The Emergent Landscape of Detecting EGFR Mutations Using Circulating Tumor DNA in Lung Cancer.

The advances in targeted therapies for lung cancer are based on the evaluation of specific gene mutations especially the epidermal growth factor receptor (EGFR). The assays largely depend on the acquisition of tumor tissue via biopsy before the initiation of therapy or after the onset of acquired resistance. However, the limitations of tissue biopsy including tumor heterogeneity and insufficient tissues for molecular testing are impotent clinical obstacles for mutation analysis and lung cancer treatment. Due to the invasive procedure of tissue biopsy and the progressive development of drug-resistant EGFR mutations, the effective initial detection and continuous monitoring of EGFR mutations are still unmet requirements. Circulating tumor DNA (ctDNA) detection is a promising biomarker for noninvasive assessment of cancer burden. Recent advancement of sensitive techniques in detecting EGFR mutations using ctDNA enables a broad range of clinical applications, including early detection of disease, prediction of treatment responses, and disease progression. This review not only introduces the biology and clinical implementations of ctDNA but also includes the updating information of recent advancement of techniques for detecting EGFR mutation using ctDNA in lung cancer

Liquid biopsy genotyping in lung cancer: ready for clinical utility?

Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy

A Liposomal Formulation Able to Incorporate a High Content of Paclitaxel and Exert Promising Anticancer Effect

A liposome formulation for paclitaxel was developed in this study. The liposomes, composed of naturally unsaturated and hydrogenated phosphatidylcholines, with significant phase transition temperature difference, were prepared and characterized. The liposomes exhibited a high content of paclitaxel, which was incorporated within the segregated microdomains coexisting on phospholipid bilayer of liposomes. As much as 15% paclitaxel to phospholipid molar ratio were attained without precipitates observed during preparation. In addition, the liposomes remained stable in liquid form at 4°C for at least 6 months. The special composition of liposomal membrane which could reduce paclitaxel aggregation could account for such a capacity and stability. The cytotoxicity of prepared paclitaxel liposomes on the colon cancer C-26 cell culture was comparable to Taxol. Acute toxicity test revealed that LD50 for intravenous bolus injection in mice exceeded by 40 mg/kg. In antitumor efficacy study, the prepared liposomal paclitaxel demonstrated the increase in the efficacy against human cancer in animal model. Taken together, the novel formulated liposomes can incorporate high content of paclitaxel, remaining stable for long-term storage. These animal data also demonstrate that the liposomal paclitaxel is promising for further clinical use

Refinement treatment of nasal bone fracture: A 6-year study of 329 patients

SummaryBackgroundThe reliability of X-ray radiography for diagnosing nasal bone fractures (NBFs) remains controversial. Recent studies show that, for determining the orientation and location of the displaced/depressed fracture, nasal sonography is as accurate as facial computed tomography. This retrospective study compared conductor-assisted nasal sonography (CANS) to conventional diagnostic tools and reported subjective patient satisfaction and discomfort after closed reduction combined with tube technique.MethodsThis retrospective study reports the results of 329 refinement treatments for nasal bone fracture (including 199 men and 130 women) performed from 2005 to 2011. All patients were assessed with CANS and completed a survey immediately prior to removing the packing. Questionnaires were adapted from the nasal obstruction symptom evaluation (NOSE) scale.ResultsThe study found that CANS has a 97.2% rate of accuracy in diagnosing NBF. The visual analog scale scores of nasal obstruction, nasal congestion, sleep disturbance, trouble breathing, and inability to move air through the nose were analyzed. The experimental group scores were significantly different from the control group for all scores (p < 0.001).ConclusionCompared to conventional methods, CANS is more accurate for detecting NBF. We recommend its use as an alternative tool for diagnosing a nasal fracture. Because the tube technique balances pressure between the nasopharynx and middle ear during swallowing, patient comfort is enhanced. Application of these modifications can improve accuracy in diagnosing NBF and can improve the quality of NBF treatment

