Prognostic impact of nestin expression in resected large cell neuroendocrine carcinoma of the lung.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is categorized as a high-grade neuroendocrine carcinoma with an aggressive clinical behavior. Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during central nervous system development. Recently, we reported that nestin expression is a prognostic indicator of a poorer survival probability in patients with resected NSCLC. In the present study, we aimed to determine its prognostic significance concerning survival in patients with resected LCNEC. MATERIALS AND METHODS: Nestin expression in tumor cells was immunohistochemically studied in 30 patients with resected LCNEC, and its associations with clinicopathologic parameters including the Ki-67 labeling index (LI) and TTF-1 expression were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. RESULTS: Nestin expression was observed in 8 of the 30 (26.7%) LCNECs. Clinicopathologically, although no significant association between nestin expression and age, gender, smoking habits, p-TNM stage, tumor size, nodal status, or TTF-1 expression was observed, nestin expression was significantly associated with a high Ki-67 LI (P=0.012). On survival analysis, nestin expression was significantly associated with a poorer prognosis in patients with LCNEC (P=0.016). The Cox proportional regression model confirmed that the crude hazard ratio (95%CI) of nestin expression was 3.40 (1.18-9.77). CONCLUSIONS: The present study suggests that nestin expression seems to be a prognostic indicator of a poorer survival probability in patients with resected LCNEC, although its prognostic significance still requires confirmation with larger patient populations.

Pediatric cardiac surgery without homologous blood transfusion, using a miniaturized bypass system in infants with lower body weight.

OBJECTIVE: We have established a low-priming volume cardiopulmonary bypass system for pediatric heart surgery to avoid homologous blood transfusion. The priming volume of our system is down to 140 mL for patients weighing less than 7 kg. We can prime the bypass circuits without blood products for patients weighing more than 4 kg. METHODS: Seventy consecutive patients weighing 4 to 7 kg underwent heart surgery with a bloodless prime from October 2003 to September 2006. The type of procedures (Risk Adjustment in Congenital Heart Surgery category) included the following: category 1: atrial septal defect (n = 3); category 2: ventricular septal defect, tetralogy of Fallot, bidirectional Glenn shunt, and others (n = 55); category 3: atrioventricular septal defect, double-outlet right ventricle, and others (n = 8); category 4: Rastelli procedure for transposition of the great arteries (n = 3); and category 6, Damus-Kaye-Stansel procedure (n = 1). Transfusion criteria were hematocrit less than 20%, mixed venous oxygen saturation less than 70%, regional cerebral oxygenation less than 50%, and plasma lactate level greater than 4.0 mmol/L during bypass. RESULTS: The mean age and body weight were 7.3 +/- 5.4 months and 5.4 +/- 0.8 kg, respectively. Forty-five patients (64%) underwent transfusion-free procedures. Preoperative hematocrit, age, body weight, complexity of procedure and cardiopulmonary bypass time were compared between patients with and without transfusion. Bypass time and Risk Adjustment in Congenital Heart Surgery risk category in patients with transfusion were significantly greater than those in patients without (P < .0001, and P < .05, respectively). Body weight in patients without transfusion was significantly greater than that in patients with (P < .01). In multiple regression analysis, the determinants of blood transfusion were the bypass time and body weight (odds ratio 1.026, 95% confidence interval 1.011-.040, P < .0001, and odds ratio 0.366, 95% confidence interval 0.171-0.785, P < .01). CONCLUSIONS: It is possible to do complex transfusion-free procedures safely for patients weighing more than 4 kg by using the low-priming volume circuit. The limiting factors of bloodless heart surgery are not preoperative hematocrit and complexity of procedure but the cardiopulmonary bypass time and the patient's body weight.

A prospective study of whether radiation pneumonitis is influenced by low-dose irradiated lung volume in primary lung cancer with chronic pulmonary disease.

The current study prospectively investigated the optimal dose-volume condition in cases of lung cancer with chronic pulmonary disease compared to those without chronic pulmonary disease. Cases of primary lung cancer treated with intended curative radiation therapy were registered in the current study. Their fraction size was limited to 2-3 Gy, so-called standard fractionation. They were prescribed a total dose of 60 Gy for non-small cell lung cancer (NSCLC; n=17) and a total dose of 54 Gy for small cell lung cancer (SCLC; n=4). Of the 21 patients enrolled in this study, 4 had chronic pulmonary disease (study arm), and the others had no chronic pulmonary disease (control arm). Seven received chemotherapy. Symptomatic radiation pneumonitis occurred in 5. Of the four patients in the study arm, two (50%) experienced symptomatic radiation pneumonitis; only 3 of the 17 patients in the control arm (17.6%) experienced symptomatic radiation pneumonitis. Furthermore, the median V(20) of patients who experienced symptomatic radiation pneumonitis in the study arm was 14%, which was higher than that of patients with no symptomatic radiation pneumonitis in the study arm, 5.8%. On the other hand, in the control arm, the median V(20) of patients with symptomatic radiation pneumonitis was 14.2%, about the same as that of patients with no symptomatic radiation pneumonitis in the control arm, 15.1%. The current study suggested that, as much as 15% of V(20), might play an important role in cases of lung cancer with chronic pulmonary disease.

