Search

Objective: To discuss the effects of 5-aza-2'-deoxycytidine (5-Aza-CdR) on autophagy and apoptosis of the TPC-1 cells in subcutaneous xenograft tumor tissue of the nude mice, and to clarify its mechanism. Methods: Sixteen female BALB/c nude mice were inoculated with human papillary thyroid carcinoma (PTC) TPC-1 cells in the right axilla to establish the xenograft tumor model. After tumor formation, the mice were randomly divided into control group and experiment group (n=8). The nude mice in control group were given an intraperitoneal injection of saline, while the nude mice in experiment group were given the intraperitoneal injection of 5-Aza-CdR, administered once every other day for four weeks. The growth status of xenograft tumor of the mice in both groups was observed, and the mice were sacrificed after the final administration and the tumor weights of the nude mice in two groups were detected. HE staining was used to observe the pathomorphology of xenograft tumor tissue of the nude mice in both groups; immunohistochemistry was used to detect the expression levels of microtubule-associated protein light chain 3 (LC3), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) in xenograft tumor tissue of the nude mice in two groups; real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting methods were used to detect the expression levels of LC3, Beclin-1, Bcl-2, Bax, mitogenactivated protein kinase kinase (MEK), extracellular signal-regulated kinase 1 (ERK1), extracellular signal-regulated kinase 2 (ERK2), phosphorylated EPK1 (p-ERK1), and phosphorylated EPK2 (p-ERK2) mRNA and proteins in xenograft tumor tissue of the nude mice in two groups. Results: Compared with control group, the tumor volume and weight of the nude mice in experiment group were significantly decreased (P<0. 01). The number of cancer cells of the nude mice in control group was high, and the cells were densely arranged, with irregular shapes, clear nuclear staining, large overlapping nuclei, and lobulation, showing significant pathological mitotic figures consistent with PTC pathological characteristics. The number of cancer cells of the nude mice in experiment group showed a significant decresing trend, and the cells were sparse arrangement, nuclear shrinkage, and less distinct nuclei, with a significant increase in connective tissue. Compared with control group, the expression levels of LC3B and Beclin-1 mRNA and proteins in xenograft tumor tissue of the nude mice in experiment group were significantly increased (P<0. 05) and the ratio of and Bax/Bcl-2 was increased (P<0. 05 or P<0. 01), while the expression levels of MEK, ERK1/2, and p-ERK1/2 mRNA and proteins were significantly decreased (P<0. 05 or P<0. 01). Conclusion: 5-Aza-CdR can inhibit the growth of TPC-1 cells in subcutaneous xenograft tumor tissue of the nude mice, induce the autophagy, and promote the apoptosis of the tumor cells. The mechanism may be related to the inhibition of the mitogen-activated protein kinase (MAPK) /MEK/ extracellular signal-regulated kinase (ERK) signaling pathways. [ABSTRACT FROM AUTHOR]

Lung cancer is the malignant tumor with the highest incidence and mortality rate worldwide. For lung adenocarcinoma, identifying specific gene mutations, fusions, and giving corresponding targeted drugs can greatly improve the survival time of the patients. Among them, anaplastic lymphoma kinase (ALK) fusion occurs in 3%-7% of non-small cell lung cancer (NSCLC). In clinical practice, a variety of detection methods can be used to determine the ALK fusion status, but false negative test results are possible. This paper retrospectively analyzed the diagnosis and treatment of a patient with lung adenocarcinoma, judged the ALK fusion status by various detection methods. Among them, immunohistochemistry (IHC)(Ventana D5F3), RNA based next-generation sequencing (RNA-based NGS) confirmed positive echinoderm microtubule associated protein like 4 (EML4)-ALK fusion, while DNA-based NGS was negative. This paper analyzed the detection methods of ALK fusion, in order to clarify which detection method is the most accurate and simple to choose in different clinical cases and guide the subsequent treatment.

Multiple primary lung cancer (MPLC) refers to patients with two or more primary lesions of lung cancer. It can be divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC) based on the timing of occurrence. In recent years, the detection rate of MPLC has gradually increased. However, considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis (IM), especially when the histopathological types are identical. Given the significant differences in treatment strategies and prognosis in clinical practice currently, accurate diagnosis of MPLC is crucial for personalized precision therapy. Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors. There have been reports of coexisting mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion genes in non-small cell lung cancer, but case of EGFR mutation following an ALK mutation has not been mentioned. This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery, and reviews the relevant literature. This paper aims to deepen the understanding of mMPLC and provide clinical references for the diagnosis and treatment of such patients. [ABSTRACT FROM AUTHOR]

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a specific subtype of inflammatory myofibroblastic tumor. It is a rare malignant mesenchymal tumor with clinical features such as anaplastic lymphoma kinase (ALK) positivity, high aggressiveness, and poor prognosis. ALK inhibitors (TKI) are targeted drugs for the treatment of these tumors. We report a case of pelvic-abdominal EIMS that was difficult to be resected by surgery. The patient was a young woman with clinical manifestations of left lower abdominal pain with fever, and was clearly diagnosed by pathology as EIMS with RANBP2-ALK fusion mutation of ALK gene, and the symptoms of abdominal pain and other symptoms were rapidly relieved after TKI-targeted therapy, and with the prolongation of the time of administration, the lesion in the pelvic-abdominal cavity progressively shrunken. The patient was treated with TKI for 3 years, and no signs of recurrence or metastasis of the tumor lesions were seen on any of the imaging examinations. A successful case of sustained response to targeted therapy is provide, and confirm the possibility of TKI targeted therapy for patients with unresectable, refractory ALK-positive EIMS. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusion gene is one of the most common driver gene in non-small cell lung cancer (NSCLC). Epidemiological data showed that ALK gene fusion is detected in 9.06% of Chinese advanced NSCLC patients. ALK-tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced NSCLC patients with ALK gene fusion. Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. Iruplinalkib is a novel new-generation ALK-TKI independently developed in China. On June 27, 2023, the NMPA approved iruplinalkib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients whose disease has progressed after previous treatment with crizotinib or who are intolerant to crizotinib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the “Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)”. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non-small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support.

Lung cancer is one of the most lethal malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for approximately 80%-85% of all pathological types. Approximately 30%-55% of NSCLC patients develop brain metastases. It has been reported that 5%-6% of patients with brain metastases harbor anaplastic lymphoma kinase (ALK) fusion. ALK-positive NSCLC patients have shown significant therapeutic benefits after treatment with ALK inhibitors. Over the past decade, ALK inhibitors have rapidly evolved and now exist in three generations: first-generation drugs such as Crizotinib; second-generation drugs including Alectinib, Brigatinib, Ceritinib, and Ensartinib; and third-generation drugs like Lorlatinib. These drugs have exhibited varying efficacy in treating brain metastases in ALK-positive NSCLC patients. However, the numerous options available for ALK inhibition present a challenge for clinical decision-making. Therefore, this review aims to provide clinical guidance by summarizing the efficacy and safety of ALK inhibitors in treating NSCLC brain metastases. [ABSTRACT FROM AUTHOR]

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.

