Thoughts on the timing of targeted therapy initiation for thyroid cancer / 中华核医学与分子影像杂志

The treatment of persistent/recurrent and metastatic thyroid cancer and medullary thyroid cancer has made significant progress through the use of molecule-targeted therapy. While this approach has shown promise in improving patient outcomes and clinical symptoms, it also carries potential risks. The primary focus and challenge of targeted therapy is to optimize benefits while managing risks within predetermined thresholds. This review examines current targeted treatment practices in thyroid cancer and investigates the correlation between the timing of targeted therapy initiation and the patient benefits, aiming to lay the groundwork for subsequent research.

Study of 68Ga-NODAGA-RGD PET/CT in predicting short-term efficacy of tyrosine kinase inhibitor in the treatment of distant metastatic differentiated thyroid cancer / 中华核医学与分子影像杂志

Objective:To investigate the clinical application of 68Ga-cyclo( L-arginylglycyl- L-α-aspartyl- D-tyrosyl-N6-(((4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)acetyl))- L-lysyl) (NODAGA-RGD) PET/CT to evaluate short-term efficacy of tyrosine kinase inhibitor (TKI) in distant metastatic differentiated thyroid cancer (dmDTC). Methods:From October 2019 to March 2023, 13 dmDTC patients (5 males, 8 females; age: 68(65, 69) years) from Nanjing First Hospital were retrospectively enrolled, of which 9 were clinically confirmed as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and 4 were dmDTC without radioactive iodine treatment. All patients underwent 68Ga-NODAGA-RGD PET/CT to assess neovascularization of the target lesions (TL), and the SUV max and target background ratio (T/B) were recorded. After 3 months of TKI treatment (anrotinib ( n=9) or apatinib ( n=4)), change rates of the maximum diameter of TL and thyroglobulin (Tg) were measured. The correlation of SUV max, T/B and the change rate of the maximum diameter of TL were analyzed by Spearman rank correlation analysis. ROC curve analysis was performed for the effectiveness of the T/B and TKI therapy, and the difference of the remission rate of lesions was analyzed by Fisher exact test. Results:In 13 patients, 36 TL were measured by 68Ga-NODAGA-RGD PET/CT with SUV max of 5.44(3.43, 7.56) and T/B of 5.25(4.50, 7.23). The change rate of the maximum diameter of TL was -30%(-39%, -21%) and the change rate of Tg was -68%(-96%, -52%). T/B was negatively correlated with the change rate of the maximum diameter of TL after TKI therapy ( rs=-0.46, P=0.005), while SUV max was not correlated with the change rate of the maximum diameter of TL ( rs=0.03, P=0.883). ROC curve analysis showed that the optimal cut-off value for T/B was 4.95, with the AUC of 0.698, the sensitivity of 87.5%, and the specificity of 60.0%. Compared to lesions with T/B<4.95, those with T/B≥4.95 showed higher remission rate (2/14 vs 63.6%(14/22); P=0.006). After 3 months of TKI treatment, the disease control rate was 12/13. Conclusion:68Ga-NODAGA-RGD PET/CT can effectively reflect tumor neovascularization, predict efficacy of TKI therapy, and provide powerful imaging evidence for TKI therapy in dmDTC.

Application of PET/CT in the treatment of epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced non-small cell lung cancer / 中华核医学与分子影像杂志

The morbidity and mortality of lung cancer rank first in the world. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can significantly prolong survival of patients with advanced non-small cell lung cancer (NSCLC). 18F-FDG PET/CT can evaluate EGFR mutation status and EGFR-TKI efficacy. This article reviews the role of 18F-FDG PET/CT in predicting EFGR mutation, the efficacy and survival prognosis evaluation of EGFR-TKI therapy, as well as the development of latest EGFR-TKI PET imaging agents.