Bepridil inhibits sub-acute phase of atrial electrical remodeling in canine rapid atrial stimulation model.

Background The effect of bepridil, a multichannel blocker, on atrial electrical remodeling was evaluated in a canine rapid atrial stimulation model. Methods and Results In 10 beagle dogs, the right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. The atrial electrophysiological parameters, including effective refractory period (AERP), were evaluated at three atrial sites: RAA, the right atrium close to the inferior vena cava (IVC) and the left atrium (LA), during the time course of rapid pacing. Five of the dogs were given bepridil (10 mg . kg (-1) . day(-1) po). In the control group, AERP was significantly shortened at all atrial sites and the AERP shortening (DeltaAERP) was larger for the RAA and LA than at the IVC site (p<0.05). In the bepridil group, DeltaAERP was smaller than that of the controls at all atrial sites, and the AERP started to return slowly to the pre-pacing level in the second week, regardless of the continuation of rapid pacing. Conclusions In a canine rapid atrial stimulation model, bepridil suppressed AERP shortening. Bepridil might have a reverse electrical remodeling effect, at least for AERP shortening, because it showed slow recovery of AERP in the subacute phase of rapid atrial pacing. (Circ J 2006; 70: 206 - 213).

Fluorinated diamond-like carbon as antithrombogenic coating for blood-contacting devices.

Diamond-like carbon (DLC) is being considered for widespread clinical use as a surface coating for cardiovascular devices. We synthesized fluorinated DLC (F-DLC) coatings in order to create a more hydrophobic surface with improved antithrombogenicity and flexibility when compared with conventional DLC coatings by combining the inertness of DLC films with the advantage of fluorination. The purpose of this study was to evaluate the in vitro hemocompatibility and in vivo biocompatibility of the F-DLC coating for medical devices. The in vitro whole blood model confirmed that platelet loss was lower in the F-DLC group than in the noncoated group (SUS316L), which suggests the adhesion of a smaller number of platelets to F-DLC-coated materials. Furthermore, the biomarkers of mechanically induced platelet activation (beta-thromboglobulin) and activated coagulation (thrombin-antithrombin-three complex) were markedly reduced in the F-DLC-coated group. In vivo rat implant model studies revealed no excessive local and systemic inflammatory responses in the F-DLC group. The thickness of the fibrous tissue capsule surrounding the F-DLC-coated disk was almost equal to that of the noncoated SUS316L disk, which has the favorable biocompatibility for metallic implant materials. F-DLC coating thus appears to be a promising candidate for use as a coating material in blood-contacting devices.

Arch reconstruction without circulatory arrest in neonates.

Between May 2000 and December 2002, 10 neonates underwent arch reconstruction without circulatory arrest. Age at surgery ranged from 1 to 18 days, and body weight ranged from 1.62 to 3.38 kg. The diagnosis was interrupted aortic arch in 4, hypoplastic left heart syndrome in 3, and coarctation complex in 3. A 3 mm polytetrafluoroethylene graft was anastomosed to the innominate artery, and the brain was perfused via this graft while the aortic arch was reconstructed. Regional cerebral oxygen saturation and the right and left radial artery pressures were monitored. There were 2 deaths: one because of low cardiac output syndrome after a Norwood operation; another from multiple organ failure due to preoperatively undetected congenital biliary atresia. Regional cerebral oxygen saturation was kept constant at over 40% during regional cerebral perfusion. There were no neurologic sequelae observed postoperatively. It was concluded that the regional cerebral perfusion technique can be safely applied during neonatal aortic arch reconstruction, and deep hypothermic circulatory arrest should be avoided.

Does a bidirectional Glenn shunt improve the oxygenation of right ventricle-dependent coronary circulation in pulmonary atresia with intact ventricular septum?

