Severe Drug-Induced Interstitial Lung Disease After Administration of Osimertinib as Adjuvant Treatment for Resected EGFR-Mutated NSCLC: A Case Report.

Osimertinib administration has been approved as an adjuvant treatment after complete surgical resection in patients with EGFR-mutated NSCLC. This article presents the first report of life-threatening postoperative osimertinib-induced interstitial lung disease. An 83-year-old male patient underwent right upper lobectomy (pathologic stage IIA) and osimertinib (80 mg/d) was initiated on postoperative day 75. On day 44 of osimertinib administration, chest computed tomography revealed diffuse ground-glass opacities; accordingly, osimertinib-induced interstitial lung disease was diagnosed. Steroid pulse therapy was initiated using a high-flow nasal cannula to treat dyspnea and hypoxemia, rapidly improving the respiratory status and imaging findings; moreover, the patient's clinical course was excellent. This case report suggests that the postoperative occurrence of severe osimertinib-induced interstitial lung disease is a crucial factor that must be considered in patient decision-making regarding perioperative treatment.

The cytotoxicity of gefitinib on patient­derived induced pluripotent stem cells reflects gefitinib­induced liver injury in the clinical setting.

Gefitinib is a key drug used in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. Gefitinib therapy is superior to conventional chemotherapy for the progression-free survival rate of patients with EGFR mutations. However, 10-26% of patients develop grade 3 or higher hepatotoxicity during gefitinib treatment; therefore, the development of preclinical tests for hepatotoxicity prior to clinical use is desirable. The present study evaluated the use of induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iPSC-heps), as a platform for preclinical test development. Patient-derived iPSCs were generated by reprogramming peripheral blood mononuclear cells obtained from two groups of gefitinib-treated patients with severe hepatotoxicity [toxicity group (T group)] or mild hepatotoxicity [no clinical toxicity group (N group)]. To examine the hepatotoxicity, the iPSCs from both T and N groups were differentiated into hepatocytes to obtain iPSC-heps. Differentiation was confirmed by measuring the expression levels of hepatocyte markers, such as albumin or α-fetoprotein, via western blotting and quantitative PCR analyses. Cytotoxicity in iPSCs and iPSC-heps after gefitinib treatment was evaluated using a lactate dehydrogenase release assay. The gefitinib-induced cytotoxicity in iPSCs from the T group was significantly higher than that from the N group, whereas there were no significant differences between the groups of iPSC-heps. These results suggested that using iPSCs in preclinical assessment may be a good indicator for the prediction of gefitinib-induced cytotoxicity in clinical use.

Comparison Between Second- and Third-generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors as First-line Treatment in Patients With Non-small-cell Lung Cancer: A Retrospective Analysis.

BACKGROUND: For epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), administration of EGFR tyrosine kinase inhibitors (TKIs) is mandatory to prolong survival. To date, a comparison of second- and third-generation EGFR-TKIs has not been reported as far as we are aware. PATIENTS AND METHODS: We retrospectively investigated the survival time of patients diagnosed with EGFR-mutated advanced or recurrent NSCLC who had received afatinib, a second-generation EGFR-TKI, or osimertinib, a third-generation EGFR-TKI, as the first-line treatment. RESULTS: Among the 49 patients included in the study, 15 received afatinib and 34 received osimertinib. No significant differences in overall survival were observed between the two groups [afatinib vs. osimertinib=36 vs. 33 months (hazard ratio=2.917, 95% confidence interval=0.780-10.905; p=0.112)]. T790M mutation was detected in three of the patients in the afatinib group, and all three subsequently received osimertinib. The median overall survival of these three patients and of the 12 without the mutation were 63 and 36 months, respectively. CONCLUSION: There was no apparent difference in the effect on survival between second- and third-generation EGFR-TKIs, whereas the sequential administration of second- followed by third-generation EGFR-TKIs appeared to confer a better long-term prognosis.

Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor is dependent on its time of administration in mice.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have made an immense breakthrough in cancer therapeutics, they can exert unique, immune-related adverse events. Among them, myocarditis is less frequent, but it is serious and often follows a lethal course. METHODS: To examine the changes in cardiac autoimmunity after ICI administration, we developed a mouse experimental autoimmune myocarditis (EAM) model via intraperitoneal administration of murine α-cardiac myosin heavy chain (MyHC-α) fragment. Thereafter, the mouse anti-PD-1 antibody (mPD1ab) was administered at two time points, subsequent to and concurrent with MyHC-α fragment administration. RESULTS: Severe EAM developed in 3 weeks; wide inflammatory lesions were observed in the cardiac sections. Furthermore, inflammatory/fibrotic genes, such as interleukin 1ß, interleukin 6, and collagen 1, were upregulated, although the cardiac function was not significantly affected. The subsequent administration of mPD1ab at 2 weeks post administration of the first MyHC-α fragment exacerbated EAM, whereas the administration of mPD1ab concurrent with MyHC-α fragment administration did not exacerbate EAM. The subsequent administration of mPD1ab significantly increased the infiltration of cluster of differentiation (CD)4- and F4/80-positive cells, whereas the concurrent administration of mPD1ab significantly decreased the infiltration of CD4-positive cells, indicating that the concurrent and subsequent administration of mPD1ab had opposite effects on immune/inflammatory cell infiltration. CONCLUSIONS: These data suggest that the appearance of ICI-induced autoimmune myocarditis might be related to autoimmune system activity before ICI administration. Although ICIs do not adversely affect patients with normal immune systems, we propose that ICI administration should be avoided in patients with autoimmune disorders.

Large cell neuroendocrine carcinoma of the lung with cancer-associated retinopathy.

We report a rare case of large cell neuroendocrine carcinoma (LCNEC) of the lung with cancer-associated retinopathy (CAR). To our knowledge, only two cases of LCNEC with CAR have been reported, one in 1995 and another in 2013. CAR, typically associated with small cell lung cancer (SCLC), is one of the paraneoplastic syndromes with deterioration of visual acuity, visual field constriction, and photophobia. CAR is caused by an autoimmune system reaction against the same antigen in the tumor and retinal photoreceptor cells. To diagnose CAR, genetic retinal dystrophies or any other medical causes of retinopathy should be excluded, but there are no standard diagnostic criteria. Anti-retinal antibodies are known to be positive in CAR patients, and anti-recoverin antibodies are thought to be sensitive and specific to CAR. In our case, anti-recoverin antibodies were not detected by serum tests, but CAR could be diagnosed on the basis of ophthalmological findings including clinical symptoms, electroretinographic findings, and visual field tests. CAR with clinical features of rapid visual disorder should be considered in LCNEC patients as well as in SCLC patients.