Incidence and clinical significance of FLT3 and nucleophosmin mutation in childhood acute myeloid leukemia in Chile

Abstract Introduction Acute myeloid leukemia (AML) is a heterogeneous disease and approximately one-third of its carriers do not have evident genetic abnormalities. The mutation of specific molecular markers, such as fms-like tyrosine kinase 3 (FTL3) internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD) and nucleophosmin (NPM1), are associated with an adverse and favorable prognosis, respectively. Objective The objective was to determine the prevalence of FLT3/ITD and NPM1 in Chilean patients and their association with clinical data and prognosis. Method and Results Two hundred and thirty-two children were studied between 2011 and 2017, the median being 8.6 years (ranging from 1 to 18 months). Acute promyelocytic leukemia (APL) was diagnosed in 29%. The FLT3/ITD-mutated in non-promyelocytic AML was at 10% (14/133) and the FLT3/TKD, at 3.7% (2/54). In APL, it was at 25.4% (16/63). In non-promyelocytic AML, the FLT3/ITD-mutated was associated with a high leucocyte count, the median being 28.5 x mm3 (n= 14) versus 19.4 x mm3 (n= 119), (p= 0.25), in non-mutated cases. In APL, the median was 33.6 x mm3 (n= 15) versus 2.8 x mm3 (n= 47), (p < 0.001). The five-year overall survival (OS) in non-promyelocytic AML with non-mutated and mutated FLT3/ITD were 62.7% and 21.4%, respectively, (p < 0.001); the 5-year event-free survival (EFS) were 79.5% and 50%, respectively, (p < 0.01). The five-year OS in APL with non-mutated and mutated FLT3/ITD was 84.7% and 62.5%, respectively, (p= 0.05); the 5-year EFS was 84.7% and 68.8%, respectively, (p= 0.122). The NPM1 mutation was observed in 3.2% (5/155), all non-promyelocytic AML with the normal karyotype. Conclusion The FLT3/ITD mutation was observed more frequently in APL and associated with a higher white cell count at diagnosis. However, the most important finding was that the FLT3/ITD mutation was associated with a shorter survival in non-promyelocytic AML.

Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer (2023 edition) / 中华肿瘤杂志

To standardize the prevention and clinical management of lung cancer, improve patients' survival outcomes, and offer professional insight for clinicians, the Oncology Society of Chinese Medical Association has summoned experts from departments of pulmonary medicine, oncology, thoracic surgery, radiotherapy, imaging, and pathology to formulate the Oncology Society of Chinese Medical Association guideline for clinical diagnosis and treatment of lung cancer in China (2023 edition) through consensus meetings. Updates in this edition include 1) cancer screening: deletion of high-risk traits of lung cancer based on epidemiological investigations in the Caucasian population, while preserving features confirmed by research on the Chinese population. Advice on screening institutions is also added to raise awareness of the merits and demerits of lung cancer screening through detailed illustrations. 2) Principles of histopathologic evaluation: characteristics of four types of neuroendocrine tumors (typical carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma) are reviewed. 3) Surgical intervention: more options of resection are available for certain peripheral lesions based on several clinical studies (CALGB140503, JCOG0802, JCOG1211). 4) neoadjuvant/adjuvant therapy: marked improvement in the prognosis of non-small cell lung cancer (NSCLC) patients receiving neoadjuvant immunotherapy are reviewed; more options for consolidation immunotherapy after radiochemotherapy have also emerged. 5) Targeted and immune therapy: tyrosine kinase inhibitors of sensitive driver mutations such as EGFR and ALK as well as rare targets such as MET exon 14 skipping, RET fusion, ROS1 fusion, and NTRK fusion have been approved, offering more treatment options for clinicians and patients. Furthermore, multiple immune checkpoint inhibitors have been granted for the treatment of NSCLC and SCLC, resulting in prolonged survival of late-stage lung cancer patients. This guideline is established based on the current availability of domestically approved medications, recommendations of international guidelines, and present clinical practice in China as well as integration of the latest medical evidence of pathology, genetic testing, immune molecular biomarker detection, and treatment methods of lung cancer in recent years, to provide recommendations for professionals in clinical oncology, radiology, laboratory, and rehabilitation.

Application of the WHO Classification of Thoracic Tumors (2021) grading system in invasive pulmonary adenocarcinoma and its correlation with the targeted genes' variations / 中华病理学杂志