Efficacy and safety of baricitinib in the treatment of moderate-to-severe atopic dermatitis: a clinical observation / 中华皮肤科杂志

Objective:To evaluate the efficacy and safety of baricitinib in the treatment of moderate-to-severe atopic dermatitis (AD) .Methods:From June 2020 to June 2021, patients with moderate-to-severe AD who were insensitive or intolerant to topical agents were enrolled from Department of Dermatology, Peking University First Hospital. Before treatment, the patients were evaluated by 4 scales, including the Investigator′s Global Assessment (IGA), Eczema Area and Severity Index (EASI), Itch Numeric Rating Scale (NRS), and Dermatology Life Quality Index (DLQI) ; meanwhile, photos of skin lesions were taken, routine blood test was performed, blood biochemical indices and total IgE levels were measured. After exclusion of contraindications, the patients were treated with oral baricitinib at a dose of 2 mg/d for 16 weeks. Regular follow-up was conducted at weeks 1, 2, 4, 8, 12, 16 and 20 after the start of treatment, clinical evaluation was carried out with the above 4 scales, and adverse events were recorded during the treatment.Results:A total of 24 patients were enrolled in the study, and all completed 16-week oral treatment and 20-week follow-up. All the 4 scale scores showed a continuous downward trend within 20 weeks after the start of treatment. At week 20, the patients′ IGA, EASI, NRS, and DLQI scores significantly decreased from 4.13 ± 0.61, 37.59 ± 14.86, 6.83 ± 2.26 and 18.67 ± 8.64 points respectively at baseline to 1.12 ± 0.49, 4.53 ± 3.78, 0.72 ± 0.58 and 1.39 ± 0.85 points respectively ( t = 22.70, 10.55, 10.69, 8.40, respectively, all P < 0.001). During the follow-up period, no serious adverse reactions were observed; 3 patients experienced gastric discomfort at the start of oral treatment, but the symptoms disappeared after the treatment continued; 3 developed acute allergic manifestations (1 case of allergic conjunctivitis, 2 cases of acute urticaria), which resolved rapidly after the use of antihistamines without recurrence. Conclusion:Baricitinib can provide a safer and more effective treatment option for patients with moderate-to-severe AD, especially those who are insensitive or intolerant to topical agents and need systemic treatments.

Preparation of N- 18F-fluoroethyl-tofacitinib and its application in the imaging of rheumatoid arthritis / 中华核医学与分子影像杂志

Objective:To synthesize N- 18F-fluoroethyl-tofacitinib, and explore its feasibility in the diagnosis of rheumatoid arthritis (RA). Methods:The " two-step method" was used to modify tofacitinib with 18F-fluoroethyl, and the labeling rate and radiochemical purity of the probe were measured by high performance liquid chromatography (HPLC), and the stabilities of the probe in vivo and in vitro were investigated. BALB/c mice (normal group; n=3) and collagen-induced arthritis (CIA) model mice (CIA group; n=3) were injected with N- 18F-fluoroethyl-tofacitinib and CIA model mice injected with tofacitirrib and N- 18F-fluoroethyl-tofacitinib were as blocking group ( n=3). All mice underwent microPET imaging and the percentage injection dose per gram of tissue (%ID/g) and the uptake ratio of inflamed joints to muscle (T/M) were calculated. One-way analysis of variance and the least significant difference (LSD) t test were used to analyze the data. Results:The synthesis time of N- 18F-fluoroethyl-tofacitinib was about 120 min, with the yield approximately 1%, the specific activity >13.6 GBq/μmol, and the radiochemical purity >99%. After the probe incubated with PBS, plasma or in vivo for 2 h, the radiochemical purity was still more than 95%. MicroPET imaging showed that 30 min after injection, the uptake of N- 18F-fluoroethyl-tofacitinib in the inflamed joints of CIA group was higher than that of normal group and blocking group ((10.22±1.64), (2.71±0.26) and (2.81±0.33) %ID/g; F=58.26, t values: 7.83, 7.67, P values: 0.001, 0.002). The T/M of CIA group was also higher than that of normal group and blocking group (24.73±5.77, 2.75±1.36 and 2.89±0.54; F=40.64, t values: 6.42, 6.53, P values: 0.003, 0.003). Conclusions:N- 18F-fluoroethyl-tofacitinib is successfully prepared and it is stable in vitro with good imaging performance in vivo. It may be used in clinic for the diagnosis of RA.

