Dexamethasone pretreatment impairs the thymidylate synthase inhibition mediated flare in thymidine salvage pathway activity in non-small cell lung cancer.

INTRODUCTION:Successful inhibition of thymidylate synthase (TS) by pemetrexed, a TS inhibitor, results in a reproducible transient burst or "flare" in thymidine salvage pathway activity at 2 hrs. of therapy which can be measurable with FLT-PET ([18F]fluorothymidine-positron emission tomography) in non-small cell lung cancer (NSCLC). Routine administration of dexamethasone with pemetrexed-based therapy could potentially confound this imaging approach since dexamethasone is known to inhibit expression of thymidine kinase 1, a key enzyme in the thymidine salvage pathway. Here we examine the potential impact of dexamethasone on the TS inhibition-mediated thymidine salvage pathway "flare" in NSCLC. MATERIALS AND METHODS:In order to determine NSCLC cell line sensitivity to dexamethasone and pemetrexed, IC50 studies were performed on NSCLC cell lines H23, H1975, H460, H1299. TS inhibition-mediated "flare" in thymidine salvage pathway activity was then measured at 2hrs. of exposure to pemetrexed and cisplatin in NSCLC cells lines following using 3H-thymidine incorporation assays under the following conditions: control (no chemotherapy or dexamethasone), or treated with pemetrexed and cisplatin without dexamethasone, with 24 hrs. pre-treatment of dexamethasone or with dexamethasone administered together with chemotherapy. These conditions were chosen to model the delivery of pemetrexed-based therapy in the clinic. RESULTS:The IC50 of H23, H1975, H460, H1299 for dexamethasone and pemetrexed were 40, 5.9, 718, 362 μM and 0.22, 0.73, 0.14 and 0.66 μM respectively. Significant blunting of the thymidine salvage pathway "flare" is observed at 2hrs. of pemetrexed-based therapy when dexamethasone sensitive cell lines H23 and H1975 were pretreated with dexamethasone but not when dexamethasone was given together with pemetrexed therapy or in the setting of dexamethasone resistance (H460 and H1299). CONCLUSION:24 hr. pretreatment with dexamethasone, but not same day co-administration of dexamethasone with therapy, impairs the TS inhibition-mediated "flare" in thymidine salvage pathway activity in NSCLC

Imaging in pleural mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group

Mesothelioma patients rely on the information their clinical team obtains from medical imaging. Whether x-ray-based computed tomography (CT) or magnetic resonance imaging (MRI) based on local magnetic fields within a patient's tissues, different modalities generate images with uniquely different appearances and information content due to the physical differences of the image-acquisition process. Researchers are developing sophisticated ways to extract a greater amount of the information contained within these images. This paper summarizes the imaging-based research presented orally at the 2018 International Conference of the International Mesothelioma Interest Group (iMig) in Ottawa, Ontario, Canada, held May 2-5, 2018. Presented topics included advances in the imaging of preclinical mesothelioma models to inform clinical therapeutic strategies, optimization of the time delay between contrast administration and image acquisition for maximized enhancement of mesothelioma tumor on CT, an investigation of image-based criteria for clinical tumor and nodal staging of mesothelioma by contrast-enhanced CT, an investigation of methods for the extraction of mesothelioma tumor volume from MRI and the association of volume with patient survival, the use of deep learning for mesothelioma tumor segmentation in CT, and an evaluation of CT-based radiomics for the prognosis of mesothelioma patient survival

Patient-Centered and Specialty-Specific Case Work-Up: An Effective Method for Teaching Appropriateness of Imaging to Medical Students.

RATIONALE AND OBJECTIVES: Our institution has developed a mini-course program within the diagnostic radiology elective curriculum that promotes active learning, using patient cases specifically tailored to students\u27 future specialties. The purpose of this study is to evaluate the effectiveness of this mini-course on medical student knowledge of imaging appropriateness and attitude toward radiologist consultation. MATERIALS AND METHODS: During each month-long radiology elective course, students were divided into teams of up to four students based on their specialty interest and assigned recent patient cases with imaging findings relevant to their specialties. The students researched their customized patient cases, integrated pertinent clinical and imaging findings, and presented their findings in a final preceptor-led session. A five-point Likert-type item preprogram and postprogram survey assessing knowledge of imaging appropriateness and attitude toward radiologist consultation was sent to the enrolled medical students. RESULTS: Out of 36 medical students, 33 (92%) completed the preprogram survey and 31 (86%) completed the postprogram survey. Students reported improved confidence in knowledge of imaging appropriateness, such as indications for intravenous contrast (p \u3c 0.0005) and oral contrast (p \u3c 0.0005). Furthermore, students reported an improved understanding of how to utilize radiologists (p \u3c 0.005) and how to provide pertinent clinical historical information when requesting a radiology exam (p \u3c 0.0005). Students reported that researching the patient\u27s historical and clinical information in conjunction with the radiology images made them more invested in the case. CONCLUSION: Assigning customized patient cases to medical students on diagnostic radiology elective, tailored to their future specialties, is an effective and active way to teach imaging appropriateness and to improve attitudes toward radiologist consultation

