repression of protein synthesis - rank among the factors linked to the development and progression of DKD. This study aimed to offer a narrative review on investigations around the use of microRNAs in the diagnosis, monitoring, and treatment of DKD. Various microRNAs are involved in the pathogenesis of DKD, while others have a role in nephroprotection and thus serve as promising therapeutic targets for DKD. Serum and urine microRNAs levels have also been considered in the early diagnosis and monitoring of individuals with DKD, since increases in albuminuria, decreases in the glomerular filtration rate, and progression of DKD have been linked to changes in the levels of some microRNAs.

Resumo A doença renal do diabetes (DRD) é uma complicação crônica do diabetes mellitus associada à elevada morbidade e mortalidade, considerada um problema de saúde mundial. Dentre os fatores associados ao desenvolvimento e à progressão da DRD, destacam-se os microRNAs, que consistem em pequenas moléculas de RNA que regulam a expressão gênica por meio da degradação pós-transcricional do RNA mensageiro ou inibição translacional da síntese proteica. Este estudo teve como objetivo realizar uma revisão narrativa buscando investigar os microRNAs como auxiliares no diagnóstico, monitoramento e tratamento da DRD. Vários microRNAs estão envolvidos na patogênese da DRD, enquanto que outros têm papel nefroprotetor, consistindo assim em alvos terapêuticos promissores para o tratamento da DRD. A dosagem laboratorial dos microRNAs no soro e na urina também é muito promissora para o diagnóstico precoce e o monitoramento da DRD, já que os níveis de alguns microRNAs se alteram antes do aumento da albuminúria e da diminuição da taxa de filtração glomerular e podem ainda se alterar com a progressão da DRD.

Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia

ABSTRACT Background: Older patients with acute myeloid leukemia are particularly difficult to treat, as they have a high risk of comorbidities, poor performance status and less tolerability to chemotherapy, as well as a more aggressive disease biology, responsible for the resistance to treatment. There is a need to explore novel therapeutic agents that are more effective and tolerable. Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. Objective: To review the available data about venetoclax in acute myeloid leukemia and how it can influence the treatment in older patients. Methods: Using the Pubmed database, we selected 29 articles published within the last 15 years, considering preclinical and clinical trials and review studies that combined venetoclax with acute myeloid leukemia. Results: Venetoclax has demonstrated promising results in preclinical and clinical trials, especially in patients with poor prognosis and the IDH mutation, with an excellent side-effect profile. However, resistance seems to develop rapidly with venetoclax monotherapy, because of antiapoptotic escape mechanisms. Conclusions: While the results with the use of venetoclax seem encouraging, it is not likely that targeting a single pathway will result in long-term disease control. The solution includes the use of combined therapy to block resistance mechanisms and enhance apoptosis, by reducing MCL-1, increasing BIM or inhibiting the complex IV in the mitochondria.

Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. MATERIALS AND METHODS: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. RESULTS: Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). CONCLUSION: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Immunotherapy in endometrial cancer: new scenarios on the horizon / 부인종양

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.