Progress of immunological surveillance in the treatment-free remission of chronic myelogenous leukemia / 白血病·淋巴瘤

With the wide application of tyrosine kinase inhibitor (TKI), to obtain treatment-free remission (TFR) has gradually become the long-term goal for patients with chronic myelogenous leukemia (CML). Self-renewing leukemia stem cells during disease progression are related with the recurrence, and surveillance of residual leukemic cells is hypothesized to be one of the critical factors in successful TFR. On the way to obtain TFR, many breakthroughs have been made in innate and adaptive immunity of CML cells. This paper reviews the immune function of CML patients, the role of the immune markers in maintaining TFR, and the exploration of TKI combined with new immunomodulator therapy to achieve a greater degree of TFR.

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.

Overall survival predictors in hepatocellular carcinoma patients treated with sorafenib

SUMMARY Malignant liver tumors are the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) accounts for 75-85% of these. Most patients are diagnosed at incurable stages. Palliative care is the appropriate treatment course in these circumstances (chemoembolization and sorafenib). There are few national studies on sorafenib. The objective is to evaluate survival predictors of HCC patients treated with sorafenib and evaluate the compliance of its indication in relation to BCLC recommendations. METHODS A total of 88 patients with an indication of sorafenib from 2010 to 2017 at the ISCMSP were retrospectively analyzed. Univariate and multivariate analyzes were performed in the search for predictors of survival. RESULTS The mean age was 61.2 years, 70.5% were men, most were classified as Child-Pugh A (69.3%), and BCLC C (94.3%). Cirrhosis was present in 84.6% and portal hypertension in 55.7%. Hepatitis C virus was the most common etiology (40.9%). Sixty-nine (78.4%) patients received the medication, with the average duration of treatment being 9.7 months. The mean overall survival was 16.8 months. Significant differences were observed in the multivariate analysis: ECOG PS (p = 0.024): Child-Pugh (p = 0.013), time of medication use (p <0.001), clinical worsening (p = 0.031) and portal thrombosis (p = 0.010). CONCLUSION Absence of portal thrombosis, Child-Pugh A, longer time of medication use, ECOG PS 0, and absence of suspension due to clinical worsening were predictors of better overall survival in the study. The drug's indication complies with BCLC guidelines in 94% of patients.

RESUMO Tumores malignos do fígado são a quarta maior causa de morte por câncer, sendo que o carcinoma hepatocelular (CHC) corresponde a 85-90% desses casos. A maioria dos doentes apresenta-se, ao diagnóstico, sem possibilidade de tratamento curativo, restando apenas as opções paliativas (quimioembolização e sorafenibe). Há poucos estudos nacionais acerca do sorafenibe. OBJETIVO Avaliar fatores preditivos de sobrevida em pacientes com CHC que tiveram indicação de tratamento com sorafenibe na Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) e avaliação da conformidade da indicação da medicação em relação às recomendações do BCLC. MÉTODOS Foram analisados retrospectivamente os dados de 88 pacientes que tiveram indicação de tratamento com sorafenibe no período de 2010 a 2017 na ISCMSP. Análises univariada e multivariada foram realizadas na busca de preditores de sobrevida global nos pacientes que receberam a medicação. RESULTADOS Idade média de 61,2 anos, sendo 70,5% homens. A maioria (69,3%) foi classificada como Child Pugh A e BCLC C (94,3%). A cirrose esteve presente em 84,6% e a hipertensão portal em 55,7% desses. O vírus da hepatite C foi a etiologia mais comum (40,9%) do CHC. Sessenta e nove (78,4%) pacientes receberam a medicação, sendo o tempo médio de duração do tratamento 9,7 meses e a sobrevida global média, 16,8 meses. Diferenças significativas foram observadas na análise multivariada: Ecog PS (p=0,024), CP (p=0,013), tempo de uso de medicação (p<0,001), suspensão por piora clínica (p=0,031) e trombose portal (p=0,010). CONCLUSÃO Ausência de trombose portal, Child Pugh A, Ecog PS 0, tempo maior de uso de medicação e ausência de suspensão por piora clínica foram fatores preditores de melhor sobrevida global e a indicação da medicação esteve em conformidade com as orientações do BCLC em 94% dos pacientes.

