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Subsecond and Submillimeter Resolution Positional Verification for Stereotactic Irradiation of Spinal Lesions.

Spine stereotactic body radiation therapy (SBRT) requires highly accurate positioning. We report our experience with markerless template matching and triangulation of kilovoltage images routinely acquired during spine SBRT, to determine spine position.
Kilovoltage images, continuously acquired at 7, 11 or 15 frames/s during volumetric modulated spine SBRT of 18 patients, consisting of 93 fluoroscopy datasets (1 dataset/arc), were analyzed off-line. Four patients were immobilized in a head/neck mask, 14 had no immobilization. Two-dimensional (2D) templates were created for each gantry angle from planning computed tomography data and registered to prefiltered kilovoltage images to determine 2D shifts between actual and planned spine position. Registrations were considered valid if the normalized cross correlation score was ≥0.15. Multiple registrations were triangulated to determine 3D position. For each spine position dataset, average positional offset and standard deviation were calculated. To verify the accuracy and precision of the technique, mean positional offset and standard deviation for twenty stationary phantom datasets with different baseline shifts were measured.
For the phantom, average standard deviations were 0.18 mm for left-right (LR), 0.17 mm for superior-inferior (SI), and 0.23 mm for the anterior-posterior (AP) direction. Maximum difference in average detected and applied shift was 0.09 mm. For the 93 clinical datasets, the percentage of valid matched frames was, on average, 90.7% (range: 49.9-96.1%) per dataset. Average standard deviations for all datasets were 0.28, 0.19, and 0.28 mm for LR, SI, and AP, respectively. Spine position offsets were, on average, -0.05 (range: -1.58 to 2.18), -0.04 (range: -3.56 to 0.82), and -0.03 mm (range: -1.16 to 1.51), respectively. Average positional deviation was &lt;1 mm in all directions in 92% of the arcs.
Template matching and triangulation using kilovoltage images acquired during irradiation allows spine position detection with submillimeter accuracy at subsecond intervals. Although the majority of patients were not immobilized, most vertebrae were stable at the sub-mm level during spine SBRT delivery.
Copyright © 2016 Elsevier Inc. All rights reserved.

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DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1.

An anti-HER2 antibody drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new anti-tumor drug candidate, and its preclinical pharmacological profile was assessed.
In vitro and in vivo pharmacological activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.
DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable to unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a’s being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated anti-tumor efficacy against several breast cancer PDX models with low HER2 expression.
DS-8201a exhibited a potent anti-tumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1 insensitive HER2 positive cancers and low HER2-expressing cancers.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

Trabectedin (Yondelis, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.

Predictors of lapse and relapse to smoking in successful quitters in a varenicline post hoc analysis in Japanese smokers.

The efficacy of the smoking-cessation agent varenicline has been reported in Asian smokers; however, few studies have investigated factors that contribute to lapse and relapse.
This post hoc analysis aimed to identify predictors of smoking lapse and relapse.
This was a post-hoc analysis based on a double-blind, placebo-controlled, randomized, parallel-group study in which Japanese smokers (aged 20-75 years) who smoked ≥ 10 cigarettes/day and were motivated to quit were randomized to receive varenicline (0.25 mg twice daily [BID], 0.5 mg BID, 1 mg BID) or placebo for 12 weeks followed by a 40-week non-treatment follow-up. For inclusion in this analysis, participants must have been nicotine dependent (Tobacco Dependence Screener score ≥ 5) and must have successfully quit smoking continuously for 4 weeks (weeks 9-12). Lapse was defined by answering yes to ≥ 1 question in the Nicotine Use Inventory. Relapse was defined by participants having smoked for ≥ 7 days during follow-up measured by the Nicotine Use Inventory.
Of the 619 randomized individuals, 515 had a Tobacco Dependence Screener score of ≥ 5, and 277 quit smoking continuously from weeks 9 to 12. Approximately 75% were male, with a mean (SD) BMI of 23.0 (3.0) kg/m(2). Maximum length of continuous abstinence (CA) during treatment and age (both P &lt; 0.0001) were significant predictors of lapse. Maximum CA (P &lt; 0.0001), age (P = 0.0002), Minnesota Nicotine Withdrawal Scale (MNWS) score for urge to smoke (P = 0.0019), and having made ≥ 1 serious quit attempt (P = 0.0063) were significant predictors of relapse. For participants with a maximum CA of 4 to 6 weeks versus those with a maximum CA of 10 to 11 weeks, the ORs for lapse and relapse were 4.649 (95% CI, 2.071-10.434) and 3.337 (95% CI, 1.538-7.239), respectively. In participants aged 21-34 years versus those aged 47-72 years, the ORs for lapse and relapse were 3.453 (95% CI 1.851, 6.441) and 3.442 (95% CI 1.795, 6.597), respectively. Participants with a MNWS urge to smoke score of 2 to 4 versus 0 had an OR for relapse of 3.175 (95% CI, 1.166-8.644). Participants having made ≥ 1 versus no serious quit attempts had an OR for relapse of 2.108 (95% CI, 1.168-3.805).
Shorter maximum CA and younger age at quit attempt were associated with increased risk of lapse and relapse. Higher MNWS urge to smoke score and having made ≥ 1 serious quit attempt were associated with increased relapse risk. ClinicalTrials.gov identifier: NCT00139750.
Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.