Objective: To investigate the applicability of the 2021 WHO classification of thoracic tumors' new grading system for invasive pulmonary adenocarcinoma (IPA) with different clinical stages and its correlation with the characteristics of targeted genes' variation. Methods: A total of 2 467 patients with surgically resected primary IPA in Shanghai Pulmonary Hospital, Shanghai, China from September to December 2020 were retrospectively analyzed. Eligible cases were graded using the new grading system of IPA of the 2021 WHO classification of thoracic tumors. The clinicopathological data and targeted-gene abnormality were collected. The utility of new grading system of IPA in different clinical stages was investigated. The correlation of clinicopathological features and targeted-gene abnormality in different grades of IPA were compared. Results: All 2 311 cases of IPA were included. There were 2 046 cases of stage Ⅰ IPA (88.5%), 169 cases of stage Ⅱ (7.3%), and 96 cases of stage Ⅲ (4.2%). According to the new classification system of IPA, 186 cases (9.1%), 1 413 cases (69.1%) and 447 cases (21.8%) of stage-Ⅰ adenocarcinoma were classified as Grade 1, Grade 2 and Grade 3, respectively. However, there were no Grade 1 adenocarcinomas in stages Ⅱ and Ⅲ cases. Among stage-Ⅱ and Ⅲ IPA cases, there were 38 Grade 2 cases (22.5%) and 131 Grade 3 cases (77.5%), and 3 Grade 2 cases (3.1%) and 93 Grade 3 cases (96.9%), respectively. In stage-Ⅰ cases, no tumor cells spreading through airspace (STAS), vascular invasion or pleural invasion was found in Grade 1 of IPA, while the positive rates of STAS in Grade 2 and 3 IPA cases were 11.3% (159/1 413) and 73.2% (327/447), respectively. There was a significant difference among the three grades (P<0.01). Similarly, the rates of vascular and pleural invasion in Grade 3 IPA cases were 21.3% (95/447) and 75.8% (339/447), respectively, which were significantly higher than those of 1.3% (19/1 413) and 3.0% (42/1 413) in Grade 2 (P<0.01). EGFR mutational rates in Grades 1, 2 and 3 IPA were 65.7% (94/143), 76.4% (984/1 288) and 51.3% (216/421), respectively. The differences among the three grades were statistically significant (P<0.01). No fusion genes were detected in Grade 1 IPA, while the positive rates of ROS1 and ALK fusion genes in Grade 3 were 2.4% (10/421) and 8.3% (35/421), respectively, which were significantly higher than that of 0.5% (7/1 288) and 1.6% (20/1 288) in Grade 2 (P<0.01). In stage-Ⅱ cases, only EGFR mutation rate in Grade 2 adenocarcinoma (31/37, 83.8%) was higher than that in Grade 3 adenocarcinoma (71/123, 57.7%; P<0.01). However, the correlation between the new grade system of IPA and the distribution characteristics of targeted-gene variation cannot be evaluated in stage Ⅲ cases. Conclusions: The new grading system for IPA is mainly applicable to clinical stage-Ⅰ patients. Tumor grades of IPA are strongly correlated with the high-risk factors of prognosis and the distribution features of therapeutic targets. It is of great significance and clinical value to manage postoperative patients with early-stage IPA.

Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer / 中华病理学杂志

Objective: To investigate the clinicopathological features, treatment and prognosis of patients with RET fusion positive non-small cell lung cancer (NSCLC). Methods: A total of 1 089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020. In all cases, multiple gene fusion detection kits (fluorescent PCR method) were used to detect the gene status of RET, EGFR, ALK, ROS1, KRAS, BRAF and HER2; and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins. The correlation between RET-fusion and patients' age, gender, smoking history, tumor stage, grade, pathologic type, and PD-L1, mismatch repair related protein expression was analyzed. Results: There were 22 cases (2.02%) detected with RET fusion-positive in 1 089 NSCLC patients, in which 11 males and 11 females; and the median age was 63.5 years. There were 20 adenocarcinomas, including 11 acinar predominant adenocarcinoma (APA), five solid predominant adenocarcinoma (SPA) and four lepidic predominant adenocarcinoma (LPA); There were one case each of squamous cell carcinoma (non-keratinizing type) and sarcomatoid carcinoma (pleomorphic carcinoma). There were 6 and 16 patients with RET fusion-positive who were in stage Ⅰ-Ⅱ and Ⅲ-Ⅳ respectively, and 16 cases with lymph node metastasis, 11 cases with distant metastasis. Among RET fusion-positive cases, one was detected with HER2 co-mutation. The tumor proportion score of PD-L1≥1% in patients with RET fusion positive lung cancer was 54.5% (12/22). Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC. Four patients with RET fusions positive (two cases of APA and two cases of SPA) received pratinib-targeted therapy, and two showed benefits from this targeted therapy. Conclusions: The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA. RET fusion-positive NSCLC patients are associated with advanced clinical stage, lymph node metastases, and they may benefit from targeted therapy with RET-specific inhibitors.