Anaplastic lymphoma kinase (ALK) is one of the common oncogenic driver genes in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have achieved excellent therapeutic effects in patients with ALK fusion positive NSCLC. However, patients will eventually develop resistance to TKIs. Acquired molecular drug resistance mechanisms, such as ALK kinase domain mutation, ALK gene amplification and abnormal activation of bypass, are important drug resistance mechanisms affecting the effect of targeted therapy for ALK+ NSCLC. Acquired ALK kinase domain resistance mutations have become the focus of attention. With the deepening and popularization of next-generation sequencing (NGS), the drug resistance mutation spectrum of ALK TKI is becoming clearer, and acquired drug resistance may change dynamically. First, after the treatment failure of the first (G1)/second generation (G2) TKI, the secondary ALK kinase domain resistance mutation is mainly a single point mutation. About 20% of patients develop drug resistance mutations after failure of treatment with crizotinib, mainly L1196M, G1269A, C1156Y and F1174L. The incidence of point mutations following drug resistance to second-generation TKIs (including alectinib, ceritinib, brigatinib and ensartinib) is as high as 50%, and the types are more abundant, such as G1202R/del, F1174C/V and I1171T/N/S. In preclinical trials, compared with crizotinib, the G2 TKI has a higher inhibitory effect on ALK kinase and can cover most ALK resistance mutations, except G1202R/del. In addition to G1202R, F1174C/L and I1171N/S/T are the main drug-resistant mutations of ceritinib and alectinib respectively, and G1269A and E1210K are the main drug-resistant mutations of ensartinib. Secondly, the proportion of ALK double mutation and "off target" increase significantly following the resistance to the G2 TKIs. Following resistance to third generation (G3) TKI lorlatinib, almost all of them are compound mutations, and the degree of resistance is higher. I1171N double mutation and G1202R double mutation spectrum have been found. Among them, G1202R+L1196M double mutation shows high resistance to all ALK TKIs. In addition, after the progress of sequential multi-generation ALK TKI treatment, the original drug resistance sites change, the ratio of wild-type is increased, and the drug resistance mechanism may be more complex. At present, sequential G2/G3 TKIs can inhibit most drug-resistant mutations after crizotinib resistance. After the treatment progress of G2 TKI, the tumor inhibition effect can be achieved by sequential use of other G2 TKI or lorlatinib. For stubbern solvent frontier region mutation, lorlatinib has a significant inhibitory effect on G1202R mutation, while the lorlatinib resistant L1198F mutation and L1198F double mutation can be resensitized to crizotinib. Some compound mutations are sensitive to G2 TKIs, such as I1171N+L1196M and I1171N+G1269A mutations. Most compound drug-resistant mutations have not found effective inhibitors. The new generation TPX-0131 and NVL-655 show excellent antitumor effect in preclinical experiments, especially can overcome ALK compound drug resistance mutation, however, they still need to be verified by clinical trials. Identifying the kinase domain resistance mutation spectrum of ALK TKI and selecting sensitive and efficient TKIs treatment are the research hotspots in recent years. This paper focused on the mechanism of acquired ALK kinase domain resistance, and systematically summarized the relationship between ALK gene background and kinase domain resistance, ALK TKI kinase domain resistance mutation spectrum and treatment strategies. At the same time, repeated biopsy after tumor progression is very important for identifying ALK kinase domain mutations and selecting the most effective treatment strategy.

OBJECTIVE: To evaluate the clinical efficacy of lorlatinib in the treatment of non-small cell lung cancer (NSCLC) based on Meta-analysis method, and to probe into the clinical manifestations, characteristics, patterns and outcomes of adverse drug reactions (ADR) induced by lorlatinib, so as to provide references for the clinical safe medication. METHODS: By retrieving CNKI, Wanfang Data, PubMed, Web of Science and other database, randomized controlled trials (RCT) on lorlatinib in the treatment of NSCLC [the lorlatinib group was given lorlatinib regimen with or without other medication, and the control group was given the first and (or) the second generation of anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) regimen] were enrolled for Metaanalysis, and studies on ADR induced by lorlatinib were also analyzed. RESULTS: Totally 5 eligible RCT were enrolled, including 622 patients (308 cases in the lorlatinib group, 314 cases in the control group), the objective remission rate (ORR) was used as the main outcome indicator. The results of Meta-analysis showed that the ORR of the lorlatinib group was higher than that of the control group, with statistically significant difference(OR = 2. 31,95%CI = 1. 62-3. 28,P<0. 000 01), which indicated that the efficacy of lorlatinib was significant compared with the previous 2 generations of drugs. Fourteen cases of ADR induced by lorlatinib were also collected, including 6 male patients and 8 female patients; there were more patients in the age group of >60 to 70 years old, with 7 cases; most ADR occurred at 2 weeks after medication, mainly involved cardiovascular system damage and respiratory system damage; all ADR were improved after drug withdrawal and (or) symptomatic supportive treatment; 2 cases showed no improvement or aggravation of symptoms at recurrence. CONCLUSIONS: As the third generation of ALK-TKI to treat NSCLC, the level of loratinib to treat NSCLC was significantly improved. However, clinical application of lorlatinib requires strict monitoring on cholesterol and triacylglycerol levels, as well as vigilance against central nervous system damage and cross-adverse drug reactions in the early phase of drug administration. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Tus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V ) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 9 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Lung Cancer is the property of Chinese Journal of Lung Cancer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and objective At present, the research progress of targeted therapy for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene mutations in lung adenocarcinoma is very rapid, which brings new hope for the treatment of advanced lung adenocarcinoma patients. However, the specific imaging and pathological features of EGFR and ALK gene mutations in adenocarcinoma are still controversial. This study will further explore the correlation between EGFR, ALK gene mutations and imaging and pathological features in invasive lung adenocarcinoma. Methods A total of 525 patients with lung adenocarcinoma who underwent surgery in our center from January 2018 to December 2019 were included. According to the results of postoperative gene detection, the patients were divided into EGFR gene mutation group, ALK gene mutation group and wild group, and the EGFR gene mutation group was divided into exon 19 and exon 21 subtypes. The pathological features of the mutation group and wild group, such as histological subtype, lymph node metastasis, visceral pleural invasion (VPI) and imaging features such as tumor diameter, consolidation tumor ratio (CTR), lobulation sign, spiculation sign, pleural retraction sign, air bronchus sign and vacuole sign were analyzed by univariate analysis and multivariate Logistic regression analysis to explore whether the gene mutation group had specific manifestations. Results EGFR gene mutation group was common in women (OR=2.041, P=0.001), with more pleural traction sign (OR=1.506, P=0.042), and had little correlation with lymph node metastasis and VPI (P>0.05). Among them, exon 21 subtype was more common in older (OR=1.022, P=0.036), women (OR=2.010, P=0.007), and was associated with larger tumor diameter (OR=1.360, P=0.039) and pleural traction sign (OR=1.754, P=0.029). Exon 19 subtype was common in women (OR=2.230, P=0.009), with a high proportion of solid components (OR=1.589, P=0.047) and more lobulation sign (OR=2.762, P=0.026). ALK gene mutations were likely to occur in younger patients (OR=2.950, P=0.045), with somking history (OR=1.070, P=0.002), and there were more micropapillary components (OR=4.184, P=0.019) and VPI (OR=2.986, P=0.034) in pathology. Conclusion The EGFR and ALK genes mutated adenocarcinomas have specific imaging and clinicopathological features, and the mutations in exon 19 or exon 21 subtype have different imaging features, which is of great significance in guiding the clinical diagnosis and treatment of pulmonary nodules.

