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심종민,김현진,현지연,최윤라,한정호 대한의학회 2018 Journal of Korean medical science Vol.33 No.15
Background: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed. Methods: We selected combined neuroendocrine differentiation in pulmonary adenocarcinoma cases with positive ALK immunostaining. Neuroendocrine differentiation was confirmed by CD56 immunohistochemical stain. Additional ALK fluorescence in situ hybridization (FISH) study and epidermal growth factor receptor (EGFR) mutation tests were also performed. Results: All four cases were positive for ALK immunohistochemistry and no EGFR mutations were detected. Interestingly, the results of ALK FISH assays showed rearrangement in only two cases. Three cases showed combined adenocarcinoma and neuroendocrine component without history of ALK-TKI administration; one of them was treated with crizotinib and experienced partial tumor regression. The remaining case had an adenocarcinoma at initial biopsy and she showed a partial response to crizotinib, and neuroendocrine changes were visible on second biopsy. Then she was treated with ceritinib and achieved a partial response. Conclusion: We suggest that ALK-rearranged adenocarcinoma with combined neuroendocrine component is responsive to ALK-TKIs. Moreover, even after neuroendocrine transformation as a result of resistance to ALK-TKIs, the tumor may have partial response to second generation ALK-TKIs.
[P330] A case of primary cutaneous cd30+ anaplastic large cell lymphoma
( Jeong-wan Seo ),( Ho-jin Kim ),( Tae-hoon Kim ),( Ki-hoon Song ),( Ki-ho Kim ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.1
Epithelial Membrane Antigen(EMA) and Anaplastic Lymphoma Kinase (ALK) expressions are uncommon in primary cutaneous T-cell-lymphomas (CTCL). We report a patient who was initially clinically diagnosed with squamous cell carcinoma, and eventually developed an unusual manifestation of CTCL. His disease was presented as aggressively ulcerating plaques and tumors of the entire skin. Histopathologic examination revealed monoclonal proliferation of atypical T-lymphocytes with positivities for CD30, EMA, but, negative for ALK. Extensive staging work-ups confirmed the primary cutaneous of the anaplastic large cell lymphoma(C-ALCL). Because distinguishing C-ALCL from systemic ALCL is important to provide adequate treatments for systemic lymphoma patients without overtreatment, the differential diagnosis is often made with the aid of immunohistochemistry and molecular genetics. Despite the positive findings for ALK and EMA favor systemic ALCL, the clinical course and histopathologic findings clearly indicates C-ALCL in this patients. Such studies should be useful for improving the diagnosis and predicting the prognosis of C-ALCL, and may identify a subset of this disease and it would be amenable to therapies targeted against ALK.
Characteristics of Renal Cell Carcinoma Harboring TPM3-ALK Fusion
우창곡,윤석중,손승명,임영현,이옥준 연세대학교의과대학 2020 Yonsei medical journal Vol.61 No.3
The World Health Organization 2016 edition assigned anaplastic lymphoma kinase (ALK) rearrangement-associated renal cellcarcinoma (ALK-RCC) as an emerging renal tumor entity. Identifying ALK-RCC is important because ALK inhibitors have beenshown to be effective in treatment. Here, we report the case of a 14-year-old young man with ALK-RCC. Computed tomographyrevealed a well-demarcated 5.3-cm enhancing mass at the upper pole of the left kidney. There was no further history or symptomsof the sickle-cell trait. The patient underwent left radical nephrectomy. Pathologically, the mass was diagnosed as an unclassifiedRCC. Targeted next-generation sequencing identified a TPM3-ALK fusion gene. The present report and literature review demonstratethat TPM3-ALK RCC may be associated with distinct clinicopathological features. Microscopically, the tumors showed diffusegrowth and tubulocystic changes with inflammatory cell infiltration. Tumor cells were dis-cohesive and epithelioid with abundanteosinophilic cytoplasm and cytoplasmic vacuoles. If morphological features and TFE3 expression are present in adolescentand young patients, molecular tests for ALK translocation should be performed. This awareness is critically important, because ALKrearrangement confers sensitivity to ALK inhibitors.
비소세포성 환자에서 Anaplastic Lymphoma Kinase 유전자 변이 진단검사
오현주,김다운 한국보건의료기술평가학회 2014 보건의료기술평가 Vol.2 No.1
Accurate determination of anaplastic lymphoma kinase (ALK) rearrangement is important in lung cancer patients, especially in determining their eligibility for crizotinib therapy. Basically immunohistochemistry (IHC) mothod and fluorescence in situ hybridization (FISH) has been used to detect ALK gene rearrangement. IHC mothod has been used for primary test and FISH has been regarded as the gold standard method for detecting ALK rearrangement in determining their eligibility for crizotinib therapy. However FISH requires a fluorescence microscope, and the signals are labile and rapidly fade over time. In this study, we reviewed current diagnostic tests for ALK gene rearrangement in non-small-cell lung cancer in Korea and potentiality of the new improved test for new alternative test to FISH
Mathi, Gangadhar Rao,Kang, Chung Hyo,Lee, Heung Kyoung,Achary, Raghavendra,Lee, Ha-Yeon,Lee, Joo-Youn,Ha, Jae Du,Ahn, Sunjoo,Park, Chi Hoon,Lee, Chong Ock,Hwang, Jong Yeon,Yun, Chang-Soo,Jung, Hee Jun Elsevier 2017 European journal of medicinal chemistry Vol.126 No.-
<P><B>Abstract</B></P> <P>The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound <B>10</B> shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC<SUB>50</SUB> of 1.8 nM. Furthermore, pharmacokinetic profiles of <B>10</B> is apparently better than that of ceritinib. In murine xenograft studies, compound <B>10</B> turns out to be as active as ceritinib, suggesting that further optimization of <B>10</B> may lead to clinical candidates overcoming ALK mutant issues.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The terminal piperidine in ceritinib was replaced with diverse alkyl amines. </LI> <LI> Most of the analogs were as active as crizotinib against ALK wild-type and L1196M mutant. </LI> <LI> Compound <B>10</B> has excellent ALK mutant activities including extremely resistant G1202R. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Novel 2,4-dianilino-5-fluoropyrimidine derivatives possessing ALK inhibitory activities
Yun, Jeong In,Yang, Eun Hye,Latif, Muhammad,Lee, Hyeon Ji,Lee, Kwangho,Yun, Chang-Soo,Park, Chi Hoon,Lee, Chong Ock,Chae, Chong Hak,Cho, Sung Yun,Jung, Hee Jung,Kim, Pilho,Choi, Sang Un,Kim, Hyoung Ra 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.7
A new series of 2,4-dianilino-5-fluoropyrimidine derivatives were designed and synthesized and their anaplastic lymphoma kinase (ALK) inhibitory activities were evaluated by biochemical and cell-based assays in order to discover a new ALK inhibitor. Most compounds synthesized showed good inhibitory activities against ALK and good cytotoxic activities in H3122 cell line. The best compound 6f showed good activity against wild-type ALK along with crizotinib-resistant mutant ALK, and it showed 6 times better activity in cell-based assay than crizotinib. Some SAR studies were performed by the comparisons of the activities between 6 and the designed-synthesized compounds.
New Pyrimidine Derivatives possessing ALK Inhibitory Activities
Yang, Eun Hye,Yun, Jeong In,Latif, Muhammad,Lee, Hyeon Ji,Yun, Chang-Soo,Lee, Kwangho,Park, Chi Hoon,Cho, Sung Yun,Jung, Hee Jung,Kim, Pilho,Ha, Jae Du,Kim, Hyoung Rae Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.10