Brazilian chronic myeloid leukemia working group recommendations for discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia in clinical practice

ABSTRACT Introduction: Treatment-free remission (TFR) is a new goal of chronic myeloid leukemia (CML) therapy. TFR is feasible when the patient has achieved a deep and stable molecular response and met the criteria required to ensure its success. Treatment discontinuation should not be proposed to the CML patient if minimum conditions are not met. In Brazil, for example, molecular tests (BCR::ABL1) are not broadly available, making it difficult to monitor the patients adequately. Objective: In this sense, providing TFR recommendations for Brazilian physicians are therefore necessary. These recommendations include the main criteria checklist to start the TKIs treatment discontinuing process in patients diagnosed with CML and the population-eligible characteristics for treatment discontinuation. Method: Age, risk score at diagnosis, TKI treatment duration, BCR::ABL1 transcripts type, depth of the molecular response for treatment discontinuation, treatment adherence, patient monitoring and withdrawal syndrome are essential factors to consider in TFR. After TKI discontinuation, BCR::ABL1 transcripts monitoring should be more frequent. When a major molecular response loss is observed during the monitoring of a patient in TFR, the TKI treatment should be resumed. Conclusion: These recommendations should serve as a basis for medical professionals interested in proposing TKI discontinuation for CML patients in clinical practice. It is important to highlight that, despite the benefits of TFR for the patients and the health system, it should only be feasible following the minimum standards proposed in this recommendation.

Desenvolvimento de inibidores duais de histona desacetilase 6 (HDAC6) e tirosina quinase (TQ) com vistas ao tratamento do câncer / Design of histone deacetylase 6 (HDAC6) and tyrosine kinase (TK) dual inhibitors for cancer treatment

Câncer é a denominação atribuída a um conjunto de doenças que são responsáveis pela segunda maior causa de morte no Brasil e no mundo. A quimioterapia figura entre uma das estratégias utilizadas para o tratamento e cura do câncer, sendo amplamente empregada em estratégias terapêuticas isoladas, ou em associação à radioterapia e cirurgia. A enzima histona desacetilase 6 (HDAC6) é responsável por desacetilar a cadeia lateral de N-acetillisinas em -tubulinas, desempanhando papel crítico na dinâmica do citoesqueleto celular, estando superexpressa em uma série de neoplasias. Neste sentido, na última década os receptores tirosina quinase (TQ) foram os principais alvos de fármacos aprovados para o tratamento do câncer e de doenças autoimunes e continuam atraindo a atenção de grupos de pesquisa dada a exorbitante diversidade do quinoma humano. É sabido que a monoterapia seja com inibidores de HDAC, seja com inibidores TQ, apresenta problemas de toxicidade, reações adversas, ineficácia, resistência e/ou recidiva. Diversos estudos relatam o desenvolvimento de inibidores duais de HDAC-TQ, almejando tanto a simplificação do tratamento, quanto sinergismo terapêutico e redução de efeitos adversos. Assim, o presente trabalho apresenta o planejamento, síntese e avaliação da citotoxicidade de inibidores duais, potencialmente seletivos para HDAC6 e receptores TQ. No total, 23 compostos foram sintetizados entre 2 a 4 etapas. Todos os compostos finais foram caracterizados por RMN (1H e 13C) e espectrometria de massas de alta resolução (HRMS). A citotoxicidade foi determinada pelo ensaio de MTT, em linhagens derivadas de tumores sólidos (HCT116 e MCF-7) e hematológicos (Jurkat e Namalwa). Os compostos apresentaram citotoxicidade em concentrações micro e nanomolares em todas as linhagens testadas, sendo que a linhagem MCF-7 foi a mais resistente à ação dos compostos, e as linhagens hematológicas foram as mais sensíveis. Os inibidores 4d-f foram os mais ativos na triagem por MTT, com IC50 iguais a 20, 30 e 50 nM, respectivamente, em células Jurkat. Estudos mecanísticos do efeito citotóxico indicaram que os compostos 4d-f exercem atividade de forma tempo-dependente, e majoritariamente por ação antiproliferativa, embora estímulos apoptóticos também tenham sido observados nos estudos. Simulações de ancoramento molecular (docking) e de relação entre as estruturas químicas dos compostos e suas respectivas atividades biológicas (REA) permitiram identificar padrões moleculares, propriedades físico-químicas e eletrônicas que potencialmente possuem relação com a atividade biológica dos compostos, permitindo futuras otimizações do arcabouço molecular desta série de compostos. Tomados em conjunto, os resultados deste trabalho revelam o potencial terapêutico de inibidores duais de HDAC6-TQ. Notadamente, os compostos apresentados aqui podem ser os primeiros potenciais inibidores duais de HDAC6-TQ a serem reportados na literatura