Application of small molecule protein kinase inhibitors in tumor therapy / 中国肿瘤临床

Abnormal function of protein kinases has been closely related to tumors and thus, the development of corresponding protein kinase inhibitors to regulate the relevant signal transduction pathways is the current focus of anti-tumor drug development research. Since the first protein kinase inhibitor was licensed by the FDA in 2001, more than 50 protein kinase inhibitors have been approved for the treatment of malignant tumors such as breast and lung cancers, playing important roles in cancertreatment. However, small molecule kinase inhibitors also have several issues that need to be addressed. Hence, researchers continue to develop new kinase-targeting drugs to resolve these issues. Nevertheless, many new small molecule kinase inhibitors are being tested in clinical trials. This review summarizes the classification, substrates, and anti-tumor mechanisms of small molecule protein kinase inhibitors. Moreover, the advances in research and trends in the development of anti-tumor small molecule kinase inhibitors have been described systematically.

Progress of Waldenstrom macroglobulinemia / 白血病·淋巴瘤

Waldenstrom macroglobulinemia (WM) is a rare and incurable indolent lymphoma, characterized by serum monoclonal IgM. Whole-genome sequencing has showed that MYD88 and CXCR4 gene mutations are the most common molecular genetic changes in WM. In recent years, with the development of next-generation sequencing and other technologies, the research on the pathogenetic mechanism of WM has been continuously explored. Clinical trials of Bruton tyrosine kinase (BTK) inhibitors, proteasome inhibitors and other new drugs have been continuously carried out, improving the prognosis of WM. This paper reviews the latest research on treatment and prognosis analysis of WM in the 61st American Society of Hematology Annual Meeting.

Progress of phosphatidylinositol 3-kinase signaling pathway and its inhibitors in lymphoma / 白血病·淋巴瘤

The over-activation of phosphatidylinositol 3-kinase (PI3K) signaling pathway is closely related to the occurrence and development of malignant tumors. The abnormal expression of this pathway is involved in the regulation of cell growth, malignant transformation, apoptosis and metastasis. The targeted therapy for specific sites of PI3K signaling pathway is a new research hotspot. A variety of different types of PI3K inhibitors have been marketed or entered clinical trials and have shown considerable efficacy in the treatment of malignant lymphomas. In this view, the recent advances in activation patterns of PI3K signaling pathway in lymphoma and PI3K inhibitors are summarized.

Progress of phosphatidylinositol 3-kinase signaling pathway and its inhibitors in lymphoma / 白血病·淋巴瘤

The over-activation of phosphatidylinositol 3-kinase (PI3K) signaling pathway is closely related to the occurrence and development of malignant tumors. The abnormal expression of this pathway is involved in the regulation of cell growth, malignant transformation, apoptosis and metastasis. The targeted therapy for specific sites of PI3K signaling pathway is a new research hotspot. A variety of different types of PI3K inhibitors have been marketed or entered clinical trials and have shown considerable efficacy in the treatment of malignant lymphomas. In this view, the recent advances in activation patterns of PI3K signaling pathway in lymphoma and PI3K inhibitors are summarized.

Research advance on difference of efficacy and prognosis of tyrosine kinase inhibitor treatment for advanced non-small cell lung cancer patients with 19del and L858R mutation / 中国医师杂志

The epidermal growth factor receptor (EGFR) exon 19 deletion (19del) and the L858R point mutation of exon 21 are the most common types of EGFR mutations in non-small cell lung cancer (NSCLC). Treatment with EGFR tyrosine kinase inhibitors (TKI) can provide better survival benefit for some patients with advanced NSCLC. Clinical studies have shown that patients with these two types of mutations have different benefits in EGFR-TKI therapy. However, most patients treated with EGFR-TKI develop resistance after 12 months of treatment, the most common of which is the EGFR gene T790M mutation. In order to study the mechanism of resistance to TKI in NSCLC patients, and to develop new therapeutic methods and rational treatment strategies, further research on tumor characteristics in the whole disease progression and treatment process is indispensable. Exploring and comparing the differences between 19del and L858R and T790M in obtaining resistance to TKI is of great clinical significance.

