Lung cancer is the most common cancer in China and even in the world, and it is also the main cause of cancer death. Patients with anaplastic lymphoma kinase (ALK) gene alterations have the opportunity to receive molecularly targeted therapies. The inhibitors of anaplastic lymphoma kinase, such as ALK-tyrosine kinase inhibitors (ALK-TKIs) significantly prolong the survival of patients. ALK gene variant types include point mutation, amplification, fusion/rearrangement, and ALK fusion is more common than other types. However, the effect of different types of gene changes in molecular targeted therapy is different. Therefore, this paper introduced the relevant contents of different variants of ALK gene, focused on the research progress of targeted therapy, and proposed the future development direction.
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Humans ; Lung Neoplasms/pathology* ; Anaplastic Lymphoma Kinase ; Molecular Targeted Therapy ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors* ; Protein Kinase Inhibitors/therapeutic use*

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic tumor originated from hematopoietic stem cells. FLT3 is an important receptor tyrosine kinase in cell signal transduction pathway and one of the common mutated genes in AML. AML patients with FLT3-ITD mutation have a poor prognosis and tendency to relapse. Therefore, early identification of FLT3 gene mutation and selection of appropriate treatment are particularly important. Currently, the small moleculetargeted drugs have been new treatment methods for AML patients with FLT3-ITD mutation, but accompanied drug resistance need to be solved. This paper reviews the mechanism of FLT3 mutation, the clinical significance of FLT3 mutation in AML, FLT3 inhibitors and drug resistance mechanism.
Humans ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Signal Transduction ; Receptor Protein-Tyrosine Kinases/therapeutic use* ; Leukemia, Myeloid, Acute/drug therapy* ; fms-Like Tyrosine Kinase 3/genetics*

OBJECTIVE: To evaluate the clinical characteristics, treatment and prognosis of systemic anaplastic large cell lymphoma(sALCL). METHODS: The clinical data of 90 cases with sALCL treated in the Department of Hematology of the Affiliated Xijing Hospital of Air Force Medical University from November 2018 to October 2021 were retrospectively analyzed. The clinical features, treatment and prognosis were summarized and the prognostic factors were investigated. RESULTS: There were 58 males and 32 females, with a median age of 32 (12-73) years old. 69 (76.7%) patients had Ann Arbor stage Ⅲ-Ⅳ disease and half of the patients had extranodal infiltration. The median age was 27(12-72) years of the 60 ALK⁺ patients while 53(15-73) years of the 30 ALK^- patients, and it was significantly different in the age of onset between the two group(P<0.01). 88 patients received first line chemotherapy, and 50(568%) cases achieved complete remission(CR). IPI score≥3 was an independent risk factor for CR. The median progressive free survival(PFS) and overall survival(OS) of the patients were not reached. Multivariate analysis showed that no achievement of CR after first-line therapy was a significant prognostic factor influencing PFS and OS. CONCLUSION sALCL mainly occurs in males and most patients were in advanced stage. Half of the patients had extranodal involvement. The CR rate after first-line chemotherapy was 568%, and IPI score≥3 was a significant prognostic factor for CR. No achievement of CR after first-line therapy is poorly prognostic for PFS and OS.
Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child ; Disease-Free Survival ; Female ; Humans ; Lymphoma, Large-Cell, Anaplastic/diagnosis* ; Male ; Middle Aged ; Prognosis ; Receptor Protein-Tyrosine Kinases ; Retrospective Studies ; Young Adult

