[Palbociclib in a Postmenopausal Metastatic Breast Cancer Patient].

The purpose of our study was to test the efficacy and toxicity of palbociclib therapy for breast cancer treatment. Ten patients diagnosed with breast carcinoma were selected for this retrospective study between 2017 and 2018. After the patients had previously been administered palbociclib, they received either capecitabine or eribulin. As a result, the median PFS of capecitabine and eribulin were 6.4 months(3-10)and 5.8 months(4-7), respectively. Therefore, the treatment administered after palbociclib therapy may be useful for breast cancer patients.

[The Treatment of Olaparib for BRCA Positive-Metastatic Breast Cancer Patient].

Breast cancer patient(invasive ductal carcinoma, ER[+], PgR[+], HER2[3+], Ki-67: 30%)had neoadjuvant chemotherapy( FEC followed by docetaxel plus trastuzumab). After surgical operation(mastectomy and Ax)was performed and she received trastuzumab plus hormone therapy. After 2 years later, she had liver metastasis that showed IDC, ER(+), PgR (+), HER2(-). In addition, BRCA positive was shown. Therefore, the patient received olaparib tablets(300 mg twice daily). After 2 months later, liver metastasis reduced dramatically.

A novel selective prostaglandin E2 synthesis inhibitor relieves pyrexia and arthritis in Guinea pigs inflammatory models.

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Simultaneous Inhibition of PGE2 and PGI2 Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models.

Prostaglandin E2 (PGE2) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE2 synthesis inhibitor, compound I, 2-methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE2 selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2 signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE2 receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2 signaling, especially through the EP4 receptor, and PGI2 signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.

[Local Microwave Hyperthermia for Advanced or Recurrent Breast Cancer].

The purpose of our study was to test the efficacy and toxicity of hyperthermia for treating breast cancer. Ten patients received treatment (AC, paclitaxel, S-1, and aromatase inhibitor) in combination with hyperthermia. The hyperthermia device was a microwave heating device with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Two patients had a partial response to treatment with only mild toxicity (grade 1 acute skin toxicity). Therefore, hyperthermia combined with chemotherapy for treating breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results in the future.

[The synergistic effect of local microwave hyperthermia and chemotherapy for advanced or recurrent breast cancer].

The purpose of our study was to test the efficacy and toxicity of hyperthermia in conjunction with chemotherapy for breast cancer. Between 2009 and 2014, 6 patients diagnosed with breast carcinoma were selected for this retrospective study. Patients received standard chemotherapy (AC followed by paclitaxel ) in combination with hyperthermia. The hyperthermia device employed microwave heating with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Following hyperthermia therapy, 4 patients had a partial response to treatment and the toxicity was mild, consisting of Grade 1 acute skin toxicity. Therefore, hyperthermia combined with chemotherapy for breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results.

Simultaneous development of adenocarcinoma and gastrointestinal stromal tumor (GIST) in the stomach: case report.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) and adenocarcinoma are distinct neoplasms originating from different cell layers. Approximately 20% of patients with GIST develop other cancers. CASE PRESENTATION: We report a case of the coexistence of adenocarcinoma and gastrointestinal stromal tumor (GIST). Gastric endoscopy showed the ulcerated tumor with bleeding along the lesser curvature of the proximal stomach and a submucosal nodule that measured about 3 cm in diameter in the lower part of the stomach body. Their pathological examination showed gastric cancer (poorly differentiated diffuse adenocarcinoma) and GIST (low-risk category). Further, immunohistochemical staining for C-kit and CD34 was positive, while that for SMA and S-100 was negative. CONCLUSION: Although it is not easy to speculate on the coexistence of adenocarcinoma and GIST, pre-and post-operative diagnoses may be essential, and such cancer development is not considered to be unusual.

Intrathecal morphine exacerbates paresis with increasing muscle tone of hindlimbs in rats with mild thoracic spinal cord injury but without damage of lumbar α-motoneurons.

Adverse effects of morphine on locomotor function after moderate to severe spinal cord injury (SCI) have been reported; however, the effects after mild SCI without damage of lumbar α-motoneurons have not been investigated. We investigated the effects of lumbar intrathecal morphine on locomotor function after mild thoracic SCI and the involvement of classic opioid receptor activation. A mild thoracic contusive SCI was induced in adult rats at the T9-T10 spine level under sevoflurane anesthesia. We evaluated the effects of single doses of intrathecal morphine and selective µ-, δ-, and κ-opioid receptor agonists, continuous infusion of intrathecal morphine for 72 hours, and administration of physiological saline on locomotor function and muscle tone in the hindlimbs. The numbers of damaged and total α-motoneurons in the lumbar spinal cord were also investigated. Single doses of morphine aggravated residual locomotor function after SCI but did not affect functional recovery. Single doses of morphine and µ- and δ-opioid receptor agonists significantly aggravated residual locomotor function with increases in muscle tone after SCI, and the effects of the drugs were reversed by naloxone. In contrast, continuous infusion of morphine led to persistent decline in locomotor function with increased muscle tone, which was not reversed by naloxone, but did not increase the number of damaged lumbar α-motoneurons. These results indicate that a single dose of morphine at an analgesic dose transiently increases muscle tone of the hindlimbs via activation of spinal µ- and δ- opioid receptors, resulting in further deterioration of locomotor function in the acute phase of mild SCI. Our results also suggest that an increased dose of morphine with prolonged administration leads to persistent decline in locomotor function with increased muscle tone via mechanisms other than direct activation of classical opioid receptors. Morphine should be used cautiously even after mild SCI.

Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 µM) and in vivo antithrombotic efficacy.

Structure-activity relationships of 1,3-benzoxazole-4-carbonitriles as novel antifungal agents with potent in vivo efficacy.

A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.

[Anesthetic management of patients with neuronal ceroid lipofusucinosis].

Neuronal ceroid lipofuscinoses (NCL) are in a group of autosomal recessive inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material in many cell types. Clinical manifestations of NCL are progressive mental and motor deterioration, seizures, and visual loss. We report anesthetic management for two siblings with NCL. Placement of percutaneous endoscopic gastrostomy tubes were scheduled for both 31-year-old woman and her 29-year-old sister with NCL. Although they were treated with several anticonvulsants, the grand mal and myoclonic seizures persisted. Anesthesia was maintained with propofol, nondepolarizing muscle relaxant, and narcotics. They showed no complications except for mild hypothermia during anesthesia. However, BIS index fluctuated widely during anesthesia in both cases. Their postoperative course was uneventful.

Novel pyridobenzimidazole derivatives exhibiting antifungal activity by the inhibition of beta-1,6-glucan synthesis.

Based on the HTS hit compound 1a, an inhibitor of beta-1,6-glucan synthesis, we synthesized novel pyridobenzimidazole derivatives and evaluated their antifungal activity. Among the compounds synthesized, we identified the potent compound 15e, which exhibits excellent activity superior to fluconazole against both Candida glabrata and Candida krusei. From the SAR study, we revealed essential moieties for antifungal activity.

Novel antifungal agents: triazolopyridines as inhibitors of beta-1,6-glucan synthesis.

Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of beta-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species.

1,3-Benzoxazole-4-carbonitrile as a novel antifungal scaffold of ß-1,6-glucan synthesis inhibitors.

Synthesis and in vitro antifungal evaluations of 1,3-benzoxazole-7-carbonitrile 3, 1,3-benzoxazole-4-carbonitrile 4, benzofuran 5, benzoxazine 7, and benzimidazole 8 were reported. Among them, 1,3-benzoxazole-4-carbonitrile was found to be a superior scaffold structure with moderate growth inhibition against Candida species. 1,3-Benzoxazole-4-carbonitrile 6 showed potent activity against Candida species compared to 5-desmethyl compound 4 and triazolopyridine 2. Compound 6 was efficiently prepared from versatile intermediate 24, which possessed six different substituents on the benzene ring. Conversion of benzene 24 into various 1,3-benzoxazole derivatives such as 2-aliphatic 34, 2-amino 35, and lactone 38 was demonstrated.

Effect of beta-1,6-glucan inhibitors on the invasion process of Candida albicans: potential mechanism of their in vivo efficacy.

Beta-1,6-glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of beta-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against Candida glabrata. Interestingly, although it only weakly reduced the growth of Candida albicans in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited beta-1,6-glucan synthesis of C. albicans, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of C. albicans cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of C. albicans without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against C. albicans by inhibiting its invasion process.

Metastatic gastric tumor from renal cell carcinoma.

Metastatic tumors of the stomach are rare, with an incidence of 0.2%-0.7%, and they have been reported to result mainly from primary breast cancers, lung cancers, and melanoma. Further, among such metastatic tumors, the metastasis of renal cell carcinoma (RCC) to the stomach is an extremely rare disease, and it is usually reported in autopsy series. We report a rare case of metastatic gastric tumor derived from right renal carcinoma. Gastric endoscopy confirmed a large, polypoid, friable mass (type 1 tumor, about 7 cm in diameter) in the middle part of the stomach body. The mass was surgically excised and pathological examination showed that the gastric tumor was derived from a metastasis from the right kidney, because it was composed of malignant cells that were identical to those from the removed RCC. In addition, the tumor cells were immunoreactive for CD10, CD15, Ecadherin, early membrane antigen (EMA), and vimentin, but no reactivity was observed for cytokeratins 7 and 20 or c-KIT. Although gastric metastatic tumor derived from renal carcinoma is rare, the precise pre- and postoperative diagnosis may be important; thus, investigation for such metastatic tumors should be performed routinely in the follow up of patients who have been treated for RCC.

Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.

A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.

Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents.

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.

Effect of As2O3 on cell cycle progression and cyclins D1 and B1 expression in two glioblastoma cell lines differing in p53 status.

Recent clinical studies have demonstrated that As2O3 is an effective drug in the treatment of acute promyelocytic leukemia (APL) by inducing apoptosis and inhibiting the proliferation of leukemia cells both in vitro and in vivo. As a novel anticancer agent for the treatment of solid cancer, As2O3 is promising, but no experimental investigations of its efficacy on glioblastoma have been conducted at concentrations that may be achieved clinically. In addition, the cell proliferation and cell cycle regulating mechanism of As2O3 has not yet to be clarified, especially in solid cancers. We investigated the effect of As2O3 on proliferation and cell cycle regulation with change in cyclins in two human glioblastoma cell lines differing in p53 status (U87MG-wt; T98G-mutated). Sensitivity to As2O3 varied depending on the dose with the IC50 of the U87MG and T98G cells being 1.78 and 3.55 microM, respectively. Analysis by laser scanning cytometry (LSC) indicated that As2O3 inhibited the proliferation of the two cell lines via cell cycle arrest both at the G1 and G2 phases. To address the mechanism of the antiproliferative effect of As2O3, we examined its effect on cell cycle-related proteins by means of LSC, confocal microscopy and Western blot analysis. As2O3 induced an increase in p53 level and a decrease in level of cyclin B1 combined with cell arrest at G2/M in both cell lines. Cell arrest in G1, however, was associated with a decline in cyclin D1 expression only in the wt U87MG cells. As2O3 also induced apoptosis of U87MG cells as evidenced by the presence of cells with fractional DNA content ( cell populations). The present evidence that As2O3 at relatively low concentration effectively inhibited proliferation of U87MG and T98G cells in vitro, suggests that the drug may be considered for in vivo testing on animal models and possibly clinical trials on glioma patients.