Research advance on difference of efficacy and prognosis of tyrosine kinase inhibitor treatment for advanced non-small cell lung cancer patients with 19del and L858R mutation / 中国医师杂志

The epidermal growth factor receptor (EGFR) exon 19 deletion (19del) and the L858R point mutation of exon 21 are the most common types of EGFR mutations in non-small cell lung cancer (NSCLC).Treatment with EGFR tyrosine kinase inhibitors (TKI) can provide better survival benefit for some patients with advanced NSCLC.Clinical studies have shown that patients with these two types of mutations have different benefits in EGFR-TKI therapy.However,most patients treated with EGFR-TKI develop resistance after 12 months of treatment,the most common of which is the EGFR gene T790M mutation.In order to study the mechanism of resistance to TKI in NSCLC patients,and to develop new therapeutic methods and rational treatment strategies,further research on tumor characteristics in the whole disease progression and treatment process is indispensable.Exploring and comparing the differences between 19del and L858R and T790M in obtaining resistance to TKI is of great clinical significance.

Situación actual de la leucemia mieloide crónica en Costa Rica / (Current situation of chronic myeloid leukemia in Costa Rica)

Resumen Justificación y objetivo: la leucemia mieloide crónica constituye un paradigma de reversión de neoplasia con un tratamiento específico basado en los inhibidores de tirosina quinasa. Aunque la situación epidemiológica ha sido estudiada en países primermundistas, los estudios en Latinoamérica son escasos. Con el fin de actualizar la situación real de la LMC en la región centroamericana, el estudio pretende describir la epidemiología de la leucemia mieloide crónica en Costa Rica. Métodos: se evaluaron 133 pacientes con la enfermedad, mediante monitoreo hematológico y molecular. Se analizó la respuesta de estos casos a tratamiento conforme a las siguientes variables: respuesta hematológica, respuesta molecular y supervivencia global, libre de evento, progresión, así como la prevalencia de mutaciones que confieren resistencia al tratamiento. Resultados: la respuesta hematológica completa fue del 97,7%, y la molecular mayor, a los 12 meses, fue del 43,4%. El seguimiento recomendado por la guía European LeukemiaNet se alcanzó solo en un 68,4% de los pacientes en el primer año, bajando al 57,7%, posteriormente. Un total de 92 pacientes alcanzó respuesta molecular mayor en algún momento; de ellos, el 87,0% conservó respuesta. La supervivencia libre de evento a 3 años fue del 65,7%, libre de progresión del 92,2% y global del 89,2%. La mutación más frecuente encontrada en el gen ABL fue la T315I. Conclusión: el tratamiento de la leucemia mieloide crónica en Costa Rica presenta una eficacia comparable a lo reportado en otros países, con una respuesta molecular mayor inferior a lo esperado, debido a dificultades de acceso al medicamento y monitoreo de la enfermedad.

Abstract Background and aim: Chronic myeloid leukemia is a paradigm of reversion of neoplasia with a specific treatment based on tyrosine kinase inhibitors. Although the epidemiological situation has been studied in first world countries, studies in Latin American countries are scarce. In order to update the real situation of the chronic myeloid leukemia in our Central American region, this study aims to describe the epidemiology of chronic myeloid leukemia in Costa Rica. Methods: 133 patients with the disease were evaluated through hematological and molecular monitoring. The response of these cases to treatment was analyzed by the following variables: haematological response, molecular response and overall survival, event-free, progression, as well as the prevalence of mutations that confer resistance to treatment. Results: The complete haematological response was 97.7% and the molecular response greater than 12 months was 43.4%. The follow-up recommended by the European LeukemiaNet guideline was reached in only 68.4% of the patients in the first year, decreasing to 57.7% later on. A total of 92 patients achieved a higher molecular response at some point, of which 87.0% retained a response. The 3-year event-free survival was 65.7%, progression free of 92.2% and overall of 89.2%. The most frequent mutation found in the ABL gene was T315I. Conclusion: The treatment of chronic myeloid leukemia in Costa Rica presents an efficacy comparable to that reported in other countries, with a lower molecular response than expected due to difficulties in accessing medication and monitoring the disease.

