Pulmonary Spindle Cell Carcinoma Presenting Anaplastic Lymphoma Kinase Rearrangement
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SUBMITTER: Sonehara K
PROVIDER: S-EPMC10601751 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Renal cell carcinoma (RCC) with anaplastic lymphoma kinase (ALK) rearrangement is rare, and the genetic profiles of the tumor have not been elucidated. Here, we report a case with recurrent papillary RCC and lung metastasis after nephrectomy for nearly 7 years. The patient first received sunitinib, whereas the drug toxicity was intolerable. Combined Immunohistology (IHC) and fluorescence in situ hybridization (FISH) revealed the patient has an ALK rearrangement, and the patient then was treated with crizotinib. The patient had good tolerance, and a partial response in the target lesions was achieved. In order to further understand the benefit of crizotinib in ALK-rearranged RCC, the patient was detected with whole exome sequencing (WES) to study her genetic profiles. Compared those of RCC cases without ALK rearrangement (nALK-RCC), the patient and nine RCC cases with ALK rearrangement (ALK-RCC) revealed unique genetic characteristics: 1) The common mutations that occurred in RCC were not found in ALK-RCC.; 2) A total of 11 co-existing mutations in ALK-RCC were found, and they occurred in nALK-RCC at a relatively low frequency. DNMT3A mutations were concurrent with ALK fusions in our case. These findings indicated a different genetic alteration pattern of ALK-RCC from nALK-RCC. Our case demonstrated the efficacy of crizotinib in an RCC patient with ALK rearrangement.
| S-EPMC7807375 | biostudies-literature
Project description:BackgroundIt has not been determined if adjuvant chemotherapy would be helpful for completely resected early-stage lung adenocarcinoma even with unfavorable genetic markers. As the positive anaplastic lymphoma kinase (ALK) rearrangement is associated with aggressive clinical feature in lung adenocarcinoma, we evaluated the treatment outcomes of completely resected stage IA lung adenocarcinoma according to initial ALK status.MethodsThis is a retrospective cohort study including 309 patients with surgically resected stage IA lung adenocarcinoma from February 2010 to December 2013. Patients were screened for ALK rearrangement using immunohistochemistry. A positive ALK status was defined as an immunohistochemistry score of 2+ or more. Both disease-free survival (DFS) and the initial recurrence pattern were analyzed according to ALK status.ResultsTwenty-three (7.4%) patients had ALK-positive adenocarcinoma. During the median follow-up of 35.8 months, recurrence developed in 34 (11.0%) patients. The patients with ALK-positive tumor had significantly lower 5-year DFS rate (62.4%) compared to those with ALK-negative tumor (86.5%; P=0.038). The multivariable analysis showed that ALK rearrangement was associated with a higher risk of disease recurrence (adjusted hazard ratio =2.64; 95% confidence interval, 1.08-6.44). In addition, patient with ALK-positive tumor showed more frequent recurrence in regional lymph nodes compared with those with ALK-negative tumor (83.3% vs. 28.6%; P=0.031).ConclusionsIn patients with completely resected stage IA lung adenocarcinoma, ALK rearrangement was associated with unfavorable DFS and more frequent regional lymph node metastasis. Therefore, careful surveillance for recurrence should be performed in this subset of patients.
| S-EPMC6051845 | biostudies-literature
Project description:As one of the most common types of renal cancer, clear cell renal cell carcinoma (ccRCC) in advanced stages constitutes a continued major challenge for uro?oncologists, as the identification of novel driver mutations and the development of novel targeted therapies against them remain an unmet need. Aberrations in anaplastic lymphoma kinase (ALK), a rational therapeutic target, as verified in lung cancer with ALK rearrangement, have been implicated in the pathogenesis of multiple human cancers. In the present study, we screened ALK expression in 87 pathologically defined ccRCCs via immunohistochemistry (IHC) using a newly developed rabbit anti?human ALK monoclonal antibody (clone D5F3). Four patients tested positive for ALK expression, as confirmed by IHC. Among them, 2 patients were further confirmed with fluorescence in situ hybridization (FISH) assay with the use of the Vysis LSI ALK dual color break?apart probe. Furthermore, we detected the existence of the echinoderm microtubule?associated protein?like 4/anaplastic lymphoma kinase (EML4?ALK) (E13:A20, variant 1) fusion gene in tumors from these two patients by using rapid amplification of cDNA ends (RACE)?coupled PCR sequencing and RT?PCR. Notably, we first showed that enforced EML4?ALK expression could significantly promote in vitro proliferation, clonogenic colony formation and apoptosis resistance in HK2 immortalized normal renal tubal epithelial cells and their in vivo outgrowth when injected into immunocompromised nude mice. Importantly, this pro?tumorigenic effect was completely abolished by the ALK?specific inhibitor crizotinib, indicating the potential effectiveness of ALK?specific inhibitors in treating ALK?rearranged ccRCC patients. Our data revealed that ALK fusions exist in adult ccRCC, providing a rationale for ALK inhibitor therapy in selected patients with ccRCC.
