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Background: Adenocarcinoma with positive echinoderm microtubuleassociated protein-like 4 gene and anaplastic lymphoma kinase (EML4-ALK) gene fusion accounts for 3-7% of lung cancer cases and can be targeted with ALK tyrosine kinase inhibitors (TKIs). Second-generation TKIs are the standard of care for targeted populations, especially those with central nervous system (CNS) metastasis. However, most patients eventually experience disease progression because of drug resistance caused by multiple mechanisms, predominantly secondary mutations. Case description: We present a female advanced non-small cell lung cancer (NSCLC) case with positive EML4-ALK gene fusion, in which disease progression occurred in only 3 months after first-line treatment with alectinib. Two secondary mutations were detected by next-generation sequencing; one was V1180L located in exon 23, and the other was E803Q located in exon 14, which was a novel mutation that had never been reported. Ensartinib and ceritinib were administered as second-line and third-line treatments. However, the response to these TKIs was poor, and her overall survival was only 7 months. Conclusion: The secondary mutation E803Q located in exon 14 seems resistant to most second-generation ALK-TKIs. If there is an opportunity, the efficacy of the third-generation ALK-TKI loratinib should be tested. [ABSTRACT FROM AUTHOR]

Abstract Background With the widespread use of low-dose computed tomography for lung cancer screening, the detection rate of pulmonary lesions manifesting as ground-glass opacities (GGOs) has been increasing dramatically. The volume doubling time (VDT) has been introduced in clinical practice to monitor the potential growth rate of GGOs during long-term follow-up periods. Case presentation A 72-year-old never-smoker female diagnosed with mixed GGO manifested abruptly accelerated growth with sudden decreased VDT from 400 to 36 days. A thoracoscopic left lower lobectomy with mediastinal lymph node dissection was performed, and the diagnosis was stage IB large-cell neuroendocrine carcinoma (LCNEC). Next-generation sequencing of the tumor highlights an EML4-ALK gene fusion. Conclusions The LCNEC may present as GGO with longer VDT in the early stage. VDT should calculate by the whole size either on the entire tumor diameter or on consolidation diameter. It is recommended that meticulous long-term follow-up with dynamic VDT monitoring may help select high-risk GGOs performing timely semi-elective surgical resection in clinical practice.

Background: With the widespread use of low-dose computed tomography for lung cancer screening, the detection rate of pulmonary lesions manifesting as ground-glass opacities (GGOs) has been increasing dramatically. The volume doubling time (VDT) has been introduced in clinical practice to monitor the potential growth rate of GGOs during long-term follow-up periods. Case presentation: A 72-year-old never-smoker female diagnosed with mixed GGO manifested abruptly accelerated growth with sudden decreased VDT from 400 to 36 days. A thoracoscopic left lower lobectomy with mediastinal lymph node dissection was performed, and the diagnosis was stage IB large-cell neuroendocrine carcinoma (LCNEC). Next-generation sequencing of the tumor highlights an EML4-ALK gene fusion. Conclusions: The LCNEC may present as GGO with longer VDT in the early stage. VDT should calculate by the whole size either on the entire tumor diameter or on consolidation diameter. It is recommended that meticulous long-term follow-up with dynamic VDT monitoring may help select high-risk GGOs performing timely semi-elective surgical resection in clinical practice. [ABSTRACT FROM AUTHOR]

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line 'JVE404' derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient's treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a 6-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks' use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML4- ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine. [ABSTRACT FROM AUTHOR]