Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

Extracellular signal‐regulated kinase activation of self‐healing Langerhans cell histiocytosis: A case report

A 3‐month‐old boy developed small papules on his trunk. After the papules increased in number, the patient was diagnosed with Langerhans cell histiocytosis based on the pathological findings. He was referred to our department for further examination. Upon initial examination, the papules and nodules were scattered on his back, abdomen and lumbar region. Because he did not present with any organ involvement except the skin, he was diagnosed with single‐system and skin‐limited Langerhans cell histiocytosis. Skin rashes were treated with a topical steroid and started regressing 3 months after onset. All papules disappeared 6 months after onset. In this boy, the Langerhans cell histiocytosis tumor cells expressed phosphorylated extracellular signal‐regulated kinases. In Langerhans cell histiocytosis, BRAF V600E and other genes are known to mutate to act as driver mutations in stem cells of the myeloid dendritic cell lineage. Consequently, extracellular signal‐regulated kinases are continuously activated, which contributes to Langerhans cell histiocytosis carcinogenesis.     

MicroRNA‐361‐3p is a potent therapeutic target for oral squamous cell carcinoma

MicroRNAs (miRNAs) can act not only as tumor suppressor genes but also as oncogenes. Oncogenic miRNAs (oncomiRs) could therefore provide opportunities for the treatment of human malignancies. Here, we aimed to identify oncomiRs present in oral squamous cell carcinoma (OSCC) and addressed whether targeting these miRNAs might be useful in treatment for cancer. Functional screening for oncomiRs in a human OSCC cell line (GFP‐SAS) was carried out using the miRCURY LNA microRNA Knockdown Library – Human version 12.0. We identified a locked nucleic acid (LNA)/DNA antisense oligonucleotide against miR‐361‐3p (LNA‐miR‐361‐3p) which showed the largest degree of growth inhibition of GFP‐SAS cells. Transfection with a synthetic mimic of mature miR‐361‐3p resulted in an approximately 20% increase in the growth of GFP‐SAS cells. We identified odd‐skipped related 2 (OSR2) as a miR‐361‐3p target gene. Transfection of GFP‐SAS cells with LNA‐miR‐361‐3p caused a significant increase in the expression levels of OSR2. Cotransfection of a OSR2 3′‐UTR luciferase reporter plasmid and LNA‐miR‐361‐3p into GFP‐SAS cells produced higher levels of luciferase activity than in cells cotransfected with the LNA‐nontarget. We assessed the effect of LNA‐miR‐361‐3p on the in vivo growth of GFP‐SAS cells. We found that LNA‐miR‐361‐3p significantly reduced the size of s.c. xenografted GFP‐SAS tumors, compared to the control group treated with LNA‐NT. Finally, we observed that miR‐361‐3p is overexpressed in OSCC tissues. These results suggest that miR‐361‐3p supports the growth of human OSCC cells both in vitro and in vivo and that targeting miR‐361‐3p could be a useful therapeutic approach for patients with OSCC.     

Guidelines for standardizing cleansing and disinfection of gastrointestinal endoscopes

As part of the activities toward standardizing endoscopy procedures, the Japan Gastroenterological Endoscopy Society has prepared guidelines for cleansing and disinfection of gastrointestinal endoscopes. The environment of gastrointestinal endoscopy differs between Japan and advanced Western countries. In advanced Western countries, gastrointestinal endoscopy is performed almost exclusively at specialized facilities, where strict provisions are observed for cleansing and disinfecting endoscopes. In Japan, however, gastrointestinal endoscopy is performed even in small clinics, and the annual number of gastrointestinal endoscopy cases is enormous. In addition, the method for cleansing and disinfecting endoscopes differs among hospitals. Although there is a distinct lack of evidence for how gastrointestinal endoscopes are cleaned and disinfected, it is necessary to standardize the method for doing so to advance the field of endoscopic medicine.     

Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute‐phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti‐aquaporin‐4‐positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice. J. Clin. Apheresis 30:43–45, 2015. © 2014 Wiley Periodicals, Inc.     

Detailed Analysis of Puncture Site Vascular Complications in Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2

A subgroup analysis of access site complications in the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2, which were retrospective registry studies, was performed. Puncture site vascular complications occurred in 195 (0.63%, mean age: 69.2) of all 31,836 patients. Most of these complications resulted from surgery in main hospitals (186 patients, 0.67%, P < 0.001) and scheduled surgery (167 patients, 0.73%, P < 0.001). Carotid artery stenting (81 patients, 1.04%, p < 0.001), extracranial percutaneous transluminal angioplasty (PTA) (15 patients, 1.02%, p < 0.001), and intracranial PTA (10 patients, 0.81%, p < 0.05) were associated with significantly higher incidence of complications. The incidence of puncture site vascular complications was correlated with the number of antiplatelet drugs (p < 0.001) and intraoperative heparinization (p < 0.05).