| S-EPMC7041106 | biostudies-literature
Project description: Not available
| S-EPMC4559938 | biostudies-literature
Project description:Purpose:To develop a radiogenomics classifier to assess anaplastic lymphoma kinase (ALK) gene rearrangement status in pretreated solid lung adenocarcinoma noninvasively. Materials and Methods:This study consisted of 140 consecutive pretreated solid lung adenocarcinoma patients with complete enhanced CT scans who were tested for both EGFR mutations and ALK status. Pre-contrast CT and standard post-contrast CT radiogenomics machine learning classifiers were designed as two separate classifiers. In each classifier, dataset was randomly split into training and independent testing group on a 7:3 ratio, accordingly subjected to a 5-fold cross-validation. After normalization, best feature subsets were selected by Pearson correlation coefficient (PCC) and analysis of variance (ANOVA) or recursive feature elimination (RFE), whereupon a radiomics classifier was built with support vector machine (SVM). The discriminating performance was assessed with the area under receiver-operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results:In classifier one, 98 cases were selected as training data set, 42 cases as independent testing data set. In classifier two, 87 cases were selected as training data set, 37 cases as independent testing data set. Both classifiers extracted 851 radiomics features. The top 25 pre-contrast features and top 19 post-contrast features were selected to build optimal ALK+ radiogenomics classifiers accordingly. The accuracies, AUCs, sensitivity, specificity, PPV, and NPV of pre-contrast CT classifier were 78.57%, 80.10% (CI: 0.6538-0.9222), 71.43%, 82.14%, 66.67%, and 85.19%, respectively. Those results of standard post-contrast CT classifier were 81.08%, 82.85% (CI: 0.6630-0.9567), 76.92%, 83.33%, 71.43%, and 86.96%. Conclusion:Solid lung adenocarcinoma ALK+ radiogenomics classifier of standard post-contrast CT radiomics biomarkers produced superior performance compared with that of pre-contrast one, suggesting that post-contrast CT radiomics should be recommended in the context of solid lung adenocarcinoma radiogenomics AI. Standard post-contrast CT machine learning radiogenomics classifier could help precisely identify solid adenocarcinoma ALK rearrangement status, which may act as a pragmatic and cost-efficient substitute for traditional invasive ALK status test.
| S-EPMC7371989 | biostudies-literature
Project description:Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients' anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients' immune response.
| S-EPMC5830391 | biostudies-literature
Project description:BackgroundLymphomas originating in bone but not involving visceral or regional lymph nodes are diagnosed as primary bone lymphoma (PBL). Few case reports of anaplastic large-cell lymphoma (ALCL) originating in bone have been reported. The purpose of this report is to describe the difficulty in diagnosing and complete treatment process of this rare type of bone lymphoma.Case descriptionWe describe a case of anaplastic lymphoma kinase positive (ALK+) ALCL patient with primary multiple bone lesions. The patient was initially in the local hospital due to lumbosacral pain and was diagnosed with multiple myeloma. However, after receiving two cycles of bortezomib, lenalidomide and dexamethasone (VRD) chemotherapy, the patient's pain increased. After discussion with the patient and his family, the patient finally agreed to accept the biopsy of the T10 and L2 vertebral bodies and diagnosed as ALK+ ALCL stage IV with primary bone involvement. After receiving multiple cycles of chemotherapy, local bone radiotherapy and denosumab treatment, the patient's bone pain and osteolytic lesions were improved. Regular follow-up shows that the patient's bone pain has been controlled and he is generally in good condition.ConclusionsALK+ ALCL originating primarily in the bone may be easily misdiagnosed and hence require appropriate evaluation in the upfront setting. In consideration of the lack of relevant experience due to the rarity of the disease, choosing a suitable treatment regimen requires comprehensive consideration. In the next clinical work, we must observe relevant cases to summarize the treatment experience better.
| S-EPMC10789887 | biostudies-literature
Project description:BackgroundMore than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma.Materials and methodsWe studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations.ResultsIn our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy.ConclusionsThis ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.
| S-EPMC8271116 | biostudies-literature
Project description:Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin's lymphoma that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. The proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filament assembly in a pattern similar to T-cell receptor-stimulated cells. NPM-ALK formed a complex with the guanine exchange factor VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity, and in turn, Cdc42 regulated the shape and migration of ALCL cells. In vitro knockdown of VAV1 or Cdc42 by short hairpin RNA, as well as pharmacologic inhibition of Cdc42 activity by secramine, resulted in a cell cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cell growth through Cdc42.
| S-EPMC2596920 | biostudies-literature
Project description:The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.
| S-EPMC3926823 | biostudies-literature