OBJECTIVE: There is a risk of myocardial ischemia in patients with pulmonary atresia and intact ventricular septum associated with the right ventricle-dependent coronary circulation. In this patient group, the oxygen delivery to the myocardium depends on the oxygen saturation of the right ventricular cavity. We hypothesized that bidirectional Glenn shunt would improve the oxygenation of right ventricle-dependent coronary circulation relative to a systemic-pulmonary artery shunt. The reduction of systemic venous return to the right atrium due to a bidirectional Glenn shunt could increase the oxygen saturation of the right ventricle in the clinical setting, when the mixture of systemic and pulmonary venous blood is unchanged at the atrial level. METHODS: Patients with right ventricle-dependent coronary circulation were defined as those with right ventricle-coronary artery fistulas plus stenoses of the right or left coronary arteries. For 7 patients with right ventricle-dependent coronary circulation before and after bidirectional Glenn shunt, cardiac catheterization was performed and the oxygen saturation of the right ventricular cavity was measured. RESULTS: For all 7 patients, the bidirectional Glenn shunt was performed at a mean age of 18 months. Ischemic changes in the electrocardiogram before the bidirectional Glenn shunt improved after the procedure in 2 patients. The oxygen saturation of the right ventricular cavity before the bidirectional Glenn shunt was 54.6 +/- 8.8%, and that after the BGS significantly increased to 75.6% +/- 5.8% (P < .01). All 7 patients have subsequently undergone the Fontan procedure with excellent results. CONCLUSION: Early bidirectional Glenn shunt could prevent progression of myocardial ischemia in pulmonary atresia with intact ventricular septum with right ventricle-dependent coronary circulation.

Prognosis of 6644 resected non-small cell lung cancers in Japan: a Japanese lung cancer registry study.

For the scheduled future revision of the TNM staging system for lung cancer, it is important that the present 1997 version be evaluated in a large population. In 2001, the Japanese Joint Committee of Lung Cancer Registry sent a questionnaire to 320 Japanese institutions regarding the prognosis and clinicopathological profiles of patients who underwent the resection for primary lung neoplasms in 1994. We compiled the data for 7408 patients from 303 institutions (94.7%). Among these, 6644 patients with non-small cell histology were studied in terms of prognosis. The 5-year survival rate of the entire group was 52.6%. The 5-year survival rates by clinical (c-) stage were as follows: 72.1% for IA (n = 2423), 49.9% for IB (n = 1542), 48.7% for IIA (n = 150), 40.6% for IIB (n = 746), 35.8% for IIIA (n = 1270), 28.0% for IIIB (n = 366) and 20.8% for IV (n = 147). The difference in prognosis between neighboring stages was significant except for between IB and IIA and between IIIB and IV. The 5-year survival rates by pathological (p-) stage were as follows: 79.5% for IA (n = 2009), 60.1% for IB (n = 1418), 59.9% for IIA (n = 232), 42.2% for IIB (n = 757), 29.8% for IIIA (n = 1250), 19.3% for IIIB (n = 719) and 20.0% for IV (n = 259). The difference in prognosis between neighboring stages was significant except for between IB and IIA and between IIIB and IV. The survival curves of stages IB and IIA were almost superimposed in both c- and p-settings. These findings indicated that the present stages IB and IIA should be merged into the same stage category. Otherwise, the present TNM staging system seemed to well characterize the stage-specific prognosis in non-small cell lung cancer. The future revision should focus on the subdivision of stages I and II.

Bioprosthetic dysfunction caused by preserved native valve in tricuspid position.

We report a 4-year-old girl who underwent replacement of a bioprosthetic valve in the tricuspid position due to rare bioprosthetic dysfunction. The bioprosthetic valve showed marked tricuspid insufficiency as well as stenosis caused by the adhesion of the preserved native valve leaflets to the undersurface of the implanted bioprosthesis.

Pulmonary artery sling associated with tetralogy of fallot.

We describe a rare case of pulmonary artery sling occurring simultaneously with tetralogy of Fallot. This report describes the successful concomitant repair of both intracardiac anomalies.

One-lung ventilation for video-assisted thoracoscopic interruption of patent ductus arteriosus.

PURPOSE: Video-assisted endoscopic techniques have recently been employed in congenital heart surgery for patent ductus arteriosus (PDA) interruption. We report our preliminary experience of using a new technique of single-lung ventilation to perform video-assisted thoracoscopic PDA interruption (VATS-PDA) in small infants and children. METHODS: Sixteen infants with a mean body weight of 6.5 +/- 2.4 kg (range 2.6-12.8 kg) underwent VATS-PDA under selective right-lung ventilation using a 2-F balloon catheter for arterial embolectomy. RESULTS: We did not need to reposition the retractor or reinflate the atelectatic lung, as there was no transient hypoxia or hypercarbia. The mean procedure time was 81 +/- 27 min (range 45-145 min) and all patients, with the exception of one with a total anomalous pulmonary venous connection, were extubated in the operating room. CONCLUSION: This technique using single-lung ventilation for infants and small children was safe and effective in providing pediatric thoracic access and exposure within confined and delicate anatomic spaces.

[Traumatic lung injury].

