Application of therapeutic drug monitoring of imatinib for individual treatment of gastrointestinal stromal tumor

Many molecular target agents are continuously administered at fixed dosages. Imatinib, which can control the growth of a gastrointestinal stromal tumor, is administrated at 400 mg/day. However, many patients cannot continue treatment because of adverse events, such as neutropenia. To obtain the best therapeutic response while maintaining quality of life, individualization should be considered. Study participants were gastrointestinal stromal tumor patients who required treatment with imatinib. Therapeutic drug monitoring was conducted using high-performance liquid chromatography. In our study, the trough (lowest) concentration that a drug reaches before the next dose is administered differed among patients. The grades of adverse events also differed individually. Moreover, the dosage that was necessary to shrink gastrointestinal stromal tumor differed in cases by cases. Dosage was modified according to the balance between blood concentration and therapeutic responses in order to minimize adverse events for individual patients, and to maximize the effect as the responses differed among patients. It was shown that based on therapeutic drug monitoring, individualization enabled the patients who may not normally continue the typical treatment to tolerate imatinib. According to the therapeutic drug monitoring, individualization of dosage of imatinib could improve the patients’ outcomes in both ends, therapeutic and adeverse responses. 

Clinical Course of a Rare Epstein-Barr Virus-Associated Smooth Muscle Tumor and Its Genomic Analysis

Epstein-Barr virus (EBV) can rarely induce smooth muscle tumors (SMTs). A 20-year-old female patient underwent kidney transplantation for renal failure. Since then, she has been treated with immunosuppressants, including a calcineurin inhibitor, tacrolimus, and prednisolone, owing to the immunological rejection. Three years later, she developed large liver tumors (diameter >5 cm) and multiple small lung tumors that were identified as EBV-SMTs based on the results of liver biopsy/histopathology. No intervention was performed except for the addition of a mammalian target of the rapamycin inhibitor, everolimus, which inhibits both immune reaction and SMT growth. Finally, after 8 years, the transplanted kidney became nonfunctional, and immunosuppressant administration became unnecessary as urinary dialysis was started. Under these circumstances, SMT growth was observed despite the absence of immunosuppressant administration. Three months after the cessation of the immunosuppressants, EBV-SMTs in the liver and lungs shrank slightly. To the best of our knowledge, this is the first report on the genomic profile of this rare tumor. The clinical course of our patient indicates that EBV can induce SMTs, and immunological suppression of EBV may inhibit the activity of these tumors

Curcumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75mol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078

Yttrium’s Effect on the Hot Cracking and Creep Properties of a Ni-Based Superalloy Built Up by Additive Manufacturing

We studied the effects of the rare earth element yttrium (Y) on the hot cracking and creep properties of Hastelloy-X processed by selective laser melting. We used two different alloys to study hot cracking in Hastelloy-X: one with 0.12 mass% yttrium added and one with no yttrium. Y-free Hastelloy-X exhibited less cracks, mainly due to the segregation of Si, W, and C resulting in SiC- and W6C-type carbides at the grain boundary and interdendritic regions. On the other hand, more cracks formed in the Y-added Hastelloy-X specimen because of segregation of Y, resulting in the formation of yttrium-rich carbide (YC). Post-heat treatment was conducted at 1177 °C for 2 h, followed by air cooling, to obtain good creep properties. We carried out a creep test along the vertical and horizontal directions. Despite having more cracks, the Y-added as-built Hastelloy-X specimen showed longer creep life and ductility than the Hastelloy-X specimen. This was mainly because of the formation of Y2O3 and SiO2 inside the grains. After solution treatment, the Y-added specimen’s creep life was eight times longer than that of the Y-free solution-treated specimen. This was mainly because of the maintenance of the columnar grain morphology even after solution treatment. In addition, the formation of M6C carbides, Y2O3, and SiO2 improved creep life. To summarize the effect of Y, Y addition promoted the formation of cracks, which brought about creep anisotropy; however, it improved creep properties through the stabilization of oxygen and the promotion of discrete carbide precipitation, which prohibited the migration and sliding of grain boundary

Application of therapeutic drug monitoring of imatinib for individual treatment of gastrointestinal stromal tumor

Many molecular target agents are continuously administered at fixed dosages. Imatinib, which can control the growth of a gastrointestinal stromal tumor, is administrated at 400 mg/day. However, many patients cannot continue treatment because of adverse events, such as neutropenia. To obtain the best therapeutic response while maintaining quality of life, individualization should be considered. Study participants were gastrointestinal stromal tumor patients who required treatment with imatinib. Therapeutic drug monitoring was conducted using high-performance liquid chromatography. In our study, the trough (lowest) concentration that a drug reaches before the next dose is administered differed among patients. The grades of adverse events also differed individually. Moreover, the dosage that was necessary to shrink gastrointestinal stromal tumor differed in cases by cases. Dosage was modified according to the balance between blood concentration and therapeutic responses in order to minimize adverse events for individual patients, and to maximize the effect as the responses differed among patients. It was shown that based on therapeutic drug monitoring, individualization enabled the patients who may not normally continue the typical treatment to tolerate imatinib. According to the therapeutic drug monitoring, individualization of dosage of imatinib could improve the patients’ outcomes in both ends, therapeutic and adeverse responses.  </p

Seasonal and Diurnal Fluctuations in the Concentrations of Pharmaceuticals and Personal Care Products (PPCPs) in Residential Sewage Water

Seasonal and diurnal fluctuations in pharmaceuticals and personal care products (PPCPs) concentrations in residential sewage water were ascertained in an area with no businesses industry (e.g., plants or offices) upstream. PPCPs with high detection rates included ibuprofen, acetaminophen and indomethacin (antipyretic analgesics), atenolol and disopyramide (antiarrhythmics), clarithromycin (antibiotic), levofloxacin (synthetic antimicrobial agent) and triclosan (disinfectant). In summer, the concentration of triclosan was the highest, while in winter, the concentrations of ibuprofen and acetaminophen were higher than the others. Moreover, three types of diurnal fluctuations were observed: no marked diurnal changes (triclosan), high daytime concentrations (disopyramide) and high nighttime concentrations (acetaminophen)