Suppression of pulmonary metastasis using adenovirally motility related protein-1 (MRP-1/CD9) gene delivery.

Previously we showed that MRP-1/CD9 might prevent tumor metastasis by suppression of cell motility and invasion of tissue barriers. The present study explored the possibility of preventing metastasis of mouse melanoma BL6 by expression of MRP-1/CD9 through gene transfer. A replication-deficient adenovirus vector was used for the in vivo transfer of MRP-1/CD9 cDNA. Intratumor injection of an adenovirus vector (rAd-MRP-1/CD9) expressing MRP-1/CD9 resulted in a 73.7% reduction in the number of pulmonary metastases of mice and the median survival time of mice treated with rAd-MRP-1/CD9 was significantly longer than those treated with the rAd-beta-gal vector (103.2 approximately plus;8.5 days vs 71.2 approximately plus;5.2 days, P<0.001 respectively). These results support the expression of MRP-1/CD9 through gene transfer as a therapeutic strategy for preventing metastases and prolonging survival, and support the feasibility of gene transfer in a clinically relevant setting.

Clinical significance of CD151 gene expression in non-small cell lung cancer.

Transmembrane 4 superfamily (TM4SF) is a recently described gene family, and TM4SF members are known to play roles in the signal transduction pathways and to regulate cell activation, development, proliferation, and motility. MRP-1/CD9, KAI1/CD82, and ME491/CD63, members of the TM4SF, have been reported to suppress tumor progression or metastasis. Previously, we showed that MRP-1/CD9 suppressed cell motility and metastatic potential to lungs. Moreover, reduction of MRP-1/CD9 and KAI1/CD82 gene expression was found to be a factor in a poor prognosis for patients with non-small cell lung cancer. However, among TM4SF, CD151 is identical to an existing gene, PETA-3, which may promote tumor metastasis of malignant cells, and its expression may be involved in the malignant progression of cancer. The function of CD151 is opposite that of the metastasis suppressor genes, MRP-1/CD9 and KAI1/CD82. On the basis of these results, we used reverse transcription-PCR and immunohistochemical techniques for a retrospective study of CD151 gene expression in tumor tissues from 145 lung cancer patients; 72 tumors were stage I, 29 stage II, 27 stage IIIA, and 17 stage IIIB. Whereas 86 patients had tumors positive for the CD151 gene, 59 had tumors that were negative for the CD151 gene. The overall survival rate of patients with CD151-positive tumors was much lower than that of CD151-negative patients (51.9% versus 73.1%; P = 0.013). Our findings suggest that high CD151 gene expression in lung cancer may be associated with a poor prognosis. Assessment of CD151 could be instrumental for improvements in lung cancer diagnosis and therapies.

Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus.

1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists. 4 The selective P2-adrenoceptor antagonist ICI 118551 (3-100nM) shifted the concentration-effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration-dependent manner.ICI 118551 (3 nM) also shifted the concentration-effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nM, when a further rightward shift was obtained.5. The selective alpha 1-adrenoceptor antagonist, prazosin (30-300 nM), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.6. In conclusion, it appears that beta2-adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The alpha l-agonist, phenylephrine, appears to interact with beta2-adrenoceptors on this preparation.beta 3-Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of beta 3-receptors in the canine striated muscle part of the oesophagus.

Comparison of three-field esophagectomy for esophageal cancer incorporating open or thoracoscopic thoracotomy.

BACKGROUND: Thoracoscopic esophagectomy for esophageal cancer has been performed as an alternative to open surgery to reduce surgical trauma. However, its effect on pulmonary function, exercise tolerability, and quality of life is unknown. METHODS: Fifty-one patients with esophageal cancer underwent thoracic esophagectomy with radical lymphadenectomy by posterolateral thoracotomy (29 cases) or thoracoscopic surgery (22 cases). Patients performed spirometry and exercise tolerance testing and completed a quality-of-life questionnaire before and 3 months after surgery. RESULTS: Pre-to-postoperative change in vital capacity was 74.3 +/- 10.6% in the thoracotomy group and 84.9 +/- 10.4% in the thoracoscopy group (p = 0.021). Maximum oxygen uptake was similar, but dyspnea was the more common factor limiting exercise tolerance postoperatively in the thoracotomy group. Change in pre-to-postoperative performance status was 1.20 +/- 0.62 in the thoracotomy group and 0.55 +/- 0.51 in the thoracoscopy group (p = 0.0003). CONCLUSIONS: Thoracoscopic esophagectomy for esophageal cancer has better preservation of pulmonary function and quality-of-life.