Time-Frequency Analysis of Superorbital Modulation of X-ray Binary SMC X-1 by Hilbert-Huang Transform

The high-mass X-ray binary (HMXB) SMC X-1 exhibits a superorbital modulation with a dramatically varying period ranging between ~40 d and ~60 d. This research studies the time-frequency properties of the superorbital modulation of SMC X-1 based on the observations made by the All-Sky Monitor (ASM) onboard the Rossi X-ray Timing Explorer (RXTE).We analyzed the entire ASM database collected since 1996. The Hilbert-Huang Transform (HHT), developed for non-stationary and nonlinear time series analysis, was adopted to derive the instantaneous superorbital frequency. The resultant Hilbert spectrum is consistent with the dynamic power spectrum while it shows more detailed information in both the time and frequency domains. The RXTE observations manifest that the superorbital modulation period was mostly betweenn ~50 d and ~65 d, whenas it changed to ~45 d around MJD 50,800 and MJD 54,000. Our analysis further indicates that the instantaneous frequency changed in a time scale of hundreds of days between ~MJD 51,500 and ~MJD 53,500. Based on the instantaneous phase defined by HHT, we folded the ASM light curve to derive a superorbital profile, from which an asymmetric feature and a low state with barely any X-ray emissions (lasting for ~0.3 cycles) were observed. We also calculated the correlation between the mean period and the amplitude of the superorbital modulation. The result is similar to the recently discovered relationship between the superorbital cycle length and the mean X-ray flux for Her X-1.Comment: 26 pages, 9 figures, accepted for publication in The Astrophysical Journa

Spontaneous Dissecting Aneurysm of the Renal Artery: A Case Report

Primary dissecting aneurysms of the renal artery are exceedingly rare. The triad of flank pain, hematuria, and hypertension of acute onset in the absence of urinary obstruction should suggest this rare condition. We report a case of spontaneous dissecting aneurysm of the renal artery treated using conservative medical treatment. The diagnosis, therapeutic management, and outcome are discussed

Phase Ib/II study of ceritinib in combination with ribociclib in patients with ALK-rearranged non–small cell lung cancer

ALK inhibitors; Ceritinib; RibociclibInhibidores de ALK; Ceritinib; RibociclibInhibidors d'ALK; Ceritinib; RibociclibBackground Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non–small cell lung cancer (NSCLC). Methods This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy. Results Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300–450 mg/day) and ribociclib (range, 100–300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4–57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5–25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5–25.1). Safety profile of the combination therapy was consistent with single-agent safety data. Conclusion Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.This study was supported by Novartis Pharmaceuticals Corporation

Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells

<p>Abstract</p> <p>Background</p> <p>Spontaneous interleukin-6 (IL-6) production has been observed in various tumors and implicated in the pathogenesis, progression and drug resistance in cancer. However, the regulation of IL-6 autocrine production in cancer cells is not fully understood. IL-6 is auto-regulated in many types of cell. Two of the three major downstream pathways of IL-6, MEK/extracellular signal-related kinase (Erk) pathway and phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, have been shown to regulate IL-6 expression through the activation of AP-1 and NF-κB. However, it is not clear what the role of Janus kinase (Jak) 2/signal transducer and activator of transcription (Stat) 3 pathway. This study was designed to determine the role of Jak2/Stat3 pathway in the regulation of IL-6 autocrine production in cancer cells.</p> <p>Results</p> <p>Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3. Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells. Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6. In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells. The pharmacological inhibition of NF-κB, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells.</p> <p>Conclusions</p> <p>This study is the first to directly address the role Stat3 plays on the autocrine production of IL-6, which occurs through a positive-feedback loop. Our biochemical and genetic studies clearly demonstrated that Jak2/Stat3, in combination with other IL-6 downstream pathways, contributed frequently and substantially to IL-6 autocrine production in a broad spectrum of cancer cell lines as well as in clinical cancer samples. Our findings suggest that Stat3 could potentially be regulated to suppress IL-6 autocrine production in cancer cells to inhibit the progression of cancer and reduce drug resistance.</p