The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

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On March 24, 2016 The Merck Foundation (the Foundation) and the American Cancer Society (ACS) reported that the Foundation provided a grant of $1.58 million over four years to the ACS to implement a comprehensive Patient Navigation Program in three U.S. communities where substantial cancer care disparities exist (Press release, Merck & Co, MAR 24, 2016, View Source [SID:1234509919]). This funding will allow the ACS to enhance its already substantial Patient Navigation Program and expand its focus on access to high-quality care, patient empowerment and care coordination.

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Sites selected to participate in the community-based program include the Queens Hospital Center in Queens, N.Y.; the Phoenix Cancer Center/Maricopa Integrated Health System in Phoenix; and the University of New Mexico Cancer Center in Albuquerque, N.M. The organizations were selected because they provide services to diverse, low-income and often underserved patient populations.

"For 125 years, Merck has focused on finding solutions to improve care for patients facing devastating diseases like cancer," said Brenda D. Colatrella, president, Merck Foundation and executive director, Corporate Responsibility, Merck. "Receiving a cancer diagnosis can be an overwhelming experience, and we are proud to work with the American Cancer Society to help empower those touched by cancer to navigate the often complicated path to finding the best care available."

"Many people don’t know how to access the health care system. They don’t have insurance, they’re afraid or they have personal beliefs that lead them to ignore their health and avoid the health care system altogether," said Katherine Sharpe, senior vice president, Patient and Caregiver Support, American Cancer Society. "The Patient Navigation Program addresses these issues and helps people get the care they need even under very difficult cultural, economic, educational and financial circumstances. At the heart of patient navigation is the lesson that offering an ear to listen and a hand to help can have remarkable impact on the health of those most in need. We are grateful to the Merck Foundation for providing this grant to bring much-needed support to cancer patients in vulnerable communities in Arizona, New Mexico and New York."

The Patient Navigation Program is a proactive approach to providing guidance and support for cancer patients, their families and caregivers. Currently, more than 100 Patient Navigators are working in hospitals and cancer treatment centers nationwide. They help with identifying and reducing barriers to treatment, such as challenges with language, transportation and health insurance. In 2015, the Patient Navigation Program provided services to more than 44,000 patients across the nation, more than one-third of whom were covered by Medicaid or were uninsured.

About the American Cancer Society

The American Cancer Society is a global grassroots force of 2.5 million volunteers saving lives and fighting for every birthday threatened by every cancer in every community. As the largest voluntary health organization, the Society’s efforts have contributed to a 22 percent decline in cancer death rates in the U.S. since 1991, and a 50 percent drop in smoking rates. Thanks in part to our progress,14.5 million Americans who have had cancer and countless more who have avoided it will celebrate more birthdays this year. We’re determined to finish the fight against cancer. We’re finding cures as the nation’s largest private, not-for-profit investor in cancer research, ensuring people facing cancer have the help they need and continuing the fight for access to quality health care, lifesaving screenings, clean air and more. For more information, to get help, or to join the fight, call us anytime, day or night, at (800) 227-2345 or visit cancer.org.

Over the past decade, oncology therapies have trended toward orally administered regimens, and there has been growing attention on evaluation of factors that affect adherence. There has not been a rigorous investigation of factors associated with adherence to intravenous (IV) and oral anticancer drugs in the setting of metastatic colorectal cancer (mCRC).
To (a) assess potential patient-specific factors related to adherence to mCRC chemotherapy regimens and (b) compare adherence with IV versus oral dosage forms.
A retrospective analysis was performed using the Optum Oncology Management claims database. Patients aged 18 years and older diagnosed with mCRC between July 1, 2004, and December 31, 2010, who were insured by a commercial health plan were included in the study. Adherence to IV and oral chemotherapy regimens was assessed using the National Comprehensive Cancer Network (NCCN) guidelines as the standard for expected cycle/regimen duration. The most commonly prescribed chemotherapy regimens were assessed. Adherence was evaluated using the medication possession ratio (MPR), calculated as the number of days a patient was covered by their chemotherapy regimen, according to NCCN guidelines, divided by the number of days elapsed from the first to the last infusion of that regimen. For most analyses, the MPR was considered a continuous variable that could take on values between 0 and 1. In other analyses, a dichotomous categorical variable designated if the MPR was at least 0.8 versus less than 0.8. The Wilcoxon rank sum, Kruskal-Wallis, and Student’s t-test were used to detect differences in continuous measures between patients receiving oral capecitabine therapy versus IV chemotherapy. The chi square test (X(2) test) or Fisher’s exact test was used to assess differences in the dichotomous MPR variable. Generalized estimating equation (GEE) models were used for regimen-level analyses to account for correlated responses within individuals.
A total of 6,780 patients were included in the analysis, virtually all (98%) with commercial insurance coverage and the remaining (2%) with Medicare Advantage. Patients with mCRC received 17,095 regimens of chemotherapy, including 2,252 regimens of oral capecitabine. Of the 17,095 regimens, 6,780 (40%) were first-line regimens (i.e., the first time mCRC was treated for a given patient). The most common chemotherapy regimen, regardless of line of therapy, was FOLFOX (2,991 regimens, 17.5% of all regimens used). FOLFOX-based therapies with or without bevacizumab were the most common regimens for first- and second-line chemotherapy, while oral capecitabine treatment was the most commonly prescribed regimen for patients in third- or fourth-line therapy. Overall, medication adherence across all regimens was relatively high, with a mean MPR of 0.87 (SD = 0.17). Evaluation of the distribution of IV and oral capecitabine regimens revealed that 28% of all regimens were associated with an MPR of less than 0.8. The average MPR was clinically similar, but statistically higher for IV chemotherapy regimens (0.881) compared with oral capecitabine regimens (0.799; P < 0.0001). In the multivariable GEE model, lung or liver metastases were associated with a higher MPR, while lower Charlson Comorbidity Index and oral anticancer therapy were associated with lower MPR. Furthermore, as line of therapy increased, the difference in MPR between patients receiving oral capecitabine and IV chemotherapy increased.
This analysis determined that adherence with IV chemotherapy regimens was clinically similar, but statistically higher, compared to oral capecitabine therapy. The difference in adherence rates between the 2 routes of administration increased as the line of anticancer regimen increased. These results suggest that there should be an increased focus on improving adherence rates in patients receiving oral capecitabine.
This study was funded by Bayer HealthCare Pharmaceuticals. At the time of this study, Seal was an employee with Bayer HealthCare Pharmaceuticals; Anderson is employed by Bayer HealthCare Pharmaceuticals. Study concept and design were contributed by Seal and Shermock. Seal was responsible for data acquisition. Data analysis was conducted by Shermock. Interpretation of analyses was conducted by Shermock, Seal, and Anderson. The manuscript was written by Shermock, and all authors shared equally in revisions and final approval of the submitted manuscript.

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Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or β-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.

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Conventional two-dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver-specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg-Gly-Asp (RGD) and galactose-conjugated substratum with an optimized hybrid ratio as an in vitro three-dimensional (3D) human hepatocyte model. The liver-specific gene expression level and drug metabolizing enzyme activities in HepaRG-tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug-induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG-tethered spheroid would be an alternative in vitro model suitable for drug safety screening.
Copyright © 2014 John Wiley & Sons, Ltd.

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