Usefulness of self-expandable metallic stent with an antireflux mechanism as a palliation for malignant strictures at the gastroesophageal junction.

BACKGROUND: Patients with unresectable malignant gastroesophageal strictures often are troubled with reflux esophagitis after stent placement. METHODS: A self-expandable metallic stent (SEMS) without an antireflux mechanism was placed in seven patients with unresectable malignant gastroesophageal strictures (group A), and SEMS with an antireflux mechanism was placed in five patients (group B). After we obtained monitoring systems, two patients in group A and all the patients in group B underwent measurement of bilirubin and pH in the esophagus using a 24-h bilirubin and pH monitor. RESULTS: The mean percentage of total time less than 0.14 for use of the bilirubin absorbance unit was 12.4% in group B and 64.0% in group A. The mean percentage of total time for a pH less than 4 was 2.9% in group B and 37.8% in group A. CONCLUSION: The placement of SEMS with the antireflux mechanism can be effective not only for palliation of gastroesophageal stricture, but also for prevention of reflux.

Perforated duodenal diverticulum: report of two cases.

Duodenal diverticula may be complicated by diverticulitis, perforation, hemorrhage, pancreatitis, or biliary obstruction. Two cases of perforated duodenal diverticulum are reported. Both patients were elderly females. Computed tomography of the abdomen showed retroperitoneal air around the duodenum in the first case, and an enterolith in a duodenal diverticulum and a retroperitoneal abscess in the second case. Laparotomy and diverticulectomy with two-layer closure of the duodenum was performed in the first case. The second patient was treated conservatively with antibiotics, percutaneous abscess drainage, and endoscopic lithotomy. Both recovered well. Computed tomography is useful in the diagnosis of a perforated duodenal diverticulum. Although surgical intervention is the standard treatment, conservative therapy is also an option. Duodenal enteroliths are rare but may cause perforation of a diverticulum or biliary obstruction. The duodenal blind loop created by a Billroth II gastrectomy provides a static environment for the formation of enteroliths in duodenal diverticula.

Chylothorax after thoracoscopic esophagectomy.

Among 30 patients who underwent thoracoscopic esophagectomy with lymphadenectomy for thoracic esophageal cancer, from July 1995 to May 1997, chylothorax developed in 2 patients (7%). In Case 1, the ligation of the thoracic duct under conventional right thoracotomy was performed on the 9th day after esophagectomy. After ligation, the pleural effusion was decreased, and the patient was discharged from hospital on the 25th day after the second operation. In Case 2, massive pleural effusion developed on the 10th day after esophagectomy (at 3 days after thoracic drainage tube was removed). The thoracic duct was ligated at the level just cranial to the diaphragm thoracoscopically on the 14th day after esophagectomy. The patient was discharged from hospital on the 30th day after the second operation. Injury to the thoracic duct due to a magnification effect of the view of scopic surgery remains a pitfall in thoracoscopic esophagectomy. But thoracoscopic ligation of thoracic duct was effective and safe for these two cases of chylothorax after esophagectomy.

[Changes of serum cytokine levels after thoracoscopic esophagectomy].

We introduced thoracoscopic esophagectomy with extended lymphadenectomy for reduction of respiratory dysfunction and less surgical intervention in July 1995. In this study, we investigated the changes in serum interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) levels in 8 patients (TS Group) who underwent thoracoscopic esophagectomy with extended lymphadenectomy and compared them with the changes in patients who underwent conventional thoracotomy (CT Group). The duration of the operation and intrathoracic procedure in the TS group were significantly longer than in the CT group. However, the amount of blood loss and intrathoracic blood loss of the TS group were not significantly higher than in the CT group. The number of dissected lymph nodes was not significantly larger. The serum IL-6 levels reached maximum levels 3 hours from the end of operation. In the TS group, the changes in IL-6 levels were significantly larger (p < 0.05). On the other hand, the changes in CRP levels were also significantly larger (p < 0.01). Significant correlation was observed between the duration of the intrathoracic procedure and the maximum levels of IL-6. On the other hand, serum IL-1ra levels were not significantly. At present, these results suggest that the surgical intervention of thoracoscopic esophagectomy are more larger than that of conventional thoracotomy. We think that the length of intrathoracic procedure of thoracoscopic esophagectomy may make more large surgical stress.

