Synthesis and biological evaluation of a 6-aminofuro[3,2-c]pyridin-3(2H)-one series of GPR 119 agonists.

G protein-coupled receptor 119 (GPCR 119 (GPR119)) agonists have received considerable attention as a promising therapeutic option for treatment of type 2 diabetes mellitus. GPR119 is one of the GPCRs expressed in pancreatic islet ß-cells and its activation enhances stimulation of insulin secretion in a glucose-dependent manner. We have recently described a series of 6-amino-1H-indan-1-ones as potent, selective, and orally bioavailable GPR119 agonists with an amino group that plays important roles not only in their drug-like properties, such as high aqueous solubility, but also in their potent agonistic activity. However, many of these compounds displayed strong to moderate inhibition of human ether-à-go-go related gene channel. Attenuation of the basicity of the amino group by replacing the adjacent benzene ring with electron-deficient heteroaromatic rings provided several heterocyclic cores among which 6-aminofuro[3,2-c]pyridin-3(2H)-one was selected as a promising scaffold. Further optimization around the side chain moiety led to the discovery of 17i, which showed not only strong human GPR119 agonistic activity (EC50=14 nM), but also beneficial effects on gastric emptying and plasma total glucagon-like peptide-1 levels in mice.

[Clinical effect of the cauterization for emphysematous bulla].

The purpose of performing pleural cauterization is developing heat denaturation, and we can induce pleural thickening and also reduce the bullae by shrinking the pleura It originates in a method of the cauterization whether there will be tissue damage. So a safe and reliable method of cauterization is required. Here, we investigated the indications for and effectiveness of cauterization techniques performed at our facility. We perform cauterization while dropping saline solution, so when using a Salient Monopolar Sealer, we can avoid excessive thermo-coagulation and more easily control cauterization. Furthermore, on the basis that only emphysematous pleura will turn white on cauterization, bullae can be distinguished, which is particularly effective in the case of lesions with unclear borders. In the case of a large emphysematous bulla, shrinkage of the bulla by cauterization can provide a sufficient surgical field, and a smaller lesion can then be stapled.

[Quality of life of long-term survivors of surgically treated lung cancer].

Quality of life (QOL) of long-term survivors (more than 3 years after surgery) of primary non-small cell lung cancer was studied. QOL was analyzed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, 30-Item version 3.0 (QLQ-C30) and Hospital Anxiety and Depression Scale (HADS). Sixty of 91 patients (66%) participated in this study 87 +/- 5 (38-172) months postoperatively. In QLQ-C30, calculated scores of physical (84.0 +/- 2.4), role (81.3 +/- 3.6), cognitive (79.7 +/- 2.6), emotional (86.8 +/- 1.9), and social (91.0 +/- 1.9) functioning, and global QOL (72.6 +/- 2.9) were obtained. Calculated HADS A (anxiety) was 3.3 +/- 0.3 and HADS D (depression) was 4.0 +/- 0.4. Postoperative follow-up duration was correlated with financial impact only. QOL of long-term survivors was influenced by gender histology, marital status, employment status, and academic carrier.

[Changing pattern of the respiratory function associated with resected lung lobe].