Time and dose effects of AKT inhibitor GSK2141795 on apoptosis of human hepatocellular carcinoma cell line Huh7 / 第二军医大学学报

Objective To explore the time and dose effects of AKT (a kind of protein serine/threonine kinase) inhibitor GSK2141795 on the apoptosis of human hepatocellular cell line Huh7. Methods Huh7 cells were treated with GSK2141795 at the concentrations of 0, 0.3, 1, 3, 10 and 30 µmol/L for 24 h. A concentration of 10 µmol/L GSK2141795 was selected to treat Huh7 cells for 0, 2, 6, 12, 24 and 48 h. The protein expression levels of AKT and phosphorylated AKTS473 (p-AKTS473) were determined by Western blotting and cell apoptosis was detected by flow cytometry. The expression levels of apoptosis-related proteins (Bad, Bcl-2 and Caspase-9) were measured by qPCR and Western blotting. Results With the increase of GSK2141795 concentration, AKT protein level in Huh7 cells was gradually decreased and the p-AKTS473 protein level was gradually increased within the range of 0-10 µmol/L. With the prolongation of GSK2141795 treatment time, the AKT protein level was gradually decreased and the p-AKTS473 protein level was gradually increased within the range of 0-24 h. At 48 h of treatment, the AKT protein and p-AKTS473 protein expression levels were increased compared with 0 h. With the increase of GSK2141795 concentration and treatment time, the proportion of apoptotic cells was gradually increased, the expression levels of apoptotic molecules Bad and Caspase-9 were gradually increased, and the expression level of apoptotic antagonist Bcl-2 was gradually decreased. Conclusion AKT inhibitor GSK2141795 can effectively inhibit AKT protein expression, and induce apoptosis of Huh7 cells through Bad-Bcl-2 pathway in a dose-and time-dependent manner. In addition, the expression level of AKT protein in Huh7 cells can increase again after long-term stimulation by GSK2141795, suggesting the existence of a negative feedback signal loop.

Analysis of effectiveness of tyrosine kinase inhibitors in non-small cell lung cancer patients with epidermal growth factor receptor double mutations containing rare mutations / 国际肿瘤学杂志

Objective To explore the effectiveness of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR double mutations containing rare mutations.Methods From March 2007 to January 2017,NSCLC patients with EGFR double mutations containing rare mutations confirmed by histopathology and EGFR mutation detections at Renmin Hospital of Wuhan University,Zhongnan Hospital of Wuhan University and Hubei Cancer Hospital were enrolled.According to the mutation types,patients were divided into double activating mutations group and activating mutations with insensitive mutations group.The effectiveness of TKIs in NSCLC patients with EGFR double mutations containing rare mutations and different mutation types was analysis.Results Among the 2 637 NSCLC patients underwent EGFR mutation detections,19 patients were confirmed as EGFR double mutations containing rare mutations.Fifteen patients received EGFR-TKIs therapy,the objective response rate (ORR),disease control rate (DCR) and median progression free survival (PFS) were 46.7％ (7/15),73.3％ (11/15) and 8.1 months,respectively.In patients with double activating mutations,two patients had partial response (PR),one patient had a stable disease (SD).In the activating mutations with insensitive mutations group,five patients had PR,three patients had SD,four patients had no effect.Conclusion Patients with EGFR double mutations containing rare mutations have a general response to EGFR-TKIs,and this result can provide a reference for the treatment of those patients.