PURPOSE: Molecular testing in non-small cell lung cancer (NSCLC) aids in identifying oncogenic alterations. The aim of this study was to compare the rates of detection of oncogenic alterations and responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) according to EGFR mutation status as determined by peptide nucleic acid (PNA) clamping or direct sequencing (DS). MATERIALS AND METHODS: We performed a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register. Data from included studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and receiver operating characteristic curves. A meta-regression analysis was conducted to identify potential sources of heterogeneity between selected studies. RESULTS: We identified 10 studies comprising 924 patients. Oncogenic alterations were detected in 340 of 924 cases (36.8%) with PNA clamping and in 250 of 924 (27.1%) with DS. The pooled sensitivities of PNA clamping and DS were 0.93 [95% confidence interval (CI): 0.90−0.95] and 0.69 (95% CI: 0.64−0.73), respectively. According to meta-regression analysis, none of the covariates were found to be significant sources of heterogeneity. With respect to treatment responses to EGFR-TKIs, there was no significant difference therein between EGFR mutations detected by PNA clamping and DS (53.4% vs. 50.8%; risk ratio, 0.99; 95% CI 0.83−1.19; p=0.874). CONCLUSION: We demonstrated that PNA clamping has a higher sensitivity than DS for detecting oncogenic alterations in NSCLC. Our findings suggest that PNA clamping is a more useful method for clinical practice.
Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics ; Constriction ; Humans ; Lung Neoplasms/*genetics ; Molecular Diagnostic Techniques ; Mutation ; Peptide Nucleic Acids/*genetics ; Protein Kinase Inhibitors/*therapeutic use ; Receptor Protein-Tyrosine Kinases/*genetics ; Receptor, Epidermal Growth Factor/*genetics ; Sensitivity and Specificity ; Sequence Analysis ; Sequence Analysis, DNA ; Translocation, Genetic

PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.
Adult ; Aged ; Antineoplastic Agents/*therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/mortality ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms/*drug therapy/enzymology/mortality ; Male ; Middle Aged ; Mutation ; Pemetrexed/*therapeutic use ; Receptor Protein-Tyrosine Kinases/genetics ; Retrospective Studies ; Survival Rate ; Treatment Outcome

The incidence of ALK gene rearrangement in non-small cell lung cancer (NSCLC) was about 3% to 5%. ALK gene inhibitors have made great breakthrough in recent years, significantly extending the survival period of patients with ALK(+) advanced NSCLC. But the majority of patients will be acquired drug resistance after treatment. This article has been explained separately from the ALK genetic background, the detection method, the treatment of the three generations of ALK inhibitors and the strategy after drug resistance. It is desire to have reference value and reference meaning for clinical work.
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Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; Drug Resistance, Neoplasm ; genetics ; Gene Fusion ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; genetics

OBJECTIVEThis study aims to evaluate the efficacy and safety of crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) patients.

METHODSTwenty-eight patients with advanced ALK-positive NSCLC were given orally crizotinib 250 mg b. i.d., and were followed up to evaluate the therapeutic efficacy and safety.

RESULTSAmong the 28 patients, the objective response rate (ORR) was 71.4% (20/28) and disease control rate (DCR) was 92.9% (26/28). Three patients achieved complete response. Seventeen patients had partial response. The most common drug-related adverse events were mild flickering vision and gastrointestinal reaction. Eleven patients experienced flickering vision. Nine patients had nausea and vomiting. Eight patients had diarrhea. They were all reversible and of grade I or II. Only one patient had grade III myelosuppression. Among the 28 patients, 16 cases were disease-free and 12 cases had progressive disease, with a progression-free survival of 8.2 months.

CONCLUSIONSCrizotinib is effective and tolerable in the treatment of advanced ALK-positive NSLCC. However, its long-term treatment efficacy requires to be further studied.

Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; pathology ; Diarrhea ; chemically induced ; Disease-Free Survival ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; pathology ; Nausea ; chemically induced ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrazoles ; adverse effects ; therapeutic use ; Pyridines ; adverse effects ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; Vomiting ; chemically induced