KLF5 and p53 comprise an incoherent feed-forward loop directing cell-fate decisions following stress

Abstract In response to stress, cells make a critical decision to arrest or undergo apoptosis, mediated in large part by the tumor suppressor p53. Yet the mechanisms of these cell fate decisions remain largely unknown, particularly in normal cells. Here, we define an incoherent feed-forward loop in non-transformed human squamous epithelial cells involving p53 and the zinc-finger transcription factor KLF5 that dictates responses to differing levels of cellular stress from UV irradiation or oxidative stress. In normal unstressed human squamous epithelial cells, KLF5 complexes with SIN3A and HDAC2 repress TP53, allowing cells to proliferate. With moderate stress, this complex is disrupted, and TP53 is induced; KLF5 then acts as a molecular switch for p53 function by transactivating AKT1 and AKT3, which direct cells toward survival. By contrast, severe stress results in KLF5 loss, such that AKT1 and AKT3 are not induced, and cells preferentially undergo apoptosis. Thus, in human squamous epithelial cells, KLF5 gates the response to UV or oxidative stress to determine the p53 output of growth arrest or apoptosis

Impact of Interobserver Variability in Manual Segmentation of Non-Small Cell Lung Cancer (NSCLC) Applying Low-Rank Radiomic Representation on Computed Tomography

This study tackles interobserver variability with respect to specialty training in manual segmentation of non-small cell lung cancer (NSCLC). Four readers included for segmentation are: a data scientist (BY), a medical student (LS), a radiology trainee (MH), and a specialty-trained radiologist (SK) for a total of 293 patients from two publicly available databases. Sørensen–Dice (SD) coefficients and low rank Pearson correlation coefficients (CC) of 429 radiomics were calculated to assess interobserver variability. Cox proportional hazard (CPH) models and Kaplan-Meier (KM) curves of overall survival (OS) prediction for each dataset were also generated. SD and CC for segmentations demonstrated high similarities, yielding, SD: 0.79 and CC: 0.92 (BY-SK), SD: 0.81 and CC: 0.83 (LS-SK), and SD: 0.84 and CC: 0.91 (MH-SK) in average for both databases, respectively. OS through the maximal CPH model for the two datasets yielded c-statistics of 0.7 (95% CI) and 0.69 (95% CI), while adding radiomic and clinical variables (sex, stage/morphological status, and histology) together. KM curves also showed significant discrimination between high- and low-risk patients (p-value < 0.005). This supports that readers’ level of training and clinical experience may not significantly influence the ability to extract accurate radiomic features for NSCLC on CT. This potentially allows flexibility in the training required to produce robust prognostic imaging biomarkers for potential clinical translation

Considerations for Imaging of Malignant Pleural Mesothelioma: A Consensus Statement from the International Mesothelioma Interest Group (iMig)

Malignant pleural mesothelioma (MPM) is an aggressive primary malignancy of the pleura that presents unique radiologic challenges with regard to accurate and reproducible assessment of disease extent at staging and follow-up imaging. By optimizing and harmonizing technical approaches to imaging MPM, the best quality imaging can be achieved for individual patient care, clinical trials, and imaging research. This consensus statement represents agreement on harmonized, standard practices for routine multimodality imaging of MPM, including radiography, computed tomography, 18F-2-deoxy-D-glucose positron emission tomography, and magnetic resonance imaging, by an international panel of experts in the field of pleural imaging assembled by the International Mesothelioma Interest Group. In addition, modality-specific technical considerations and future directions are discussed. A bulleted summary of all technical recommendations is provided

A trial of intrapleural adenoviral-mediated Interferon-α2b gene transfer for malignant pleural mesothelioma.

New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe flu-like symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367)