Respiratory function before and 2 months after lung lobectomy was analyzed associated with resected lobe. Post- or preoperative ratios of FEV1.0 or VC were compared among (1) predicted value by the number of subsegments using bronchofiberscopy, (2) predicted value by the lobar volume ratio using computed tomography (CT), and (3) actually measured value. Using subsegments method, post- or preoperative predicted VC ratios were 85 +/- 1% after right upper lobectomy (RU), 69 +/- 1% after right lower lobetomy (RL), 74 +/- 1% after left upper lobectomy (LU), and 75 +/- 1% after left lower lobectomy (LL). Using CT method, post- or preoperative predicted VC ratios were 80 +/- 2% after RU, 76 +/- 4% after RL, 74 +/- 2% after LU, and 79 +/- 3% after LL. Actually measured post- or preoperative FEV1.0 ratios were 82 +/- 3% after RU, 89 +/- 8% after RL, 73 +/- 3% after LU, and 86 +/- 5% after LL, and the VC ratios were 88 +/- 5% after RU, 79 +/- 3% after RL, 77 +/- 4% after LU, and 94 +/- 3% after LL. In the FEV1.0 analysis using both subsegments method and CT method, the predicted value was correlated with upper lobectomy but was overestimated in case of lower lobectomy. This phenomenon might be caused by the postoperative bronchial branching deformity after upper lobectomy. In the VC analysis using subsegments method, the predicted value was correlated with upper lobectomy but was overestimated in case of lower lobectomy. Meanwhile, in the VC analysis using CT method, the predicted value was correlated with RL or LU but was overestimated in case of RU or LL. This may due to the fact that RL and LU had large lobar volumes. In conclusion, postoperative predicted and actually measured values were different associated with resected lobe. In the FEV1.0 and VC analysis using subsegments method, the predicted value was strongly correlated with upper lobectomy but was overestimated (10%) in case of lower lobectomy.

[Postoperative temporal elevation of tumor marker in primary lung cancer patients].

Serum tumor marker measurement in addition to radiological examination is useful to detect postoperative recurrence and metastasis. Surgically treated 8 primary non-small cell lung cancer patients who showed negative serum tumor marker postoperatively elevated their markers temporally. Five of the 8 patients did not show recurrence or metastasis in their last confirmation days. These 5 patients had inflammatory disease when the postoperative marker became positive temporally. Remaining 3 patients did not have inflammatory disease when the marker elevated temporally. The marker of the 3 patients became negative again, however, the 3 patients showed recurrence or metastasis during 1 year after temporally elevated day. In conclusion, if there is no inflammatory disease when the negative marker becomes positive temporally, the recurrence or metastasis may be observed during 1 year after temporally elevated day. And when the recurrence or metastasis is observed radiologically, the marker may become negative.

[Acute pulmonary thromboembolism complicating lung lobectomy; report of a case].

Acute pulmonary thromboembolism is fatal if the diagnosis and treatments are delayed. Here we present a case of acute thromboembolism to the right and left pulmonary arteries after right lung lobar resection. A 52-year-old woman who admitted to our hospital with lung cancer was performed right upper lobectomy with mediastinal lymph node dissection (pT1N0M0, well differentiated adenocarcinoma). Two days after surgery, she complained sudden chest discomfort and dyspnea. The blood pressure and oxygen saturation were rapidly decreased. Because there was no lung edema or atelectasis in the chest portable roentgenogram and no ischemic change in the electrocardiogram, pulmonary thromboembolism was suspected and emergency chest computed tomography (CT) was performed. The CT showed left and right pulmonary arterial thromboembolism and immediate anti-coagulator therapy was started. Her condition was improved and chest CT, which was performed three days after the onset of the thromboembolism, showed decreased but still remained thrombus. The anti-coagulator therapy was continued and one month after the onset of the thromboembolism, thrombus was disappeared on chest CT. She is doing well 17 months after surgery. Early diagnosis and treatments are critical for the pulmonary thromboembolism.

[Surgically treated pancoast tumor].

A 40-year-old male was detected his right apical lung tumor by roentgenographic screening on January 1997, but he did not refer to a hospital since he had no symptom. He went a orthopedics because of his right chest, back, and arm pain on October 1997, and he received traction and physical therapy. He went roentgenographic screening again on January 1998 and he was pointed out that the tumor increased. He admitted our hospital. Biopsy using bronchofiberscopy revealed adenocarcinoma and induction radiotherapy (40 Gy) was performed. Right upper lobectomy with chest wall resection and lymph node dissection was performed under hook approach. This approach was useful to dissect the tumor from the invaded plexus brachialis. Postoperative radio-chemotherapy was added but the patient died 7-postoperative months because of multiple metastases. Early detection should be led to early starting of the therapy.

