[Using Mohs' Paste for Disease Control in a Case of Advanced Mucinous Breast Cancer with Continuous Bleeding from the Primary Tumor Surface].

We present the case of a 70-year-old woman with cancer affecting a substantial area of her breast, characterized by persistent bleeding from the primary tumor. Pathological findings revealed a hormone-sensitive mucinous carcinoma. CT indicated a primary tumor in close proximity to the greater pectoral muscle, left axillary lymph node metastasis, and oligometastases in her right lung. Although she declined surgery and chemotherapy, she agreed to receive Mohs' paste and endocrine therapy. The paste was applied locally, and local control was achieved after 2 weeks. Five years later, CR was still maintained in her left breast. Mohs' paste played a crucial role in achieving local control of the exudation and bleeding from the exposed, unresected cancer. It proved to be an outstanding component of hormone-sensitive local treatment, working synergistically with systemic drug therapy and hormonal therapy.

[A Case Report of Laparoscopy Assisted Distal Gastrectomy for Gastric Cancer with an Adachi Type VI Anomaly (Group 27)Institution].

We report the case of a 79-year-old man, with gastric cancer detected on upper gastrointestinal endoscopic examination performed by a nearby medical clinic, and referred to our hospital, in April 201X. He was diagnosed with gastric cancer(ML, less, 0- II a+ II c, tub 1-2, cT1bN0M0, cStage I A). We performed laparoscopy assisted distal gastrectomy, D1+lymph node dissection, and Billroth I (B- I )reconstruction. Abdominal CT scan before surgery confirmed vascular anomaly of the celiac artery. We diagnosed Adachi type VI, preserved hepato-gastric artery trunk, and performed D1 plus dissection plus B- I reconstruction with small incision in the epigastrium. The operation time was 244 minutes and the blood loss was 5 mL. There were no postoperative complications, and the patient was discharged from hospital 7 days after the surgery. Pathological findings revealed pT4aN0M0, pStage II B, and the patient has been treated with TS-1®postoperative adjuvant chemotherapy. At present, there is no recurrence. As vascular anomalies of the celiac artery branch exhibit various forms, occasional blood vessel preventing surgery is required. Examining blood vessels through CT scan before the surgery made it possible to perform Laparoscopic gastrectomy safely.

[Surgical Resection of Solitary Brain Metastasis from Breast Cancer].

BACKGROUND: Brain metastasis from breast cancer has a poor prognosis. For solitary cerebral metastases, surgical resection may contribute to the improvement of survival and QOL. We studied the prognosis and characteristics of solitary brain metastasis from breast cancer in patients undergoing surgical resection. METHODS: Seventeen patients had tumors metastatic to the brain at Kasukabe Municipal Hospital between June 2009 and May 2016, and 7 of them underwent craniotomy. Their treatment outcomes were analyzed retrospectively. RESULTS: The median age at diagnosis of brain metastasis was 56 years. The median survival duration was 19.6 months. With regard to radiation therapy after surgery, 3 patients received whole brain irradiation, 2 patients received stereotactic brain irradiation, and 2 patients received both. The site of brain metastasis was the cerebellum in 6 patients, and the occipital lobe in 1 patient. The number of HER2-positive breast cancer patients was 5, and lapatinib and capecitabine were administered to 4 out of these 5 patients. CONCLUSION: For solitary brain metastasis, the improvement in symptoms and the extension of the survival can be achieved using multidisciplinary treatment with surgery, radiation, and molecular targeting drugs.

Vitamin D3 modulates the expression of bile acid regulatory genes and represses inflammation in bile duct-ligated mice.

Vitamin D receptor (VDR), a nuclear receptor that regulates calcium homeostasis, has been found to function as a receptor for secondary bile acids. Because the in vivo role of VDR in bile acid metabolism remains unknown, we investigated the effect of VDR activation in a mouse model of cholestasis. We treated mice with 1alpha-hydroxyvitamin D(3) [1alpha(OH)D(3)] after bile duct ligation (BDL) and examined mRNA expression and cytokine levels. 1alpha(OH)D(3) treatment altered the expression of genes involved in bile acid synthesis and transport in the liver, kidney, and intestine but did not decrease bile acid levels in the plasma and liver of BDL mice. 1alpha(OH)D(3) treatment suppressed mRNA expression of proinflammatory cytokines in the liver and strongly decreased the plasma levels of proinflammatory cytokines in BDL mice. These findings indicate that 1alpha(OH)D(3) regulates a network of bile acid metabolic genes and represses proinflammatory cytokine expression in BDL mice. VDR ligands have the potential to prevent the cholestasis-induced inflammatory response.

