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.
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.
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.
Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal-dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken together, our results demonstrated that TAS0728 may offer a promising therapeutic option with improved efficacy as compared with current HER2 inhibitors for HER2-activated cancers. Assessment of TAS0728 in ongoing clinical trials is awaited (NCT03410927).
AIMTo investigate the location to which a pancreatic stent should be inserted to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).METHODSOver a ten-year period at our hospital, 296 patients underwent their first ERCP procedure and had a pancreatic stent inserted; this study included 147 patients who had ERCP performed primarily for biliary investigation and had a pancreatic stent inserted to prevent PEP. We divided these patients into two groups: 131 patients with a stent inserted into the pancreatic head (head group) and 16 patients with a stent inserted up to the pancreatic body or tail (body/tail group). Patient characteristics and ERCP factors were compared between the groups.RESULTSPancreatic amylase isoenzyme (p-AMY) levels in the head group were significantly higher than those in the body/tail group [138.5 (7.0-2086) vs 78.5 (5.0-1266.5), P = 0.03] [median (range)]. No cases of PEP were detected in the body/tail group [head group, 12 (9.2%)]. Of the risk factors for post-ERCP hyperamylasemia (≥ p-AMY median, 131 IU/L), procedure time ≥ 60 min [odds ratio (OR) 2.65, 95%CI: 1.17-6.02, P = 0.02) and stent insertion into the pancreatic head (OR 3.80, 95%CI: 1.12-12.9, P = 0.03) were identified as independent risk factors by multivariate analysis.CONCLUSIONStent insertion up to the pancreatic body or tail reduces the risk of post-ERCP hyperamylasemia and may reduce the risk of PEP.
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