Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients.

Most patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI). The mechanisms of resistance to EGFR-TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR-TKI therapy. We evaluated the feasibility of a molecular barcode method using next-generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation-positive NSCLC patients after the development of EGFR-TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next-generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR-sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR-sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell-free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.

Efficacy of bevacizumab and erlotinib combination for leptomeningeal carcinomatosis after failure of erlotinib.

In patients with non-small-cell lung cancer harboring an epithelial growth factor receptor (EGFR) active mutation, central nervous system progression after a response to EGFR tyrosine kinase inhibitors is frequent. Central nervous system metastasis, especially leptomeningeal carcinomatosis (LMC), is a serious complication and no standard treatment has been established for LMC. Here, we report two cases in which the addition of bevacizumab to erlotinib enhanced the efficacy against LMC; as a result, radiographic abnormalities decreased markedly and symptoms were well controlled. This combination treatment may be useful to treat LMC in patients with EGFR-positive non-small-cell lung cancer.

Dramatic response to alectinib in inflammatory myofibroblastic tumor with anaplastic lymphoma kinase fusion gene.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.

Solid phase stability of a double-minimum interaction potential system.

We study phase stability of a system with double-minimum interaction potential in a wide range of parameters by a thermodynamic perturbation theory. The present double-minimum potential is the Lennard-Jones-Gauss potential, which has a Gaussian pocket as well as a standard Lennard-Jones minimum. As a function of the depth and position of the Gaussian pocket in the potential, we determine the coexistence pressure of crystals (fcc and bcc). We show that the fcc crystallizes even at zero pressure when the position of the Gaussian pocket is coincident with the first or third nearest neighbor site of the fcc crystal. The bcc crystal is more stable than the fcc crystal when the position of the Gaussian pocket is coincident with the second nearest neighbor sites of the bcc crystal. The stable crystal structure is determined by the position of the Gaussian pocket. These results show that we can control the stability of the solid phase by tuning the potential function.

The First Case Report of Effective Treatment With Sotorasib for Metastatic Atypical Lung Carcinoid Harboring KRAS G12C Mutation and Aggressive Disseminated Lung Metastasis: A Case Report.

Pulmonary neuroendocrine tumors are rare, accounting for approximately 1% to 2% of lung cancers. Atypical carcinoids account for approximately 10% of pulmonary neuroendocrine tumors and are categorized as moderately malignant. Treatment options for advanced-stage atypical carcinoids include everolimus, cytotoxic anticancer agents, and peptide receptor radionuclide therapy. In this report, we present the first case of KRAS G12C mutation-positive atypical carcinoid that was successfully treated with sotorasib. Therapeutically important mutations observed in non-small cell lung cancer are seldom found in atypical carcinoid tumors. Nonetheless, it is worthwhile to search for genetic mutations in atypical carcinoid tumors, considering the potential for molecular targeted therapy to be effective in their treatment as well.

[Drunkenness caused by isoniazid in a tuberculosis patient with extrapulmonary lesions on hemodialysis: a case report].

The patient was a 55-year-old man who had been on hemodialysis for 6 years for diabetic nephropathy. He was clinically diagnosed with pulmonary tuberculosis with extrapulmonary lesion after 3 years of chronic fever. His fever subsided immediately after the beginning of antituberculosis drug therapy and the antituberculosis drugs were discontinued 3 days after the initiation of the therapy. He experienced a sense of drunkenness when he received isoniazid, apparently not in association with any of the other antituberculosis drugs given. His blood trough concentration of isoniazid was nearly equal to the usual peak levels measured in patients with normal renal function. Isoniazid is often prescribed for patients with chronic renal failure without dose-reduction, because of its hepatic metabolism. But blood level of INH was found to accumulate at high levels in this patient. The high blood concentration of isoniazid in this patient with chronic renal failure may have elicited his neurological side effect.

Subsequent treatment for locally advanced non-small-cell lung cancer that progressed after definitive chemoradiotherapy and consolidation therapy with durvalumab: a multicenter retrospective analysis (TOPGAN 2021-02).

