Preoperative prognostic nutritional index predicts postoperative infectious complications and oncological outcomes after hepatectomy in intrahepatic cholangiocarcinoma.

BACKGROUND: In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. PATIENTS AND METHODS: Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. RESULTS: Severe complications (Clavien-Dindo grade III-V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI <  50 (odds ratio [OR] = 2.22, P = 0.013), hilar lesion (OR = 2.46, P = 0.026), and long operation time (OR = 1.003, P = 0.029) as independent risk factors for severe complications. In comparing a high-PNI group (PNI ≥ 50, n = 142) and a low-PNI group (PNI <  50, n = 174), the low-PNI group showed higher rates of both major complications (27% vs. 13.4%; P = 0.003) and infectious complications (14.9% vs. 3.5%; P = 0.0021). Furthermore, median survival time and 1- and 5-year overall survival rates were 34.2 months and 77.4 and 33.8% in the low-PNI group, respectively, and 52.4 months and 89.3 and 47.5% in the high-PNI group, respectively (P = 0.0017). CONCLUSION: Preoperative PNI appears useful as an INI correlating with postoperative severe complications and as a prognostic indicator for ICC.

A new hexenoic acid glycoside with cytotoxic activity from the leaves of Psychotria luzoniensis.

A new hexenoic acid glycoside (1) together with known compounds, flavonol glycosides (2-4), iridoid glycoside (5), megastigmane glycoside (6), and amino acid (7) were isolated from the leaves of P. luzoniensis by resin column chromatography and preparative HPLC. Their structures were determined based on spectroscopic analysis, including HRFABMS and NMR (1H and 13C, 1H-1H COSY, HMQC, and HMBC) data. All compounds tested for cytotoxicity were active (IC50 < 50 µM) with IC50 values ranging from 1.97 to 32.85 µM against human colon adenocarcinoma cell line, compared to etoposide (IC50 1.19 µM).

Biological Properties, Bioactive Constituents, and Pharmacokinetics of Some Capsicum spp. and Capsaicinoids.

Pepper originated from the Capsicum genus, which is recognized as one of the most predominant and globally distributed genera of the Solanaceae family. It is a diverse genus, consisting of more than 31 different species including five domesticated species, Capsicum baccatum, C. annuum, C. pubescen, C. frutescens, and C. chinense. Pepper is the most widely used spice in the world and is highly valued due to its pungency and unique flavor. Pepper is a good source of provitamin A; vitamins E and C; carotenoids; and phenolic compounds such as capsaicinoids, luteolin, and quercetin. All of these compounds are associated with their antioxidant as well as other biological activities. Interestingly, Capsicum fruits have been used as food additives in the treatment of toothache, parasitic infections, coughs, wound healing, sore throat, and rheumatism. Moreover, it possesses antimicrobial, antiseptic, anticancer, counterirritant, appetite stimulator, antioxidant, and immunomodulator activities. Capsaicin and Capsicum creams are accessible in numerous ways and have been utilized in HIV-linked neuropathy and intractable pain.

Bioactive Compounds, Pharmacological Actions, and Pharmacokinetics of Wormwood (Artemisia absinthium).

Plants have been used since ancient times to cure certain infectious diseases, and some of them are now standard treatments for several diseases. Due to the side effects and resistance of pathogenic microorganisms to antibiotics and most drugs on the market, a great deal of attention has been paid to extracts and biologically active compounds isolated from plant species used in herbal medicine. Artemisia absinthium is an important perennial shrubby plant that has been widely used for the treatment of several ailments. Traditionally, A. absinthium has always been of pharmaceutical and botanical importance and used to manage several disorders including hepatocyte enlargement, hepatitis, gastritis, jaundice, wound healing, splenomegaly, dyspepsia, indigestion, flatulence, gastric pain, anemia, and anorexia. It has also been documented to possess antioxidant, antifungal, antimicrobial, anthelmintic, anti-ulcer, anticarcinogenic, hepatoprotective, neuroprotective, antidepressant, analgesic, immunomodulatory, and cytotoxic activity. Long-term use of A. absinthium essential oil may cause toxic and mental disorders in humans with clinical manifestations including convulsions, sleeplessness, and hallucinations. Combination chemotherapies of artemisia extract or its isolated active constituents with the currently available antibabesial or anti-malarial drugs are now documented to relieve malaria and piroplasmosis infections. The current review examines the phytoconstituents, toxic and biological activities of A. absinthium.

