Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug–drug interaction study in patients with ALK + advanced tumors

Cancer shared this article with you from Inoreader Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug–drug interaction study in patients with ALK  + advanced tumors Via Latest Results for Cancer Chemotherapy and Pharmacology Abstract Purpose Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug–drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. Methods This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. Results Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. Conclusion Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MiR-200c/FUT4 axis prevents the proliferation of colon cancer cells by downregulating the Wnt/β-catenin pathway

Cancer shared this article with you from Inoreader MiR-200c/FUT4 axis prevents the proliferation of colon cancer cells by downregulating the Wnt/β-catenin pathway Via Latest Results for BMC Cancer Abstract Background MicroRNA (miR)-200c has been widely reported to be involved in colon cancer progress. However, the mechanisms of miR-200c in regulating tumor metastasis and growth remain to be fully elucidated. This study aimed to investigate the mechanism of miR-200c targets fucosyltransferase 4 (FUT4) on the proliferation of colon cancer. Methods The miR-200c and FUT4 mRNA levels in LoVo and SW480 cells were measured by real-time quantitative polymerase chain reaction. Further, miR-200c mimic, FUT4 siRNA and FUT4 mimic were transfected into cells, separately. Cell counting kit-8, plate colony formation and transwell assays were used to analyse the cells biological behaviour.. Immunofluorescence was used to analyse the Ki-67 expression Moreover, the Wnt/β-catenin pathway-related proteins were detected by western blots. A double luciferase experiment was performed to confirm the relationship between miR-200c and FUT4. In vivo, tumour growth and Wnt/β-catenin pathway-related proteins were also analysed. Results In vitro, the expression of miR-200c and FUT4 were negatively correlated in LoVo and SW480 cells (correlation coefficients were − 0.9046 and − 0.9236, respectively). MiR-200c overexpression inhibited the proliferation, migration and invasion of LoVo and SW480 cells by downregulating FUT4. The Ki67-positive cells and Wnt/β-catenin signalling pathway-related proteins were reduced in the miR-200c overexpression and FUT4 silencing groups. A dual luciferase reporting system identified FUT4 as the target of miR-200c. The results in vivo were further confirmed the foundation of cells study. Conclusions In summary, miR-200c overexpression inhibits proliferation of colon cancer targeting FUT4 to downregulate the Wnt/β-catenin pathway, which promises molecular targets to inhibit metastasis for colon cancer therapy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Designing an exercise intervention for adult survivors of childhood cancers

Cancer shared this article with you from Inoreader Designing an exercise intervention for adult survivors of childhood cancers Via Latest Results for BMC Cancer Abstract Background This study examined current physical activity levels and preferences for exercise settings and activities among adult survivors of childhood cancers as a strategy to inform the feasibility and design of such programs. Methods A mixed-methods design was used to investigate current activity levels as well as barriers to and preferences for physical activity among 20 adult survivors of pediatric cancer. Results One-half of participants reported engaging in regular physical activity, although the frequency, intensity, and duration varied. Overall, 17 of the 20 participants (85%) stated they would be interested in participating in a structured exercise intervention, and they expressed a strong interest in walking (76%), bicycling (53%), and weight training (53%). Common barriers to participation in a potential structured exercise program were insufficient time, current health issues, and program location/distance. Nearly all participants agreed that information on nutrition and diet should be included as part of an exercise intervention. Conclusions These findings will help inform the design and implementation of future exercise programs to enhance physical activity among this high-risk group of cancer survivors. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care

Cancer shared this article with you from Inoreader A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care Via Latest Results for Journal of Neuro-Oncology Abstract Introduction Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2 years due to GBM's aggressive cellular migration and genetically driven treatment escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future. Methods We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies. Results Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy. Conclusion In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient's diverse genetic variations and therapy response/escape patterns. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Predictors of postoperative biochemical remission in acromegaly

