Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer.

BACKGROUND: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). METHODS: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. RESULTS: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. CONCLUSIONS: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

Regional and annual patterns in respiratory virus co-infection etiologies and antibiotic prescriptions for pediatric mycoplasma pneumoniae pneumonia.

OBJECTIVE: Mycoplasma pneumoniae (M. pneumoniae) pneumonia is the second-most common cause of community-acquired pneumonia (CAP). This study aimed at investigating into the prevalence of macrolide-resistant M. pneumoniae (MRMP) with respiratory virus co-infection and the antibiotic prescriptions in children with CAP in four provinces in Korea, and to assess the variations in the findings across regions and throughout the year. PATIENTS AND METHODS: This prospective study was conducted in 29 hospitals in Korea between July 2018 and June 2020. Among the enrolled 1,063 children with CAP, all 451 patients with M. pneumoniae underwent PCR assays of M. pneumoniae and respiratory viruses, and the presence of point mutations of residues 2063 and 2064 was evaluated. RESULTS: Gwangju-Honam (88.6%) showed the highest prevalence of MRMP pneumonia, while Daejeon-Chungcheong (71.3%) showed the lowest, although the differences in prevalence were not significant (p=0.074). Co-infection of M. pneumoniae pneumonia and respiratory virus was observed in 206 patients (45.4%), and rhinovirus co-infection (101 children; 22.2%) was the most frequent. The prevalence of MRMP pneumonia with respiratory virus co-infection and the antibiotic prescriptions differed significantly among the four provinces (p < 0.05). The monthly rate of MRMP pneumonia cases among all cases of M. pneumoniae pneumonia and tetracycline or quinolone prescriptions did not differ significantly among the four regions (trend p > 0.05) during the study period. CONCLUSIONS: The prevalence of M. pneumoniae pneumonia with virus co-infection and antibiotic prescriptions could differ according to region, although the MRMP pneumonia rate showed no difference within Korea.

Distribution of transferrin binding protein immunoreactivity in the chicken central and peripheral nervous systems.

Transferrin binding protein (TfBP) is a glycoprotein originally purified from chicken oviduct that exhibits transferrin binding activity. Recent work has shown that TfBP is a post-translationally modified form of the heat shock protein (HSP108), the avian homologue of a glucose regulated protein, GRP94. The function of this protein, however, has not yet been clearly defined. Antiserum to TfBP was found to selectively stain oligodendrocytes of the avian brain. In this study, we further describe these oligodendrocytes and other cell types positive to anti-TfBP in the chick nervous system. In accordance with previous studies, the most prominent cell type that labels with antiserum to TfBP is the oligodendrocyte. At the electron microscopic level, the immunoreactive product is confined to the perinuclear cytoplasm and fine processes of the oligodendrocytes, whereas myelin and axoplasm are devoid of staining. The immunoreactive product is found both in the cytoplasmic matrix and bound to the endoplasmic reticulum and plasma membrane, suggesting that TfBP may have properties of both a soluble and an integral membrane protein. There is great variability in the number of TfBP-oligodendrocytes in different areas of the central nervous system (CNS); large numbers of cells are associated with the white matter regions and are found in the myelinated tracts, whereas few cells are present in the gray matter regions. In the retina, TfBP is localized specifically in the cells, that are morphologically oligodendrocytic and is present in the optic nerve fiber layer and the ganglion cell layer. Obvious staining is also seen in the Bergmann glial cells of the cerebellum and in the Schwann cells of the sciatic nerve. Furthermore, the choroid plexus cells similarly exhibit a strong reaction. The association of TfBP in these specific cell types responsible for myelination and sequestering iron and transferrin implies that TfBP may be involved in myelination and iron metabolism of the chick nervous system, perhaps through a role in transferrin concentration in these cells. A putative role of TfBP, as HSP108, is considered.

Cerebellar alterations induced by chronic hypoxia: an immunohistochemical study using a chick embryonic model.

A model of fetal aerogenic hypoxia was developed in which fertilized chicken eggs were half-painted with melted wax and incubated under normal conditions. The cerebellum of the hypoxic chick embryos at a later stage of development (E18-20) was analyzed immunochemically. Hypoxic insult resulted in considerable neurocytological deficits of the Purkinje cells and altered glial fibrillary acid protein (GFAP) immunoreactivity in the fetal cerebellum. Purkinje cells in the hypoxic embryos were marked by small cell size, poorly developed dendrites, low cell density, deletion and ectopia. On the other hand, enhanced GFAP immunoreactivity was found in astrocytes and Bergmann glia of the hypoxic embryos. Our results indicate that chronic hypoxia in the chick fetus can cause severe disorders of neuronal development as well as glial activation. We suggest that our hypoxic model of chick embryos could be an accessible animal model for further elucidating fetal hypoxia.

Radiolabeling of paclitaxel with electrophilic 123I.

123I-Labeled paclitaxel, [123I]-1 was prepared by electrophilic aromatic radioiodination of 3'-N-(p-trimethylstannylbenzoyl)-3'-debenzoylpaclitaxel 2 with 123I- in the presence of peracetic acid.

Synthesis and biology of 3'-N-acyl-N-debenzoylpaclitaxel analogues.

The, 3'-N-acyl-N-debenzoylpaclitaxel analogues 1a-d were synthesized and evaluated on biological systems. Some of the analogues 1a-d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against i.p. implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.