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Opuntia ficus-indica seed attenuates hepatic steatosis and promotes M2 macrophage polarization in high-fat diet-fed mice.

Opuntia ficus-indica (L.) is a popular edible plant that possesses considerable nutritional value and exhibits diverse biological actions including anti-inflammatory and antidiabetic activities. In this study, we hypothesized that DWJ504, an extract of O ficus-indica seed, would ameliorate hepatic steatosis and inflammation by regulating hepatic de novo lipogenesis and macrophage polarization against experimental nonalcoholic steatohepatitis. Mice were fed a normal diet or a high-fat diet (HFD) for 10 weeks. DWJ504 (250, 500, and 1000 mg/kg) or vehicle (0.5% carboxymethyl cellulose) were orally administered for the last 4 weeks of the 10-week HFD feeding period. DWJ504 treatment remarkably attenuated HFD-induced increases in hepatic lipid content and hepatocellular damage. DWJ504 attenuated increases in sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein expression and a decrease in carnitine palmitoyltransferase 1A. Although DWJ504 augmented peroxisome proliferator-activated receptor α protein expression, it attenuated peroxisome proliferator-activated receptor γ expression. Moreover, DWJ504 promoted hepatic M2 macrophage polarization as indicated by attenuation of the M1 marker genes and enhancement of M2 marker genes. Finally, DWJ504 attenuated expression of toll-like receptor 4, nuclear factor κB, tumor necrosis factor α, interleukin 6, TIR-domain-containing adapter-inducing interferon β, and interferon β levels. Our results demonstrate that DWJ504 prevented intrahepatic lipid accumulation, induced M2 macrophage polarization, and suppressed the toll-like receptor 4-mediated inflammatory signaling pathway. Thus, DWJ504 has therapeutic potential in the prevention of nonalcoholic fatty liver disease.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Next-Generation Sequencing-Based HPV Genotyping Assay Validated in Formalin-Fixed, Paraffin-Embedded Oropharyngeal and Cervical Cancer Specimens.

Available clinical human papilloma virus (HPV) diagnostics for head and neck cancer have limited sensitivity and/or fail to define the HPV genotype. Common HPV genotyping assays are costly and labor intensive. We sought to develop a next-generation sequencing (NGS)-based HPV genotyping assay that was sensitive enough to work on formalin-fixed paraffin-embedded (FFPE) samples. We developed an ion torrent NGS HPV genotyping assay using barcoded HPV PCR broad-spectrum general primers 5(+)/6(+) (BSGP)5(+)/6(+). To validate genotype specificity and use in archived clinical FFPE tumor samples, we compared NGS HPV genotyping at 2 sequencing centers with typing by Roche Linear Array assay in 42 oropharyngeal and cervical cancer specimens representing 10 HPV genotypes, as well as HPV-negative cases. To demonstrate the detection of a broad range of HPV genotypes, we genotyped a cohort of 266 cervical cancers. A comparison of NGS genotyping of FFPE cancer specimens with genotyping by Linear Array showed concordant results in 34/37 samples (92%) at sequencing site 1 and 39/42 samples (93%) at sequencing site 2. Concordance between sites was 92%. Designed for use with 10 ng genomic DNA, the assay detected HPV using as little as 1.25 ng FFPE-derived genomic DNA. In 266 cervical cancer specimens, the NGS assay identified 20 different HPV genotypes, including all 13 carcinogenic genotypes. This novel NGS assay provides a sensitive and specific high-throughput method to detect and genotype HPV in a range of clinical specimens derived from FFPE with low per-sample cost.

Chemotherapy following radium-223 dichloride treatment in ALSYMPCA.

Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following radium-223.
In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2:1 to receive six injections of radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed.
Overall, 142 radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% radium-223, 72% placebo) and mitoxantrone (16% radium-223, 20% placebo). The majority of patients (61% radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3-4 hematologic values (&lt;10%). Platelet count decline, from last measurement before chemotherapy, was numerically greater in radium-223 versus placebo patients. Median overall survivals from start of chemotherapy were 16.0 and 15.8 months following radium-223 and placebo, respectively.
Chemotherapy following radium-223, regardless of prior docetaxel, is feasible and appears to be well tolerated in patients with CRPC and symptomatic bone metastases. Prostate. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.

Factors Associated with Adherence Rates for Oral and Intravenous Anticancer Therapy in Commercially Insured Patients with Metastatic Colon Cancer.

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 &lt; 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.

The association between general practitioner participation in joint teleconsultations and rates of referral: a discrete choice experiment.

Joint consultations – such as teleconsultations – provide opportunities for continuing education of general practitioners (GPs). It has been reported this form of interactive case-based learning may lead to fewer GP referrals, yet these studies have relied on expert opinion and simple frequencies, without accounting for other factors known to influence referrals. We use a survey-based discrete choice experiment of GPs’ referral preferences to estimate how referral rates are associated with participation in joint teleconsultations, explicitly controlling for a number of potentially confounding variables.
We distributed questionnaires at two meetings of the Portuguese Association of General Practice. GPs were presented with descriptions of patients with dermatological lesions and asked whether they would refer based on the waiting time, the distance to appointment, and pressure from patients for a referral. We analysed GPs’ responses to multiple combinations of these factors, coupled with information on GP and practice characteristics, using a binary logit model. We estimated the probabilities of referral of different lesions using marginal effects.
Questionnaires were returned by 44 GPs, giving a total of 721 referral choices. The average referral rate for the 11 GPs (25%) who had participated in teleconsultations was 68.1% (range 53-88%), compared to 74.4% (range 47-100%) for the remaining physicians. Participation in teleconsultations was associated with reductions in the probabilities of referral of 17.6% for patients presenting with keratosis (p = 0.02), 42.3% for psoriasis (p &lt; 0.001), 8.4% for melanoma (p = 0.14), and 5.4% for naevus (p = 0.19).
The results indicate that GP participation in teleconsultations is associated with overall reductions in referral rates and in variation across GPs, and that these effects are robust to the inclusion of other factors known to influence referrals. The reduction in range, coupled with different effects for different clinical presentations, may suggest an educational effect. However, more research is needed to establish whether there are causal relationships between participation in teleconsultations, continuing education, and referral rates.