Pulmonary injuries include a wide variety of clinical conditions. Most patients with blunt chest trauma can be managed with conservative treatment. Only about 10 to 15% of patients with severe chest injuries require major thoracotomy. Management of pulmonary contusion, pulmonary laceration, pneumothorax or hemothorax by oxygen inhalation, respirator assist and chest drainage can usually result in complete recovery. However, pulmonary injuries sometimes lapse into fatal condition if they are improperly treated. Open thoracotomy is required in cases with persistent massive air leakage or massive bleeding with the use of chest drainage. It is crucial to evaluate the extent and severity of the injuries based on chest X-ray and computed tomography (CT) findings for the proper initial treatment in patients with pulmonary injuries.

COX-2/VEGF-dependent facilitation of tumor-associated angiogenesis and tumor growth in vivo.

Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis.

Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth.

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.

Total cavopulmonary connection via a thoracotomy.

We report a patient who underwent a total cavopulmonary connection with an extracardiac conduit through a right thoracotomy. The thoracotomy approach was useful in circumventing possible hazardous complications at the sternal reentry for the completion of a staged Fontan due to previous mediastinitis in this patient.

Double-patch closure using gelatin resorcine formol glue of a ventricular septal perforation following acute myocardial infarction.

Complete closure is most important when attempting acute-phase closure of a ventricular septal perforation following acute myocardial infarction. Here, we present a case of a 76-year-old male with a ventricular septal perforation following acute myocardial infarction. The ventricular septal perforation was repaired by stitching small and large bovine pericardial patches onto the affected septum from the side of the left ventricle, then cementing the two patches together with gelatin resorcine formol glue injected into the space between them. Complete closure of the ventricular septal perforation was accomplished. Simultaneously, right coronary artery bypass grafting was performed using a saphenous vein. The postoperative course was uneventful, and the patient was discharged, with a favorable post-discharge course for 24 months to date after surgery.

Cyclooxygenase-2 and adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in rat sponge implants.

Angiogenesis is reportedly enhanced by prostaglandins (PGs). In the present experiment, we tested whether or not COX-2 and adenylate cyclase/protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Angiogenesis was enhanced by topical injection of human recombinant basic fibroblast growth factor (bFGF). The enhanced angiogenesis by bFGF was inhibited by indomethacin or selective COX-2 inhibitors, NS398, nimesulide, and JTE-522. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis in a dose-dependent manner, as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by bFGF, 8-bromo-cAMP, forskolin, and amrinone. Angiogenesis was inhibited by indometacin or selective COX-2 inhibitors, NS-398, nimesulide, and JTE-522. In addition, angiogenesis without topical injections of the above compounds was also suppressed by SQ22,536, an inhibitor for AC. or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. These results suggested that COX-2 and AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis, and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.

A prematurely terminated phase III trial of intraoperative intrapleural hypotonic cisplatin treatment in patients with resected non-small cell lung cancer with positive pleural lavage cytology: the incidence of carcinomatous pleuritis after surgical intervention.

BACKGROUND: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. METHODS: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes. RESULTS: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008). CONCLUSIONS: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.

The role of kinin B1 in the plasma extravasation of carrageenin-induced pleurisy.

The role of des-Arg9-bradykinin (des-Arg9-BK) and kinin B1 receptor in the plasma extravasation of rat carrageenin-induced pleurisy was investigated employing B1 receptor agonist and antagonists and kininogen-deficient rats. Expression of the B1 receptor mRNA in pleura was induced from 3 to 5 h after the injection of carrageenin into the pleural cavity of Sprague-Dawley rats. Exogenous injection of des-Arg9-BK into the pleural cavity provoked a significant increase in plasma extravasation in 5 h carrageenin-induced pleurisy, but not in 20 min kaolin-induced pleurisy. The level of immunoreactive des-Arg9-BK in the exudate of 5 h carrageenin-induced pleurisy was higher than that of bradykinin (BK). Administration of the B1 receptor antagonists, des-Arg9-[Leu8]-BK or des-Arg9-D-Arg-[Hyp3, Thi5, D-Tic7,Oic8]-BK significantly reduced the exudation rate. However, intrapleural administration of des-Arg9-BK to plasma kininogen-deficient. Brown Norway-Katholiek rats did not result in a further increase in the plasma extravasation. In conclusion, endogenously generated des-Arg9-BK could contribute to the plasma extravasation in carrageenin-induced pleurisy via mediation of the inducible B1 receptor.

Open surgical intervention to recurrent aortic dissection after endovascular stent grafting.

We report the case of a 49-year-old man who received open-heart surgery for recurrent aortic dissection after endovascular stent grafting. Stent grafting had been successfully performed in the acute phase. Recurrent dissection became obvious 5 months later, and at the same time, aneurysmal change was detected between the left subclavian artery and the proximal end of the stent graft. We employed a "Y arch" surgical procedure and "elephant trunk" technique to treat, and the entry tear was completely sealed and the aneurysm was excluded by elephant trunk segment. We believe that this approach could be a new option for treatment for complicated aortic aneurysms.