Health economic evaluation of Gd-EOB-DTPA MRI versus ECCM-MRI and multidetector computed tomography in patients with suspected hepatocellular carcinoma in Thailand and South Korea.

Objective The effectiveness of treatment decisions and economic outcomes of using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI) were compared with extracellular contrast media-enhanced MRI (ECCM-MRI) and multidetector computed tomography (MDCT) as initial procedures in patients with suspected hepatocellular carcinoma (HCC) in South Korea and Thailand. Methods A decision-tree model simulated the clinical pathway for patients with suspected HCC from the first imaging procedure to a confirmed treatment decision. Input data (probabilities and resource consumptions) were estimated and validated by clinical experts. Costs for diagnostic alternatives and related treatment options were derived from published sources taking into account both payer’s and hospital’s perspectives. Results All experts from Korea and Thailand agreed that Gd-EOB-DTPA-MRI yields the highest diagnostic certainty and minimizes the need for additional confirmatory diagnostic procedures in HCC. In Korea, from the payer’s perspective, total cost was USD $3,087/patient to reach a confirmed treatment decision using Gd-EOB-DTPA-MRI (vs. $3,205/patient for MDCT and $3,403/patient for ECCM-MRI). From the hospital’s perspective, Gd-EOB-DTPA-MRI incurred the lowest cost ($2,289/patient vs. $2,320/patient and $2,528/patient, respectively). In Thailand, Gd-EOB-DTPA-MRI was the least costly alternative for the payer ($702/patient vs. $931/patient for MDCT and $873/patient for ECCM-MRI). From the hospital’s perspective, costs were $1,106/patient, $1,178/patient, and $1,087/patient for Gd-EOB-DTPA-MRI, MDCT, and ECCM-MRI, respectively. Conclusions Gd-EOB-DTPA-MRI as an initial imaging procedure in patients with suspected HCC provides better diagnostic certainty and relevant statutory health insurance cost savings in Thailand and Korea, compared with ECCM-MRI and MDCT.

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Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer.

Recent studies suggest that an elevated preoperative platelet to lymphocyte ratio (PLR) may be considered a poor prognostic biomarker in patients with colorectal cancer (CRC). The aim of this study was to evaluate the prognostic impact of PLR in patients with CRC.
We enrolled 1314 patients who underwent surgery for CRC between 2005 and 2011. Preoperative PLR level was stratified into quintiles for Kaplan-Meier analysis and multivariable Cox proportional hazard regression models.
Higher PLR quintiles were significantly associated with poorer overall survival (P = 0.002). Multivariate analysis showed that PLR was an independent risk factor for overall survival (OS) (P = 0.034). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 1.701, 95% confidence interval (CI): 1.267-2.282, P < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.522, 95% CI: 1.114-2.080, P = 0.008), this association was not significant after multivariable adjustment (P = 0.075). In the subgroup analysis, PLR remained an independent factor in terms of advanced tumor stage (III, IV), male sex, carcinoembryonic antigen (≤ 5 ng/ml), age (> 65 years) and body mass index (≤ 25) (P < 0.05 for all measurements). The results remained unchanged when the PLR was analyzed as a dichotomous variable by applying different cut-off values of 150, 185, 220.
Elevated preoperative PLR was independently associated with an increased risk of mortality in patients with CRC. The utility of PLR may help to improve prognostic predictors.

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JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells’ dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.
Copyright © 2016, American Association for the Advancement of Science.

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5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation.

While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.

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Dual-targeting of tissue factor and CD105 for preclinical PET imaging of pancreatic cancer.

Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly-specific non-invasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention.
A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bioorthogonal "click" reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with <sup>64</sup>Cu for positron emission tomography (PET) imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors.
PET imaging of BXPC-3 (TF/CD105<sup>+/+</sup>) xenograft tumors with <sup>64</sup>Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 {plus minus} 3.2 %ID/g; n = 4, SD) at 30 h post-injection (p.i.), as compared to each of their monospecific Fab tracers (12.5 {plus minus} 1.4 and 7.1 {plus minus} 2.6 %ID/g; n = 3, SD). In addition, the activity-concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 {plus minus} 9.4 at 30 h p.i.; n = 4, SD). Furthermore, <sup>64</sup>Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 {plus minus} 4.9 %ID/g at 30 h p.i. and tumor/muscle ratio of 72.3 {plus minus} 46.7.
This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assists in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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