To explore the automated immunostainer screening anaplastic lymphoma kinase (ALK) gene fusion non-small cell lung cancer (NSCLC) and clinicopathological characteristics of the molecular subtype lung cancers. Methods Five hundred and sixty-six cases of NSCLC were collected over a 16 month period. The test for ALK was performed by Ventana automated immunostainer with anti-ALK D5F3. The histological features, treatment and outcome of patients were assessed. Results Thirty-eight cases (6.7%, 38/566) of NSCLC showed ALK gene fusion. The frequency of ALK gene fusion was higher in male (7.1%, 25/350) than that in female (6.0%, 13/216) patients, but not achieving statistical significance (chi2 = 0.270, P = 0.604). ALK + NSCLC was more significantly more frequent in patients < or = 60 years (9.9%, 28/282) than >60 years (3.5% , 10/284) of age. Histologically, the ALK + NSCLCs were mostly adenocarcinoma (81.6%, 31/38) , among which eighteen cases were solid predominant subtype with mucin production; nine cases were acinar predominant subtype; one case was papillary predominant subtype and three cases were invasive mucinous adenocarcinoma. The ALK + non-adenocarcinoma included three cases of squamous cell carcinoma, three cases of adenosquamous carcinoma and one case of pleomorphic carcinoma. Among the ALK + NSCLC patients, the number of non/light cigarette smokers (86. 8% , 33/38) was more than that of heavy smokers. Twenty-nine cases were stages III and IV; twenty-nine cases showed lymph node metastasis; twenty cases showed metastases mostly to brain and bone; and one case showed EGFR gene mutation coexisting with ALK gene fusion. Twelve of fifteen patients received crizotinib therapy and remained stable. Conclusions NSCLC with ALK gene rearrangement shows distinctive clinical and histological features. Ventana-IHC may he a feasible and valid technique for detection of ALK rearrangement in NSCLC.
Adenocarcinoma ; genetics ; pathology ; Carcinoma, Adenosquamous ; genetics ; pathology ; Carcinoma, Non-Small-Cell Lung ; genetics ; pathology ; Carcinoma, Squamous Cell ; genetics ; pathology ; Female ; Gene Fusion ; Gene Rearrangement ; Humans ; Lung Neoplasms ; genetics ; pathology ; Male ; Middle Aged ; Protein Kinase Inhibitors ; therapeutic use ; Pyrazoles ; therapeutic use ; Pyridines ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; genetics ; Sex Factors

For patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the relationship between the dose or duration of treatment with tyrosine kinase inhibitor (TKI) and overall survival remains unclear. Here, we analyzed clinical data of 39 patients who were diagnosed with EGFR mutation-positive non-small cell lung cancer and treated with TKI, but subsequently died. Several parameters were measured in this study: overall survival; first, second, and overall TKI therapy durations; first TKI intensity (actual dose/normal dose); and TKI rate (overall TKI therapy duration/overall survival). The response rate to TKI therapy was 50%, and the median survival was 553 days. After TKI therapy failed, 38.5% patients were re-challenged with TKI. We observed a moderate relationship [r = 0.534, 95% confidential interval (CI) = 0.263 to 0.727, P < 0.001] between overall TKI therapy duration and overall survival. However, we found no relationship between overall survival and first TKI intensity (r = 0.073, 95% CI = -0.380 to 0.247, P = 0.657) or TKI rate (r = 0.0345, 95% CI = -0.284 to 0.346, P = 0.835). Non-small cell lung cancer patients with mutation-positive tumors remained on TKI therapy for, on average, 33% of the overall survival time. These findings suggest that patients with EGFR mutation-positive tumors should not stick to using TKIs.
Aged ; Aged, 80 and over ; Antineoplastic Agents ; administration & dosage ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Dose-Response Relationship, Drug ; Erlotinib Hydrochloride ; Female ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; Male ; Middle Aged ; Mutation ; Protein Kinase Inhibitors ; administration & dosage ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Quinazolines ; administration & dosage ; therapeutic use ; Receptor, Epidermal Growth Factor ; genetics ; Survival Rate

A 31-year-old Korean male presented with altered consciousness and severe headache. Brain MRI delineated focal leptomeningeal enhancement without any intracerebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for anaplastic lymphoma kinase (ALK) and an absence of involvement in any other organs; specifically, the primary central nervous system ALK+ALCL. Complete remission was achieved following 5 cycles of systemic chemotherapy with a high dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemotherapy. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rarity and non-specific symptoms along with non-pathognomonic radiologic findings. We present the first case of primary leptomeningeal ALK-positive ALCL where the clinical course, pathologic characteristics and treatment modality are described as well as a review of literature.
Adult ; Antineoplastic Agents/therapeutic use ; Biopsy ; Brain/metabolism/pathology ; Diagnosis, Differential ; Humans ; Immunohistochemistry ; Lymphoma, Large-Cell, Anaplastic/*diagnosis/drug therapy/pathology ; Male ; Meningeal Neoplasms/*diagnosis/drug therapy/pathology ; Receptor Protein-Tyrosine Kinases/*metabolism