Enhanced Anti-Tumor Activity in Mice with Temozolomide-Resistant Human Glioblastoma Cell Line-Derived Xenograft Using SN-38-Incorporated Polymeric Microparticle.

Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM.

A three-year clinical investigation of a Chinese child with craniometaphyseal dysplasia caused by a mutated ANKH gene.

BACKGROUND: Craniometaphyseal dysplasia (CMD) is a rare genetic disorder. Autosomal dominant CMD (AD-CMD) is caused by mutations in the ANKH gene. Affected individuals typically have distinctive facial features including progressive thickening of the craniofacial bones. Treatment for AD-CMD primarily consists of surgical intervention to release compression of the cranial nerves and the brain stem/spinal cord. To alleviate progression of the clinical course and improve the quality of life in children waiting to undergo the necessary surgery, we investigated clinical changes in a diagnosed patient with AD-CMD over three years. CASE SUMMARY: A 17-mo-old boy presented with progressive nasal obstruction, snoring and hearing loss symptoms. Physical examination showed enlargement of the head circumference and clinical features such as wide nasal bridge, paranasal bossing, widely spaced eyes with an increased bizygomatic width, and a prominent mandible. The patient underwent otolaryngological examination, endoscopy, hearing test, laboratory examination of phosphorus and bone metabolism, cranial and femoral computed tomography, X-ray and next-generation sequencing. The patient was diagnosed with AD-CMD due to p.Phe377 deletion (c.1129_1131del) on exon 9 of the ANKH gene. After adherence to a prescribed low-calcium diet, the boy's alkaline phosphatase (ALP) levels continuously decreased to within the normal range. However, after 14 mo of dietary intervention, his parents altered his diet to an intermittent low-calcium diet to include milk and eggs. The patient's ALP was slightly higher than normal after the dietary change but remained close to the normal range. His serum osteocalcin changed to within normal levels after dietary regulation for 33 mo. His serum combined beta C-terminal telopeptide of type I collagen also continuously decreased after the nutritional intervention, although still slightly higher than normal levels. Despite fluctuating blood test results, the boy's nasal symptoms were markedly relieved and steadily improved after dietary intervention. No significant changes were found in the craniofacial bones by cranial radiography. Close monitoring of clinical features is still ongoing. Calcitriol treatment is currently under consideration and a surgical procedure is planned as necessary in the future. CONCLUSION: We herein report the first Chinese case of AD-CMD with heterozygous mutation of p.Phe377 deletion (c.1129_1131del) on the ANKH gene. Biochemical alterations were significantly improved after dietary intervention indicating that a low-calcium diet may be applied in pediatric AD-CMD patients with ANKH mutations to help alleviate phenotypic manifestations and improve the quality of life before surgical intervention. Further large scale studies are needed to replicate these findings and to establish the appropriate timing for nutritional and surgical interventions.