PURPOSE: For patients with locally advanced non-small-cell lung cancer (LA-NSCLC) that progressed after definitive chemoradiotherapy (CRT) and durvalumab consolidation therapy, no subsequent standard treatment exists. The type of treatment selected for each timing of disease progression and its efficacy have not been investigated. METHODS: We retrospectively enrolled patients with LA-NSCLC or inoperable NSCLC that progressed after definitive CRT and durvalumab consolidation therapy at 15 Japanese institutions. Patients were classified into the following: Early Discontinuation group (disease progression within 6 months after durvalumab initiation), Late Discontinuation group (disease progression from 7 to 12 months after durvalumab initiation), and Accomplishment group (disease progression from 12 months after durvalumab initiation). RESULTS: Altogether, 127 patients were analyzed, including 50 (39.4%), 42 (33.1%) and 35 (27.5%) patients from the Early Discontinuation, Late Discontinuation, and Accomplishment groups, respectively. Subsequent treatments were Platinum plus immune checkpoint inhibitors (ICI) in 18 (14.2%), ICI in 7 (5.5%), Platinum in 59 (46.4%), Non-Platinum in 35 (27.6%), and tyrosine kinase inhibitor in 8 (6.3%) patients. In the Early Discontinuation, Late Discontinuation, and Accomplishment groups, 4 (8.0%), 7 (16.7%), and 7 (20.0%) patients were receiving Platinum plus ICI; 21 (42.0%), 22 (52.4%), and 16 (45.7%) were receiving Platinum, and 20 (40.0%), 8 (19.0%), and 7 (20.0%) were receiving Non-Platinum, respectively. No significant difference in progression-free survival was observed in the timing of disease progression. CONCLUSION: In patients with LA-NSCLC hat progressed after definitive CRT and durvalumab consolidation therapy, subsequent treatment may change depending on the timing of disease progression.

Clinical efficacy of amrubicin in patients with small cell lung cancer relapse after first-line treatment including immune checkpoint inhibitors: A retrospective multicenter study (TOPGAN 2021-01).

BACKGROUND: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC. PATIENTS AND METHODS: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR. RESULTS: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity. CONCLUSIONS: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.

A case of non-neutropenic invasive pulmonary aspergillosis under immune checkpoint inhibitor therapy for malignant melanoma.

The patient was a 70-year-old man with diabetes mellitus, alcoholic liver disease and bronchial asthma treated with corticosteroid and long-acting ß-agonist inhalants. He had also been treated with nivolumab for advanced malignant melanoma for two years with a partial response. He presented to our department with intractable cough, which was attributed to uncontrolled bronchial asthma. Two weeks later, he presented with a high fever and worsened cough. He was diagnosed with bacterial pneumonia based on severe inflammation revealed by laboratory tests and right upper lung consolidation on chest radiography. Antibiotics via either oral or parenteral administration were ineffective and no pathogen was detected in sputum or blood cultures. Based on the air-crescent sign observed on chest computed tomography and a diffuse pseudomembranous lesion on the airway epithelium that was observed via bronchoscopy along with positive serum Aspergillus antigen, a clinical diagnosis of invasive pulmonary aspergillosis (IPA) was made and liposomal amphotericin B was initiated. Three days later, the patient developed massive hemoptysis, and he died of respiratory failure. Later, aspergillus-like mycelia were observed in the pathology of bronchial biopsy, supporting the clinical diagnosis of IPA. Although the use of immune checkpoint inhibitors has been reported to be beneficial for patients with some infectious diseases, it does not seem to be the case for patients with other infectious diseases including our patient.

Dramatic response to alectinib in an ALK-positive LCNEC patient with a poor performance status: A case report.

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene, a driver mutation in lung carcinoma, is fairly common in lung adenocarcinoma but rare in large cell neuroendocrine carcinoma (LCNEC). Here we report a case of stage IV LCNEC positive for this fusion gene in a patient with a poor performance status (PS) who was effectively treated with alectinib. The patient was a 72-year-old non-smoking man diagnosed as LCNEC with multiple metastases. Because of his poor PS, cytotoxic chemotherapy was not indicated, but he was later found to be positive for the ALK fusion gene and treated with alectinib as first-line therapy. One month later, the tumour had shrunk remarkably, and the therapeutic effect was rated as a partial response. The PS also improved from 4 to 1. Investigating actionable driver mutations seems worth doing for advanced LCNEC, especially if the patient's PS is poor.