[Endobronchial brachytherapy for intra-luminal recurrence after lung cancer resection].

A 63-year-old man who had squamous cell carcinoma in left lung was received left lower lobectomy with lymph node dissection (pT3N0M0). Twenty months after surgery, the patient showed bloody sputum and bronchofiberscopy revealed intra-luminal recurrence on trachea. Endobronchial brachytherapy in combination with external beam radiotherapy was selected and complete remission was achieved. After the brachytherapy, bronchitis was observed and was healed 23 months after the therapy.

[A surgically treated case of capsulated thymoma with thymic cyst].

A 56-year-old woman was pointed out an abnormal shadow on chest roentgenogram. Chest CT and MRI showed a solid mass with a cyst at right anterior mediastinum. Clinical diagnosis was thymoma with cyst, and surgical excision was performed. The histopathological examination of the resected specimen demonstrated that the epithelia of the cyst wall was single cuboidal or squamous cells and contained some foci of thymic tissue. The solid mass was capsulated and predominantly composed of lymphocytes. The pathological diagnosis was a thymoma (predominantly lymphocytic type) with thymic cyst. She is doing well for 10 years postoperatively.

[Incomplete resection for primary non-small cell lung cancer].

A superior outcome is observed for cases of complete resection compared with that of incomplete resection. The reason and the countermeasure of the incomplete resection for lung cancer were analyzed. During 12 years, 274 patients with primary non-small cell lung cancer were surgically treated. Two hundred and forty-eight patients underwent complete resection and 26 incomplete resection. Three-year survival was 62% for patients with complete resection and 17% for patients with incomplete resection. Survival rates were not different between the paroative reduction surgery and the exploratory thoracotomy. Tiny but multiple pleural dissemination or small amount of the malignant pleurfal effusion was not able to detect preoperatively. In these cases, preoperative thoracoscopic observation may useful for avoiding the meaningless thoracotomy. Postoperative radiochemotherapy may improve the prognosis if the therapy is effective. Chemotherapy on the basis of the sensitivity assay is warranted.

[Leiomyoma of the esophagus shown as a cervical tumor].

A 44-year-old female was admitted to our hospital because of the left cervical tumor. Radiologic examination showed that the tumor was 5 cm in diameter and was inhomogeneous. The tumor was spread to the upper mediastinum. Esophagoscopy showed that the tumor was covered by the normal mucosa. Percutaneous fine needle biopsy did not appear the histopathological diagnosis. The patient underwent surgical resection through the cervical approach and the tumor was located between the mucosal and muscular layers of the esophagus. The tumor was enucleated without any complication. Histopathological diagnosis was leiomyoma. Postoperative course was uneventful. Expecting diagnosis and positive complete resection is recommended for leiomyoma of the esophagus.

Post radiation inflammatory malignant fibrous histiocytoma arising from the chest wall.

A 59-year-old man who underwent radiation therapy (41 Gy) to the mediastinum through the anterior chest for Hodgkin's disease presented with a painful anterior chest wall tumor 18 years later. The tumor originated from the left parasternal region and was excised with the sternum. Chest wall reconstruction was performed. The tumor measured 45 x 45 mm and invaded the sternum. The pathologic diagnosis was malignant fibrous histiocytoma. Early and complete excision of the tumor is indicated.

Analysis of the anatomic changes in the thoracic cage after a lung resection using magnetic resonance imaging.

The thoracic cage after a lung resection is filled by the remaining lobes, the elevated diaphragm, the diminished thoracic cage, and by mediastinal shifting. The changes in the thorax after a lung resection were quantified using magnetic resonance imaging. The study group consisted of 39 patients who had undergone a lobectomy, four who had undergone a pneumonectomy, and 14 controls. The left ventricular angle, ascending aortic angle, mediastinal shift, longitudinal length of the thoracic cage, the distance between the thoracic apex and the level of the aortic valve, and diaphragmatic elevation were all measured. After a right lower lobectomy, the mediastinum shifted more rightward than after a right upper lobectomy. The diaphragm became more greatly elevated after a right upper lobectomy than after a right lower lobectomy. When a chest wall resection was added to a right upper lobectomy, the mediastinal anatomical changes decreased. After a left upper lobectomy, the degree of mediastinal shifting was greater than after a left lower lobectomy. A left upper lobectomy shifted the mediastinum at the level of the right atrium. This method is easily reproducible and was found to be effective for quantifying the changes in the thorax after a lung resection.