Endobronchial stenting as a palliation for advanced esophageal cancer.

Three cases of airway invasion of esophageal cancer treated palliatively by endobronchial stenting are reported. In case 1 (a 60-year-old male) expandable metallic stents were inserted into the totally occluded left main bronchus. In case 2 (a 45-year-old male) a Dumon stent was inserted into the totally occluded left main bronchus. Both patients recovered from performance status 4 to performance status 1 or 0 and were in good condition before they died of cancer, 150 and 54 days after stenting in cases 1 and 2, respectively. In case 3, a Dumon stent was inserted into the left main bronchus before total occlusion. The patient recovered from performance status 3 or 2 to performance status 1 or 0 and survived 40 days after stenting with no signs of airway obstruction. Endobronchial stenting is a useful palliation for keeping the performance status at a good level in patients with esophageal cancer obstructing or narrowing the main airway.

Acute acalculous cholecystitis complicated by penetration into the liver after coronary artery bypass grafting.

BACKGROUND: Perforation or penetration due to acute acalculous cholecystitis is a rare complication after open-heart surgery. The mortality rate of this disease is high. METHODS: A 71-year-old woman complained of a sudden onset of right upper abdominal pain with development of peritoneal signs at 21 days after coronary artery bypass grafting. Abdominal ultrasonography and laboratory examination performed at 1 day earlier had revealed no abnormalities. Neither anticoagulants nor antiplatelet agents were administered following the bypass operation. An exploratory laparotomy was performed to locate a presumed embolization to the superior mesenteric artery. RESULTS: Laparotomy revealed acute acalculous cholecystitis complicated by penetration into the liver, causing a subserosal hematoma. The hematoma had ruptured into the abdominal cavity. A cholecystectomy was performed. The gallbladder wall which was in contact with the liver was necrotic. Most of the gallbladder mucosa was necrotic. Microscopical examination revealed atherosclerosis of the cystic artery which was partially obstructed by thrombus. CONCLUSIONS: Given the atherosclerotic condition of the cystic artery, hypotension during the bypass in combination with postoperative total parenteral nutrition and hypovolemia may have induced the cystic artery thrombosis. Surgeons who manage patients with cardiovascular disease should be aware of this potentially lethal development.

Neutral endopeptidase/CD10 and aminopeptidase N/CD13 gene expression as a prognostic factor in non-small cell lung cancer.

OBJECTIVES: Neutral endopeptidase modulates the growth of lung cancer, while aminopeptidase N degrades the extracellular matrix and is involved in cell motility. We studied the metastasis mechanism to detect novel metastasis-associated molecules and to evaluate them for clinical application. METHODS: We studied the relationship between the expression of neutral endopeptidase and aminopeptidase N by quantitative reverse transcript-polymerase chain reaction analysis in 132 patients with non-small cell lung cancer undergoing radical surgery from 1991 to 1996. RESULTS: Patients with neutral endopeptidase-positive and aminopeptidase N-negative tumors were defined as group A, those with neutral endopeptidase-positive and aminopeptidase N-positive or neutral endopeptidase-negative and aminopeptidase N-negative tumors as group B, and those with neutral endopeptidase-negative and aminopeptidase N-positive tumors as group C. The 5-year survival of group A patients (92.9%) was significantly better than that of group B patients (64.7%) and much better than that of group C patients (38.2%) (P = 0.0011). Neutral endopeptidase and aminopeptidase N thus have statistically significant P in overall survival in Cox regression (P = 0.019). CONCLUSION: Neutral endopeptidase and aminopeptidase N gene expressions are significant indicators of prognosis.

[Usefulness of Roux-Y type bypass operation using pedicled jejunum in unresectable esophageal cancer].

Twelve patients underwent bypass operation for unresectable esophageal cancer in our department in recent 5 years were reviewed. A group of 8 patients who had Roux-Y type bypass operation using pedicled jejunum was compared with a group of 4 patients who had bypass operation using gastric roll. 1) The anastomotic leakage was found in one patients in each group of patients. 2) The operating time and amount of bleeding were significantly less in the patients being used the jejunal pedicle than in the patients being used the gastric roll. 3) No significant difference was found in the possibility of oral uptake and discharge from hospital and postoperative survival period between these two groups. The bypass operation for unresectable esophageal cancer is a riskful operation. But, we found that the Roux-Y type bypass operation using the pedicled jejumun was a safe and uninvasive procedure for a patient with high risk.