Objective To explore the characteristics of ALK fusion gene in patients with primary lung adenocarcinoma in Gannan region, with hopes of scientifically guiding such patients towards selecting targeted drugs. Methods 5′/3′ imbalance strategy for qRT-PCR was used to detect the expression of ALK fusion gene in 233 cases of primary pulmonary adenocarcinoma and the clinical pathological characteristics were analyzed. Results The expression rate of ALK fusion genes was 9.01% (21/233). The expression rate of ALK fusion gene in female and N1-3 patients was significantly higher than that in male and N0 patients (P < 0.05); The expression rate of ALK fusion gene in patients with no smoking history, age < 55 years, M1 stage and fresh biopsy specimens was relatively high (P > 0.05); The expression of ALK fusion gene was not correlated with TNM stage, T stage, surgical treatment or tumor distribution location (P > 0.05). Moreover, in the subgroup analysis of 153 M1-stage cases, no correlation was found between the expression of ALK fusion gene and the metastasis of common sites of lung cancer (bone, brain, opposite lung, pleural dissemination adrenal glands and liver) (P > 0.05). Conclusion The expression rate of ALK fusion gene in primary lung adenocarcinoma in Gannan region is relatively high, which is common in female patients with lymph node metastasis.

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BACKGROUND: Steroid-induced avascular necrosis of the femoral head is still a difficult problem, and it is of great significance to study its pathogenesis. OBJECTIVE: To discuss the role of autophagy gene microtubule-associated protein 1 light chain 3 (MAP1LC3) in steroid-induced avascular necrosis of the femoral head and the effect of 3-methyladenine on MAP1LC3. METHODS: A total of 36 healthy New Zealand white rabbits, aged 5 months, were randomly divided into 3 groups, with 12 rabbits in each group. Control group was given intramuscular injection of normal saline, 2 mL per rabbit, once a week, four times in total. Model group was given intramuscular injection of 4 mg/kg methylprednisolone, once a week, four times in total. 3-Methyladenine group was given intramuscular injection of 4 mg/kg methylprednisolone followed by intramuscular injection of 3-methyladenine, 2 μL per rabbit, once a week, four times in total. Three animals from each group were sacrificed at 1, 2, 3, and 4 weeks for sampling. The femoral heads of the bilateral hindlimbs were taken. Empty bone lacunae were counted under optical microscope. mRNA and protein expression levels of MAP1LC3 were detected by RT-PCR and western blot assay, respectively. RESULTS AND CONCLUSION: Compared with the control group, the rate of empty lacunae increased significantly in the model and 3-methyladenine groups (P < 0.05), but the rate of empty lacunae was significantly lower in the 3-methyladenine group than the model group (P < 0.05). The expression of MAP1LC3 mRNA in the model group was higher than that in the 3-methyladenine group (P < 0.05), indicating the activation of autophagy is inhibited by 3-methyladenine. These findings indicate that MAP1LC3 is expressed in the animal model, confirming that autophagy plays a certain role in the pathogenesis of steroid-induced avascular necrosis of the femoral head; 3-methyladenine inhibits the expression of MAP1LC3 and reduces the occurrence and development of steroid-induced avascular necrosis of the femoral head. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Lung Cancer is the property of Chinese Journal of Lung Cancer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Lung cancer is a malignant tumor with high incidence rate and mortality rate in China and even the whole world, of which non-small cell lung cancer accounts for about 80%. Anaplastic lymphoma kinase (ALK) gene mutation accounts for about 5%. Alectinib, ALK-tyrosine kinase inhibitor (ALK-TKI), has great performance in clinical. The early detection and treatment of adverse drug reactions can greatly improve clinical benefits. This paper reports a patient of ALK positive non-small cell lung cancer was admited to Baotou Central Hospital in April 2020. The diagnosis and treatment was retrospectively analyzed, and the literature was reviewed.

Anaplastic lymphoma kinase (ALK) is one of the common oncogenic driver genes in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have achieved excellent therapeutic effects in patients with ALK fusion positive NSCLC. However, patients will eventually develop resistance to TKIs. Acquired molecular drug resistance mechanisms, such as ALK kinase domain mutation, ALK gene amplification and abnormal activation of bypass, are important drug resistance mechanisms affecting the effect of targeted therapy for ALK+ NSCLC. Acquired ALK kinase domain resistance mutations have become the focus of attention. With the deepening and popularization of next-generation sequencing (NGS), the drug resistance mutation spectrum of ALK TKI is becoming clearer, and acquired drug resistance may change dynamically. First, after the treatment failure of the first (G1)/second generation (G2) TKI, the secondary ALK kinase domain resistance mutation is mainly a single point mutation. About 20% of patients develop drug resistance mutations after failure of treatment with crizotinib, mainly L1196M, G1269A, C1156Y and F1174L. The incidence of point mutations following drug resistance to second-generation TKIs (including alectinib, ceritinib, brigatinib and ensartinib) is as high as 50%, and the types are more abundant, such as G1202R/del, F1174C/V and I1171T/N/S. In preclinical trials, compared with crizotinib, the G2 TKI has a higher inhibitory effect on ALK kinase and can cover most ALK resistance mutations, except G1202R/del. In addition to G1202R, F1174C/L and I1171N/S/T are the main drug-resistant mutations of ceritinib and alectinib respectively, and G1269A and E1210K are the main drug-resistant mutations of ensartinib. Secondly, the proportion of ALK double mutation and "off target" increase significantly following the resistance to the G2 TKIs. Following resistance to third generation (G3) TKI lorlatinib, almost all of them are compound mutations, and the degree of resistance is higher. I1171N double mutation and G1202R double mutation spectrum have been found. Among them, G1202R+L1196M double mutation shows high resistance to all ALK TKIs. In addition, after the progress of sequential multi-generation ALK TKI treatment, the original drug resistance sites change, the ratio of wild-type is increased, and the drug resistance mechanism may be more complex. At present, sequential G2/G3 TKIs can inhibit most drug-resistant mutations after crizotinib resistance. After the treatment progress of G2 TKI, the tumor inhibition effect can be achieved by sequential use of other G2 TKI or lorlatinib. For stubbern solvent frontier region mutation, lorlatinib has a significant inhibitory effect on G1202R mutation, while the lorlatinib resistant L1198F mutation and L1198F double mutation can be resensitized to crizotinib. Some compound mutations are sensitive to G2 TKIs, such as I1171N+L1196M and I1171N+G1269A mutations. Most compound drug-resistant mutations have not found effective inhibitors. The new generation TPX-0131 and NVL)655 show excellent antitumor effect in preclinical experiments, especially can overcome ALK compound drug resistance mutation, however, they still need to be verified by clinical trials. Identifying the kinase domain resistance mutation spectrum of ALK TKI and selecting sensitive and efficient TKIs treatment are the research hotspots in recent years. This paper focused on the mechanism of acquired ALK kinase domain resistance, and systematically summarized the relationship between ALK gene background and kinase domain resistance, ALK TKI kinase domain resistance mutation spectrum and treatment strategies. At the same time, repeated biopsy after tumor progression is very important for identifying ALK kinase domain mutations and selecting the most effective treatment strategy. [ABSTRACT FROM AUTHOR]