Involvement of prostacyclin/IP receptors in decreased acid response of damaged stomachs--mediation by somatostatin/SST2 receptors.

AIMS: We examined the effect of a prostacyclin (PGI(2)) analog iloprost on histamine-induced acid secretion and investigated how endogenous PGI(2) mediated the decreased secretory response in the damaged stomach after exposure to taurocholate (TC). MAIN METHODS: Male C57BL/6 mice, both wild-type (WT) and IP receptor knockout (IP-KO) animals, were used after 18 h of fasting. Under urethane anesthesia, the abdomen was incised, and an acute fistula was provided in the stomach. KEY FINDINGS: Acid secretion in WT and IP-KO mice was similarly and dose-dependently increased by histamine. Iloprost decreased the histamine-stimulated secretion in WT but not IP-KO mice. The inhibitory effect of iloprost in WT mice was totally abrogated by the prior administration of CYN154806, a selective somatostatin SST2 receptor antagonist. On the other hand, the acid secretion in WT mice was decreased after exposure of the stomach to 20 mM TC for 20 min, with an increase in mucosal PGI(2) content, but the decrease was significantly less marked in IP-KO mice. The decreased acid response to TC in WT mice was totally prevented by the prior administration of CYN154806 as well as indomethacin. Somatostatin contents in the stomach were reduced after the administration of iloprost or the mucosal exposure to TC, while the blood levels increased. SIGNIFICANCE: Somatostatin/SST2 receptors are involved in the decreased acid response of the damaged stomach, in addition to PGI(2)/IP receptors. It is assumed that PGI(2) releases somatostatin from D cells, which in turn decreases acid secretion via the activation of SST2 receptors.

[A case of advanced breast cancer with skin ulceration successfully treated with paclitaxel and toremifene therapy].

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0, Stage IIIC) achieving a significant improvement of QOL by paclitaxel (PTX) and toremifene (TOR) therapy. The patient was a 31-year-old woman who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. She received 4 courses of tri-weekly CEF (C: 500 mg, E: 60 mg, F: 500 mg/m2/tri-weekly) and 4 courses of weekly PTX (80 mg/m2) with TOR (120 mg/day). The bleeding from the tumor disappeared after CEF chemotherapy. The response for breast tumor after PTX and TOR therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) without skin transplantation were performed. She had no recurrence during one year after operation. PTX and TOR therapy were effective for advanced breast tumor, and can improve patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer.

[Treatment strategy of breast carcinoma in the elderly patient-surgery, hormone therapy, and chemotherapy].

We report an elderly breast carcinoma patient with complication. The patient was a 91-year-old woman who had breast lump. The tumor was 3 cm in diameter. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and positive for HER2/neu protein expression. She received tumorectomy. After operation, she was administered aromatase inhibitor. After six months from operation, metastases of lymph nodes and lung were observed. Although she had administered another aromatase inhibitor, the metastases were rapidly growing. Eight months after operation, she died from carcinomatous lymphangitis. Even the less invasive operation by local anesthesia can progress metastases rapidly in elderly breast cancer patients. This case suggested that a treatment strategy for elderly breast cancer patients should have been determined carefully.

[A case of curatively resected AFP producing gastric cancer with massive lymph node metastasis effectively treated by neoadjuvant-chemotherapy of S-1 and CDDP].

A 65-year-old man who had AFP producing gastric cancer with massive lymph-node metastasis was admitted to our institution. Because of bulky lymph-node metastasis, the tumor was considered unresectable. He was treated with neoadjuvant chemotherapy of S-1 and cisplatin (CDDP).S-1 (80 mg/m2/day) was administered for 21 consecutive days followed by 14 days rest as one course,and CDDP (60 mg/m2) was infused over 2 hours on day 8. After 1 course, radiographic examination showed remarkable improvement in the tumor size of the stomach, and computed tomography showed markedly reduced paraaortic lymph node metastasis. However, surgery was performed after 3 weeks,because of the adverse effect of diarrhea grade 3 after one course of the chemotherapy. This is a rare case in which neoadjuvant chemotherapy of S-1 and CDDP may well be an effective treatment for unresectable AFP producing gastric cancer with bulky lymph-node metastasis.

Impairment of bilirubin clearance and intestinal interleukin-6 expression in bile duct-ligated vitamin D receptor null mice.

The vitamin D receptor (VDR) mediates the physiological and pharmacological actions of 1α,25-dihydroxyvitamin D(3) in bone and calcium metabolism, cellular growth and differentiation, and immunity. VDR also responds to secondary bile acids and belongs to the NR1I subfamily of the nuclear receptor superfamily, which regulates expression of xenobiotic metabolism genes. When compared to knockout mouse investigations of the other NR1I nuclear receptors, pregnane X receptor and constitutive androstane receptor, an understanding of the role of VDR in xenobiotic metabolism remains limited. We examined the effect of VDR deletion in a mouse model of cholestasis. We performed bile duct ligation (BDL) on VDR-null mice and compared blood biochemistry, mRNA expression of genes involved in bile acid and bilirubin metabolism, cytokine production, and expression of inflammatory regulators with those of wild-type mice. VDR-null mice had elevated plasma conjugated bilirubin levels three days after BDL compared with wild-type mice. Urine bilirubin levels and renal mRNA and/or protein expression of multidrug resistance-associated proteins 2 and 4 were decreased in VDR-null mice, suggesting impaired excretion of conjugated bilirubin into urine. While VDR-null kidney showed mRNA expression of interleukin-6 (IL-6) after BDL and VDR-null macrophages had higher IL-6 protein levels after lipopolysaccharide stimulation, the induction of intestinal Il6 mRNA expression and plasma IL-6 protein levels after BDL was impaired in VDR-null mice. Immunoblotting analysis showed that expression of an immune regulator, IκBα, was elevated in the jejunum of VDR-null mice, a possible mechanism for the attenuated induction of Il6 expression in the intestine after BDL. Increased expression of IκBα may be a consequence of compensatory mechanisms for VDR deletion. These results reveal a role of VDR in bilirubin clearance during cholestasis. VDR is also suggested to contribute to tissue-selective immune regulation.

Aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin enhances liver damage in bile duct-ligated mice.

The environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1ß, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.

Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists.

A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These results provide a basis for constructing new tools for probing the biology of GPR120 and for developing new candidate therapeutic agents.

Tacrolimus (FK506), an immunosuppressive agent, prevents indomethacin-induced small intestinal ulceration in the rat: inhibition of inducible nitric oxide synthase expression.

We examined the effect of tacrolimus (FK506), an immunosuppressive drug, on indomethacin-induced small intestinal ulceration in rats. Animals were given indomethacin (10 mg/kg, s.c.), killed 24 h later, and myeloperoxidase (MPO) activity and thiobarbituric acid reactants (TBARS) were evaluated in intestinal lesions. Tacrolimus (0.3 - 3 mg/kg) was administered p.o. twice 0.5 h before and 6 h after indomethacin injection. The expression of inducible nitric oxide synthase (iNOS) mRNA was determined by a TaqMan real-time RT-PCR, while the activity of nuclear factor (NF)-kappaB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA) 6 h after indomethacin treatment. Indomethacin provoked severe hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum, accompanied with increases in MPO activity and TBARS. Oral administration of tacrolimus reduced the severity of indomethacin-induced intestinal lesions in a dose-dependent manner. The increases in MPO activity and TBARS were also significantly attenuated by tacrolimus. The expression of iNOS mRNA was markedly enhanced when examined 6 h after indomethacin administration, and this response was counteracted by tacrolimus. Indomethacin also activated NF-kappaB in a tacrolimus-preventable manner. These results suggest that tacrolimus prevents indomethacin-induced small intestinal ulceration in the rat. This effect may be due to inhibition of iNOS induction through suppression of NF-kappaB activation.

Synthesis and evaluation of 2-Nonylaminopyridine derivatives as PPAR ligands.

To find novel PPAR ligands, we prepared several 3-{3 or 4-[2-(nonylpyridin-2-ylamino)ethoxy]phenyl}propanoic acid derivatives which were designed based on the structure of our previous PPARgamma ligand 1. In PPAR binding affinity assays, compound 4, which had an ethoxy group at the C-2 position of the propanoic acid of 1, showed selective binding affinity for PPARgamma. Compound 3, with an ethyl group at the C-2 position, was found to be a PPARalpha/gamma dual ligand. Compound 6, the meta isomer of 1, has been shown to be a PPARalpha ligand. The introduction of methyl (7) and ethyl (8) groups to the C-2 position of the propanoic acid of 6 further improved PPARalpha-binding potency. In cell-based transactivation assay, compounds 3 and 4 showed dual-agonist activity toward PPARalpha and PPARgamma. Compound 6 was found to be a triple agonist and compound 8 proved to be a selective PPARalpha agonist. In the human hypodermic preadipocyte differentiation test, it was demonstrated that the maximal activity of compounds 3 and 4 was higher than that of rosiglitazone.

Phenylpropanoic acid derivatives bearing a benzothiazole ring as PPARdelta-selective agonists.

To find novel PPARdelta-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARdelta agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARdelta appropriately.

Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists.

A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARdelta transactivation activity, comparable with or somewhat superior to that of the known PPARdelta-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARdelta function, but also as a candidate drug for the treatment of metabolic syndrome.