Constituents of the Fruiting Body of Poisonous Mushroom Omphalotus japonicus.

Six new sesquiterpenes, tsukiyols A-C, neoilludin C, and 4-O-methylneoilludins A and B, were isolated from the fruiting body of Omphalotus japonicus (Kawam.) Kirchm. & O. K. Mill. Additionally, six known compounds, illudin S, neoilludins A-B, 5-hydroxydichomitol, ergosterolperoxide, and 3ß,5α,9α-trihydroxyergosta-7,22-diene-6-one, were also obtained. Their chemical structures were determined with MS, IR, and NMR spectra and the absolute configurations of neoilludins A-C, 4-O-methylneoilludins A, and B were determined with electronic circular dichroism (ECD). Illudin S and 3ß,5α,9α-trihydroxyergosta-7,22-diene-6-one showed cytotoxicity against human acute promyelocytic leukemia HL60 cells. Illudin S, 4-O-methylneoilludin A, B, and tsukiyol C showed growth-restoring activity against mutant yeast via Ca2+-signal transduction.

Inhibitory activities of phenylpropanoids from Lycopus lucidus on amyloid aggregation related to Alzheimer's disease and type 2 diabetes.

The number of patients with Alzheimer's disease (AD) and type 2 diabetes (T2D) is increasing rapidly, and thus more research has been focused on the relationship between these two age-related chronic diseases. According to the amyloid hypothesis, prevention of the aggregation of amyloid ß (Aß) and human islet amyloid polypeptide (hIAPP) is a promising strategy for AD and T2D. In this study, thioflavin-T assay and transmission electron microscopy were performed to evaluate the inhibitory effect of three phenylpropanoids isolated from Lycopus lucidus-schizotenuin A and lycopic acids A and B-on both Aß and hIAPP fibrillization. All tested compounds exhibited similarly strong inhibitory activity toward amyloid aggregation. These results suggested that catechol moieties play important roles in the inhibition of amyloid plaque formation.

Indirubin promotes adipocyte differentiation and reduces lipid accumulation in 3T3­L1 cells via peroxisome proliferator­activated receptor γ activation.

The peroxisome proliferator­activated receptor Î³ (PPARγ) plays an important role in insulin sensitivity and adipocyte differentiation. It is known as ligand­receptor that improves insulin sensitivity in type 2 diabetes mellitus. Several kinds of indigo plant have been already used to treat diabetes in oriental traditional medicine, but its mechanism has not been clarified yet. To investigate the effect of indirubin, which is a component of Polygonum tinctorium on the cell differentiation and adipprocess in 3T3­L1 cells, 3T3­L1 cells were cultured to determine the effect of cell differentiation and glucose uptake with indirubin. As a result, Indirubin compound enhanced adipocyte differentiation in 3T3­L1 cells similar to rosiglitazone. This effect was terminated by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3­L1 adipocytes, the lipid droplet size and accumulation were reduced by this compound. The basal and insulin­stimulated glucose uptakes were also significantly increased. In addition, indirubin treatment significantly enhanced estrogen level by 1.64­fold with mature adipocytes which can be attributed to its aromatase activity. Conclutionaly, this finding suggested that indirubin is a potential anti­diabetic compound for type 2 diabetes mellitus by promoting adipocyte differentiation and glucose uptake via PPARγ.

[Complete Remission of Advanced Gastric Cancer with Tumor Embolism in the Right Gastric Vein Treated with Radical Resection after Chemotherapy].