Background and objective Anaplastic lymphoma kinase (ALK) is an important therapeutic target for advanced non-small cell lung cancer (NSCLC). In recent years, with the emergence of several ALK tyrosine kinase inhibitors (TKI), the overall survival (OS) of ALK fusion positive patients is gradually extended. This paper reports the treatment of a late stage non-small cell lung cancer (NSCLC) patient with ALK fusion positive for more than 5 years, and analyzes the treatment process and effect evaluation, so as to provide experience for the follow-up treatment of patients. Methods The diagnosis and treatment process of a patient with advanced ALK fusion mutation positive lung cancer admitted to the third ward of Department of oncology, Chifeng hospital, Inner Mongolia on July 3, 2015 was retrospectively analyzed. Results A 42 years old male patient was admitted to our department on July 3, 2015 for "intermittent cough, chest tightness for 2 months, diagnosed with lung adenocarcinoma for 1 day". Imaging examination showed a space occupying lesion in the left lower lobe of the lung, accompanied by mediastinal lymphadenopathy and left encapsulated pleural effusion. Bronchoscopic pathology showed non-small cell carcinoma, and adenocarcinoma was tentatively suggested. Diagnosis: left lower lobe adenocarcinoma T1bN2M1a stage IV. Fluorescence in situ hybridization (FISH) indicated the translocation of ALK (2p23) chromosome. After 2 cycles of docetaxel+cisplatin (DP) regimens chemotherapy, disease progression occurred, so we used 6 cycles of pemetrexed+carboplatin to apply combination chemotherapy, 4 cycles of pemetrexed monotherapy were used after that. The efficacy evaluation: PR. On April 9, 2016, the patient was treated with crizotinib. In August 2019, multiple intracranial metastases were found and whole brain radiotherapy was given. Since September 4, 2019, oral administration of nsatinib has been carried out. As of March 1, 2021, the patients were followed up well. Conclusion The advanced ALK fusion positive lung adenocarcinoma patients, though the first-line and the second-line chemotherapy, and the follwing application of ALK-TKI treatment, has procured a total OS has reached 68 months, and the current follow-up is good.

Patients with brain metastasis from non-small cell lung carcinoma(NSCLC) have poor prognosis and short natural median survival. The application of targeted drugs can significantly prolong the survival of patients with brain metastases from NSCLC. Among the driving genes found so far, epidermal growth factor receptor ( EGFR) mutation accounts for the largest proportion, and anaplastic lymphoma kinase(ALK) rearrangement has the highest incidence of brain metastasis. Targeted drugs for the above two genes are constantly being developed, and the National Comprehensive Cancer Network(NCCN) guidelines recommend different targeted treatment options. This paper reviews the current status of research on drugs targeting EGFR mutation and ALK rearrangement based on NCCN guidelines, focusing on the intracranial effects of drugs, with the aim of providing reference for targeted therapy for patients with brain metastases from the above two driving genes. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusion gene, as a tumor driver gene, was crucial for the occurrence and development of non-small cell lung cancer (NSCLC). Recently, targeted ALK fusion gene has become the main treatment method for ALK-positive NSCLC. The first and second generation ALK inhibitors (ALKi), such as crizotinib, ceritinib, alectinib and ensartinib have been approved in China. However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions. [ABSTRACT FROM AUTHOR]

Echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion accounts for 3%-5% of non-small cell lung cancer (NSCLC) patients. With the in-depth study of the EML4-ALK driver gene, ALK inhibitors represented by crizotinib have been gradually developed and applied in the clinic. However, the response to ALK-targeted therapy is heterogeneous among different patients. Most patients with ALK-targeted therapy will inevitably develop drug resistance, leading to tumor progression. Monitoring the efficacy of patients with prognostic markers to change the treatment in time, and selecting individualized follow-up treatment according to the mechanism of drug resistance, can effectively improve the prognosis of patients. This article will review the mechanism of ALK tyrosine kinase inhibitor (ALK-TKI) resistance and related prognostic markers to discuss the prediction for ALK-targeted therapy and the choice of subsequent treatment for drug-resistant patients.

Background and objective Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study. Methods From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib. Results A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%). Conclusion The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.

Lung cancer is the malignant tumor with the highest incidence and mortality rate worldwide. For lung adenocarcinoma, identifying specific gene mutations, fusions, and giving corresponding targeted drugs can greatly improve the survival time of the patients. Among them, anaplastic lymphoma kinase (ALK) fusion occurs in 3%-7% of non-small cell lung cancer (NSCLC). In clinical practice, a variety of detection methods can be used to determine the ALK fusion status, but false negative test results are possible. This paper retrospectively analyzed the diagnosis and treatment of a patient with lung adenocarcinoma, judged the ALK fusion status by various detection methods. Among them, immunohistochemistry (IHC)(Ventana D5F3), RNA based next-generation sequencing (RNA-based NGS) confirmed positive echinoderm microtubule associated protein like 4 (EML4)-ALK fusion, while DNA-based NGS was negative. This paper analyzed the detection methods of ALK fusion, in order to clarify which detection method is the most accurate and simple to choose in different clinical cases and guide the subsequent treatment.
.

OBJECTIVE: To probe into the effects of alectinib on heart rate of patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). METHODS: Retrospective analysis was adopted, 35 patients with ALK-positive NSCLC treated with aletinib in Beijing Tiantan Hospital, Capital Medical University from Aug. 2018 to Jun. 2021 were enrolled to analyze the difference between the baseline heart rate and post-treatment heart rate, and to compare the difference between baseline minimum heart rate and post-treatment minimum heart rate and the mean 24 h post-treatment dynamic electrocardiogram heart rate. RESULTS: Of the 35 patients, 8 cases had sinus bradycardia, the incidence of bradycardia was 22.86%, the median time of occurrence was 6.65 months after taking aletinib. The rating of sinus bradycardia in 8 patients was grade 1, and no grade 2 or above bradycardia was observed. All patients had no complaints of cardiac-related discomfort and continued to take aletinib without relevant interventions, and were under continuous dynamic observation. The mean baseline minimum heart rate of patients was 65 beats/ min, and the mean minimum heart rate of patients with bradycardia after treatment with alectinib was 43 beats/ min, the difference was statistically significant (P <0. 000 1). The mean 24 h dynamic electrocardiogram heart rate was 57 beats/ min (<60 beats/ min in 5 cases, ≥60 beats/ min in 3 cases), the difference was statistically significant compared with the baseline minimum heart rate (P =0. 020 7). There was statistically significant difference between the mean heart rate of 5 patients with dynamic electrocardiogram <60 beats/ min and baseline minimum heart rate (P = 0. 006 9), but there was no statistically significant difference between the mean heart rate of 3 patients with dynamic electrocardiogram ≥60 beats/ min and baseline minimum heart rate (P =0. 713 3). The optimal response rate of patients with bradycardia (87. 50%, 7/8) was significantly higher than that of patients without bradycardia (44. 44%, 12/27), and the difference was statistically significant (P =0. 047 2). However, there was no statistically significant difference in the progression-free survival between patients with bradycardia and those without bradycardia ( P = 0. 181 1). CONCLUSIONS: The incidence of bradycardia in ALK-positive NSCLC patients treated with alectinib is 22. 86%, significantly higher than that reported in literature (from 6% to 9%), and the median occurrence time was 6. 65 months. The occurrence of bradycardia does not affect the continued use of drugs. As a measure to monitor the adverse reactions, Holter monitoring electrocardiogram of average heart rate has clinical application value. [ABSTRACT FROM AUTHOR]

The echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) were fractured and fused to become EML4-ALK. Most of these EML4-ALK-positive non-small cell lung cancer patients respond well to the ALK inhibitor. Many patients can benefit from drug target therapy for a long time, and some patients can achieve long-term survival of more than 7 years under the optimized treatment mode. This patient has lung adenocarcinoma positive for EML4-ALK fusion gene, but the treatment outcome is obviously different from that of other patients with lung cancer positive for EML4-ALK fusion gene. After the first to third generations of ALK inhibitor targeted therapy and chemotherapy, the disease progresses rapidly, the drug resistance time is short, the survival time is short, and the benefit is limited. The patient received targeted therapy of Crizotinib, Ceritinib and Lorlatinib successively from July 15, 2019, followed by two chemotherapy courses of Bevacizumab combined with Pemetrexed and Carboplatin. The patient died on September 10, 2020, with a survival of 15 months. At the same time, the treatment showed common adverse reactions of ALK inhibitors. This paper analyzed the therapeutic effect and treatment dilemma of this patient, and provided an exploration direction for the treatment of patients with EML4-ALK fusion gene positive lung cancer. [ABSTRACT FROM AUTHOR]

Objective: To investigate the function of mutant KEAP1 and its mutation in lung cancer cells. Methods: Western blot were conducted to determine the expression of Nrf2 and its target gene HO-1 in lung cancer cells with or without KEAP1 mutation. A549-constantly expressing pMSCV, wild type KEAP1 and mutant KEAP1were established by retroviral transfection. The clonogenic assay was performed to explore the effect of wild type Keap1 and mutant Keap1 on the proliferation ability of lung cancer cells. Results: The protein expression of NRF2 downstream gene HO-1 in KEAP1 / NRF2 mutant lung cancer cell lines group were increased compared with the non-mutant lung cancer cell lines group, and the level of reactive oxygen species (ROS) in the mutant group was significantly inhibited compared with the control group (P<0.01). Wide-type KEAP1 overexpression decreased the mRNA and protein expression of NRF2 target genes, increased the MDA level and suppressed proliferation in A549 cells compared with empty vector-transfected A549 cells (P<0.01), while over expression of mutant KEAP1 caused no significant differences (P>0.05). Conclusions: KEAP1 mutation may cause the loss of KEAP1 function, KEAP1mutation may cause tumor genesis and development by changing the oxidative stress of tumor cells. [ABSTRACT FROM AUTHOR]

Objective To analyze the clinical-pathological features of brain metastases of lung adenocarcinoma and detect the expressions of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) in order to guide the targeted drug therapy of patients with advanced lung cancer. Methods A total of 86 cases of brain metastases from non-small cell lung cancer (NSCLC) in Huashan Hospital, Fudan University from January 2013 to December 2016 were selected for pathological analysis by HE staining and immunolabeling, ALK and EGFR expression were detected by immunohistochemical staining. Results Among 86 cases of brain metastases from NSCLC, 74 cases (86.05%) were adenocarcinoma, 3 cases (3.49%) of squamous cell carcinoma, and 9 cases (10.47%) of neuroendocrine tumors. Among the 74 brain metastases from lung adenocarcinoma, there were 44 cases (59.46%) of solid type, 9 cases (12.16%) of acinar type, 14 cases (18.42%) of papillary type and 7 cases (9.46%) of micropapillary type, which were significantly different from the pathological subtypes of primary lung adenocarcinoma reported in the literature (χ² = 97.858, P = 0.000). The expression rate of ALK protein was 9.46% (7/74), the expression rates were not statistically significant in different pathological types (χ² = 1.690, P = 0.639). The expression rate of EGFR non-mutant protein was 52.70% (39/74), and the expression rates were statistically significant in different pathological types (χ² = 7.938, P = 0.047). Fourteen cases (18.92%, 14/74) showed positive staining by specific mutation antibody of exon 19 of EGFR gene, while 12 cases (16.22%, 12/74) having exon 21 of EGFR gene mutation, and the total positive rate was 33.78% (25/74), the expression rates were not statistically significant in different pathological types (χ² = 1.721, P = 0.632). The expression levels of ALK and EGFR in brain metastases from lung adenocarcinoma were mutually exclusive (χ² = 12.462, P = 0.001). Conclusions Among lung adenocarcinoma, the solid lung type and the micropapillary type have higher tendencies of brain metastasis. The expression rates of ALK and EGFR in brain metastases were consistent with those of primary lung adenocarcinoma, and their expression was mutually exclusive. [ABSTRACT FROM AUTHOR]

Summary: Anaplastic lymphoma kinase (ALK) rearrangement is identified in approximately 3-7% of all metastatic non-small cell lung cancer (NSCLC) patients, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of lung cancer cases. Purpose: This study aims to show alectinib (TKI) effectiveness and safety with focus on alectinib intracranial efficacy for ALK+ NSCLC patients. Case presentation: Patient 1 was a 46-year-old woman diagnosed with non-small cell lung cancer with an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (ALK+). She presented with intracranial and liver metastases and poor performance status of ECOG 3. Alectinib was initiated as a second line therapy, after whole brain irradiation and discontinuation of first line chemotherapy after two cycles, due to the central nervous system progression and liver metastases. Good response was consequently achieved, characterized with improved overall performance and without significant adverse events. Patient 2 was a 53-year old man with left sided lung adenocarcinoma surgically treated in 2017. Post-operative pTNM stage was IIB with a positive resection margin- R1. He received adjuvant chemotherapy and radiotherapy. In 2019, after two and half years of being disease free, he presented with severe cerebral symptoms leading to poor performance status. CT scan of the brain showed multiple brain metastases. He was treated with first line alectinib after completion of whole brain radiotherapy. In 5 months period he got significantly better and able for work again. Conclusions: We recommend alectinib as a first and second line treatment approach for ALK+ NSCLC patients, in particular the ones with brain metastases at the time of diagnosis and poor PS. [ABSTRACT FROM AUTHOR]

Background and objective Leptomeningeal metastasis (LM) are a severe complication of non-small cell lung cancer (NSCLC), and normally accompanied by poor prognosis. For the patients with targetable mutations, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment, but the acquired TKI resistance is inextricable. The aim of this study is to analyze the different gene mutation spectrum and mutation frequency of the cerebrospinal fluid (CSF) and plasma in NSCLC patients with LM, and screen out the drug-resistant mutations so as to guide the choice of treatment accurately. Methods The paired CSF and plasma samples were collected from the NSCLC-LM patients with acquired TKI resistance. Next generation sequencing (NGS) was used to detect the gene variations of circulating tumor DNA (ctDNA). Results A total of 18 NSCLC patients with LM were collected. Of the basic mutations, 11 cases (61.11%) were EGFR, 6 cases (33.33%) were anaplastic lymphoma kinase (ALK), and 1 case (5.56%) was ROS proto-oncogene 1, receptor tyrosine kinase (ROS1). Tumor protein p53 gene (TP53) and mesenchymal-epithelial transition factor (MET) were the two most frequently accompanying mutated genes in CSF ctDNA. The detected mutation rate of CSF samples was higher than that of plasma samples (100.00% vs 66.67%, P=0.006), and the maximum allelic fractions were all higher in CSF than in plasma (P<0.001). Abundant single-nucleotide variations (SNV) and copy number variants (CNV) were detected in CSF, the amount of both of which were more than in blood. In addition, the CSF and plasma samples of patients treated with several TKIs had more SNV mutations than patients who received only a single TKI treatment. Conclusion For the patients of NSCLC, ctDNA in CSF could reveal genomic alterations of LM more exactly and overally than it in plasma, thus could be an optimal source of liquid biopsy for guiding therapy, monitoring therapeutic effect, and predicting prognosis. [ABSTRACT FROM AUTHOR]

