Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor. A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100 mg kg⁻¹, q3d × 4) alone or GEM plus iRGD peptide (8 μmol kg⁻¹). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC). We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens. Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.

Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease.

Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8-cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway.

Abdominal computed tomography of a 71-year-old man revealed a 3-cm mass in gastric cardia. Although the mass was widely attached to the gastric wall, no clear contrast enhancement was observed. Abdominal magnetic resonance imaging revealed the mass to have homogenous high intensity on T2W1 images and isointensity on T1W1 images. On diffusion-weighted imaging, no high intensity was observed. However, the mass had a smooth surface and was widely attached to the gastric wall, consistent with computed tomography findings. A gastric submucosal tumor was suspected. Laparoscopic tumor resection was performed. Histopathologic diagnosis of the mass was a bronchogenic cyst derived from the respiratory primordium originating in the foregut of the primitive intestine. Such cysts are mostly found in the mediastinum or thoracic cavity; their occurrence on the gastric wall is extremely rare. Despite this, we think that bronchogenic cysts should be considered in the differential diagnosis of abdominal unilocular cystic diseases.

INTRODUCITON: We report a recent case of strangulated bowel obstruction due to an incarcerated secondary perineal hernia that developed after laparoscopic rectal resection. PRESENTATION OF CASE: A 75-year-old man undergoing treatment for alcoholic cirrhosis underwent laparoscopic abdominoperineal resection of the rectum (APR) for lower rectal cancer after preoperative chemoradiotherapy. Lung metastases were diagnosed 2 months postoperatively. Ten days after chemotherapy initiation, the patient was hospitalized on an emergency basis due to hepatic encephalopathy. Ten days thereafter, we observed perineal skin protrusion. Moreover, the skin disintegrated spontaneously, resulting in ascetic fluid outflow. Pain and fever developed, with inflammatory reactions. Contrast-enhanced computed tomography showed strangulated small bowel obstruction due to perineal hernia. We performed an emergency surgery, during which we found small intestine wall incarcerated in the pelvic dead space, with thickening and edema; no necrosis or perforation was observed. We performed internal fixation by introducing an ileus tube into the ileocecum and fixing its balloon at the cecal terminus. DISCUSSION: Secondary perineal hernia is rare and can develop after APR. Its prevalence is likely to increase in future because of the increasing ubiquity of laparoscopic APR, in which no repair of peritoneal stretching to the pelvic floor is performed. However, only two case of secondary perineal hernia causing strangulated bowel obstruction has been reported in the literature. The follow-up evaluation of our procedures and future accumulation of cases will be important in raising awareness of this clinical entity. CONCLUSION: We suggest that the pelvic floor and the peritoneum should be repaired. Highlights:

Liver cirrhosis is the end stage of chronic liver disease, but no definitive pharmacological treatment is currently available. It has been reported that thrombopoietin (TPO) promotes liver regeneration and improves liver cirrhosis by increasing platelet count. We have shown the direct effect of platelet transfusion on the improvement of liver function in patients with chronic liver disease. However, platelet transfusion often causes adverse events, such as platelet transfusion refractoriness and pruritus. Therefore, we conducted an exploratory clinical trial and administered eltrombopag, an orally bioavailable, small-molecule, non-peptide TPO receptor agonist that has been approved for the treatment of chronic idiopathic thrombocytopenic purpura. The study included five male patients, aged from 49 to 75 years (57.6 ± 10.4 years), with both chronic liver disease and hepatitis C virus infection, who presented with thrombocytopenia but without cancer. Eltrombopag, ranged from 6.25 to 50 mg/day (18.75 ± 18.22 mg/day), was administrated to the five patients during six months. All of the patients maintained platelet counts between 10 and 15 × 1010/L during the study. The indicators of liver function in patients were stable throughout the clinical trial, although we had predicted the same degree of the improvement of liver function, compared to platelet transfusion. Importantly, the liver volumes were also stable, and no cancerous lesions were observed. These results indicate the safety of long-term eltrombopag administration for patients with chronic liver disease and hepatitis C virus infection.