• International journal of thyroidology
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• v.11 no.2
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• pp.88-91
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• 2018

After introducing tyrosine kinase inhibitors (TKIs) as promising treatments for radioactive iodine refractory advanced thyroid cancer patients, we more often meet patients with TKI-related hormone and electrolyte imbalances in clinics. Hypocalcemia associated with TKI is associated with an imbalance in calcium-vitamin D metabolism. TKI-related hypothyroidism is related to the metabolic rate of thyroid hormones. The two side effects usually occur in the early stages of TKI treatment, and if the imbalance is corrected appropriately, the effects are minor, but in severe cases, the TKI should be discontinued. The authors reported a case of severe hypocalcemia and thyroid dysfunction after TKI treatment. A 56-year-old man suffered from symptomatic hypocalcemia during TKI treatment, which was resolved after he stopped taking the TKI medication. Although calcium and vitamin D replacement have increased, hypocalcemia was recurred and TKI treatments have been permanently stopped due to serious weight loss in grade 3. After the interruption, his calcium levels normalized.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2915-2921
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• 2015

Background: Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. Materials and Methods: We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS), overall survival (OS) and major toxicity. Results: Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68-1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05-2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62-0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. Conclusions: Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.

• Korean Journal of Clinical Pharmacy
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• v.29 no.4
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• pp.223-230
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• 2019

Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

• Tuberculosis and Respiratory Diseases
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• v.80 no.2
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• pp.187-193
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• 2017

Background: Third-generation tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have proved efficacious in treating non-small cell lung cancer (NSCLC) patients with acquired resistance resulting from the T790M mutation. However, since almost 50% patients with the acquired resistance do not harbor the T790M mutation, retreatment with first- or second-generation EGFR-TKIs may be a more viable therapeutic option. Here, we identified positive response predictors to retreatment, in patients who switched to a different EGFR-TKI, following initial treatment failure. Methods: This study retrospectively reviewed the medical records of 42 NSCLC patients with EGFR mutations, whose cancers had progressed following initial treatment with gefitinib or erlotinib, and who had switched to a different first-generation EGFR-TKI during subsequent retreatment. To identify high response rate predictors in the changed EGFR-TKI retreatment, we analyzed the relationship between clinical and demographic parameters, and positive clinical outcomes, following retreatment with EGFR-TKI. Results: Overall, 30 (71.4%) patients received gefitinib and 12 (28.6%) patients received erlotinib as their first EGFR-TKI treatment. Following retreatment with a different EGFR-TKI, the overall response and disease control rates were 21.4% and 64.3%, respectively. There was no significant association between their overall responses. The median progression-free survival (PFS) after retreatment was 2.0 months. However, PFS was significantly longer in patients whose time to progression was ${\geq}10months$ following initial EGFR-TKI treatment, who had a mutation of exon 19, or whose treatment interval was <90 days. Conclusion: In patients with acquired resistance to initial EGFR-TKI therapy, switched EGFR-TKI retreatment may be a salvage therapy for individuals possessing positive retreatment response predictors.

• Journal of Korean Neurosurgical Society
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• v.58 no.3
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• pp.205-210
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• 2015

Objective : This study was aimed at optimizing the treatment of non-small-cell lung cancer (NSCLC) patients who are candidates for stereotactic radiosurgery (SRS) for brain metastases and harbor activating epithelial growth factor receptor (EGFR) mutations. Methods : We retrospectively reviewed the medical records from 2005 to 2010 of NSCLC patients with brain metastases harboring an activating EGFR mutation. Patients who received a combination therapy of SRS and EGFR-tyrosine kinase inhibitor (TKI) for brain metastases and those who received SRS without EGFR-TKI were compared. The primary endpoint was progression-free survival (PFS) of the brain metastases. Results : Thirty-one patients were eligible for enrolment in this study (SRS with TKI, 18; SRS without TKI, 13). Twenty-two patients (71.0%) were women and the median overall age was 56.0 years. PFS of brain lesions was not significantly prolonged in SRS with TKI treatment group than in SRS without TKI group (17.0 months vs. 9.0 months, p=0.45). Local tumor control rate was 83.3% in the combination therapy group, and 61.5% in the SRS monotherapy group (p=0.23). There were no severe adverse events related with treatment in both groups. Conclusions : Therapeutic outcome of concurrent SRS and TKI treatment was not superior to SRS monotherapy, however, there was no additive adverse events related with combined treatment.

