Immunohistochemical Examination of a Resected Advanced Hilar Cholangiocarcinoma Arising in a 29-Year-Old Male without Primary Sclerosing Cholangitis

A 29-year-old man with advanced hilar cholangiocarcinoma was successfully treated with an extended right lobectomy. The carbohydrate antigen 19-9 (CA19-9) level was elevated to 939 IU/l, and the pathological findings revealed moderately differentiated tubular adenocarcinoma which involved almost the entire thickness of the hepatic duct and the adjacent liver tissue (T3) and which was associated with lymph node metastasis (N1). It was a stage IIB (T3N1M0) tubular adenocarcinoma according to UICC pathological staging. Immunohistochemical examination revealed that Ki-67, cyclin D1, and MMP-7 were positive, and 14-3-3σ and p27 were negative. The pathological and immunohistochemical findings indicated high malignant potential indicating poor prognosis. We administrated the postoperative adjunct gemcitabine combined with S-1 chemotherapy. The patient is alive without recurrence and doing well two years after surgery. We also review other reports of cholangiocarcinoma patients aged less than 30 years

Safety and Utility of Endoscopic Removal of Common Bile Duct Stones in the Elderly

We investigated the safety and utility of endoscopic removal of common　bile duct stones (CBDS) in the elderly. In all, 253 patients with CBDS who　underwent endoscopic retrograde cholangiopancreatography (ERCP) between January　2007 and December 2011 at Showa University Hospital were evaluated retorspectively. The median age of the patients was 75 years ; thus, we divided patients　into two groups, those aged ≥ 75 years (Group A ; n ＝ 134) and those aged ＜75 years (Group B ; n ＝ 119). Patients in Group A had significantly higher rates　of endoscopic sphincterotomy in palliative ERCP (24.8% vs. 10.7%; p ＝ 0.008) and　palliative removal of CBDS (34.8% vs. 20.9%; p ＝ 0.015) than patients in Group　B. However, the median dose of flunitrazepam was significantly lower for patients　in Group A than Group B (1 vs. 1.4 mg, respectively ; p ＜ 0.001). The rate of use　of pentazocine (18.5% vs. 54.7%; p ＜ 0.001) and scopolamine butylbromide (6.2%　vs. 23.9%; p ＜ 0.01) was significantly lower in Group A patients, whereas the use　of glucagon was significantly higher in this group (43.8 vs. 15.4%; p ＜ 0.001).　There were no significant differences in the rate of successful endoscopic removal　of CBDS, treatment time, complications, and the recurrence of CBDS between the　two groups. Endoscopic removal of CBDS in the elderly is a safe procedure with　good outcomes if the appropriate treatment is selected

Usefulness of Continuous Regional Arterial Infusion with Doripenem and Protease Inhibitors for Severe Acute Pancreatitis

Doripenem (DRPM) is a relatively new drug belonging to the carbapenem antibiotic group. We hypothesized that the pharmacological characteristics of DRPM could make it useful in the treatment of severe acute pancreatitis (SAP). We investigated the usefulness of continuous regional arterial infusion (CRAI) with DRPM and protease inhibitors for SAP. Two hundred and forty-two patients with SAP were admitted to Showa University Hospital between November 2002 and June 2013. Of these, 53 patients were treated with CRAI with carbapenem antibiotics and nafamostat mesilate (NM), a serine protease inhibitor, via the celiac and superior mesenteric arteries. Clinical outcomes were evaluated retrospectively in 34 patients treated with DRPM and 19 patients undergoing non-DRPM therapy (meropenem n=11, imipenem n=6; biapenem n=2). The median time to commencement of oral intake was significantly shorter in the DRPM than non-DRPM group (9 vs 14 hospital days, respectively; P<0.01). In addition, the rate of walled-off necrosis in the DRPM group tended to be lower than in the non-DRPM group (37.5 vs 64.7%, respectively, P=0.069). The results of the present study suggest that CRAI with DRPM and NM for SAP could have equivalent therapeutic effects to CRAI with other carbapenem antibiotics and NM

