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Hepatocellular carcinoma surveillance rates in commercially insured patients with noncirrhotic chronic hepatitis B.

American association for the study of liver diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend biannual hepatocellular carcinoma (HCC) screening for noncirrhotic patients with chronic hepatitis B infection (HBV), yet there are no data estimating surveillance rates or factors associated with surveillance. We performed a retrospective cohort study of US patients using the Truven Health Analytics databases from 2006 to 2010 and identified patients with noncirrhotic chronic HBV. Surveillance patterns were characterized using categorical and continuous outcomes, with the continuous measure of the proportion of time ‘up to date’ with surveillance (PUTDS), with the 6-month interval following each ultrasound categorized as ‘up to date’. During a median follow-up of 26.0 (IQR: 16.2-40.0) months among 4576 noncirrhotic patients with chronic HBV (median age: 44 years, IQR: 36-52), only 306 (6.7%) had complete surveillance (one ultrasound every 6-month interval), 2727 (59.6%) incomplete (≥1 ultrasound) and 1543 (33.7%) none. The mean PUTDS was 0.34 ± 0.29, and the median was 0.32 (IQR: 0.03-0.52). In multinomial logistic regression models, patients diagnosed by a nongastroenterologist were significantly less likely to have complete surveillance (P &lt; 0.001), as were those coinfected with HBV/HIV (P &lt; 0.001). In linear regression models, nongastroenterologist provider, health insurance subtype, HBV/HIV coinfection, rural status and metabolic syndrome were independently associated with decreased surveillance. Patients with HIV had an absolute decrease in the PUTDS of 0.24, while patients in less populated rural areas had an absolute decrease of 0.10. HCC surveillance rates in noncirrhotic patients with chronic HBV in the United States are poor and lower than reported rates of HCC surveillance in cirrhotic patients.
© 2015 John Wiley &amp; Sons Ltd.

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AZD9496: An oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1 mutant breast tumours in preclinical models.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a non-steroidal small molecule inhibitor of ERα which is a potent and selective antagonist and down-regulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumour growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth inhibitory effects compared to monotherapy alone. Tumour regressions were also seen in a long-term estrogen-deprived breast model, where significant down-regulation of ERα protein was observed. AZD9496 bound and down-regulated clinically relevant ESR1 mutants in vitro and inhibited tumour growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacological evidence showed that AZD9496 is an oral, non-steroidal, selective estrogen receptor antagonist and down-regulator in ER-positive breast cells that could provide meaningful benefit to ER-positive breast cancer patients. AZD9496 is currently being evaluated in a Phase 1 clinical trial.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Burden of symptoms associated with development of metastatic bone disease in patients with breast cancer.

Women with breast cancer frequently develop painful bone metastases. This retrospective study was designed to longitudinally characterize patterns of patient-reported symptoms among patients with breast cancer relative to the diagnosis of bone metastases.
Patient records were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database which includes outpatient oncology practices across the USA. Symptom burden was assessed by Patient Care Monitor (PCM) assessments, which are administered as part of routine care in a subset of these practices. Eligible patients were women diagnosed with breast cancer (ICD-9-CM 174.xx) who developed bone metastases (ICD-9-CM 198.5) and had ≥1 PCM assessment between January 2007 and December 2012. The pre-specified endpoint was the occurrence of moderate to severe symptom burden, defined as PCM score ≥4 (0-10 scale).
One thousand one hundred five women (median age, 61) met the eligibility criteria. Worsening of symptoms, particularly fatigue and pain, occurred in the months leading up to the diagnosis of bone metastases. After bone metastases diagnosis, the rate of increase in the proportion of patients experiencing moderate/severe symptoms slowed, but continued to climb during follow-up. Median time to moderate/severe symptoms was 0.9 month for fatigue, 1 month for pain, 2.9 months for trouble sleeping, and 7.7 months for numbness/tingling. Half of the patients received bone-targeted agents after diagnosis of bone metastases.
Symptom burden, especially pain and fatigue, increased both before and after the diagnosis of bone metastases, highlighting the need for proactive monitoring and management of symptoms in breast cancer patients.

Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.

Pharmacokinetics of Gd(DO3A-Lys) and MR imaging studies in an orthotopic U87MG glioma tumor model.

Pharmacokinetics of Gd(DO3A-Lys), a macrocyclic gadolinium-based magnetic resonance imaging (MRI) contrast agent functionalized with a lysine derivative, was studied in Wistar rats. Kinetic data were fitted using a two-compartment model and revealed Gd(DO3A-Lys) to have a distribution half-life, t1/2 (α), of 1.3 min, an elimination half-life, t1/2 (β), of 24.9 min and a large volume of distribution, VD , of 0.49 L/kg indicative of the agent being able to rapidly distribute into tissues and organs. Contrast-enhanced magnetic resonance angiography (CE-MRA) in an orthotopic U87MG glioma mouse model demonstrated considerable enhancement of both the tumor and surrounding vasculature after intravenous administration of Gd(DO3A-Lys). Applying dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the glioma of different sizes further showed distinct uptake characteristics and patterns of enhancement, which suggests the potential for differentiating changes at different stages of tumor growth. Our results indicate that Gd(DO3A-Lys) could be a promising candidate for glioma MR imaging.
Copyright © 2015 John Wiley &amp; Sons, Ltd.

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Hepatocellular carcinoma surveillance rates in commercially insured patients with noncirrhotic chronic hepatitis B.

AZD9496: An oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1 mutant breast tumours in preclinical models.

Burden of symptoms associated with development of metastatic bone disease in patients with breast cancer.

Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

Pharmacokinetics of Gd(DO3A-Lys) and MR imaging studies in an orthotopic U87MG glioma tumor model.