Two-year outcome of concurrent chemoradiation with carboplatin with or without adjuvant carboplatin/fluorouracil in nasopharyngeal cancer: A multicenter randomized trial

BackgroundAccording to the noninferiority result of chemoradiation with carboplatin in our previous nasopharyngeal carcinoma (NPC) study along with the inconclusive data on the efficacy of adjuvant chemotherapy (AC) following concurrent chemoradiotherapy (CCRT), we designed to assess the role of adjuvant carboplatin/fluorouracil following CCRT with carboplatin in locoregionally advanced NPC.Materials and MethodsA multicenter randomized trial was conducted at 5 cancer centers in Thailand. We enrolled in stage T2N0M0-T4N2M0 (American Joint Cancer Committee 7th edition) WHO Type 2 NPC patients. N3 or metastatic disease patients were excluded. Participants were randomized into 2 groups: CCRT plus AC group vs the CCRT alone group. Patients in both groups received weekly carboplatin 100 mg/m² for 6 cycles concurrently with radiotherapy 69.96-70 Gy. Patients in the AC group subsequently received 3 cycles of carboplatin area under curve-5 plus 1000 mg/m²/day of fluorouracil infusion within 96 hours every 3 weeks. We report the 2-year overall survival (OS), disease-free survival (DFS), loco-regional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Treatment-related toxicities and compliance were also explored.ResultsOf 175 patients, 82 (46.9%) were assigned to the AC group, and 93 (53.1%) to the CCRT group. The compliance rate during CCRT was 90% and 86% in the AC and CCRT group, whereas 81.7% during adjuvant treatment in the AC group. With a median follow-up time of 24.4 months (interquartile range 17.9-24.4), the 2-year OS rate was 89.6% in the AC group and 81.8% in the CCRT group (P= 0.167). The 2-year DFS rate was 86.8% in the AC group and 74.6% in the CCRT group (P = 0.042). The 2-year LRFS rate was 91.5% in the AC group and 88.2% in the CCRT group (P = 0.443). The 2-year DMFS rate was 85.4% in the AC group and 79.6% in the CCRT group (P = 0.294). The most frequent serious (grade 3/4) nonhematologic toxicity was acute mucositis, which occurred 5% in the AC group vs 4% in the CCRT group (P = 0.498). For hematologic toxicity, grade 3-4 leukopenia were found 10% and 5% in the adjuvant and CCRT groups, respectively (P = 0.003). Multivariate analyses determined stage N2 disease was an adverse prognostic factor associated with shorter OS, DFS, and DMFS. And the adjuvant treatment was a significant protective factor for only DFS.ConclusionsThe addition of adjuvant carboplatin/fluorouracil following CCRT with carboplatin significantly improved 2-year DFS in stage T2N0M0-T4N2M0 NPC albeit there was a nonsignificant trend in favor of a higher 2-year OS, LRFS, and DMFS. Long-term efficacy and late toxicities of AC still require exploration.     

Study of Pax6 mutant rat revealed the association between upper incisor formation and midface formation.

In this study, we investigated the process of supernumerary upper incisor formation in the Pax6 mutant rat, rSey(2)/rSey(2), which exhibits a facial cleft between the medial nasal and maxillary processes. Histological investigation and epithelial labeling studies of wild type rat embryos indicated that the upper incisor develops by fusion of two primary dental placodes (PDPs) in the medial nasal process with a contribution from the epithelium of the maxillary process. In the rSey(2)/rSey(2) embryo, both PDPs are formed but they stay apart, then subsequently these PDPs independently develop into upper incisor tooth buds. In order to examine if the failure of the two placodes to fuse is due to the cleft between the maxillary and medial nasal processes, maxillary and medial nasal process fusion was inhibited with a barrier in wild type embryos. This resulted in the maintenance of the two distinct PDPs. These results demonstrate that fusion of the facial processes reduces the number of odontogenic placodes and is required to assemble all components at one site for rat upper incisor formation. The results also provide further insight into the mechanism of supernumerary incisor formation in human cleft lip conditions.     

Limited and Short-Lasting Virus Neutralizing Titers Induced by Inactivated SARS-CoV-2 Vaccine

In vitro determination of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies induced in serum samples from recipients of the CoronaVac vaccine showed a short protection period against the original virus strain and limited protection against variants of concern. These data provide support for vaccine boosters, especially variants of concern circulate.     

Locomotor behavioral responses of Anopheles minimus and Anopheles harrisoni to alpha-cypermethrin in Thailand

Excito-repellency responses of 3 test populations, representing 2 sibling species within the Minimus Complex, Anopheles minimus and An. harrisoni, were characterized for contact irritant and noncontact repellent actions of chemicals during and after exposure to alpha-cypermethrin at half the recommended field (0.010 g/m2), the recommended field (0.020 g/m2), and double the recommended field concentration (0.040 g/m2), using an excito-repellency escape chamber system. Two field populations of An. minimus and An. harrisoni collected from the malaria-endemic areas in Tak and Kanchanuburi provinces in western Thailand, respectively, were tested along with a laboratory population of An. minimus maintained since 1993. Females of all 3 test populations rapidly escaped after direct contact with treated surfaces for each concentration. In general, increased escape responses in the An. minimus test populations were proportionate to increased insecticide dosages. The greatest escape response for An. harrisoni was observed at the operational field concentration of alpha-cypermethrin. The noncontact repellency response to alpha-cypermethrin was comparatively weak for all 3 test populations, but significantly different from each paired contact test and respective noncontact controls. We conclude that strong contact irritancy is a major action of alpha-cypermethrin, whereas noncontact repellency plays no role in the escape responses of 2 species in the Minimus Complex in Thailand.     

Dual odontogenic origins develop at the early stage of rat maxillary incisor development

Developmental process of rat maxillary incisor has been studied through histological analysis and investigation of tooth-related gene expression patterns at initial tooth development. The tooth-related genes studied here are fibroblast growth factor-8 (Fgf-8), pituitary homeobox gene-2 (Pitx-2), sonic hedgehog (Shh), muscle segment homeobox-1 (Msx-1), paired box-9 (Pax-9) and bone morphogenetic protein-4 (Bmp-4). The genes are expressed in oral epithelium and/or ectomesenchyme at the stage of epithelial thickening to the early bud stage of tooth development. Both the histological observation and tooth-related gene expression patterns during early stage of maxillary incisor development demonstrate that dual odontogenic origins aligned medio-laterally in the medial nasal process develop, subsequently only single functional maxillary incisor dental placode forms. The cascade of tooth-related gene expression patterns in rat maxillary incisor studied here is quite similar to those of the previous studies in mouse mandibular molar, even though the origins of oral epithelium and ectomesenchyme involved in development of maxillary incisor and mandibular molar are different. Thus, we conclude that maxillary incisor and mandibular molar share a similar signaling control of Fgf-8, Pitx-2, Shh, Msx-1, Pax-9 and Bmp-4 genes at the stage of oral epithelial thickening to the early bud stage of tooth development.