AZD5363 inhibits cell proliferation, migration and induces apoptosis of breast cancer MDA-MB-231 cells / 肿瘤

Objective: To investigate the effects of AZD5363, an inhibitor of protein kinase B (Akt), on proliferation, migration and apoptosis of human breast cancer cell line MDA-MB-231, and to further clarify their possible molecular mechanisms Methods: After treatment with different concentrations (0.5, 1, 5, 10, 20 and 50 μmol/L) of AZD5363, the viability of MDA-MB-231 cells was detected by MTT assay, the cell cycle distribution was analyzed by FCM, the cell migration ability was detected by wound healing test and Transwell chamber assay, the cell apoptosis rate was detected by TUNEL method. Then the expression levels of cell cycle- and apoptosis-related proteins were measured by Western blotting. Results: AZD5363 suppressed the cell viability in a dose-dependent manner (P < 0.05), and arrested the cell cycle progression at S phase by up-regulating the expression of p53 and down-regulating the expression of cyclin B1 (all P < 0.05). AZD5363 significantly inhibited the cell migration (P < 0.05), and induced the cell apoptosis (P < 0.05) by activating caspase-3 and poly (ADP-ribose) polymerase (PARP) proteins (both P < 0.05). Conclusion: AZD5363 can inhibit cell activity and migration, and induce apoptosis of human breast cancer cell line MDA-MB-2 31, thereby exhibiting its anticancer activity.

The effect of PKCζinhibitor on the proliferation and invasion of skin squamous carcinoma cell line A-431 / 天津医药

Objective To investigate the effect of protein kinase C (PKC)ζinhibitor T5450996 on the proliferation and invasion of skin squamous carcinoma cell line A-431. Methods PKCζinhibitor T5450996 was screened through Z′-LYTE?kit. Cell proliferation assay and cell cycle analysis were used to observe the effects of T5450996 on the proliferation of skin squamous carcinoma A-431 cells. Scratch assay and invasion assay were used to explore the effects of T5450996 on the migration and invasion of skin squamous carcinoma A-431 cells. Results The PKCζinhibitor T5450996 can inhibit the activity of PKCζkinase, and the IC50 value of T5450996 was about 35μmol/L. Compared to the control group, 35μmol/L and 70 μmol/L concentrations of T5450996 significantly suppressed the proliferation of A-431 cells and blocked the cell cycle of A-431 cells. The results of scratch assay and invasion assay indicated that the migration and invasion capacities of A-431 cells were markedly impaired after the treatments with 35μmol/L and 70μmol/L concentrations of T5450996 (P0.05). Conclusion PKCζinhibitor T5450996 significantly inhibits the proliferation and invasion capacities of skin squamous carcinoma cell line A-431, and which may be a small molecular inhibitor with potential applications in the future.

Apparent Diffusion Coefficient in Assessing Early Response to Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer / 中国医学影像学杂志

[Abstact] Purpose To investigate the value of apparent diffusion coefficient (ADC) of diffusion weighted imaging (DW1) in the evaluation of the efficacy of treatment of nonsmall cell lung cancer (NSCLC) with tyrosine kinase inhibitor (TKI).Materials and Methods Nineteen patients with advanced NSCLC who treated with TKIs from May 2014 to December 2015 were recruited prospectively.All patients underwent CT and MRI scans three times before targeted therapy,after 1 week and 4 weeks of treatment.The tumor maximal diameter and mean ADC value at different time points were compared.The correlations between mean ADC value and tumor maximal diameter and maximum diameter change rate at different time points were analyzed.Bland-Altman analysis was performed to confirm the reproducibility of measurements.Results The ADC value after 1 week of treatment was significantly increased compared with that before treatment (t=-6.329,P＜0.05),but the change of tumor maximal diameter was not significant (P＞0.05).The ADC value was significantly increased after 4 weeks of treatment compared with that before treatment (t=-4.878,P＜0.05),and the change of tumor maximal diameter was also significant (t=7.054,P＜0.05).The negative correlation was detected between the ADC before treatment and the maximal diameter change ratio after 4 weeks of treatment (r2=-0.474,P＜0.05).In the group of responders,there was significant difference between the ADC value before treatment and 1 week after treatment (P＜0.05).There was significant difference in ADC value between the groups of responders and non-responders after 4 weeks of treatment (P＜0.05).The Bland-Altman analysis showed good reproducibility among the operators.Conclusion The ADC value after 1 week of targeted therapy is more sensitive to the change of tumor than the maximal diameter,and the ADC value before treatment has a certain value in predicting the maximum diameters of the target after 4 weeks of targeted therapy with repeatability.