A 74-year-old man presented to our hospital with the chief complaint of epigastric pain; upper gastrointestinal endoscopy revealed a 7-cm-sized type 3 gastric cancer in the lesser curvature of the lower part of the stomach. Abdominal contrast computed tomography revealed a tumor embolus in the right gastric vein; the preoperative diagnosis was cT4a(SE) N3aH0P0M0, cStage ⅢC. Because the cancer could spread during surgical manipulation, performing a safe radical resection was difficult; therefore, we decided to initiate chemotherapy. The patient received 3 courses of trastuzumab plus CapeOX, which led to reduction of the primarylesion, peri-gastric lymph node, and right gastric vein tumor embolus. Partial remission was achieved after chemotherapy; therefore, distal gastrectomy, D2 lymph node dissection, and Roux-en-Y reconstruction were performed. Histopathological examination did not reveal viable tumor cells in the primarylesion, lymph nodes, or tumor embolus, and the histological effect was Grade 3. Currently, the patient is alive without relapse at 9 months post operation. Advanced gastric cancer accompanied with tumor embolism in the gastric vein is commonly observed in patients with liver metastasis and in those with severely progressed state of cancer; many of these patients have poor prognosis. Preoperative chemotherapymaybe effective in cases in which tumor embolism in the gastric vein is identified through preoperative diagnostic imaging.

[Bilateral Metastatic Lung Tumor with Different Primary Organs].

A 72-year-old woman with a history of surgery for left breast cancer was found to have sigmoid colon cancer and solitary pulmonary tumor of left upper lobe. We diagnosed adenocarcinoma of the unknown origin by a transbronchial biopsy. We performed left upper segmentectomy and sigmoidectomy. Left pulmonary tumor was diagnosed metastatic lung tumor from breast cancer. A right pulmonary tumor was confirmed by chest computed tomography(CT) after sigmoidectomy. It was also considered to be metastasis from breast cancer and treated with vinorelbine ditartrate. Since no effect was observed by chemotherapy, tumor was surgically removed by wedge resection. Right pulmonary tumor was pathologically diagnosed as metastasis from sigmoid colon cancer. In suspicious case of pulmonary metastases from double cancer, the possibility of different lesions from different primary site should be kept in mind.

[Pulmonary Pleomorphic Carcinoma Relapsed after Surgery Surviving Long-term by Chemotherapy and Nivolumab].

A 60'-year-old man was referred to our hospital because of nodular shadow found at mass screening. We diagnosed the tumor as non-small cell lung cancer by transbronchial biopsy. Chest computed tomography showed a tumor shadow of 3 cm in diameter with cavity. Right middle lobectomy was performed and the pathological diagnosis was pleomorphic carcinoma of the lung. The tumor recurrence was found at 10 months after surgery, and was treated with cisplatin, docetaxel plus bevacizumab for 6 cycles. A complete remission was achieved, but regrowth at 5 months after chemotherapy was noted. The patient was treated with nivolumab following carboplatin, gemcitabine plus bevacizumab 3 cycles. A good partial response is continuing 2 years and 5 months after confirming recurrence.

A case of small intestinal neuroendocrine carcinoma diagnosed using double-balloon endoscopy with long-term survival.

Neuroendocrine neoplasms, including neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), are rare epithelial tumors with a predominant neuroendocrine differentiation. Compared with NETs, NECs have been reported to be rarer and have a poorer prognosis. We present a rare case of small bowel NEC diagnosed using double-balloon endoscopy (DBE) and the long-term survival accomplished via intensive therapy. DBE revealed an ulcerative tumor in the deep jejunum, and biopsy specimens showed large and highly dysplastic tumor cells; immuno-histological synaptophysin and chromogranin A tests were positive, and the Ki-67 index was more than 90%. Partial intestinal resection without complete lymph node dissection was performed and, postoperatively, chemotherapy was administered. The patient was observed for 3 years after chemotherapy, and complete remission was maintained.