Patients with sensitive epidermal growth factor receptor (EGFR) mutations often respond to tyrosine kinase inhibitors (TKIs), but acquired resistance will eventually develop. The most common mechanisms of acquired resistance include secondary EGFR mutation, MET amplification, and histologic transformation. Besides, gene fusions could also mediate the process of acquired resistance. Various gene fusions including rearranged during transfection (RET), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and anaplastic lymphoma kinase (ALK) could take place after TKIs resistance, the incidence of which is around 1%. The clinical cases and experiments both in vitro and in vivo have proved the role of gene fusions in EGFR-TKI resistance. The combination of EGFR inhibitors and gene fusion inhibitors might be an effective therapeutic method. The understanding of gene fusions at EGFR-TKI resistance may contribute to the subsequent diagnosis and treatment strategy. [ABSTRACT FROM AUTHOR]

Background and objective Occurrence at a younger age has been demonstrated to be associated with a distinct biology in non-small cell lung cancer. However, genomics and clinical characteristics among younger patients with lung adenocarcinoma remain to be determined. Here we studied the potentially targetable genetic alterations by next-generation sequencing (NGS) assay in young Chinese patients with lung adenocarcinoma. Methods Eighty-nine surgically resected lung adenocarcinoma tissue samples from patients aged less than 45 years were collected with informed consent from all patients. Targeted NGS assays were used to identify actionable genetic alterations in the cancer tissues. Additionally, the genomic and clinical pathologic characteristics of 95 patients with lung adenocarcinoma who received NGS testing over the same period were analyzed retrospectively. Results The frequencies of targetable genetic alterations in 184 patients with lung adenocarcinoma were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 45 years. Notably, higher frequency of anaplastic lymphoma kinase (ALK) and human epidermal growth factor receptor 2 (HER2) genetic alterations were associated with young age. However, a reverse trend was observed for kirsten rat sarcoma viral oncogene (K^AS), serine/threonine kinase 11 (STK11) and epidermal growth factor receptor (EGFR) exon 20 mutations, which were more frequently identified in the older group, aged more than 45 years. Furthermore, concurrent EGFR/tumor protein p53 (TP53) mutations were much more prevalent in the younger patients (81.6% vs 44.9%), which might have a poor response to treatment with EGFR-tyrosine kinase inhibitor (EGFR-TKI). Conclusion NGS assay revealed a distinctive genetic profile in younger patients with adenocarcinoma. High frequency of concurrent EGFR/TP53 mutations was found in the younger patients, which especially warranted personalized treatment in this population. [ABSTRACT FROM AUTHOR]

Background and objective Non-small cell lung cancer (NSCLC) has been transformed from the treatment according to histological type to genotype treatment model. The epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes are the most important drivers in lung cancer. The aim of this study is to explore the clinical characteristics and prognostic factors of patients with advanced NSCLC with different genotypes. Methods We retrospectively reviewed the clinical data of 553 advanced NSCLC patients with EGFR mutations and ALK positive who were hospitalized in the Beijing Chest Hospital from July 2004 to December 2015, and the independent prognostic factors of patients were analyzed by Cox proportional hazards regression model. Results The clinical data of 553 patients (227 with EGFR mutations, 58 with ALK positive, 2 with EGFR and ALK co-mutation and 266 with wild-type) with advanced NSCLC were enrolled in this study. The median survival time of 227 patients with EGFR mutations was 28.7 mo (95%CI: 22.160-35.240), and the performance status (PS) score (0-1) (HR=4.451; 95%CI: 2.112-9.382; P

Background and objective Anaplastic lymphoma kinase (ALK) positive in non-small cell lung cancer (NSCLC) was about 5%-7% and ALK tyrosine kinase inhibitor (TKI) was the standard treatment in NSCLC. The aim of this study is to evaluate the efficacy and safety of crizotinib in patients with advanced ALK gene-positive or recurrent NSCLC. Methods Three methods were used to screen patients with advanced or recurrent NSCLC harboring ALK gene fusion/translocation. The patients with ALK positive tested by flourescence in situ hybridization (FISH) was given orally crizotinib, 250 mg, bid. The objective response rate (ORR), progression-free survival (PFS) and safety were evaluated. Results A total of 226 patients were screened, 39 of whom had ALK fusion or translocation, and 37 were enrolled in the study. 35 patients were evaluated for objective response, ORR was 70.3%, and disease control rate (DCR) was 94.6%, and median PFS was 11.8 mon. The main adverse reactions were elevated transaminase (Grade 1, 91.7%), elevated transaminases (Grade 2, 23.4%), nausea (Grade 1, 75.6%), anemia (Grade 1-2, 62.3%), visual impairment (Grade 1, 21.8%), weight loss (Grade 1, 31.4%), pneumonia (Grade 2, 3.5%). Conclusion Crizotinib can be used for the treatment of advanced NSCLC with ALK fusion/translocation. It is highly effective and well tolerated. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationships of the expression of epidermal growth factor receptor (EGFR) , echinoderm microtubule associated protein like 4 ( EML4) -anaplastic lymphoma kinase ( ALK) , and vascular endothelial growth factor ( VEGF) protein in pleural effusion with gender, age and smoking in patients with lung adenocarcinoma. Methods Ninety-two patients with advanced lung adenocarcinoma with pleural effusion verified by pathology were selected, and we detected the expression of EGHR , ALK, VEGF by immunohistochemical Eli Vision method, recorded the positive rates of EGFR, ALK and VEGF protein expression, and then analyzed the difference in the positive expression of each protein in patients with different gender, age and smoking. Results The positive expression rates of EGFR, ALK and VEGF in lung adenocarcinoma patients with pleural effusion were 47. 83% , 15. 22% , and 40. 22% respectively. The positive expression rates of EGFR protein in female (61.22% ) and non-smokers (61. 11% ) was higher than that in male (32. 56% ) and smokers (28. 95% ) ( all P <0. 05 ). The positive expression rate of ALK protein in young patients ( < 60 years old, 23.81% ) with lung adenocarcinoma and pleural effusion was higher than that in elderly patients (≥60 years old, 8.00% ) (P <0. 05). The positive expression rate of VEGF was not related to gender, age or smoking (all P > 0.05). Conclusion The positive expression of EGFR and ALK protein in patients with lung adenocarcinoma and pleural effusion is related to gender, age, and smoking. [ABSTRACT FROM AUTHOR]

