RESUMO
BACKGROUND: A major obstacle to using recombinant adenoviral vectors in gene therapy is the natural ability of human adenovirus to activate the classical and alternate complement pathways. These innate immune responses contribute to hepatic adenoviral uptake following systemic delivery and enhance the humoral immune responses associated with adenoviral infection. METHODS: A recombinant Ad5 vector was genetically modified to display a peptide sequence ("rH17d'"), a known inhibitor of the classical complement pathway. The replication-defective vectors Ad5.HVR2-rH17d' and Ad5.HVR5-rH17d' were constructed by engineering the rH17d' peptide into the hypervariable region (HVR)-2 or HVR5 of their major capsid protein hexon. Control Ad5 vectors were created by incorporation of a 6-histidine (His6)-insert in either HVR2 or HVR5 (Ad5.HVR2-His6 and Ad5.HVR5-His6, respectively). All vectors encoded CMV promoter-controlled firefly luciferase (Luc). The four vectors were evaluated in TIB76 mouse liver cells and immunocompetent mice to compare infectivity and liver sequestration, respectively. RESULTS: In vitro studies demonstrated that preincubation of all the Ad5 vectors with fresh serum significantly increased their gene transfer relative to preincubation with PBS except Ad5.HVR5-rH17d', whose infectivity of liver cells showed no serum-mediated enhancement. In line with that, mice injected with Ad5.HVR2-rH17d' or Ad5.HVR5-rH17d' showed significantly lower luciferase expression levels in the liver as compared to the respective control vectors, whereas efficiency of tumor transduction by rH17d' and His6 vectors following their intratumoral injection was similar. CONCLUSIONS: Displaying a complement-inhibiting peptide on the Ad5 capsid surface by genetic modification of the hexon protein could be a suitable strategy for reducing Ad5 liver tropism (Ad5 sequestration by liver), which may be applicable to other gene therapy vectors with natural liver tropism.
Assuntos
Adenovírus Humanos/genética , Ativação do Complemento/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Neoplasias/terapia , Adenovírus Humanos/imunologia , Animais , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Terapia Genética/efeitos adversos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Humanos , Imunidade Humoral/imunologia , Injeções Intralesionais , Fígado/citologia , Fígado/imunologia , Masculino , Camundongos , Neoplasias/imunologia , Peptídeos/genética , Transdução GenéticaRESUMO
BACKGROUND: The purpose of this study was to examine the cost differences between preoperative and postoperative placement of gastrostomy tubes (G-tubes) in patients with head and neck cancer. METHODS: We conducted a retrospective chart review of patients with aerodigestive tract cancers from 2010 to 2015. Data included inpatient and postdischarge costs, demographics, tumor characteristics, surgical treatment, length of stay (LOS), time spent in the intensive care unit (ICU), and readmissions. RESULTS: Five hundred ninety patients were included in this study. There was a $7624 inpatient cost savings (P = .002) for those G-tubes placed preoperatively ($26 060) versus postoperatively ($33 754). Postdischarge costs did not differ significantly between groups (P = .60). There was a $9248 total costs savings (P = .009) for those patients with G-tubes placed preoperatively ($39 751) versus postoperatively ($48 999), despite patients with preoperative G-tubes having lower body mass index (BMI; P = .009), higher Association of Anesthesiologist (ASA) class (P = .02), more preoperative radiation (P < .001), and more free tissue transfer reconstruction (P = .007). CONCLUSION: There is potential for savings by placing G-tubes preoperatively, possibly driven by decreased LOS, despite data suggesting that patients with G-tubes placed preoperatively are higher risk.