Antioxidant Flavonols and Phenolic Compounds from Atraphaxis frutescens and Their Inhibitory Activities against Insect Phenoloxidase and Mushroom Tyrosinase.

Chemical investigation of the aerial parts of Atraphaxis frutescens resulted in the isolation of five 7-methoxyflavonols with pyrogallol B-ring moieties (1-5), a fisetinidol glucoside (13), and a benzyl glycoside (18), together with 26 known compounds including flavonoids, phenylpropanoid amides, anthraquinone glycosides, lignans, and a benzyl derivative. The principal chemical structural feature of the isolated compounds was either a pyrogallol or catechol B-ring moiety, and they showed potent 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. To assess the effects of these antioxidants on biological enzymes, their inhibitory effects against an insect phenoloxidase and a mushroom tyrosinase were evaluated. This study indicated that insect phenoloxidase was inhibited by phenylpropanoid amides and that mushroom tyrosinase was inhibited by the characteristic 7-methoxyflavonol 3-O-rhamnopyranosides.

Clinical characteristics and treatment outcomes of nineteen Japanese patients with gastrointestinal bezoars.

OBJECTIVE: To analyze the clinical characteristics of patients with gastrointestinal bezoars and their response to therapy. Patients We retrospectively reviewed the cases of 19 patients diagnosed with gastrointestinal bezoars at the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences or one of 15 collaborating institutions between December 2004 and August 2013. We investigated the epidemiology and etiology of the gastrointestinal bezoars by determining the gender, age at diagnosis, medical history, symptoms, complications, modalities used for diagnosis, treatments, outcomes and bezoar location, color and contents. RESULTS: There were 17 patients with gastric bezoars and two patients with small intestinal bezoars. All patients were 62 years of age or older, except for one case of a trichobezoar in a 10-year-old patient. Some of the patients had a history of surgery of any part of the gastrointestinal tract (n=5) and/or diabetes mellitus (n=2). The two patients with small intestinal bezoars required surgical removal in order to relieve ileus. Approximately one-half of the patients with gastric bezoars had ulcerations in the stomach (9/17 patients, 52.9%) and/or gastrointestinal bleeding (8/17, 47.1%). Endoscopic fragmentation was performed in 10 patients, whereas bezoar dissolution was achieved with a gastroprokinetic agent (n=1) and without any treatment (n=3) in the remaining cases. CONCLUSION: As previously reported, elderly individuals with a positive history of surgery and/or diabetes mellitus were observed in this bezoar patient series. Gastric ulcers and gastrointestinal bleeding were frequently observed. The majority of patients underwent endoscopic fragmentation, while spontaneous resolution of the gastric bezoar was observed in several cases.

Localization of FAK is related with colorectal carcinogenesis.

Focal adhesion kinase (FAK) is an important mediator functioning between cells and the extracellular matrix and is closely related with the integrin-signaling pathway. FAK has been reported to be involved in the proliferation, differentiation and apoptosis of cells. To date, no report has demonstrated the involvement of FAK in the carcinogenesis of the digestive tract. Therefore, we examined colorectal, esophageal, pancreatic and mammary cancers for expression of FAK and Phospho (P)-FAK by immunohistochemistry. Strong expression of FAK in the cytoplasm was detected in all 4 tumor types and expressions of FAK and P-FAK increased as the degree of cell differentiation became higher in colorectal and esophageal carcinomas. Interestingly P-FAK expression was confined to the nuclei, which was an unexpected result. No previous report of such a finding has been published for gastrointestinal cancer. All four of the organs investigated in the present study showed P-FAK expression in the nuclei, suggesting an association between FAK activation and abnormal cell proliferation. We also performed immunostaining of P-FAK in cell lines to examine the significance of its experience in the nuclei. However, unlike clinical specimens, the cell lines did not show P-FAK expression in the nuclei. Moreover, the injection of cancer cells into the peritoneal cavity of mice also failed to demonstrate P-FAK expression in the nuclei. These results may be related with the function of carrier proteins of FAK such as Hic-5 and Zyxin, which are found only in humans. Taken together, FAK and P-FAK are involved in the carcinogenesis of digestive organs.

