No abstract

HER2‐targeting antibodies (trastuzumab, pertuzumab) and a HER2‐directed antibody‐drug conjugate (trastuzumab emtansine: T‐DM1) are used for the treatment of HER2‐overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small‐molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T‐DM1 for evaluating the effect of TAS0728 on HER2 antibody‐resistant populations. Treatment with trastuzumab and pertuzumab or with T‐DM1 initially induced tumor regression in NCI‐N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T‐DM1, HER2‐HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti‐tumor effect associated with HER2‐HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient‐derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T‐DM1, TAS0728 exerted a potent anti‐tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T‐DM1 are still dependent on oncogenic HER2‐HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti‐HER2 therapies.

Predicting the postoperative course

Predicting the prognosis of unresectable pancreatic ductal adenocarcinoma (PDAC) is useful in determining the appropriate management strategy. The present study aimed to investigate the association between PDAC prognosis and inflammation-based markers, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, prognostic nutritional index, modified Glasgow prognostic score (mGPS) and controlling nutritional status score. A total of 72 patients with unresectable PDAC who received chemotherapy were included. Inflammation-based markers were measured prior to treatment. The median progression-free survival (PFS) and overall survival (OS) were 117 days (range, 10-781 days) and 244 days (range 43-781 days), respectively. The cut-off value of continuous variables that predicted the median OS (244 days) was calcualted. Univariate analysis of PFS showed that disease stage, first-line chemotherapy regimen, carcinoembryonic antigen (CEA), NLR, platelet-to-lymphocyte ratio (PLR), mGPS and controlling nutritional status (CONUT) scores were associated with PFS. Among them, stage, first-line chemotherapy regimen, CEA, NLR and mGPS were independent prognostic factors for PFS in multivariate analysis. Univariate analysis of OS showed that stage, first-line chemotherapy regimen, CA19-9, NLR, PLR, prognostic nutritional index (PNI), mGPS and CONUT score were associated wtih OS. Among them, first-line chemotherapy and mGPS were independent prognostic factors for OS according to multivariate analysis. Univariate and multivariate analyses revealed that a NLR ≥4.0 and mGPS 2 were independent prognostic factors for PFS. For OS, mGPS 2 was an independent prognostic factor. In conclusion, mGPS was the most useful marker in predicting the prognosis of patients with unresectable PDAC who received chemotherapy.

The efficacy of sedation during endoscopic injection sclerotherapy (EIS) for esophageal varices (EVs) in patients with liver cirrhosis remains unclear. The aim of this study is to compare the efficacy and safety between propofoland midazolambased sedation for EIS. Methods : Twentythree patients with EVs were prospectively and randomly assigned to midazolambased (Midazolam group) or propofolbased (Propofol group) sedation. All patients underwent a number connection test (NCT) to evaluate minimal hepatic encephalopathy (MHE) on the day before and at 2 and 24 hours following EIS. The primary endpoint was exacerbation of MHE after EIS, which was defined as deterioration of the NCT. The secondary endpoints were postoperative awareness, technical success rate, frequency of body movement, patient and operator satisfaction, cardiorespiratory dynamics during EIS, and adverse events. Results : Exacerbations of MHE at 2 hours after EIS compared with those before EIS were not significantly different between the two groups. In both groups, the deterioration of NCT scores before and 2 hours after EIS was observed (Propofol group : 60.0 vs. 70.0 s, P = 0.026 ; Midazolam group : 42.5 vs. 67.0 s, P = 0.002). There were no significant differences in awareness, technical success rate, or patient satisfaction. However, the frequency of body movement in the Propofol group was significantly lower than that in the Midazolam group (1 vs. 4, P = 0.045), and operator satisfaction in the Propofol group was significantly higher than that in the Midazolam group (P = 0.016). No adverse events were observed. Conclusions : Propofolbased sedation exacerbated MHE after EIS similarly to midazolambased sedation in patients with liver cirrhosis. However, propofolbased sedation provided stable sedation with a lower frequency of body movements and high operator satisfaction.