Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements. Experimental Design:To characterize mechanisms of resistance to osimertinib, patients with metastatic EGFR-mutant lung cancers who received osimertinib at Memorial Sloan Kettering and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified.Results: Among 62 patients who met eligibility critieria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of laterline cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared to patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 + V769L and the mutation MET H1094Y were identified and validated as resistance mechanisms with potential treatment options. Conclusion:Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.Research.

Anthracene has been widely studied as an organic photoconductor during the past five decades.[1] Hole mobilities in anthracene single crystals were measured by the time-of-flight photocurrent technique and were found to reach up to 3 cm 2 V À1 s À1 at 300 K.[2] Although anthracene may be a good candidate for a p-type semiconductor for organic field-effect transistors (OFETs), [3] FET activity has not yet been observed. Recently, OFETs with tetracene were realized and showed a hole mobility of 0.01 cm 2 V À1 s À1 on SiO 2 /Si. [4] Of all the OFET materials reported so far, the highest field-effect mobility has been recorded in pentacene (0.3-0.7 cm 2 V À1 s À1

Introduction: Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. Methods: To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI-resistant patient sample. Results: We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R þ T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib.

Background. A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to compare the eradication rate between VPZ-based treatment and PPI-based one. Methods. This randomized controlled trial was designed to assign 141 patients with H. pylori-positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results. Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P = 0.00003, 95% confidence interval [CI] 88.3-99.1% versus 57.3-80.1%) and per-protocol analysis (95.7% versus 71.4%, P = 0.0002, 95% CI 88.0-99.1% versus 58.7-82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P = 0.15). Conclusion. VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy.

Novel strategies against treatment-resistant tumor cells remain a challenging but promising therapeutic approach. Despite accumulated evidence suggesting the presence of highly malignant cell populations within tumors, the unsolved issues such as in vivo targeting and clinical relevance remain. Here, we report a preclinical trial based on the identified molecular mechanisms underlying osteosarcoma-initiating cells and their clinical relevance. We identified key microRNAs (miRNAs) that were deregulated in a highly malignant CD133 high population and found that miR-133a regulated the cell invasion that characterizes a lethal tumor phenotype. Silencing of miR-133a with locked nucleic acid (LNA) reduced cell invasion of this cell population, and systemic administration of LNA along with chemotherapy suppressed lung metastasis and prolonged the survival of osteosarcoma-bearing mice. Furthermore, in a clinical study, high expression levels of CD133 and miR-133a were significantly correlated with poor prognosis, whereas high expression levels of the four miR-133a target genes were correlated with good prognosis. Overall, silencing of miR-133a with concurrent chemotherapy would represent a novel strategy that targets multiple regulatory pathways associated with metastasis of the malignant cell population within osteosarcoma. STEM CELLS 2014;32:959-973