The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRC) of the stomach exhibits diffuse growth and invasion without forming ducts. Destruction of the surrounding basal membrane and angiogenesis appear to be required for SRC to exhibit marked invasion and growth. We recently reported that heparanase (HPA) and cyclooxygenase-2 (COX-2) were strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in SRC of the stomach. We examined HPA and COX-2 expression in 3 cell lines derived from SRC of the stomach and in 50 SRC lesions of stomach by immunohistochemistry (IHC), in situ hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined the relationships among HPA expression, COX-2 expression, and the clinicopathologic features of SRC, mean age, sex, invasion depth, regional lymph node metastasis, lymphatic invasion, and venous blood vessel invasion. Of the 3 cell lines, 2 exhibited both HPA and COX-2 mRNA expression on RT-PCR. Of the 3 cell lines, 1 exhibited only HPA mRNA expression on RT-PCR. Heparanase expression was confirmed in 23 (46%) of 50 tumor samples by IHC. COX-2 expression was confirmed in 25 (50%) of the 50 tumor samples by IHC. In situ hybridization revealed messenger RNA expression in the same area as in that revealed by IHC. A close correlation was noted between HPA and COX-2 expressions (P < .0001). The present study thus elucidated the biologic features of SRC of the stomach related to growth and angiogenesis.

COX-2 induction by heparanase in the progression of breast cancer.

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

Localization of heparanase in esophageal cancer cells: respective roles in prognosis and differentiation.

In this study, we examined the distribution of heparanase protein in 75 esophageal squamous cell carcinomas by immunohistochemistry and analyzed the relationship between heparanase expression and clinicopathological characteristics. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Heparanase expression correlated significantly with depth of tumor invasion, lymph node metastasis, tumor node metastasis (TNM) stage and lymphatic invasion. Overexpression of heparanase in esophageal cancers was also associated with poor survival. In addition to its localization in the cytoplasm and cell membrane, heparanase was also identified in the nuclei of normal epithelial and tumor cells by immunohistochemistry. Furthermore, nuclear heparanase was detected in nuclear extract of cancer cell lines by Western blot and immunohistochemistry. Examination of the role of nuclear heparanase in cell proliferation and differentiation by double immunostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 10 (CK10) showed significant relationship between nuclear heparanase expression and differentiation (heparanase vs CK10), but not for proliferative state of esophageal cancer cells (heparanase vs PCNA). Our results suggest that cytoplasmic heparanase appears to be a useful prognostic marker in patients with esophageal cancer and that nuclear heparanase protein may play a role in differentiation. Inhibition of heparanase activity may be effective in the control of esophageal tumor invasion and metastasis.

Molecular mechanism of chemoresistance to cisplatin in ovarian cancer cell lines.

It is important to clarify the mechanism of resistance to cisplatin for the treatment of solid tumors. We have examined the expression of apoptosis-related proteins, Bax and Bcl-2, in ovarian cancer cells. We used the cell line 2008 and its cisplatin resistant subclone 2008 C-13. The percentage of 2008 cells showing apoptosis was significantly higher following cisplatin treatment as compared to untreated controls. 2008 C-13 cells showing apoptosis did not differ between the cisplatin-treated group and the untreated group. The expression of mRNA and protein of Bax in the two cell lines were not altered by treatment with cisplatin. Although the expression of mRNA and protein of Bcl-2 decreased in 2008 cells after treatment with cisplatin, the expression of Bcl-2 remained unchanged in 2008 C-13 cells. Our results indicate that the down-regulation of Bcl-2 plays an important role in the mechanisms of tumor resistance to anticancer drugs.

Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line.

5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.