Cancer shared this article with you from Inoreader Predictors of postoperative biochemical remission in acromegaly Via Latest Results for Journal of Neuro-Oncology Abstract Purpose Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China's vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. Methods A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. Results Of the 546 surgical cases (mean age: 36.8 years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3–4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 μg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37–0.92; p = 0.021], preoperative GH levels > 28 μg/L (OR = 0.55; 95% CI, 0.34–0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32–0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05–0.38; p < 0.001), Knosp score 3–4 (OR = 0.37; 95% CI, 0.24–0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46–3.70; p < 0.001). Conclusions In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The current burden of non-melanoma skin cancer attributable to ultraviolet radiation and related risk behaviours in Canada

Cancer shared this article with you from Inoreader The current burden of non-melanoma skin cancer attributable to ultraviolet radiation and related risk behaviours in Canada Via Latest Results for Cancer Causes Abstract Purpose Ultraviolet radiation (UVR) is an established cause of non-melanoma skin cancer (NMSC)—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The aim of this study was to estimate the current burden of BCC and SCC associated with UVR and modifiable UVR behaviours (sunburn, sunbathing, and indoor tanning) in Canada in 2015. Methods The current burden of BCC and SCC associated with UVR was estimated by comparing 2015 incidence rates with rates of less exposed body sites (trunk and lower limbs) after adjusting for estimated surface areas. The burden associated with modifiable UVR behaviours was estimated by using prevalence estimates among Caucasians from the Second National Sun Survey, and relative risks that are generalizable to Canadians from conducting meta-analyses of relevant studies. Results We estimated that 80.5% of BCCs and 83.0% of SCCs were attributable to UVR. Adult sunburn was associated with relative risks of 1.85 (95% CI 1.15–3.00) for BCC and 1.41 (95% CI 0.91–2.18) for SCC, while adult sunbathing was associated with relative risks of 1.82 (95% CI 1.52–2.17) for BCC and 1.14 (95% CI 0.53–2.46) for SCC. We estimated that 18.6% of BCCs and 9.9% of SCCs were attributable to adult sunburn, while 28.1% of BCCs were attributable to adult sunbathing. We estimated that 46.2% of BCCs and 17.3% of SCCs were attributable to modifiable UVR behaviours combined. Conclusion Our results provide quantifiable estimates of the potentially avoidable burden of NMSCs among Canadians. These estimates can be used to motivate prevention efforts in Canada. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Adherence to annual lung cancer screening with low-dose CT scan in a diverse population

Cancer shared this article with you from Inoreader Adherence to annual lung cancer screening with low-dose CT scan in a diverse population Via Latest Results for Cancer Causes Abstract Purpose Our aim was to develop a novel approach for lung cancer screening among a diverse population that integrates the Centers for Medicare and Medicaid Services (CMS) recommended components including shared decision making (SDM), low-dose CT (LDCT), reporting of results in a standardized format, smoking cessation, and arrangement of follow-up care. Methods Between October of 2015 and March of 2018, we enrolled patients, gathered data on demographics, delivery of SDM, reporting of LDCT results using Lung-RADS, discussion of results, and smoking cessation counseling. We measured adherence to follow-up care, cancer diagnosis, cancer treatment, and smoking cessation at 2 years after initial LDCT. Results We enrolled 505 patients who were 57% African American, 30% Caucasian, 13% Hispanic, < 1% Asian, and 61% were active smokers. All participants participated in SDM, 88.1% used a decision aid, and 96.1% proceeded with LDCT. Of 496 completing LDCT, all received a discussion about results and follow-up recommendations. Overall, 12.9% had Lung-RADS 3 or 4, and 3.2% were diagnosed with lung cancer resulting in a false-positive rate of 10.7%. All 48 patients with positive screens but no cancer diagnosis adhered to follow-up care at 1 year, but only 35.4% adhered to recommended follow-up care at 2 years. The annual follow-up for patients with negative lung cancer screening results (Lung-RADS 1 and 2) was only 23.7% after one year and 2.8% after 2 years. All active smokers received smoking cessation counseling, but only 11% quit smoking. Conclusion The findings show that an integrated lung cancer screening program can be safely implemented in a diverse population, but adherence to annual screening is poor. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.