[Surgically treated infectious giant bulla].

A 32-year-old man who underwent evaluation for dyspnea and left chest pain proved to have a left pneumothorax and a right giant bulla. After surgery for the left pneumothorax, drug induced liver injury was observed. Seventeen days after surgery, left giant bulla was infected and niveau formation was seen with high fever. After administration of antibiotics, the niveau was disappeared and the body temperature was down, however, drug induced liver injury was caused. After that, again, the niveau formation was noticed in the right bulla. We speculated that adequate drug therapy could not used because of liver injury if the right bulla would be infected one more time. Bullectomy of the right lung was performed. One year after surgery, there were no signs of infection. We usually administer the adequate antibiotics against the infectious giant bulla without surgical therapy because the bulla will be reduced with the infection. However, there is a situation like this case that surgical treatment is required because of the drug induced liver injury.

[Relatively non-curative resection for lung cancer: is this a complete resection?].

A superior outcome is observed for cases of curative resection compared with that of non-curative resection. The Japan Lung Cancer Society revised "General Rule for Clinical and Pathological Record of Lung Cancer" in 1999 and relatively non-curative resection (RNCR) of former rule was categorized as complete resection. The reason and the countermeasure of RNCR for lung cancer were analyzed. During 11 years, 242 patients with primary non-small cell lung cancer were surgically treated in Showa University Hospital. One hundred patients underwent absolutely curative resection (ACR); 64, relatively curative resection (RCR); 55, RNCR; 23, absolutely non-curative resection (ANCR). Three-year survival was 90% for patients with ACR, 48% with RCR, 21% with RNCR, and 13% with ANCR. The cases for RNCR were defined as follows: RNCR-a) incomplete mediastinal lymph node dissection (n = 29), RNCR-b) partial resection of the lung without lymph nodes dissection (n = 5), RNCR-c) N 2 b metastasis (n = 14), RNCR-d) N 3 lymph node dissection with N 3 metastasis (n = 0), RNCR-e) metastasis in other lobes of the ipsilateral thoracic cage (n = 7). RNCR-a) was selected in the poor risk patients who were diagnosed as clinical N 0 or N 1. Only one out of the 29 patients was diagnosed as pathological N 2 after surgery with hilar and mediastinal lymph node sampling. Because of the excellent preoperative staging, only RNCR-a) had three year survivors among RNCR cases and the three year survival rate was 39%. RNCR-b) was selected in the severe risk patients who were diagnosed as clinical N 0. There was no death associated with complication in RNCR-b) group. Some cases of RNCR-c) (pathological N 2 b) were clinical N 0 or N 1 and there was a limitation of the preoperative clinical staging. However, some cases of the clinical N 2 were surgically treated with chemo-radiotherapy and were resulted as RNCR-c). The concepts between curative resectability and complete resectability are different and RNCR-b), c), and e) should not include the curative resection because of the poor prognosis.

Hyperacute xenorejection of guinea pig-to-rat lung transplantation can be attenuated by blood which has perfused another xenograft.