Features of and Mechanisms Underlying Insulitis In aly/aly Male Mice as an Animal Model of Autoimmune Pancreatitis: Activation of CD11c+, CD4+, and Th2 Cells and Predominant Destruction of β-cells

Diabetes mellitus (DM) is observed in patients with autoimmune pancreatitis (AIP). The development of DM in AIP is believed to be due to blood flow obstruction of the endocrine gland that accompanies pancreatitis, as well as injury to the islets caused by inflammation. The latter is called insulitis and the detailed mechanisms underlying its development are not yet clear. The aim of the present study was to elucidate the mechanisms involved in the development of insulitis in AIP using aly mice as an animal model of AIP: results in aly/aly male mice, as the AIP group, were compared with those inaly/+ male mice as a control group. Mice in both groups were killed between 16 and 48 weeks of age, and pancreatitis and insulitis were evaluated histologically. Inflammatory and endocrine cells were evaluated by immunofluorescence staining with anti-CD4, anti-CD8, anti-CD11b, and anti-CD11c antibodies, as well as immunohistochemical analyses using insulin and glucagon antibodies. Plasma levels and the pancreatic content of interferon (IFN)-γ (as a Th1-secreted cytokine) and interleukin (IL)-4 (as a Th2-secreted cytokine) were determined. Pancreatitis was seen in aly/aly mice from 16 weeks of age and it developed gradually thereafter. Insulitis also developed gradually and was seen in mice after 24 weeks of age in association with a decrease in the number of islets. CD11c+ cells and CD4+ T cells were seen to infiltrate into the islets. Although the number of β-cells decreased with time, the number of α-cells was maintained until mice were 48 weeks of age. IFN-γ content peaked in mice at 16 weeks of age and declined rapidly from 20 weeks. There were two peaks in IL-4 content, one at 16 weeks and the other at 32 weeks, suggesting an association between IL-4 content and advanced insulitis after 32 weeks. In conclusion, the results suggest that insulitis in AIP is induced predominantly by the infiltration of CD11c+ cells and CD4+ T cells into the islets, and progression is facilitated by the imbalance of the activation of Th2 rather than Th1. Furthermore, insulitis in AIP predominantly involves β-cells rather than α-cells

Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation : a family report

Hypophosphatasia (HPP) is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene in an autosomal recessive or dominant manner and characterized by defective mineralization of bone and low serum ALP levels. In this report, we present a family with HPP mother (case 1) and HPP child (case 2) who have identical TNSALP gene mutation (c.1015G>A p.Gly339Arg heterozygous mutation) but distinct clinical phenotypes. Whereas case 1 appeared to be asymptomatic despite extremely low levels of serum ALP, case 2 had several HPP-related symptoms, such as tooth loss, fractures, short stature, with slightly decreased ALP levels. Upon the diagnosis of HPP, case 1 discontinued denosumab, which was used to treat her rheumatoid arthritis, concerning the risk of atypical femoral fractures. The clinical course of this family was suggestive in a genotype-phenotype imbalance in HPP, the underdiagnosis of HPP in adults, and the risk of atypical femoral fractures using bone resorption inhibitors

Potential of Photodynamic Therapy Based on Sugar-Conjugated Photosensitizers

In 2015, the Japanese health insurance approved the use of a second-generation photodynamic therapy (PDT) using talaporfin sodium (TS); however, its cancer cell selectivity and antitumor effects of TS PDT are not comprehensive. The Warburg effect describes the elevated rate of glycolysis in cancer cells, despite the presence of sufficient oxygen. Because cancer cells absorb considerable amounts of glucose, they are visible using positron emission tomography (PET). We developed a third-generation PDT based on the Warburg effect by synthesizing novel photosensitizers (PSs) in the form of sugar-conjugated chlorins. Glucose-conjugated (tetrafluorophenyl) chlorin (G-chlorin) PDT revealed significantly stronger antitumor effects than TS PDT and induced immunogenic cell death (ICD). ICD induced by PDT enhances cancer immunity, and a combination therapy of PDT and immune checkpoint blockers is expected to synergize antitumor effects. Mannose-conjugated (tetrafluorophenyl) chlorin (M-chlorin) PDT, which targets cancer cells and tumor-associated macrophages (TAMs), also shows strong antitumor effects. Finally, we synthesized a glucose-conjugated chlorin e6 (SC-N003HP) that showed 10,000–50,000 times stronger antitumor effects than TS (IC50) in vitro, and it was rapidly metabolized and excreted. In this review, we discuss the potential and the future of next-generation cancer cell-selective PDT and describe three types of sugar-conjugated PSs expected to be clinically developed in the future

Visualization of strain distribution in rubber bulk during friction

Abstract This study employed a digital image correlation method (DICM) to experimentally quantify horizontal strain distribution in silicone rubber bulk during horizontal displacement against a stainless-steel sphere with/without glycerol. The strain distribution at different depth levels was measured by capturing the position of white powders in transparent rubber bulk. The experimental results indicated that each point in the rubber bulk moved while describing a horizontal loop during horizontal displacement depending on the position and lubrication conditions. This caused changes in the horizontal strain during horizontal displacement. These results suggest that the hysteresis term could be caused by changes in the vertical and horizontal strains

A Basic Study of Photodynamic Therapy with Glucose-Conjugated Chlorin e6 Using Mammary Carcinoma Xenografts

By using the Warburg effect&#8212;a phenomenon where tumors consume higher glucose levels than normal cells&#8212;on cancer cells to enhance the effect of photodynamic therapy (PDT), we developed a new photosensitizer, glucose-conjugated chlorin e6 (G-Ce6). We analyzed the efficacy of PDT with G-Ce6 against canine mammary carcinoma (CMC) in vitro and in vivo. The pharmacokinetics of G-Ce6 at 2, 5, and 20 mg/kg was examined in normal dogs, whereas its intracellular localization, concentration, and photodynamic effects were investigated in vitro using CMC cells (SNP cells). G-Ce6 (10 mg/kg) was administered in vivo at 5 min or 3 h before laser irradiation to SNP tumor-bearing murine models. The in vitro study revealed that G-Ce6 was mainly localized to the lysosomes. Cell viability decreased in a G-Ce6 concentration- and light intensity-dependent manner in the PDT group. Cell death induced by PDT with G-Ce6 was not inhibited by an apoptosis inhibitor. In the in vivo study, 5-min-interval PDT exhibited greater effects than 3-h-interval PDT. The mean maximum blood concentration and half-life of G-Ce6 (2 mg/kg) were 15.19 &#177; 4.44 &#956;g/mL and 3.02 &#177; 0.58 h, respectively. Thus, 5-min-interval PDT with G-Ce6 was considered effective against CMC

Therapeutic Effect of an Immunomodulator on Pancreatic Endocrine Secretion Disorder and Insulitis in an Animal Model of Autoimmune Pancreatitis

Adrenocortical hormones are effective in many, but not all, cases of autoimmune pancreatitis （AIP）. While effective treatment for refractory and recurrent cases of AIP has not been established, immunomodulators are sometimes used. We examined the therapeutic effect of the immunomodulator FK506 against AIP using an animal model: aly/aly male mice. Mice were divided into three groups based on FK506 dose: 1mg/kg, 2mg/kg, and non-administration （pancreatitis） groups. Pancreatic exocrine gland injury was regarded as pancreatitis and pancreatic endocrine injury was regarded as insulitis. Histological evaluation of pancreatic tissue at 16 and 24 weeks of age was performed quantitatively using ImageJ software, and the three groups were compared. The pancreatitis group developed pancreatitis at 24 weeks of age, but onset of pancreatitis was suppressed in the 1mg group. However, pancreatitis development was not suppressed in the 2mg group, and pancreatitis developed from as early as 16 weeks of age. In the pancreatitis group, insulitis resulted in morphological changes such as shrinkage of pancreatic islets of Langerhans as inflammatory cell infiltration into pancreatic acinar cells became stronger. No significant difference was observed between the 1mg group and the pancreatitis group in the islet area but, in the 2mg group, there was significant reduction in area compared to the pancreatitis group and the 1mg group. Although administration of FK506 at a low dose had an effect of suppressing the onset of pancreatitis, administration at a higher dose appeared to exacerbate pancreatitis