Cancer is the name of a series of diseases that are the second main cause of death in Brazil and worldwide. Chemotherapy is one of the main strategies to treat and cure cancer, and has been widely applied as a single therapeutic agent, and in association with radiotherapy and surgery. Histone deacetylase 6 (HDAC6) deacetylates N-acetyllysine side chains of tubulin, playing crucial role on cytoskeletal dynamics, and could be overexpressed in several cancers. Tyrosine kinase receptors (TK) have been the main targets of FDA-approved drugs through the last decade for both cancer and autoimmune diseases, and have been attracting special attention of research groups due to the exorbitant diversity of the human kinome. It is known that either HDAC or TK single therapy have toxicity issues, adverse effects, inefficacy, resistance and/or recidive. Therefore, many studies report the design of HDAC-TK dual inhibitors aiming simpler treatments, synergism of action and side effects reduction. Herein, the design, synthesis and cytotoxic evaluation of dual and selective HDAC6-TK inhibitors are presented. A total of 23 compounds were designed and synthesized through 2 to 4 steps. All final compounds were characterized by 1H/13C NMR and high-resolution mass spectrometry (HRMS). The cytotoxicity of compounds was determined by MTT assay for both solid (HCT116 and MCF-7 cells) and hematological cancers (Jurkat and Namalwa cells). Compounds exhibited micro and nanomolar ranges of cytotoxicity for all cell lines tested. MCF-7 cells were the most resistant against the treatment, and hematological cells were more susceptible to the cytotoxic effect of the compounds. Compounds 4d-f were the most actives in the MTT screening against Jurkat cells (IC50 = 20, 30 and 50 nM, respectively). Mechanistic studies regarding the cytotoxic effects of 4d-f indicated that the compounds induced cell death in a time-dependent manner mainly via cytostatic activity even though apoptotic stimuli were observed also. Molecular docking and structure-activity relationships (SARs) allowed the identification of molecular patterns, and physicochemical and electronic properties that potentially modulate the biological activity of these compounds, allowing further optimizations of the molecular scaffold for these series of compounds. Taken together, the results of this study reveal the therapeutic potential of HDAC6-TK dual inhibitors. Noteworthy, the compounds reported herein could be the first HDAC6-TK dual inhibitors ever reported in literature

Terapias sistémicas en carcinoma hepatocelular: secuencia de tratamientos / Systemic therapies in hepatocellular carcinoma: sequencing of treatment

El carcinoma hepatocelular (CHC) es una de las principales causas de morbilidad y mortalidad relacionada con el cáncer en todo el mundo. La mayoría de los casos ocurren en un contexto de cirrosis o hepatitis crónica. Los pacientes con CHC avanzado no disponían de terapias efectivas hasta el 2008, cuando el sorafenib, un inhibidor de la tirosina quinasa multi-target, demostró un beneficio en comparación con el placebo, en términos de supervivencia y tiempo a progresión de la enfermedad. Desde el 2016, diferentes tratamientos de primera y segunda línea con mecanismos de acción similares (lenvatinib, regorafenib, cabozantinib, ramucirumab) demostraron eficacia. Sin embargo, la investigación de fármacos que inhiben otras vías tumorales seguía siendo de máxima prioridad y los inhibidores de puntos de control inmunitario (ICI) mostraron resultados prometedores en el ámbito clínico para el tratamiento del CHC, revolucionando el manejo en estos pacientes. Recientemente, el anticuerpo contra la proteína de muerte programada-1 (PD-1), atezolizumab combinado con bevacizumab, demostró superioridad sobre el sorafenib en un ensayo clínico aleatorizado de fase III, convirtiéndose en la terapia de elección en primera línea. Actualmente están emergiendo resultados de múltiples estudios de fase III, que continuarán modificando el tratamiento del CHC. En este artículo se revisa la evolución y los cambios recientes de las terapias sistémicas para CHC, mostrando la secuencia actual de estos tratamientos, una vez iniciados.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Most cases occur in the context of cirrhosis or chronic liver inflammation. Patients with advanced HCC had no effective therapies until 2008, when sorafenib, a multi-target tyrosine kinase inhibitor, showed beneficial results when compared to placebo in terms of survival and time to progression. Since 2016, different first and second line treatments with similar mechanisms of action (lenvatinib, regorafenib, cabozantinib, ramucirumab) have shown efficacy. However, researchstudies with drugs that inhibit other tumor pathways remained a top priority, and immune checkpoint inhibitors (ICIs) showed promising results in the clinical setting of HCC management. Recently, antibodies against the programmed death protein-1 (PD-1), atezolizumab combined with bevacizumab, have shown superiority over sorafenib in a randomized phase III clinical trial, becoming the first-line therapy of choice. Results from multiple phase III studies are currently emerging, which will continue to modify HCC treatment. This article reviews recent developments and changes in systemic therapies for HCC, showing the current sequencing of these treatments once they begin.

Impacto econômico da interrupção do tratamento com inibidor de tirosina quinase em pacientes com leucemia mieloide crônica em um hospital federal referência em oncologia / Economic impact of discontinuing treatment with tyrosine kinase inhibitor in patients with chronic myeloid leukemia at a federal hospital reference in oncology