Significant therapeutic effectiveness of durvalumab after chemoradiotherapy for a patient with post-operative recurrent pulmonary pleomorphic carcinoma.

Pulmonary pleomorphic carcinoma (PPC) is a poorly differentiated non-small cell lung cancer. Because of its rarity, no standard therapy has been established for advanced disease. We herein report on a 62-year-old man with recurrent post-operative PPC, for whom durvalumab after chemoradiotherapy was effective. He was referred to our hospital because of an abnormal shadow in the right upper lung on chest X-ray. After surgical resection was performed, the imaging and histopathological findings revealed PPC (T4N0M0, stage IIIA) with elevated expression of programmed cell death-ligand 1 (PD-L1). A metastasis was found in the left hemithorax 22 months later, and chemoradiotherapy consisting of 60 Gy of radiation and cisplatin plus tegafur/gimeracil/oteracil potassium was administered. Durvalumab was then begun as consolidation therapy. The efficacy of the treatments has continued for longer than 10 months. This case suggests that multidisciplinary treatment with chemoradiotherapy and consolidation immunotherapy may improve the prognosis of locally advanced PPC.

Myositis induced by durvalumab in a patient with non-small cell lung cancer: A case report.

Immune checkpoint inhibition is associated with a broad spectrum of immune toxicities referred to as immune-related adverse events (irAEs). Myositis is known to be a potentially fatal irAE. Here, we report a case of immune-related myositis after the administration of durvalumab. A 60-year-old man with stage IIIA lung adenocarcinoma was treated with durvalumab after concurrent chemoradiation therapy. After the third dose of durvalumab, his serum CK level was elevated, and soon thereafter myalgia of the proximal muscles and blepharoptosis were observed. We diagnosed immune-related myositis based on the results of pathological examination and initiated systemic corticosteroid therapy. His symptoms then improved and the serum CK level immediately dropped to within a normal range. Clinicians should be aware of possible myositis during the early phase of durvalumab therapy.

Correlation between thyroid transcription factor-1 expression, immune-related thyroid dysfunction, and efficacy of anti-programmed cell death protein-1 treatment in non-small cell lung cancer.

BACKGROUND: Recent studies have suggested a correlation between immune-related thyroid dysfunction (irTD) and the superior efficacy of anti-programmed cell death protein-1 (anti-PD-1) treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. We explored our hypothesis that TTF-1 expression in NSCLC might correlate with irTD incidence and anti-PD-1 treatment efficacy. METHODS: We identified 132 patients with NSCLC treated with anti-PD-1 antibody at our hospital between December 2015 and June 2017. We evaluated TTF-1 expression in tumor by immunohistochemistry using a mouse monoclonal antibody (clone 8G7G3/1, 1:100, Dako). IrTD was defined as two or more successive abnormal levels of thyroid-stimulating hormone (TSH) during anti-PD-1 treatment. We retrospectively assessed correlations between TTF-1 expression in tumor, irTD incidence, and anti-PD-1 treatment efficacy. RESULTS: Of 132 patients, 67 (51%) and 65 (49%) were positive and negative for TTF-1, respectively. We observed irTD in 19 patients (6 positives and 13 negatives for TTF-1). The incidence of irTD was 9% and 20% in TTF-1-positive and TTF-1-negative NSCLCs, respectively (P=0.086). Particularly, in non-squamous (NSQ) cell carcinomas, the irTD incidence was significantly higher in patients negative for TTF-1 (30%) than in those positive for TTF-1 (9%; P=0.010), and TTF-1 expression was identified as a significant risk factor for irTD on multivariate logistic regression analysis [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.05-0.59; P=0.005]. Furthermore, longer median progression-free survival (10.3 months) was observed in patients with TTF-1-negative NSCLC with irTD compared to those with TTF-1-positive NSCLC with irTD, TTF-1-positive NSCLC without irTD, and TTF-1-negative NSCLC without irTD (4.2, 1.4, and 2.4 months, respectively). CONCLUSIONS: TTF-1 expression in NSCLC might correlate with irTD and anti-PD-1 treatment efficacy.

