Arteriovenous malformation of small intestine successfully treated by double-balloon enteroscopy and laparoscope-assisted surgery.

Arteriovenous malformation (AVM) of the small bowel is a rare disease and can be sometimes difficult to treat due to the diagnostic difficulty. We herein report a case of small intestinal bleeding of AVM successfully treated with double-balloon enteroscopy (DBE) and laparoscope-assisted resection. A 44-year-old man complained of hematochezia and visited the previous doctor. He underwent gastroscopy and colonoscopy, but no bleeding site was detected. However, he rebled 2 days later and became hypotensive. Abdominal computed tomography revealed a hypervascular nodule in the jejunum. He was transferred to our institution for further treatment. DBE was performed and revealed a small pulsatile lesion with a tiny mucosal break. We then injected a marking tattoo. Two days later, he underwent an operation. We were able to easily locate the tattooed lesion laparoscopically and performed jejunal partial resection. His postoperative course was uneventful. DBE enabled a precise diagnosis and minimal invasive surgery.

Design, synthesis, and biological evaluation of novel somatostatin receptor subtype-2 agonists: Optimization for potency and risk mitigation of hERG and phospholipidosis.

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.

Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly.

Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.

Risk factors for prolonged mechanical ventilation in patients with severe multiple injuries and blunt chest trauma: a single center retrospective case-control study.

Aim: Blunt chest trauma is common and is associated with morbidity and mortality in patients with multiple injuries, frequently requiring invasive mechanical ventilation. The aim of this study was to elucidate risk factors for prolonged mechanical ventilation (PMV). Methods: Consecutive adult patients with multiple severe injuries and blunt chest trauma who treated in Chiba Emergency Medical Center (Chiba, Japan) between January 2008 and December 2015 were enrolled in this retrospective chart-review study. According to ventilatory time, the patients were divided into PMV (≥7 days) and shortened mechanical ventilation (SMV; <7 days) groups. Thoracic Trauma Severity Score (TTSS) was calculated. To identify risk factors for PMV, univariate and multivariate logistic analyses and receiver operating characteristic analysis were carried out. Results: Eighty-four and 49 patients were assigned to PMV and SMV groups, respectively. Compared with the SMV group, the PMV group had a significantly larger number of fractured ribs (P < 0.01), higher rate of severe Glasgow Coma Scale (GCS ≤8) (P < 0.05) and flail chest (P < 0.001), higher TTSS (P < 0.001), or longer intensive care unit and hospital stay (both P < 0.001). Logistic analysis showed that severe GCS (odds ratio [OR] = 4.6, P < 0.01), flail chest (OR = 3.0, P < 0.05), and TTSS (OR = 1.2; P < 0.01) were independent significant risk factors. Receiver operating characteristic analyses showed that the area under the curves for TTSS, flail chest, and severe GCS were 0.74, 0.70, and 0.58, respectively. When the three factors were combined, the area under the curve increased to 0.8. Conclusion: Severe GCS (≤8), flail chest, or TTSS may be independent risk factors. Combining the three risk factors could provide high predictive performance for PMV.

[A Case of Pneumatosis Cystoides Intestinalis Secondary to Gefitinib Therapy for Lung Adenocarcinoma].

Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition, characterized by subserosal or submucosal air within the bowel wall. Herein, we report a rare case of PCI secondary to treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). A 71-year-old man, who had received gefitinib therapy for 2 years and 5 months for lung adenocarcinoma with metastases to the bones and brain, presented with abdominal pain, diarrhea, and vomiting. Computed tomography of the abdomen revealed intramural air in the small bowel, free air in the abdomen, and moderate ascites. A diagnosis of PCI was made, and the patient was managed conservatively by discontinuing gefitinib treatment, because his vital signs were stable and there was no sign of peritonitis. The patient's symptoms gradually improved, and follow-up CT after 1 week revealed that the initial findings had almost completely resolved. Clinicians should note that treatment with gefitinib might cause PCI.

[Urgent gastrectomy in a patient who developed perforated gastric cancer during preoperative chemotherapy with S-1 plus cisplatin].

A 66 -year-old man presenting with a chief complaint of upper abdominal pain was diagnosed as having an advanced adenocarcinoma, type 2, of the lower third of the stomach after endoscopy was performed. An abdominal computed tomography( CT)scan revealed 4 lymph node metastases at the infrapyloric nodes(station No. 6)and the nodes around the proximal splenic artery(station No. 11p)and the abdominal aorta(station No. 16a2). The clinical stage was determined to be T3(SS)N2M1(LYM), Stage IV. Gastrectomy with D2 plus para-aortic node dissection was scheduled after 2 courses of S-1 plus cisplatin(CDDP)with curative intent. On day 14 after starting S-1 therapy, the patient complained of severe abdominal pain and peritoneal irritation of acute onset. Because the abdominal CT scan showed a large amount of intra-abdominal free air, we performed an urgent laparotomy with a tentative diagnosis of perforation of the gastric cancer. On laparotomy, we found a perforated malignant ulcer, 5 cm in maximum diameter, in the lesser curvature of the stomach; therefore, distal gastrectomy with D1 plus lymphadenectomy and reconstruction using the Roux-en-Y method were performed. At the end of the surgery, a macroscopic residual tumor remained in the para-aortic lymph node. The postoperative course was uneventful, and the patient was discharged on day 23 after surgery. In the present case, despite the performance of urgent gastrectomy while the patient was receiving strong chemotherapy, perioperative management was successful, with no serious postoperative complication or adverse events as a result of the chemotherapy.

2-Nitroimidazole-tricarbocyanine conjugate as a near-infrared fluorescent probe for in vivo imaging of tumor hypoxia.

We developed a novel near-infrared (NIR) fluorescent probe, GPU-167, for in vivo imaging of tumor hypoxia. GPU-167 comprises a tricarbocyanine dye as an NIR fluorophore and two 2-nitroimidazole moieties as exogenous hypoxia markers that undergo bioreductive activation and then selective entrapment in hypoxic cells. After treatment with GPU-167, tumor cells contained significantly higher levels of fluorescence in hypoxia than in normoxia. In vivo fluorescence imaging specifically detected GPU-167 in tumors 24 h after administration. Ex vivo analysis revealed that fluorescence showed a strong correlation with hypoxia inducible factor (HIF)-1 active hypoxic regions. These data suggest that GPU-167 is a promising in vivo optical imaging probe for tumor hypoxia.