Objetivo: Avaliar o impacto econômico da descontinuação do tratamento da leucemia mieloide crônica (LMC) com inibidores da tirosina quinase (ITQs) em primeira ou segunda linha. Métodos: O modelo incluiu pacientes com diagnóstico de LMC em tratamento com ITQs que iniciaram o tratamento até 2012, em condições elegíveis no ano de 2015. Foi considerado um horizonte temporal de cinco anos sob a perspectiva do sistema público de saúde. Custos associados ao tratamento, como medicamento, monitoramento e manejo de eventos adversos, foram analisados. A avaliação foi composta por dois cenários: o cenário referência, com uso contínuo do medicamento, e o cenário comparador, com a interrupção do tratamento medicamentoso. Ambos os cenários consideraram as tecnologias disponíveis no período de 2015 a 2019. A análise de sensibilidade propôs variações nos cenários com a finalidade de avaliar a robustez do modelo. Além disso, uma extrapolação para nível nacional foi realizada, utilizando dados epidemiológicos para a obtenção do número de pacientes. Resultados: Foram selecionados 268 pacientes que iniciaram o tratamento até 2012. Desses, 65 foram elegíveis à descontinuação. A análise econômica mostrou uma economia de R$ 670.558,10 no primeiro ano, uma economia acumulada em cinco anos de R$ 3.665.355,98 e de R$ 66.517.232,80 no contexto institucional e nacional, respectivamente. A análise de sensibilidade foi favorável em todos os cenários propostos. Conclusões: A descontinuidade do tratamento da LMC mostrou-se, economicamente, uma importante oportunidade sob a perspectiva do sistema de saúde em flexibilizar novos investimentos tecnológicos e/ou ampliação de cesso, além da melhoria na qualidade de vida do paciente.

Objective: To assess the economic impact of discontinuing treatment of chronic myeloid leukemia (CML) with first or second line tyrosine kinase inhibitors (ITQs). Methods: The model included patients diagnosed with CML undergoing treatment with ITQs who started treatment until 2012, under eligible conditions in the year 2015. A 5-year time horizon was considered from the perspective of the public health system. Costs associated with treatment, such as medication, monitoring and handling adverse events were analyzed. The evaluation consisted of two scenarios, the reference scenario with continuous use of the drug and the comparator scenario with the interruption of drug treatment. Both scenarios considered the technologies available in the period from 2015 to 2019. The sensitivity analysis proposed variations in the scenarios in order to assess the robustness of the model. In addition, an extrapolation to the national level was performed, using epidemiological data to obtain the number of patients. Results: 268 patients who started treatment until 2012 were selected. Of these, 65 were eligible for discontinuation. The economic analysis showed savings of R$ 670,558.10 in the first year, accumulated savings in five years of R$ 3,665,355.98 and R$ 66,517,232.80 in the institutional and national context, respectively. The sensitivity analysis was favorable in all the proposed scenarios. Conclusions: The discontinuity of CML treatment proved to be, economically, an important opportunity from the perspective of the health system in making new technological investments and / or expanding access more flexible, in addition to improving the patient's quality of life

Recommendations for the management of cardiovascular risk in patients with chronic myeloid leukemia on tyrosine kinase inhibitors: risk assessment, stratification, treatment and monitoring

ABSTRACT This manuscript summarizes the results of the consensus meeting composed of hematologists and cardiologists to establish recommendations for the prevention and follow-up of cardiovascular (CV) risk in patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors (TKIs) from the point of view of clinical practice and from the perspective of hematology consultation.In the first medical appointment, the CV risk factors should be identified to perform the baseline risk stratification, based on the Brazilian Guideline of Dyslipidemia and Atherosclerosis Prevention Update (risk levels: very high, high, intermediate and low).Once stratified, the treatment of the CV risk factors should be administered. If the patient presents risk factors, such as hypertension, diabetes, renal disease, smoking and hypercholesterolemia, the evaluation and initial treatment may be done by the hematologist, being an option the request for evaluation by a specialist. If the patient has a history of previous CV disease, we recommend referral to a specialist. As the CV risk score is dynamic and the control of risk factors can reduce the patient risk, this expert consensus recommends that the re-evaluation of the CV risk after the baseline should be performed at 3 months, 6 months and 12 months. After this period, it should be done annually and, for specific patients, at the clinician's discretion.The evaluation of the baseline CV risk and the safe administration of a TKI allow the patient to benefit from the maximum treatment, avoiding unwanted effects.

Study of EGFR mutations in head and neck squamous cell carcinomas

Introduction Squamous carcinoma is the commonest malignancy of the head and neck region. It is associated with high morbidity and mortality. Epidermal growth factor receptor (EGFR) regulates downstream signaling pathways through its tyrosine kinase (TK) domains that play a role in cell proliferation and survival. EGFR mutations have been found to occur between exons 18 to 21 on chromosome 7. Limited studies are available on EGFR-TK mutations in the head and neck squamous cell carcinoma (HNSCC) globally. This study explores EGFR mutations in 30 HNSCC cases presenting to a tertiary care hospital over a period of two years. Material and Methods Fresh tumor tissue was collected from the resection specimens of cases of primary HNSCC. Cases with pre-operative therapy were not included. Parameters in the form of patients' age, gender, smoking/tobacco intake, site of the lesion were recorded. Tumor parameters after histopathological examination were recorded in the form of TNM stage, tumor grade. DNA was extracted from fresh tissue of all the cases. EGFR Mutation Analysis Kit assay was used to detect mutations of the EGFR gene. PCR was run and results were analyzed. Results EGFR Mutations were found in 6.7%of the patients. There was no significant association of the EGFR Mutation with the studied parameters. Conclusion EGFR mutations are present in a subset of patients of HNSCC. Patients having these mutations may benefit from targeted therapy with tyrosine kinase inhibitors.

