To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating ...biomarkers.
Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients.
Forty-two patients received ramucirumab. Median PFS was 4.0 months 95% confidence interval (CI), 2.6-5.7, ORR was 9.5% (95% CI, 2.7-22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95% CI, 6.1-19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5-9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1-23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥ 3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2.
Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.
Resilience evaluation is an important foundation for sustainable rural development. Taking the 57 counties in Guangdong province as examples, this study used the CRITIC method to construct a ...comprehensive evaluation index system for rural resilience and identified the main influencing factors and their spatial heterogeneity on the basis of the geographical detector method and multiscale geographically weighted regression. The results showed that: (1) Most of the counties in Guangdong province had medium or higher values of comprehensive resilience, and the high-value areas were mainly located in the Pearl River Delta region. (2) The comprehensive resilience and each dimensional resilience measure exhibited significant positive spatial correlations. (3) The geographic detector results showed that the per capita gross regional product and the number of industries above the scale were the main influencing factors for rural resilience, and each influencing factor had an enhanced effect after interaction. (4) The effect of each factor on rural resilience demonstrated spatial heterogeneity. Specifically, the proportion of secondary and tertiary industries showed negative effects in some counties in eastern and northern Guangdong and positive effects in other counties.
We completed a Phase I trial to determine the maximum tolerated dose of samarium-153 EDTMP (153Sm) with hormonal therapy (HT) and radiation therapy (RT) in high-risk clinically nonmetastatic prostate ...cancer.
High-risk M0 prostate cancer patients (prostate-specific antigen>20 ng/mL, Gleason score>7, or>T3) were eligible for this prospective trial of dose-escalated radioactive 153Sm-EDTMP (.25-2.0 mCi/kg) as primary or postoperative therapy. After 1 month of HT, we administered 153Sm-EDTMP followed by 4 more months of HT, 46.8 Gy to the pelvic region and 23.4 Gy to the prostate target (TD=70.2 Gy). The primary endpoint was Grade III toxicity or higher by the National Cancer Institute Common Toxicity Criteria.
Twenty-nine patients enrolled (median prostate-specific antigen=8.2 ng/mL, 27/29 (93%) T stage≥T2b, 24/29 (83%) had Gleason>7) and received 153Sm-EDTMP (.25 mCi/kg, 4 patients; 0.5 mCi/kg, 4 patients; 0.75 mCi/kg, 6 patients; 1.0 mCi/kg, 6 patients; 1.5 mCi/kg, 5 patients; 2.0 mCi/kg, 4 patients). Twenty-eight patients underwent all planned therapy without delays (1 patient required surgery before the start of RT). With a median follow-up time of 23 months, there were 2 patients (7%) experiencing Grade III hematologic toxicity. There were no other Grade III or IV side effects.
Our trial demonstrates that 2 mCi/kg 153Sm -EDTMP with HT and RT was safe and feasible in men with high-risk M0 prostate cancer. A Phase II study to test this treatment is currently underway by the Radiation Therapy Oncology Group.
The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ...ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer.
In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m
) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined.
Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients.
The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m
) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.
Abstract Objective Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical ...outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR). Methods Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of < 12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks. Results Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27–80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n = 15/60, 95% CI: 14.7–37.9%). Best overall response was: partial response 5.0% (n = 3/60), stable disease 56.7% (n = 34/60), and progressive disease 33.3% (n = 20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2. Conclusions Although antitumor activity was observed, the predetermined efficacy endpoints were not met.
Our previous studies showed that 1,25-dihydroxyvitamin D3 1,25(OH)2D3 modulates the activity of the CaV1.2 α-subunit of the L-type voltage-sensitive calcium channel (VSCC) by two temporally distinct ...mechanisms. First, 1,25(OH)2D3 rapidly modulates local Ca2+ permeability in the plasma membrane of the proliferating osteoblast. Second, treatment with 1,25(OH)2D3 reduces biosynthesis of CaV1.2 such that transcript levels are half of original levels after 24 h. Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) provide important regulatory mechanisms for controlling osteoclastogenesis and Ca2+ homeostasis. Because they often control Ca2+-activated secretion, we investigated the possibility that L-type VSCCs might regulate basal OPG and RANKL secretion in osteoblasts. We also studied 1,25(OH)2D3 effects on OPG and RANKL expression. To address this, we measured changes in expression and secretion of OPG and RANKL in MC3T3-E1 cells and calvarial organ cultures after treatment with 1,25(OH)2D3, VSCC inhibitors, and inhibitors of Ca2+-regulated signaling. RANKL production was increased in calvarial cultures by 1,25(OH)2D3 but was essentially undetectable in the medium of MC3T3-E1 cells. In contrast, OPG secretion in both systems was significantly reduced after 24 h treatment with 1,25(OH)2D3, by inhibitors of L-type VSCCs and calmodulin-sensitive protein kinases but not by inhibitors of protein kinase A, MAPKs, or other families of VSCCs. OPG secretion was abrogated by transfection with decoy cAMP response element binding sites. Our results suggest that OPG secretion is regulated through calmodulin-sensitive protein kinase signaling that depends on the activity of the L-type VSCC and is mediated through the cAMP response element-binding protein.
In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect ...disability.
The g-and-h distributional family is generated from a relatively simple transformation of the standard normal and can approximate a broad spectrum of distributions. Consequently, it is easy to use in ...simulation studies and has been applied in multiple areas, including risk management, stock return analysis and missing data imputation studies. A rapidly convergent quantile based least squares (QLS) estimation method to fit the g-and-h distributional family parameters is proposed and then extended to a robust version. The robust version is then used as a more general outlier detection approach. Several properties of the QLS method are derived and comparisons made with competing methods through simulation. Real data examples of microarray and stock index data are used as illustrations.
•Introduced simple methods to estimate the g-and-h distributional parameters.•Proved consistency and asymptotic normality.•Effective robust version introduced.•Robust version used to obtain base distribution for outlier detection.•Illustrated use of proposed methods to multiple fields.
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