• Korean Journal of Veterinary Service
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• v.40 no.4
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• pp.265-275
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• 2017

The production of enzymes that help digestion, assimilation of essential nutrients, and prevent pathogenic bacteria are important for probiotics used in aquaculture. The objective of this study was to investigate enzyme activities for macromolecular organic matters and antimicrobial properties of the selected potential probiotics isolated from gut of surf clam (Tresus keenae) against well-known shellfish-pathogenic bacteria. Among 65 isolates from guts of 60 surf clams, seven Bacillus strains with outstanding degradation capability of macromolecule organic matter were selected as potential probiotics as follows: TKI01 (B. vietnamensis), TKI02, TKI26 (B. thuringiensis), TKI14, TKI32, TKI42 (B. amyloliquefaciens), and TKI18 (B. stratosphericus). After in vitro antimicrobial activity test was performed against five shellfish-pathogenic bacteria including Listonella anguillarum, Vibrio parahaemolyticus, V. splendidus, V. harveyi, V. tubiashii, PCR assay was performed to detect bacteriocin-producing strain. PCR results revealed that the five Bacillus strains possessed diverse bacteriocin genes including ericinA, coagulin, surfactin, iturin, bacyllomicin, fengycin, bacylisin, subtilin, and lantibiotics. In the present study, the selected seven Bacillus strains showed different enzyme activities according to types of macromolecule organic matters. And their antimicrobial activities varied based on the species of pathogenic bacteria. In addition, at least five Bacillus strains had genetic potential to produce several natural lipopeptide antibiotics that may help biological control of surf clam aquaculture. Therefore, mixed use of probiotics might show co-operative effect and increase the efficiency of probiotics rather than separate use. To the best of our knowledge, it is the first report on antimicrobial properties of Bacillus species isolated from surf clam.

• Biomolecules & Therapeutics
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• v.32 no.5
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• pp.582-600
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• 2024

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

• Tuberculosis and Respiratory Diseases
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• v.76 no.1
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• pp.8-14
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• 2014

Non-small cell lung cancer harboring epidermal growth factor receptor (EGFR) sensitizing mutations has a distinct disease entity. Patients with this cancer have better prognosis, and frequently achieve long-term survival. EGFR-tyrosine kinase inhibitor (TKI) is the drug of choice for this cancer; but the disease inevitably progresses, after durable response. The tumor is a mixture of EGFR-TKI sensitive clones and resistant clones, regardless of their molecular mechanisms. EGFR-TKI sensitive clones are very susceptible to this drug, but rarely eradicated; so, withdrawal of the drug permits rapid regrowth of drug sensitive clones, possibly causing "disease flare." Re-administration or continuation of EGFR-TKI can effectively suppress the expansion of drug sensitive clones, even when the total tumor volume continuously increases. Chemotherapy can definitely prolong the survival of patients experiencing EGFR-TKI failure. Prospective clinical trials are warranted to compare efficacies of chemotherapeutic agents. A few retrospective studies suggested that a taxanebased regimen may be superior to others. Here, we reviewed therapeutic options and clinical evidence about this unique disease entity.

• Tuberculosis and Respiratory Diseases
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• v.71 no.4
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• pp.286-290
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• 2011

Although failure of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) is generally believed to be associated with cross-resistance to other EGFR TKI, the benefit of administering erlotinib as a second EGFR TKI after resistance of gefitinib as the first TKI has been well known. However, good response to gefitinib after an initial response to erlotinib has been rare. We report that a 45-year-old woman (never smoked), with lung adenocarcinoma and EGFR mutation, showed an initial response to erlotinib, and then responded to gefitinib again.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.205-213
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• 2014

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages over traditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately we have to face the situation that most patients still fail to respond in the long term despite initially good control. Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we sought to compile the available clinical reports in the hope to better understanding the subsequent treatment choices, particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better option after failure of one kind of EGFR-TKI.