[Traumatic diaphragmatic hernia].

Five cases of traumatic diaphragmatic hernia were reported and 495 cases reported in Japan were reviewed. Analysis of cases of hernia following blunt trauma in the present study provided a simple classification of fissure of the diaphragm, i.e., "tension type (indirect type)" and "impact type (direct type)". In the former type, the fissure occurs in the central tendon or its vicinity in the diaphragm as a result of distortion of the bony thorax without direct force on the diaphragm, while in the latter type, the fissure occurs in the diaphragm close to the struck bony thorax as a result of blunt force on the bony thorax to which the diaphragm is attached.

[Preoperative bronchial arterial infusion of docetaxel for squamous cell carcinoma of the lung--clinical evaluation and correlation between anti-tumor effect and apoptosis].

As an induction therapy for advanced lung cancer, a patient received bronchial arterial infusion of 30 mg/m2 of docetaxel (TXT). Two weeks after infusion, although the tumor size was not reduced, the central necrotic area was significantly increased. There were no adverse effects. Nineteen days after infusion, we performed a right lower lobectomy and lymph nodal dissection. The resected specimen was examined by immunohistochemistry and biochemistry. The anti-tumor effects were evaluated clinically and the correlation between arterial TXT infusion therapy and apoptosis was studied. Hematoxylin and eosin staining demonstrated moderately differentiated squamous cell carcinoma associated with central necrosis, and cells with chromatin condensation scattered in both the necrotic areas and the margin of this area. It is thought that these findings were the result of this therapy, rather than just the self-necrosis seen in an untreated group.

[Function of the upper esophageal sphincter after denervation of recurrent laryngeal nerves and intramural nerves of the cervical esophagus in dogs].

The upper esophageal sphincter prevents reflux into the pharynx. If it functions improperly, aspiration pneumonia can result. We studied the functioning of the sphincter in unanesthetized dogs after denervation under anesthesia of the recurrent laryngeal nerves. The pressure of the sphincter at rest was measured by manometry with a transducer that measured pressure around the tip of a catheter. Then the pressure in response to inflation of a balloon to the diameter of 1.5, 2.0 and 2.5 cm at 5 and 10 cm aboral to the sphincter was measured. Next, the pressure during perfusion of 0.1 N HCl or NaOH 10 cm aboral to the sphincter was measured. These studies were done first in 10 dogs that had undergone only gastrostomy for measurements (controls). Measurements were repeated after the left recurrent laryngeal nerve in the controls was cut (L group), after the right recurrent laryngeal nerve in the L group was cut (B group), and after transection of the esophagus 7 cm aboral to the sphincter in the B group (T group). The differences in the pressure at rest were not significant. In each group, balloon inflation to any diameter tested and at either position made the pressure rise above that at rest. This pressure in the L, B, and T groups, however, was significantly lower than in the controls. When the balloon was inflated to 2.5 cm when it was 10 cm aboral to the sphincter, the pressure in the T group was significantly lower than in the B group. When HCl or NaOH were perfused, the pressure increased gradually in the controls, but not in the other groups. In conclusion, although recurrent laryngeal nerves did not affect the function of the sphincter at rest, they were the afferent routes of the contraction by the sphincter as a reflex following distension or chemical stimulation of the esophagus. The intramural nerve network of the cervical esophagus may be another reflex route of contraction of the upper esophageal sphincter.

[Clinical study on responses of the upper esophageal sphincter after subtotal esophagectomy for esophageal cancer].

Responses of the upper esophageal sphincter (UES) to distention of the esophageal wall by use of a balloon catheter were measured in 30 patients after subtotal esophagectomy for esophageal cancer and 33 volunteers with unrelated disorders (control group). Patients were divided into extended dissection group and non-extended dissection group according to the width of lymph node dissection, or palsy group and non-palsy group according to recurrent-laryngeal nerve palsy. The resting upper esophageal sphincter pressure (UESP) and the upper esophageal sphincter contraction (UESC) following UES induced by swallowing were measured after esophageal distention. Neither of UESP nor UESC without distention was significantly different among each group. But those of the extended dissection group and palsy group after esophageal distention were significantly lower values than those of control group. These findings suggest that responses of the UES to distention of esophageal wall are decreased, thus protection against aspiration is probably decreased.