Background and objective Peritoneal carcinomatosis is a rare clinical event in lung cancer and the prognosis is very poor. There are limited data on what factors predict peritoneal progression and affect the outcome. The aim of this study is to investigate investigate the factors associated with peritoneal carcinomatosis. Methods The patients with non-small cell lung cancer (NSCLC) from the Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital were eligible for retrospective analysis between August 2010 and August 2018. Clinical factors such as age, gender, histology, pleural effusion and gene mutations with epidermal growth factor receptor/anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase (EGFR/ALK/ROS1) were analyzed. Overall survival (OS) was calculated by the Kaplan-Meier method. Results 1.44% (12/836) patients in this study developed peritoneal carcinomatosis and 12 patients with adenocarcinoma had metachronous NSCLC diagnosis and PC. Malignant pleural effusion rates at baseline and at PC diagnosis were separately 50% (6/12) and 100.0% (12/12). Among the 12 patients, 9 patients harbored EGFR/ALK/ROS1 mutation. The outcome of patients with EGFR/ALK/ROS1 mutation was significantly better than that of patients without EGFR/ALK/ROS1 mutation, the mOS1 and mOS2 were separately 26.0 months and 6.0 months versus 10.0 months and 1.5 months (P<0.05). The mOS2 of patients with aggressive treatment after PC diagnosis was 6.0 months, significantly better than 1.0 month of patients with best supportive care (P<0.05). The mOS2 of the patients with angiogenesis inhibitors based-treatment after PC diagnosis was 8.5 months, significantly longer than that of patients with other treatments (P<0.05). Conclusion Adenocarcinoma and malignant pleural effusion are highly associated with peritoneal carcinomatosis in patients with advanced NSCLC. Aggressive treatment for lung cancer with PC is encouraged when possible. More patients with PC may benefit from the treatment strategies with angiogenesis inhibitors. Further prospective trials are urgently needed. [ABSTRACT FROM AUTHOR]

Background and objective Crizotinib was developed in recent years based on targets of anaplastic lymphoma kinase (ALK) fusion genes. The aim of this study is to explore the efficacy of crizotinib in treatment of non-small cell lung cancer (NSCLC) with ALK/ROS1 rearrangement. Methods Retrospective analysis of 40 patients with ALK/ROS1-positive NSCLC, who received treatment in Beijing Cancer Hospital during the period from Jun. 2013 to Dec. 2014. Results Among these cases, 39 were adenocarcinoma and adenosquamous carcinoma, with characters involving signet-ring cell carcinoma, polypoid adenocarcinoma, acini and papillary adenocarcinoma. The median age was 49.5 years old, with the overall response rate of 62.5% and disease control rate of 95.0%. Of all the cases, median follow-up was 14.6 months and median PFS 7.5 months; median OS has not been reached; the one-year survival rate was 77.4%. The median PFS and OS of patients receiving first and second-line treatment tend to be longer than those who received post-second line treatment, but with no statistical significance (PFS: 9 mo vs 6 mo, P=0.06; OS: 21.5 mo vs 14.6 mo, P=0.12). Twenty patients who experienced progression in brain metastases. After experiencing progression, the patients receiving 2nd/3rd generation ALK-TKI treatment showed efficacy of disease control and survival. The adverse events include gastrointestinal reaction, transaminase elevation, and distinctive visual abnormalities, etc. Conclusion The clinical features, efficacy, and adverse events of crizotinib in the treatment of the 40 patients with ALK/ROS1-positive NSCLC are similar to the data from the previous reports. The most common site of progression was brain metastases. The treatment of crizotinib-resistant patients using 2nd/3rd generation ALK-TKI could delay progression.

The anaplastic lymphoma kinase (ALK) gene rearrangement is a driver gene of non-small cell lung cancer (NSCLC). Positive expression of ALK gene rearrangement has been considered a molecular subtype of NSCLC, that there are special pathological characteristics and clinical prognosis. Furthermore, the tyrosine kinase inhibitor has demonstrated high effective in treating ALK positive NSCLC patients. Thus making molecular diagnostic testing for ALK expression is an important step in the process of pathological diagnosis. Currently, many detecting ALK expression assays are available or in development, clinical pathologists focus on how to choose the best method for routine diagnosis of lung cancer. There are many domestic and international authoritative guidelines recommend ALK detecting assays, technological process and relative standard. In the current review, we summarize the diagnostic tests available and the special sample types that could be used to identify patients with ALK-positive NSCLC.

Lung cancer is the common lethal disease with the highest morbidity and mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Recently, the advances in the molecular biology have transformed our view of NSCLC from histopathological descriptions to precise molecular and genetic identities that can be resolved to single-cell level. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the most crucial tumor driver genes in NSCLC. Their tyrosine kinase inhibitors (TKIs) can significantly improve survival of these patients, who have these driver genes’ mutation. Unfortunately, drug resistance would inevitably occur after almost all of initial targeted therapy. The resistance mechanism and corresponding methods on EGFR-TKIs have been reviewed elsewhere and will not be discussed. We will focus on the mechanism of first generation ALK TKI (crizotinib) resistance in patients with ALK positive NSCLC. Likewise, we will also discuss the current therapies for ALK positive NSCLC patients after crizotinib resistance.

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in multiple malignancies, including non-small cell lung cancer (NSCLC). ROS1 rearrangement defines a new molecular subset of NSCLC with the prevalence of ROS1 rearrangements around 1%-2%. ROS1-positive NSCLCs arise in young never-smokers with adenocarcinoma that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib demonstrates in vitro activity and early clinical trial shows marked antitumor activity in ROS1-rearranged patients. The overall response rate is around 56% and the disease control rate at 8 weeks is about 76%. Further understanding the ROS1 fusions in the pathogenesis of NSCLC, methods to detect ROS1 rearrangements, and targeting ROS1-rearranged NSCLC patients with specific kinase inhibitors would lead to an era of personalized medicine.

In recent years, with the deepening of the research of molecular biology, targeted therapy has become one of the trend of lung cancer treatment. The individualized treatment of lung cancer is attached great importance at present. Echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase (EML4-ALK) as a new biological marker is a hot topic in the field of lung cancer treatment. Meanwhile, with the improvement of anticancer treatment and survival, the incidence of multiple primary carcinomas (MPC) has become increasingly. But the report that malignant lymphoma complicated with lung adenocarcinoma harboring EML4-ALK fusion gene in one individual is rare. Here, we report an EML4-ALK positive non-small cell lung cancer (NSCLC) in a patient previously diagnosed with T cell lymphoma and review literature on metachronous lung cancer complicating with lymphoma.