Spindle assembly checkpoint complex-related genes TTK and MAD2L1 are over-expressed in lung adenocarcinoma: a big data and bioinformatics analysis / 南方医科大学学报

OBJECTIVE@#To screen the key genes related to the prognosis of lung adenocarcinoma through big data analysis and explore their clinical value and potential mechanism.@*METHODS@#We analyzed GSE18842, GSE27262, and GSE33532 gene expression profile data obtained from the Gene Expression Omnibus (GEO). Bioinformatics methods were used to screen the differentially expressed genes in lung adenocarcinoma tissues and KEGG and GO enrichment analysis was performed, followed by PPI interaction network analysis, module analysis, differential expression analysis, and prognosis analysis. The expressions of MAD2L1 and TTK by immunohistochemistry were verified in 35 non-small cell lung cancer specimens and paired adjacent tissues.@*RESULTS@#We identified a total of 256 genes that showed significant differential expressions in lung adenocarcinoma, including 66 up-regulated and 190 down-regulated genes. Thirty-two up-regulated core genes were screened by functional analysis, and among them 29 were shown to significantly correlate with a poor prognosis of patients with lung adenocarcinoma. All the 29 genes were highly expressed in lung adenocarcinoma tissues compared with normal lung tissues and were mainly enriched in cell cycle pathways. Seven of these key genes were closely related to the spindle assembly checkpoint (SAC) complex and responsible for regulating cell behavior in G2/M phase. We selected SAC-related proteins TTK and MAD2L1 to test their expressions in clinical tumor samples, and detected their overexpression in lung adenocarcinoma tissues as compared with the adjacent tissues.@*CONCLUSIONS@#Seven SAC complex-related genes, including TTK and MAD2L1, are overexpressed in lung adenocarcinoma tissues with close correlation with the prognosis of the patients.

Inhibitory Effect of Rosae Multiflorae Fructus Extracts on the Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis through Modulation of P38- and Ca2⁺-Mediated Nuclear Factor of Activated T-Cells Cytoplasmic 1 Expression

BACKGROUND: Rosae Multiflorae fructus (RMF), known to have anti-inflammatory and antioxidant properties, has been used as a traditional remedy for inflammatory diseases such as arthritis in Eastern Asia. However, its effect on osteoclasts, which play a crucial role in resorptive inflammatory bone diseases, is yet to be elucidated.METHODS: The effect of extract of RMF (RMF-E) on receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis was examined by tartrate-resistant acid phosphatase (TRAP) staining, real-time polymerase chain reaction and western blot analysis. In addition, RANKL-induced Ca2⁺-oscillation was also investigated.RESULTS: RMF-E remarkably inhibited TRAP+-osteoclast and resorptive pit formation in a dose-dependent manner. In addition, the expression of c-Fos and nuclear factor of activated T-cells cytoplasmic, known as pivotal transcription factors for osteoclast formation in vitro and in vivo, and that of the osteoclast differentiation markers such as Acp5, Oscar, CtsK, Atp6v0d2, Tm7sf4, and Nfatc1 were significantly decreased by RMF-E treatment during osteoclastogenesis. The inhibitory effect of RMF-E on RANKL-induced osteoclastogenesis was caused by the suppression of p38 mitogen-activated protein kinase activation, and RANKL-induced Ca2⁺-oscillation removal via inactivation of Bruton's tyrosine kinase (BTK), and subsequently phospholipase C-γ2.CONCLUSIONS: RMF-E negatively regulates osteoclast differentiation and formation. These findings suggest the possibility of RMF-E as a traditional therapeutic agent against osteoclast-related bone disorders such as osteoporosis, rheumatoid arthritis, and periodontitis.

Immunotherapy for Non-small Cell Lung Cancer: Current Landscape and Future Perspectives

Immune checkpoint inhibitors (ICIs) have shown remarkable benefit in the treatment of patients with non-small-cell lung cancer (NSCLC) and have emerged as an effective treatment option even in the first-line setting. ICIs can block inhibitory pathways that restrain the immune response against cancer, restoring and sustaining antitumor immunity. Currently, there are 4 PD-1/PD-L1 blocking agents available in clinics, and immunotherapy-based regimen alone or in combination with chemotherapy is now preferred option. Combination trials assessing combination of ICIs with chemotherapy, targeted therapy and other immunotherapy are ongoing. Controversies remain regarding the use of ICIs in targetable oncogene-addicted subpopulations, but their initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the choice. For the majority of patients without targetable driver oncogenes, deciding between therapeutic options can be difficult due to lack of direct cross-comparison studies. There are continuous efforts to find predictive biomarkers to find those who respond better to ICIs. PD-L1 protein expressions by immunohistochemistry and tumor mutational burden have emerged as most well-validated biomarkers in multiple clinical trials. However, there still is a need to improve patient selection, and to establish the most effective concurrent or sequential combination therapies in different NSCLC clinical settings. In this review, we will introduce currently used ICIs in NSCLC and analyze most recent trials, and finally discuss how, when and for whom ICIs can be used to provide promising avenues for lung cancer treatment.