Coexistence of dementia with smear-positive pulmonary tuberculosis is associated with patient in-hospital mortality.

BACKGROUND: The impact of dementia on the survival of patients with pulmonary tuberculosis (TB) remains unclear. This study sought to describe the risk factors influencing in-hospital mortality in patients with pulmonary TB and comorbid dementia. METHODS: A 9-y, medical record-based retrospective study of hospitalized adult patients with newly diagnosed, smear-positive, non-multidrug-resistant pulmonary TB without human immunodeficiency virus infection was performed. Clinical presentations, biochemical tests, radiographic findings, and clinical outcomes were collected. Variables were compared between groups. Statistically significant (p-value < 0.05) variables were entered into a multivariate stepwise logistic regression model. Survival analysis was performed using the Kaplan-Meier method, and groups were compared by log-rank test. RESULTS: Of the 279 enrolled patients (178 men; median age, 76 y), the mortality rate was 12.2% (34/279). Univariate analysis showed a higher frequency of dementia in patients who died in hospital than that in surviving patients. Multivariate stepwise logistic analysis showed that dementia was significantly associated with higher rates of in-hospital mortality (odds ratio, 3.20; 95% confidence interval, 1.15-8.88, p = 0.026). In addition, subgroup survival curves showed that dementia was associated with reduced survival rates, even after adjusting for age (log-rank test, p = 0.0007). CONCLUSIONS: The comorbidity of dementia with pulmonary TB was associated with patient in-hospital mortality. Medical practitioners should be aware of dementia in patients with smear-positive pulmonary TB to identify high-mortality groups.

Correlation between serum adenosine deaminase activity and efficacy of anti-programmed cell death-1 antibody.

OBJECTIVE: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy. MATERIALS AND METHODS: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated. RESULTS: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p = 0.002]; progressive disease [PD]: -12% [-42 to +6; p = 0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p = 0.034], day 0 of second cycle: 8% [-5 to +37; p = 0.002], day 0 of third cycle: 9% [-3 to +55; p = 0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p = 0.006). CONCLUSION: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.

Improvement in the survival of patients with stage IV non-small-cell lung cancer: Experience in a single institutional 1995-2017.

OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice. MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation. RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E. CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.

EGFR T790M mutation after chemotherapy for small cell lung cancer transformation of EGFR-positive non-small cell lung cancer.

In non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, 50%-65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) because of an EGFR T790M point mutation and 3%-14% of these cases transformed to small cell lung cancer (SCLC). Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation.

Characterization of Computed Tomography Imaging of Rearranged During Transfection-rearranged Lung Cancer.

BACKGROUND: Rearranged during transfection (RET)-rearranged non-small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented. PATIENTS AND METHODS: We identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics. RESULTS: In 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%). CONCLUSION: Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed.

High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer.

OBJECTIVES: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. MATERIALS AND METHODS: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We performed EGFR mutation analysis of cytological samples from 33 patients using droplet digital PCR. We calculated the ratio of T790M to EGFR activating mutations and correlated it with the systemic response to osimertinib. RESULTS: In tumors from the 33 patients, the average ratio of T790M to EGFR activating mutations was 0.420. Twenty-one of the 33 patients had tumors with a T790M ratio of ≥0.4. The osimertinib response rate was significantly higher (92.3%) in patients with a T790M ratio of ≥0.4 than in those with a T790M ratio of <0.4 (52.6%; p = 0.0237). We examined the correlation between the T790M ratio and the tumor reduction rate and obtained a coefficient of r = 0.417 (p = 0.0175). In patients with a T790M ratio of ≥0.4, the median progression-free survival was 355 days, which was longer, but not significant, than that in patients with a T790M ratio of <0.4 (median: 264 days). In patients with a T790M ratio of ≥0.4, the median treatment duration from first-line therapy onward was 931 days, which was significantly longer than that in patients with a T790M ratio of <0.4 (median, 567.5 days) (p = 0.044). CONCLUSION: The T790M ratio to EGFR activating mutation in tumor may correlate with the response to osimertinib, and patients with a higher T790M ratio have a longer treatment history.

Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy.

BACKGROUND/AIM: Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. PATIENTS AND METHODS: Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. RESULTS: Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/µl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. CONCLUSION: Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms.