[Spindle Cell Sarcoma Originated in the Anterior Mediastinum;Report of a Case].

An anterior mediastinal sarcoma is a very rare type of mediastinal tumor. A 45-year-old female visited our hospital with swelling in the right anterior chest wall. Radiographically, the tumor was found to originate from the thymus and to infiltrate to the major pectoral muscle through the 1st intercostal space. Positron emission tomography revealed fluorodeoxyglucose accumulation at a standardized uptake maximum value of 16.1. Percutaneous needle biopsy showed the pathological findings of sarcoma. The tumor was resected along with the thymus and chest wall tissues including the right hemi-manubrium of the sternum, clavicle head, 1st and second ribs, and major pectoral muscle. After 4 months, tumor relapse occurred at the site of needle biopsy and additional resection was performed. At 10 months after the 2nd surgery, the patient was free from disease. From histologic and immunohistochemical findings, the tumor was diagnosed as spindle cell sarcoma.

[Pulmonary Clear Cell Type Squamous Cell Carcinoma that Required Differential Diagnosis from Metastatic Ureter Cancer;Report of a Case].

A 71-year-old woman was referred to our department for a nodular lesion in the left lung. She had been followed by urology department in our hospital for 6 years since right nephrectomy for ureter cancer. Chest X-ray and computed tomography (CT) scan demonstrated a small nodular shadow in the left lower lobe. The lung tumor was removed by wedge resection, and pathologically diagnosed during the operation as a metastasis from the ureter cancer. The lung tumor consisted of clear cells similar to the ureter cancer. However, the final pathological diagnosis changed to a primary lung cancer based on the findings of stratified differentiation and cancer cell nests in the tumor. Immunohistochemical staining for ureter epithelium-related antigens confirmed the diagnosis. Although we recommended left lower completion lobectomy, the patient refused additional surgery. She is suspected to have local recurrence in the left lower lobe 18 months after the surgery.

[Outcome of pulmonary resection for metastases from hepatocellular carcinoma].

Because pulmonary metastasis is considered to be systemic spread of hepatocellular carcinoma (HCC), indication of pulmonary resection as a treatment for it is not well-described. We retrospectively reviewed clinical records of the patients who underwent pulmonary resection for metastases from HCC in our hospital. Seven patients, 6 men, 1 woman, and the mean-age 65.4 year-old, underwent pulmonary resection from April in 2001 to March in 2010. During the same period, we carried out pulmonary resection for 122 patients with metastases from other malignant diseases. Therefore, pulmonary resection for HCC metastases accounted for 5.4% of the total pulmonary metastasectomy. One of the 7 patients, a 70 year-old man, survives for 69 months after right middle lobectomy for solitary HCC metastasis. Other 6 patients with multiple pulmonary metastases or with increased level of alpha-fetoprotein (AFP) before pulmonary resection died of systemic recurrence. The mean survival time of 7 patients was 20 months and was 11.8 months except the long-time survivor. From our results, patients with multiple pulmonary metastases from HCC or with increased serum level of AFP before surgery should be carefully selected as candidates for pulmonary metastasectomy.

Orally available pyridinylpyrimidine derivatives as novel RANKL-induced osteoclastogenesis inhibitors.

An HTS campaign led to the identification of 4-pyrroldino-2-(pyridin-2-yl)pyrimidine compound 1 as an RANKL-induced osteoclastogenesis inhibitor. The compound 1 showed high clearance values in microsomes, however. Modification of the pyrrolidino group to a benzylamino group improved human microsomal stability with a slight loss of in vitro activity. Substitution at the ortho position of the benzyl group ameliorated in vitro activity, and further fluorination of the benzyl group improved microsomal stability in rodents. Representative members of this series, compounds 20 and 23, exhibited efficacy in RANKL-induced osteopenic mice when administered orally at 0.3 mg/kg.

[Diaphragmatic metastasis from uterine corpus cancer].

We report a case of metastatic diaphragm tumor from uterine corpus cancer. A 72-year-old female had a tumor on right diaphragm 4-years after operation for uterine corpus cancer. After chemotherapy, tumor resection was performed by right lung basal segmentectomy, partial liver resection, and partial diaphragm resection. The pathological examination revealed adenocarcinoma, compatible with uterine corpus cancer, metastasizing in diaphragm and involving lung and liver. After the operation, a local recurrence occurred at parasternal lymph node, which is considered to be present on the efferent route of lymph flow from diaphragm.

Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.

Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.

Comparison of 5-fluorouracil-related gene expression levels between adenocarcinomas and squamous cell carcinomas of the lung.

BACKGROUND: A recent meta-analysis study showed that post-operative adjuvant chemotherapy with UFT, an oral combination drug composed of tegafur [prodrug of 5-fluorouracil (5-FU)] and uracil [inhibitor of dihydropyrimidine dehydrogenase (DPD)] was associated with improved survival in patients with lung adenocarcinomas, but not in those with lung squamous cell carcinomas. METHODS: We investigated the 5-FU-related gene expression levels of thymidylate synthase (TS), DPD, thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) in resected tumor specimens from 51 patients with adenocarcinomas and 47 with squamous cell carcinomas using quantitative reverse transcription-PCR, and compared those levels between the two histological types. RESULTS: The relative gene expression values of TS, TP and OPRT were significantly lower in adenocarcinomas compared with squamous cell carcinomas, 1.60 +/- 0.86 versus 4.33 +/- 3.40 (P < 0.001), 0.84 +/- 0.52 versus 2.27 +/- 1.16 (P = 0.006) and 9.59 +/- 6.30 versus 16.94 +/- 12.04 (P < 0.001), respectively. The relative gene expression value of DPD was significantly greater in adenocarcinomas than those in squamous cell carcinomas, 2.33 +/- 1.22 versus 1.50 +/- 1.20 (P = 0.01). Lower expressions of TS and TP were observed more in adenocarcinomas (89.8%) than in squamous cell carcinomas (48.9%) (P < 0.001). CONCLUSION: These data may explain that post-operative adjuvant chemotherapy with UFT was associated with improved survival in stage I patients with adenocarcinoma, but less with squamous cell carcinoma.

Prognostic significance of p21 protein expression in patients with pulmonary squamous cell carcinoma following induction chemotherapy.

BACKGROUND: The prognostic value of p21 protein expression in lung cancer patients has been assessed. However, its significance in those with pulmonary squamous cell carcinoma following induction chemotherapy (IC) remains unclear. We studied on patients who did or did not undergo IC (NIC) to elucidate the prognostic value of p21 protein expression. MATERIALS AND METHODS: p21 protein expression was assessed immunohistochemically and samples with greater than 10% positive tumor cells were considered positive. We then analyzed clinical-pathological features, including p53 protein expression and prognosis, in 43 patients who underwent IC group and 40 who did not IC (NIC) group. RESULTS: Positive nuclear p21 samples were obtained from 17 (41.5%) patients in the in IC group and 22 (55.0%) in the NIC group. In the IC group, there was no significant correlation between the histological effectiveness of chemotherapy and p53 protein expression, whereas a significant correlation was observed between that and p21 protein expression (p=0.048). Further, the prognosis for p21-positive patients tended to be better (p=0.0506) than for p21-negative patients, and was significant (p=0.048) in patients with pathological stage (p-stage) II or III disease. CONCLUSION: Our findings suggest that p21 protein expression is a prognostic factor for primary patients with pulmonary squamous cell carcinoma following IC.

Physiologic aspects in human lung transplantation.

Heart-lung transplantation (HLT), followed by single lung transplantation (SLT) and subsequently bilateral lung transplantation (BLT) have been developed as treatments for patients with end-stage pulmonary diseases. Initially, SLT was limited to idiopathic pulmonary fibrosis (IPF) cases and thought to be contraindicated not only for infectious diseases, but also for non-infectious diseases, including pulmonary emphysema (PE) and primary pulmonary hypertension (PPH), based on physiologic points of view. However, SLT is now widely performed for those non-infectious diseases and most of the recipients return to a normal active life. It is quite possible that BLT is superior to SLT in terms of pulmonary function, and it has been reported that BLT is better for PE and PPH patients in regards to perioperative course, postoperative exercise capacity, and long-term survival. For those situations and because of the present scarcity of donor organs, SLT must be utilized for selected non-infectious diseases for which it is safe and effective. When a single lung is replaced for IPF, PE, and PPH recipients, different physiologic situations are produced postoperatively, the understanding of which is extremely important to achieve good results, not only in the perioperative but also in the long term.

Needlescopic operation for partial lung resection.

Needlescopic operation using instruments with a diameter of 2 mm has not been applied to partial lung resection because of the difficulty in grasping the lung firmly or the possibility of injuring the lung easily with 2-mm forceps. We have developed a technique using a mini-loop retractor and successfully performed partial lung resection in 35 patients with pneumothorax, small lung tumor, or interstitial pneumonia.

¹8F-fluorodeoxyglucose positron emission tomography for evaluation of thymic epithelial tumors: utility for World Health Organization classification and predicting recurrence-free survival.

OBJECTIVES: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) plays an important role in many oncological settings. In this study, we assessed the utility of (18)F-FDG-PET for predicting the histological classification, stage and survival of thymic epithelial tumors. METHODS: We retrospectively analyzed 37 patients with thymic epithelial tumors who underwent PET before surgical resection and investigated the relationship between the maximum of standardized uptake value (SUVmax) of each tumor and the WHO classification, recurrence-free survival, and tumor-related gene expressions. RESULTS: The study included 15 males and 22 females, ranging in age from 22 to 81 years (mean 64 years). The tumor histology of 31 tumors was thymoma and that of the remaining tumors was thymic carcinoma. The Masaoka tumor stage was as follows: stage I in 18, II in 9, III in 5 and IV in 5 patients. The patients were divided into three groups according to a simplified histologic classification: low-risk thymoma (types A, AB and B1, n = 21), high-risk thymoma (types B2 and B3, n = 10) and thymic carcinoma (n = 6). The SUVmax of low-risk group (SUVmax ≤4.27) was significantly lower than that of high-risk group (p = 0.0114) and that of thymic carcinomas (SUVmax >4.27) was also significantly higher than that of thymomas (p < 0.0001). The group of high SUVmax (SUVmax >4.27) had significantly inferior recurrence-free survival to that of less value (SUVmax ≤4.27) (p = 0.0009). The SUVmax were not correlated with tumor-related gene expressions. CONCLUSION: The SUVmax of (18)F-FDG-PET reflects WHO classification of thymic epithelial tumors. High SUVmax predicts lower recurrence-free survival of the tumors.

Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor.

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

Cytologically malignant margin without continuous pulmonary tumor lesion: cases of wedge resection, segmentectomy and lobectomy.

The surgical margin is usually investigated during the operation using a pathological method, though cytological methods are also used to identify remaining malignant cells. We reviewed cases of pulmonary resection for a malignant tumor. At our institution, an on-site surgical margin examination using a cytological method is mandated for cases of wedge resection and segmentectomy, and an option in lobectomy cases. We examined 21 wedge resection (3 primary lung cancer, 18 metastasis), 17 segmentectomy (13 primary lung cancer, 4 metastasis), and 4 lobectomy (all primarily lung cancer) cases. Six cases showed malignant cells in the surgical margin, of which one had a microscopic skip lesion pattern and five an 'occult' pattern (positive cytology, negative pathology). Cytological malignancy occurred even in cases of wedge resection of a tiny (4 mm in diameter) lesion metastasized from colon cancer, as well as segmentectomy with a sufficient gross margin containing microscopic skip lesions and right middle lobectomy with an additional right upper lobectomy due to two previous cytological malignancies in a residual lobe. Surgical margin cytology revealed remaining malignancy in the residual lobe, which provided important information for deciding additional procedures during surgery.

Lig-8, a highly bioactive lignophenol derivative from bamboo lignin, exhibits multifaceted neuroprotective activity.

Lignin is a durable aromatic network polymer that is second only to cellulose in natural abundance. Lig-8, a lignophenol derivative from bamboo lignin, is a highly potent neuroprotectant. It protects human neuroblastoma cells (SH-SY5Y) from hydrogen peroxide (H2O2)-induced apoptosis by preventing caspase-3 activation via either caspase-8 or caspase-9. It exerts this antiapoptotic effect by protecting mitochondrial membrane permeability from damage by H2O2 or the peripheral benzodiazepine receptor ligand PK11195. Lig-8 has been also shown to scavenge the reactive oxygen or nitrogen species in vitro. Furthermore, lig-8 suppresses apoptosis induced by oxygen-glucose deprivation, tunicamycin (endoplasmic reticulum [ER]-stress inducer), or proteasome inhibitor in pheochromocytoma cells. In addition, in vivo, lig-8 reduced intravitreal N-methyl-D-aspartate-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness) in mice. Lig-8 prevents neuronal damage partly by inhibiting excessive endoplasmic reticulum stress. In this article, we review the protective effects of lig-8 against apoptosis induced by various stimuli. Apoptosis is an active, energy-dependent process through which living cells initiate their own death. It can be induced by a variety of physiological and pharmacological stimuli. Apoptotic cell death is associated with neurodegenerative disorders such as Alzheimer, Parkinson, or Huntington disease as well as glaucoma. We believe that the elucidation of the mechanism of antiapoptotic action of lig-8 may help in finding new approaches to the treatment of neurodegenerative disorders.

Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.

We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.

Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors.

We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.

Lig-8, a bioactive lignophenol derivative from bamboo lignin, protects against neuronal damage in vitro and in vivo.

Lig-8, a lignophenol derivative from bamboo lignin, potently suppresses oxidative stress-induced apoptosis. Here, we first examined in vitro whether lig-8 protects against neuronal damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation, tunicamycin [endoplasmic reticulum (ER)-stress inducer], or PSI (proteasome inhibitor). In pheochromocytoma (PC12) cell cultures, lig-8 (1 to 30 microM) concentration-dependently inhibited OGD- and tunicamycin (2 microg/ml)-induced cell deaths (significant at >/=3 microM and >/=1 microM, respectively). In human neuroblastoma (SH-SY5Y) cell culture, the PSI-induced apoptotic cell death and fusion protein accumulation (revealing reduced proteasome activity) was inhibited by lig-8 (30 microM). On the other hand, lig-8 at 30 microM alone did not affect any proteasome activity under resting conditions. In vivo, lig-8 (0.1 nmol/eye) reduced intravitreal N-methyl-D-aspartate (NMDA, 20 nmol)-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness). Hence, lig-8 protects, partly by inhibiting excessive ER-stress, against neuronal damage in vitro and in vivo.

Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand.

Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.

A highly bioactive lignophenol derivative from bamboo lignin exhibits a potent activity to suppress apoptosis induced by oxidative stress in human neuroblastoma SH-SY5Y cells.

Approaches to protection against neurodegenerative diseases, in which oxidative stress and inflammation are implicated, should be based on the current concept on the etiology of these diseases. Recently, a new therapeutic strategy has been proposed to protect neurons from cell death by attenuating the apoptotic signal transduction. Lignin, a durable aromatic network polymer second to cellulose in abundance, was able to be converted into highly active lignophenol derivatives with antioxidant activity by using our newly developed phase-separation technique. These lignophenol derivatives were found to show the potent neuroprotective activity against oxidative stress. Among the compounds examined, a lignocresol derivative from bamboo (lig-8) exhibited the most potent neuroprotective activity against hydrogen peroxide (H(2)O(2))-induced apoptosis in human neuroblastoma cell line SH-SY5Y by preventing the caspase-3 activation via either caspase-8 or caspase-9. Furthermore, it was found that lig-8 exerted the antiapoptotic effect by inhibiting dissipation of the mitochondrial membrane permeability transition induced by H(2)O(2) or by the peripheral benzodiazepin receptor ligand PK11195. Lig-8 was also shown to be potent in the antioxidant activity in the cells exposed to H(2)O(2), as assessed by flow cytometry using 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and in vitro reactive oxygen species-scavenging potency. These data suggest that lig-8 is a promising neuroprotector, which affects the signaling pathway of neuronal cell death and that it would be of benefit to delay the progress of neurodegenerative diseases.