In discordant xenotransplantation, the recipientOs blood initiates hyperacute xenorejection (HXR). We hypothesized that HXR-related lung edema may be reduced if a new xenograft is perfused by blood which previously has perfused another xenograft. In a syngeneic control group (n = 6), a rat lung (lung XR) was perfused by rat blood (blood AR), following which the blood was collected (blood BR). After another rat lung (lung YR) was perfused by blood BR, the blood was collected (blood CR). In a xenogeneic experimental group (n = 6), a guinea pig lung (lung XG) was perfused by rat blood (blood AG), and the blood was collected (blood BG). Then, another guinea pig lung (lung YG) was perfused by blood BG, and once more the blood was collected (blood CG). White blood cells (WBC), polymorphonuclear leukocytes (PMN), red blood cells (RBC), hemoglobin, hematocrit, and complement (CH50) in the blood were measured pre- and post-perfusion. The wet/dry weight ratio (W/D) of the lung was calculated after the perfusion. WBC and PMN were higher in blood CR/BR than in blood BR/AR. CH50 was higher in blood CG/BG than in blood BG/AG. RBC, hemoglobin, and hematocrit were not different among the blood AR, BR, CR, AG, BG, and CG. The W/D was not different between lung XR and lung YR. The W/D of lung YG was lower than lung XG. In conclusion, the lung edema associated with HXR is reduced when blood which has perfused another xenograft is used to perfuse the new xenograft without anemia, and complement plays a critical role in reducing lung edema.

A surgical case of solitary plasmacytoma of rib origin with biclonal gammopathy.

Localized solitary plasmacytoma of the bone (SPB) is a rare disease and is characterized by only one or two isolated bone lesions with no evidence of disease dissemination. A previously healthy 44-year-old male was admitted for evaluation of an abnormal radiographic shadow in the left middle lung field with symptoms of left back pain. Radiological evaluation revealed a peripheral opacity in the left chest wall, which was highly suspected to be a chest wall tumor. CT-guided transcutaneous needle biopsy of the tumor was performed and the specimens showed a monomorphous population of mature plasma cells. The bone marrow biopsy findings revealed no evidence of myeloma and bone scanning revealed only abnormal accumulation in the left seventh rib. He had mild M-proteins in a urine sample and Bence-Jones protein was detected. Immunoelectrophoresis revealed mild biclonal gammopathy of Bence-Jones protein of both the kappa and lambda light-chain types. Under a diagnosis of solitary bone plasmacytoma, preoperative radiation therapy with doses of 40 Gy for the tumor was performed. He underwent complete en bloc resection of the chest wall, including one-third of the left sixth and seventh ribs, the intercostal muscle and the parietal pleura. The protein abnormalities in the urine sample disappeared following surgical resection. Adjuvant chemotherapy using melphalan and prednisolone was performed. He is doing well without evidence of tumor recurrence 2 years following his initial diagnosis.

[Lung resection affects the postoperative arrhythmia and electrocardiographic axis deviation].

After lung lobectomy or pneumonectomy, the mediastinal shift and diaphragmatic elevation are occurred. Because this phenomenon may affect the heart positional change, we studied the electrocardiographic QRS axis in the frontal plane (from leads I and III) and the postoperative arrhythmia. Seventy three patients who had no heart disease including arrhythmia before the surgery were recorded their electrocardiogram (ECG) before their surgery and after their discharge. When the postoperative ECG was recorded, they had no respiratory failure nor cancer recurrence, and their lungs were fully expanded in their thoracic cages. After right upper lobectomy (19 cases), the axis was twisted rightward slightly (2.1 degrees). Right middle lobectomy (2 cases, 9.5 degrees) and right upper and middle lobectomies (3 cases, 7.3 degrees) twisted the heart axes more rightwards. Right lower lobectomy (12 cases, -1.0 degree) and right middle and lower lobectomies (3 cases, -17.7 degrees) contorted their axes leftwards and right pneumonectomy (5 cases, 31.4 degrees) rightwards. The axes were turned rightwards after the left upper lobectomy (18 cases, 2.8 degrees) and the left lower lobectomy (7 cases, 3.9 degrees). Left pneumonectomy (4 cases, -4.0 degrees) twisted the axis leftwards. After the surgery, arrhythmias were recorded in 14 cases and, among these patients, 5 cases were required the oral anti-arrhythmic medication. Most of these cases changed their heart axes after the surgery and it is suggested that the axial deviation may contribute to their postoperative arrhythmia.