Objective To explore the synergistic effect of silibinin combined with crizotinib on anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) cells and its mechanism. Methods H2228 and H3122 cells were treated with silibinin, crizotinib alone or in combination. Cell proliferation was measured by 3-( 4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay. Migration or invasion ability was tested by wound healing assay or transwell assay, respectively. Expressions of E-Cadherin and vimentin protein were examined by immunofluorescence staining. The protein expressions of ALK, p-ALK, E-Cadherin and Vimentin were detected by western blotting.The anti-cancer effect of silibinin combined with crizotinib in vivo was determined by subcutaneously injecting 2xl06 H2228 cells into immunodeficient nude mice. Results The result of MIT assay showed that the cell viability of H2228 or H3122 treated with 100 μmolpL silihinin was (88.38±4.10)% or (72.27± 3.62)%, respectively, marginally decreased compared with that of the control. The 50% inhibitor)' concentration ( IC50) of H2228 cells treated with erizotinib alone or combined with 100 μmolpL silihinin was (917.10±7.75) nmolpL or (238.73±7.67) nmolpL, respectively. The IC50 of H3122 cells treated with erizotinib alone or combined with 100 μmolpL silihinin was (472.50± 15.70) nmolpL or (206.10± 12.01) nmolpL, respectively. The IC50 of H2228 and H3122 cells were significantly decreased by combined treatment of erizotinib and silihinin compared to erizotinib treatment alone (PcO.Ol). When compared with the control group, colony forming ratios of H2228 cells were (83.34± 2.72) % in 100 μmolpL silihinin treatment group, ( 69.42± 3.06)% in 400 nmolpL erizotinib treatment group and (27.32 ± 1.42)% in combined treatment group. When compared with the control group, colony forming ratios of H3122 cells were (84.45±5.67)% in 100 μmolpL silihinin treatment group, (45.02±5.83)% in 400 nmolpL erizotinib treatment group and (17.43 ± 3.83) % in combined treatment group. Silihinin combined with erizotinib treatment significantly inhibited the colony formation ability of H2228 and H3122 cells (P<0.01) .Migration and invasion results showed that combined treatment of erizotinib and silihinin markedly inhibited the migration and invasion ability of H2228 cells (P<0.01). Western blot results indicated that treated with silihinin alone or in combination of erozitinib for 48 hours, the protein level of E-cadherin in H2228 cells was upregulated, while the expressions of p-ALK and vimentin were downregulated, without obvious alteration of ALK protein expression. In the xenograft model, the mean tumor weight was (9.40±2.58) g in erizotinib treatment group and (4.58±1.07)g in the combined treatment group. The inhibitory effect of tumor growth in vivo of combined treatment was significantly superior to that of erizotinib treatment alone (P<0.05). Conclusion Silihinin enhances the inhibitor)' effect of erizotinib on ALK positive NSCLC cells, which may be associated with suppression of ALK activity and mesenchymal-epithelial transition. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinicpathological characteristics of ALK-positive anaplastic large cell lymphoma (ALCL) of the gastrointestinal tract, and to discuss its diagnosis and differential diagnosis. Methods: Five cases of gastrointestinal ALK-positive ALCL diagnosed and treated in Xijing Hospital of the Fourth Military Medical University, between 2011 and 2019 were collected. There were three male and two female patients, aged 5-42 years (mean 25 years). These patients clinically presented with fever and night sweats, weight loss, abdominal pain, abdominal mass, ulcers, bleeding, or intestinal obstruction, and underwent surgical resection of the tumors or endoscopic biopsy. The clinical manifestations, auxiliary examinations, histopathological characteristics, immunophenotypes and genetic alterations were analyzed. Results: In this cohort, one case was common type, two cases were monomorphic variant of common type, and two cases were small cell variant. The tumor cells in all cases expressed ALK, CD30, and one or more T lymphocyte markers, while all the markers of B lymphocyte and plasmacyte were negative. Clonality analysis showed that two cases had clonal T cell receptor (TCR) and immunoglobulin (Ig) gene rearrangement, one case had no clonal TCR but Ig gene rearrangement, and one case had no clonal TCR and Ig gene rearrangements. During the 4 to 67 months' follow-up, two patients died of the disease, two were alive with free of disease and one had a relapse. Conclusions: ALK-positive ALCL of the gastrointestinal tract is extremely rare, and has poor prognosis. Lymphoma originating from this site with CD30 and ALK-positive phenotypes may be considered to be ALCL; however differentiation from other tumors that had anaplastic features, expressed CD30 and or ALK, in particular, ALK positive large B-cell lymphoma is necessary.

Objective To investigate the clinical application value of combined detection of ALK fusion gene and c-ros oncogene 1 receptor tyrosine kinase (ROS1) fusion gene in non-small cell lung cancer (NSCLC) using real-time fluorescent PCR. Methods A kit for combined detection of ALK fusion gene and ROS1 fusion gene based on fluorescent PCR was used to simultaneously detect the two fusion genes in 302 cases of NSCLC specimens. The results were validated through Sanger sequencing. The consistency of the two detection methods was analyzed. Results All 302 cases of NSCLC specimens were successfully analyzed through fluorescent PCR (302/302). 12 cases (4.0%) were found to contain ALK fusion gene，including 3 cases with ALK-M1，3 with ALK-M2，3 with ALK-M3，1 with ALK-M4，and 2 with ALK-M6 fusion gene. 12 cases (4.0%) were found to contain ROS1 fusion gene，including 1 case with ROS1-M7，8 cases with ROS1-M8，1 case with ROS1-M12，1 case with ROS1-M14，and 1 case with double-positive ROS1-M3 and ROS1-M8 fusion genes. The total detection rate of ALK fusion gene and ROS1 fusion gene was 7. 9% (24/302) and 278 cases showed to be negative for ALK fusion gene and ROS1 fusion gene. The successful detection rates for Sanger DNA sequencing were also 100%. The positive， negative and total coincidence rates obtained by real-time fluorescent PCR and by Sanger DNA sequencing were all 100%. Conclusions The results of Sanger DNA sequencing demonstrate that the real-time fluorescent PCR assay is equally effective in detecting ALK and ROS1 fusion genes in NSCLC tissues. Furthermore，real-time fluorescent PCR assay can be used to detect trace ALK and ROS1 fusion gene simultaneously in tiny samples, and can save time and avoid repeated sampling. It is worthy of recommendation as a rapid and reliable detection technique. [ABSTRACT FROM AUTHOR]

Background and objective It has been proven that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS are common driver genes in non-small cell lung cancer (NSCLC). Molecular targeted therapy increases the overall response rate and progression-free survival (PFS) of patients with EGFR-sensitive mutation or echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. However, target and targeted drugs for lung squamous cell carcinoma to indicate clinical therapy remain to be confirmed. The aim of this study was to analyze the relationship between the status of driver genes and the clinicopathologic characteristics of NSCLC. Methods A total of 90 patients were recruited and tested for EGFR, ALK and KRAS mutations. The status of EGFR and KRAS was tested by amplification refractory mutation system, and the status of ALK was tested by fluorescence in situ hybridization. Results Of the 90 patients, 8 patients had EGFR mutation (8.8%), and 2 cases had KRAS mutation (2.2%). EML4-ALK fusion was found in 1 of 18 patients (5.6%). EGFR mutation occurred more frequently in females than in males (P=0.022). Significant differences were observed in pathological stage (P=0.042) and differentiation grade (P=0.003). No significant difference in PFS was observed between EGFR-TKI treatment and chemotherapy in EGFR mutation patients with squamous cell carcinoma of the lung (P=0.607). Patients with EML4-ALK fusion could benefit from targeted therapy. Conclusion EML4-ALK fusion occurred more frequently than EGFR and KRAS mutations in patients with lung squamous cell carcinoma. Clinicopathologic characteristics were different between EGFR mutation and EGFR wild-type patients. The relationship between molecular targeted therapy and status of EGFR or ALK genes in patients with lung squamous cell carcinoma needs further investigation.

It was only 3 years ago that the fusion gene between echinoderm microtubule-associated protein-like4 (EML4) and anaplastic lymphoma kinase (ALK) has been identified in a subset of non-small cell lung cancer (NSCLC). EML4-ALK is most often detected in never smokers with lung adenocarcinoma and has unique pathologic features. EML4-ALK fusion gene is oncogenic, which could be suppressed by ALK-inhibitor through blocking the downstream signaling passway of EML4-ALK. This review will focus on the molecular structure, function, biology, detection method and the diagnostic and therapeutic meaning of EML4-ALK of lung cancer.