Plasma Angiogenic Factors as Predictors of the Efficacy of Second-line Chemotherapy Combined with Angiogenesis Inhibitors in Metastatic Colorectal Cancer: Results From the GI-SCREEN CRC-Ukit Study.

BACKGROUND: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. PATIENTS AND METHODS: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. CONCLUSION: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. CLINICAL TRIAL NUMBER: UMIN000028616.

Role of plasma angiogenesis factors in the efficacy of first-line chemotherapy combined with biologics in RAS wild-type metastatic colorectal cancer: Results from the GI-SCREEN CRC-Ukit study.

BACKGROUND: Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first-line (1L) treatment in patients with RAS wild-type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. METHODS: In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression-free survival (PFS) and overall survival (OS) in patients with RAS wild-type were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS: From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild-type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti-epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin-8 (IL-8) (p = 0.0752) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (p = 0.0156). Regarding OS, IL-8 (p = 0.0283), soluble vascular endothelial growth factor-receptor-1 (sVEGFR-1) (p = 0.0777) and sVCAM-1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. CONCLUSION: Pretreatment plasma IL-8 and sVCAM-1 levels could be predictive biomarkers to distinguish BEV and anti-EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild-type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild-type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second-line treatment.

Production of interspecific hybrids between Japanese gentians and wild species of Gentiana.

Wide hybridization, which is a powerful tool to broaden genetic variation, has been used in breeding of many crops. However, in ornamental gentian few wide hybridizations have been reported. Interspecific hybridizations between two gentian cultivated species (Gentiana scabra and G. triflora) and 11 wild species, which were classified in five sections, were carried out using ovule culture. When G. scabra was used as a female parent, normal seedlings and hybrid plants were obtained from eight and five interspecific combinations, respectively. The yield of seedling produced from ovule culture depended on interspecific combinations, ranging from 0.3 to 427.7 normal seedling per flower. In the hybridization of G. triflora with five wild species, normal seedlings and plants were produced in five and four interspecific combinations, respectively. The yield of normal seedling ranging from 0.4 to 228.3 was different between not only interspecific combinations but also reciprocal crosses. Two cultivated species are classified in sect. Pneumonanthe, and successful production of hybrids was obtained from the hybridization with species classified in sections Pneumonanthe or Cruciata. The hybrid nature of the produced plants was confirmed by molecular marker and morphology. The production of interspecific hybrids opens a novel prospect in ornamental gentian breeding.

Effects of pioglitazone on cardiac and adipose tissue pathology in rats with metabolic syndrome.

BACKGROUND: Pioglitazone is a thiazolidinedione drug that acts as an insulin sensitizer. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now investigated the effects of pioglitazone on cardiac and adipose tissue pathology in this model. METHODS AND RESULTS: DS/obese rats were treated with pioglitazone (2.5 mg/kg per day, per os) from 9 to 13 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates served as controls. Pioglitazone increased body weight and food intake in DS/obese rats. It also ameliorated left ventricular (LV) hypertrophy, fibrosis, and diastolic dysfunction as well as attenuated cardiac oxidative stress and inflammation, without lowering blood pressure, in DS/obese rats, but it had no effect on these parameters in DS/lean rats. In addition, pioglitazone increased visceral and subcutaneous fat mass but alleviated adipocyte hypertrophy and inflammation in visceral adipose tissue in DS/obese rats. Furthermore, pioglitazone increased the serum concentration of adiponectin, induced activation of AMP-activated protein kinase (AMPK) in the heart, as well as ameliorated glucose intolerance and insulin resistance in DS/obese rats. CONCLUSIONS: Treatment of DS/obese rats with pioglitazone exacerbated obesity but attenuated LV hypertrophy, fibrosis, and diastolic dysfunction, with these latter effects being associated with the activation of cardiac AMPK signaling likely as a result of the stimulation of adiponectin secretion.