AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy / 中华医学杂志(英文版)

BACKGROUND@#Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.@*METHODS@#The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.@*RESULTS@#Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.@*CONCLUSIONS@#This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

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.

Analysis of Clinicopathological Features on Spread Through Air Spaces of Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#The biological and molecular characteristics of spread through air spaces (STAS), a newly recognized invasive mode of lung cancer, remain controversial. The aim of this study was to investigate the clinicopathological features and molecular characteristics of STAS in patients with pulmonary adenocarcinoma.@*METHODS@#A total of 694 resected invasive non-mucinous lung adenocarcinomas diagnosed by clinicopathology from July 2019 to March 2021 in the First Affiliated Hospital of Guangzhou Medical University were collected, and the relationship between STAS and clinicopathological factors was analyzed. The state of protein expression of anaplastic lymphoma kinase (ALK) was detected by immunohistochemical method. Epidermal growth factor receptor (EGFR) was detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). ROS proto-oncogene 1-receptor (ROS1) was detected by reverse transcription-PCR (RT-PCR).@*RESULTS@#A total of 344 STAS positive cases and 350 STAS negative cases were collected. By univariate analysis, STAS positivity was statistically associated with tumor maximum diameter (P<0.001), pleural invasion (P<0.001), lymphovascular invasion (P<0.001), nerve invasion (P=0.013), lymph node metastasis (P<0.001), clinical stage (P<0.001) and histological type (P<0.001). There was a statistical correlation between STAS and ALK protein expression (P=0.001). Multivariate analysis showed that STAS positive was correlated with pleural invasion (P=0.001), vascular invasion (P<0.001), lymph node metastasis (P=0.005)and ALK protein expression (P=0.032).@*CONCLUSIONS@#STAS is associated with highly aggressive biological behavior of lung adenocarcinoma, suggesting a poor prognosis.

Genetic insights into thymic carcinomas and thymic neuroendocrine neoplasms denote prognosis signatures and pathways / 中华医学杂志(英文版)

BACKGROUND@#Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has limited outcome. New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches.@*METHODS@#We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017. Patient samples were sequenced using a 324-gene platform with licensed technologies. In this study, we focused on clinically relevant genomic alterations (CRGAs), which are previously proven to be pathogenic alterations, to identify the pathology-specific mutational patterns, prognostic signatures of TCs and TNENs.@*RESULTS@#The mutational profiles between TCs and TNENs were diverse. The genetic alterations that ranked highest in TCs were in CDKN2A, TP53, ASXL1, CDKN2B, PIK3C2G, PTCH1, and ROS1 , while those in TNENs were in MEN1, MLL2, APC, RB1 , and TSC2 . Prognostic analysis showed that mutations of ROS1, CDKN2A, CDKN2B, BRAF, and BAP1 were significantly associated with worse outcomes in TC patients, and that mutation of ERBB2 indicated shortened disease-free survival (DFS) and overall survival (OS) in TNEN patients. Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control, chromatin remodeling/DNA methylation, phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) signaling.@*CONCLUSION@#We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.

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.

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.

Clinicopathological features of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma / 中华病理学杂志

Objective: To investigate the clinicopathological features, immunophenotype and gene alterations of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA). Methods: Fifteen case of TL-LGNPPA diagnosed at Zhejiang Cancer Hospital (5 cases) and the First Affiliated Hospital, Zhejiang University School of Medicine (10 cases) from November 2011 to August 2020 were collected. Clinical and pathological examinations, immunohistochemical staining and next-generation sequencing were performed. The clinicopathological and molecular characteristics were summarized, and relevant literature was reviewed. Results: Fifteen patients were identified and included. Their median age was 36 years (range, 20-60 years). The male-female ratio was 1.0∶1.1. The most common symptoms were epistaxis and nasal obstruction. The neoplasms were located on the roof of the nasopharynx or the posterior margin of the nasal septum. The pathological features included complex papillary and glandular structures mainly composed of single or pseudostratified cubic and columnar cells, with mild to moderate cytological atypia. In some cases, spindle cell features, nuclear grooves, ground glass nuclei, squamous metaplasia, or scattered psammoma bodies were identified. In addition, nuclear polar reversal cells, hobnail cells and micropapillary structures were found, but have not been reported in previous literature. Immunohistochemistry showed that the tumor cells were diffusely positive for TTF1, CK7, vimentin and CKpan; focally positive for p40, CK5/6 and p16; and negative for Tg, NapsinA, CK20, CDX2, S-100 and PAX8. The Ki-67 positive rates ranged from 1% to 20% and were≤10% in thirteen cases (13/15). EBER in situ hybridization was negative in all cases. DNA sequencing of 6 specimens was performed and all specimens were found harboring gene mutations (EWSR1, SMAD2, ROS1, JAK3, GRIN2A, ERRCC5, STAT3, and TET2), but no hot spot gene alterations were found. No MSI-H and MMR related gene changes were detected. All tumors showed low tumor mutation burden. All 15 patients underwent endoscopic surgery, and only 1 of them underwent radiotherapy postoperatively. All patients were recurrence free and alive at the end of follow-up periods (range: 23 to 129 months). Conclusions: TL-LGNPPA is a rare indolent tumor of the nasopharynx and exhibits a unique morphology and immunophenotype. Endoscopic resection is an effective treatment for TL-LGNPPA with excellent overall prognosis.

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.

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

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.

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.