Current Status and Future Direction of Immunotherapy in Hepatocellular Carcinoma: What Do the Data Suggest?

Most patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage of disease. Until recently, systemic treatment options that showed survival benefits in HCC have been limited to tyrosine kinase inhibitors, antibodies targeting oncogenic signaling pathways or VEGF receptors. The HCC tumor microenvironment is characterized by a dysfunction of the immune system through multiple mechanisms, including accumulation of various immunosuppressive factors, recruitment of regulatory T cells and myeloid-derived suppressor cells, and induction of T cell exhaustion accompanied with the interaction between immune checkpoint ligands and receptors. Immune checkpoint inhibitors (ICIs) have been interfered this interaction and have altered therapeutic landscape of multiple cancer types including HCC. In this review, we discuss the use of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies in the treatment of advanced HCC. However, ICIs as a single agent do not benefit a significant portion of patients. Therefore, various clinical trials are exploring possible synergistic effects of combinations of different ICIs (anti-PD-1/PD-L1 and anti-CTLA-4 antibodies) or ICIs and target agents. Combinations of ICIs with locoregional therapies may also improve therapeutic responses.

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.

Current Status of Immunotherapy for Lung Cancer and Future Perspectives / 결핵

Eficacia y seguridad de ibrutinib para el tratamiento de pacientes adultos con enfermedad de injerto contra huésped crónica post-trasplante alogénico de progenitores hematopoyéticos refractaria a corticoides / Efficacy and safety of ibrutinib for the treatment of adult patients with chronic allograft refractory hematopoietic progenitor graft-versus-host disease

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad del esquema ibrutinib + corticoides, comparado con los esquemas basados en corticoides + inmunosupresores, para el tratamiento de pacientes adultos con enfermedad de injerto contra huésped crónica (cGVHD) post-trasplante alogénico de progenitores hematopoyéticos (TACPH) refractaria a corticoides. La enfermedad de injerto contra huésped (GVHD, por sus siglas en inglés) es un desorden inflamatorio multisistémico, potencialmente mortal, que puede ocurrir tras el trasplante de un órgano o tejido. La GVHD ocurre porque las células T del donante fallan en reconocer los antígenos de histocompatibilidad principales del receptor y, por lo tanto, empiezan a atacarlo; produciendo una reacción inflamatoria exagerada. Durante el trasplante alogénico de células progenitoras hematopoyéticas (TACPH) se transfiere una mayor cantidad de células T maduras e inmunocompetentes. Por este motivo, el GVHD es más frecuente en pacientes post-TACPH que en pacientes con trasplante de órganos sólidos o de médula ósea. TECNOLOGÍA SANITARIA DE INTERÉS: Ibrutinib: Ibrutinib es un inhibidor irreversible de la tirosina quinasa de Bruton y la quinasa inducible por interleucina 2, las cuales activan las vías de señalización de los receptores de células B y células T, respectivamente (Ramachandran, Kolli, y Strowd 2019). Al inhibir estas vías, la activación, diferenciación y proliferación de células B y células T no se producirá; y en consecuencia se podrá manejar la respuesta anti-inflamatoria, la vía pro-fibrótica y la producción de anticuerpos anti-receptor (National Institute of Diabetes and Digestive and Kidney Diseases 2012; Jaglowski y Blazar 2018). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del esquema ibrutinib + corticoides en el tratamiento de pacientes adultos con cGVHD post-TACPH refractaria a corticoides. Se realizó tanto una búsqueda sistemática como una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica (GPC) y evaluaciones de tecnologías sanitarias (ETS). RESULTADOS: La presente evaluación de tecnología sanitaria muestra la evidencia encontrada luego de una búsqueda sistemática, con respecto a la eficacia y seguridad del esquema ibrutinib + corticoides, en términos de: sobrevida global, tasa de respuesta total, calidad de vida, reducción/descontinuación de corticoides e incidencia de eventos adversos, en comparación con tratamientos basados en corticoides e inmunosupresores en pacientes adultos con cGVHD post-TACPH refractaria a corticoides. Al respecto, se identificó una guía de práctica clínica (GPC) sobre el manejo de cGVHD y un ensayo clínico (EC) fase Ib/II, sin grupo de comparación, que evalúa la eficacia y seguridad de ibrutinib en el tratamiento de pacientes con cGVHD y falla al tratamiento con corticoides. La GPC publicada por la Sociedad Francófona de Trasplante de Médula Ósea y Terapia Celular (SFGM-TC, por sus siglas en francés) señala que en pacientes con cGVHD no existe un tratamiento de segunda línea de referencia, pero presenta una lista de 20 alternativas de tratamiento, entre medicamentos y otros procedimientos. Aunque el grado de recomendación de estas alternativas es bajo (grado C), muchas de estas alternativas también han sido recomendadas por otras dos GPC publicadas antes de la aprobación de ibrutinib para el tratamiento de cGVHD. La GPC de la SFGM-TC no presenta una descripción detallada de la metodología utilizada para selección de la evidencia y la formulación de las recomendaciones; sin embargo, la consistencia con las recomendaciones de otras GPC internacionales les confiere cierto grado de confianza. CONCLUSIONES: El equipo técnico del IETSI valoró los siguientes aspectos: i) La cGVHD es una condición relativamente frecuente que puede ser mortal si no es tratada ii) La evidencia disponible es escasa e insuficiente para disipar la incertidumbre sobre la eficacia de ibrutinib en el tratamiento de pacientes con cGVHD refractaria a corticoides, iii) Aproximadamente, la mitad de pacientes del único EC disponible a la fecha descontinuó el tratamiento por eventos adversos, muerte o progresión de la enfermedad, iv) La ausencia de estudios que comparen el esquema ibrutinib + corticoides con otros esquemas de tratamiento impiden formular conclusiones sobre la superioridad de ibrutinib en eficacia y seguridad y v) Actualmente, existen otras alternativas disponibles en ESSALUD que también son recomendadas por las GPC internacionales. El Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI no aprueba el uso de ibrutinib para el tratamiento de pacientes adultos con cGVHD, post-TACPH refractaria a corticoides.

Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group

Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50–60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

A Case of Achieving Partial Remission with the Combination of Sorafenib and Nivolumab in a Patient with Hepatocellular Carcinoma Showing Disease Progression after Nivolumab Therapy

Sorafenib is a well-known approved systemic therapeutic agent used in patients with advanced hepatocellular carcinoma (HCC). Regorafenib and nivolumab are approved as second-line therapeutic drugs in patients showing disease progression after sorafenib therapy. However, there is no established third- or fourth-line therapy in patients with progression after regorafenib or nivolumab treatment. Recently, the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICPIs) has been attempted as a first-line treatment strategy in advanced HCC patients based on the hypothesis that combination therapy may overcome resistance in ICPI monotherapy. On the basis of this suggestion, we herein describe the case of an HCC patient demonstrating macrovascular invasion, whereby partial remission was achieved via the combination of sorafenib and nivolumab following disease progression after nivolumab therapy. Further studies on the combination of TKIs and ICPIs are necessary to determine ways to manage HCC patients showing disease progression after ICPI therapy.

Effects of moxibustion on learning and memory ability and the hippocampal BDNF/TrkB expressions in the rats of vascular dementia / 中国针灸

OBJECTIVE@#To explore the effects of (resolving stasis, promoting collateral circulation) moxibustion on learning and memory ability and the expressions of brain derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) in the rats of vascular dementia (VD) in the microenvironment of neurovascular niche.@*METHODS@#Using 2-vessel occlusion (2-VO), the VD rat models were duplicated. The neural stem cells (NSCs) labeled with lentiviral vector-mediated enhanced green fluorescent protein (EGFP) were co-cultured with endothelial progenitor cells (EPCs) to structure the NSCs + EPCs implant. The implant was transplanted into the lateral ventricle of VD rats and the VD rat models with neurovascular niche were established. In No.1 experiment, the successful-modeled rats were divided into 3 groups, i.e. a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 12 rats in each one. No any treatment was provided in the model group and the NSCs + EPCs blank group. The moxibustion therapy was adopted in the NSCs + EPCs moxibustion group, in which, the suspending moxibustion technique was applied to "Baihui" (GV 20), "Dazhui" (GV 14) and "Shenting" (GV 24), 20 min at each acupoint. The treatment was given once every day and a 14-day treatment was as one course. Totally, 3 courses of treatment were required. At the end of treatment, Morris water maze experiment was adopted to determine the learning and memory ability of the rats in each group. In the No.2 experiment, the model rats were divided into 3 groups, a NSCs + EPCs moxibustion group, a NSCs + EPCs blank group and a model group, 18 rats in each one. In each group, according to the durations of treatment, 3 subgroups were divided and 6 rats in each one. The intervention method was same as the No.1 experiment. Additionally, after corresponding treatment course, using perfusion, the brains were collected in each subgroup and the slices were frozen. BDNF/TrkB expressions were observed in the immunofluorescence test.@*RESULTS@#After treatment, in the NSCs + EPCs moxibustion group, the escape incubation was reduced, the time of the first running-cross platform was shortened and the frequency of running-cross platform increased as compared with the model group and the NSCs + EPCs blank group (<0.01, <0.05). The protein expressions were increased in tendency among the 3 courses of treatment in the NSCs + EPCs moxibustion group, indicating the significant differences (all <0.05), in which, the increase of the protein expressions in the NSCs + EPCs moxibustion group was better than the NSCs + EPCs blank group (<0.05, <0.01).@*CONCLUSION@#The moxibustion therapy is the effective approach to VD in clinical treatment. This therapy up-regulates the BDNF/TrkB protein expressions in the microenvironment of neurovascular niche, co-modulates NSCs-EPCs coupling mechanism, promotes nerve neogenesis and repairs the injured nerve.