The Outcome of Complex Hepato-Pancreato-Biliary Surgery for Elderly Patients: A Propensity Score Matching Analysis

Background/Aims: Postoperative mortality and morbidity rates after hepato-pancreato-biliary (HPB) surgery remain high, and the number of elderly patients requiring such surgery has been increasing. This study aimed to investigate postoperative outcomes of complex HPB surgery for elderly patients. Methods: We retrospectively reviewed perioperative data of 721 patients who underwent complex HPB surgery between 2010 and 2015. The patients were divided into 2 groups: elderly (≥75 years) and non-elderly (< 75 years). Surgical outcomes of both groups were compared after propensity score-matching analysis. Subsequently, risk factors for serious postoperative morbidity were identified by multivariate analysis. Results: Before matching, the elderly group (n = 170) had more comorbidities, such as cardiovascular and renal disease, than the non-elderly group (n = 551). Matching yielded elderly (n = 170) and non-elderly groups (n = 170) with similar preoperative backgrounds. The mortality and morbidity rates did not differ significantly between the groups. In multivariate analyses, operative time (OR 1.79; p = 0.005) and blood loss (OR 1.66; p = 0.03) were identified as independent risk factors for serious postoperative morbidity, whereas older age did not have a predictive impact (OR 1.16; p = 0.52). Conclusions: Although elderly ­patients had more comorbidities and higher incidences of postoperative mortality and several complications before matching, their postoperative outcomes were equivalent to those of non-elderly patients after matching

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers