BACKGROUND The clinical significance of intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity is unclear for HER2-positive gastric cancer, although it has been reported to be a significant prognosticator for HER2-positive breast cancer, which has received trastuzumab-based chemotherapy. AIM To clarify the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer, which has received trastuzumab-based chemotherapy. METHODS Patients with HER2-positive unresectable or metastatic gastric cancer who received trastuzumab-based chemotherapy as a first line treatment were included. The patients were classified into two groups according to their intratumoral HER2 heterogeneity status examined by immunohistochemistry (IHC) on endoscopic biopsy specimens before treatment, and their clinical response to chemotherapy and survival were compared. RESULTS A total of 88 patients were included in this study, and HER2 heterogeneity was observed in 23 (26%) patients (Hetero group). The overall response rate was significantly better in patients without HER2 heterogeneity (Homo group) (Homo vs Hetero: 79.5% vs 35.7%, P = 0.002). Progression-free survival of trastuzumab-based chemotherapy was significantly better in the Homo group (median, 7.9 vs 2.5 mo, HR: 1.905, 95%CI: 1.109-3.268). Overall survival was also significantly better in the Homo group (median survival time, 25.7 vs 12.5 mo, HR: 2.430, 95%CI: 1.389-4.273). Multivariate analysis revealed IHC HER2 heterogeneity as one of the independent poor prognostic factors (HR: 3.115, 95%CI: 1.610-6.024). CONCLUSION IHC of HER2 heterogeneity is the pivotal predictor for trastuzumab-based chemotherapy. Thus, HER2 heterogeneity should be considered during the assessment of HER2 expression.

No abstract

Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The ‘4-hit’ flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. Significance: Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.

No abstract

Background Robotic gastrectomy (RG) is being increasingly performed globally; it is considered an evolved type of conventional laparoscopic surgery with excellent dexterity and precision, but higher costs and longer operation time. Thus, there is a need to identify the benefits from RG and its specific candidates. Methods This retrospective study analyzed data from a prospectively collected clinical database at our center. Data of patients with primary gastric cancer undergoing either robotic or laparoscopic radical gastrectomy from June 2014 to June 2020 were reviewed. Surgical outcomes were compared between the two groups, and multivariable analyses were performed to elucidate the relevant factors for postoperative complications in several subgroups. Results A total of 1172 patients were divided into those who underwent RG (n = 152) and those who underwent laparoscopic gastrectomy (LG) (n = 1020). Baseline characteristics were similar in the two groups, except the RG group included more patients undergoing total/proximal gastrectomy (TG/PG) and patients at clinical stage III. Compared with the LG group, the RG group had lower incidences of postoperative complications ≥ Clavien-Dindo grade III (2/152 (1.3%) versus 72/1020 (7.1%); P = 0.004), and intraabdominal complications ≥ grade II (6/152 (3.9%) versus 119/1020 (11.7%); P = 0.004). Multivariable analysis revealed that RG was a significant relevant factor for reducing overall postoperative complications (≥ grade III) (odds ratio (OR) 0.16, P = 0.013), and intraabdominal complications (≥ grade II) (OR 0.29, P = 0.002). Subgroup analyses demonstrated that this tendency was enhanced in patients undergoing TG/PG (OR 0.29, P = 0.021) or at clinical stage II/III (OR 0.10, P = 0.027). Conclusions RG reduces the incidence of postoperative complications compared with conventional LG and this tendency may be enhanced in technically complicated procedures with demanding anastomosis or D2 lymphadenectomy. Patients requiring such procedures would most benefit from RG.