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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 &lt; 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 (&gt; 65 years) and body mass index (≤ 25) (P &lt; 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.

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.

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 &quot;click&quot; reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with &lt;sup&gt;64&lt;/sup&gt;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&lt;sup&gt;+/+&lt;/sup&gt;) xenograft tumors with &lt;sup&gt;64&lt;/sup&gt;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, &lt;sup&gt;64&lt;/sup&gt;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).

EISAI TRANSFERS THE RIGHTS TO INVESTIGATIONAL ANTICANCER AGENT E7777 FOR EUROPEAN, U.S. AND CERTAIN EMERGING MARKETS TO DR. REDDY’S LABORATORIES

On March 31, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has entered into an agreement to transfer the exclusive worldwide development and marketing rights (excluding Japan and Asia) for its investigational anticancer agent E7777 to Dr. Reddy’s Laboratories Ltd. (Dr. Reddy’s) (Press release, Eisai, MAR 31, 2016, View Source [SID:1234510237]).

Under this agreement, Eisai will be responsible for development and marketing of E7777 in Japan and Asia, while Dr. Reddy’s will be responsible for development and marketing of the agent in all other regions. Furthermore, Dr. Reddy’s holds an option for the rights to develop and market the agent in India. Through this agreement, the two companies aim to accelerate development and maximize the value of E7777. From Dr. Reddy’s, Eisai will receive milestone payments in line with obtaining marketing approval and the achievement of sales targets.

E7777 is a fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. A Phase II clinical study of the agent in patients with cutaneous T-cell lymphoma or peripheral T-cell lymphoma is currently underway in Japan. Preparations are simultaneously in progress for a Phase III clinical study of the agent in patients with cutaneous T-cell lymphoma in the United States.

Eisai positions oncology as a key franchise area, and is committed to providing new treatment options for patients with cancer in order to further contribute to addressing unmet medical needs that exist in the treatment of cancer as well as increase the benefits provided to patients and their families.

About E7777

E7777 is a fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. A Phase II clinical study of the agent in patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma is currently underway in Japan. In addition, preparations are in progress for a Phase III clinical study of the agent in patients with cutaneous T-cell lymphoma in the United States.

About Cutaneous T-cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a type of cutaneous non-Hodgkin’s lymphoma that comes in a variety of forms, and is the most common type of T-cell non-Hodgkin’s lymphoma. In CTCL, T-cells (a type of lymphocyte that plays a role in the immune system) become cancerous and develop into skin lesions, leading to a decrease in quality of life (QOL) of patients with this disease due to severe pain and pruritus. While CTCL is often regarded as a low-grade lymphoma, it is slowly progressive and can take anywhere from several years to upwards of ten to reach tumor stage. Once the disease reaches this stage, the cancer is highly malignant and has usually spread to the lymph nodes and internal organs, resulting in a poor prognosis, and therefore this is currently a disease with significant unmet medical need.

About Peripheral T-cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma and classified as intermediate-grade. Often discovered once the disease has progressed, symptoms include swelling and lumps in the lymph nodes, fever, night sweats and weight loss. Among PTCLs, while prognosis is good for ALK-positive anaplastic large cell lymphoma which tends to affect adults aged between 20 and 30, other disease types often affect people aged around 60, and with poor prognosis and situations where treatment is difficult, PTCL is a disease with significant unmet medical need.