The experimental replacement of a cervical esophageal segment with an artificial prosthesis with the use of collagen matrix and a silicone stent.

OBJECTIVE: Attempts have been made to replace esophageal defects with a variety of artificial materials. However, because of the artificial nature of the materials, problems such as infection, leakage, stricture, or dislocation could not be avoided. Therefore we have designed a new type of artificial esophagus that is gradually replaced by host tissue. METHODS: Our artificial esophagus was a two-layered tube consisting of a collagen sponge matrix and an inner silicone stent. We used it to replace 5 cm esophageal segmental defects in 43 dogs, and the inner silicone stent was removed endoscopically at weekly intervals from 2 to 4 weeks. RESULTS: In the 27 dogs from which the silicone stent was removed at 2 or 3 weeks, constriction of the regenerated esophagus progressed and the dogs became unable to swallow within 6 months. In the 16 dogs from which the silicone stent was removed at 4 weeks, highly regenerated esophageal tissue successfully replaced the defect, leaving no foreign body in the host. Moreover, the regenerated esophagi had stratified flattened epithelia, striated muscle tissue composed of an inner circular and an outer longitudinal muscle layer, and esophageal glands. CONCLUSIONS: Even in mature adult higher mammals, esophageal high-order structures can be regenerated provided that an adequate three-dimensional extracellular structure is put in place for a sufficient period.

Intrathoracic tracheal reconstruction with a collagen-conjugated prosthesis: evaluation of the efficacy of omental wrapping.

Reconstructions of the intrathoracic trachea in 24 dogs were done with the use of 50 mm long collagen-conjugated tracheal prostheses. Omental wrapping was also done in 14 of the dogs (omentopexy group) to evaluate the efficacy of this option in comparison with results in the other 10 dogs (control group). All 24 dogs had uneventful postoperative courses and were killed at 4 weeks or 3, 6, or 12 months after the operation. Better epithelialization and fewer complications, such as mesh exposure and luminal stenosis, were observed in the omentopexy group than in the control group. Angiography and analysis of regenerated blood vessels revealed that vessel ingrowth had started within 4 weeks and that vessel formation reached its maximal point within 6 to 12 months in the omentopexy group. In contrast, revascularization of the subepithelial region in the control group was poor even after 3 months, and vessel formation continued for as long as 12 months. The differences between the two groups were considered to be mainly a result of the speed of blood vessel ingrowth into the regenerated mucosa. We conclude that our prosthesis can be used safely for intrathoracic tracheal reconstruction and that omental wrapping is a useful supplementary method that reduces the occurrence of complications.

Prevention of postoperative air leakage from lungs using a purified human collagen membrane-polyglycolic acid sheet.

BACKGROUND: Human amnion has useful biomedical applications because it contains a large amount of human collagen fibers. We prepared purified human collagen membrane (HCM) from human amnion and used it to develop a new sheet by combining it with synthetic bioabsorbable polyglycolic acid (PGA) mesh. We evaluated its efficacy in preventing air leakage from the lungs of dogs. METHODS: In 20 dogs, HCM-PGA sheet (n = 5), sheets using fibrin glue with a separate application method (n = 5), a mixed application method (n = 5), and fibrin glue alone (n = 5), were used as dressing materials after partial lung resection. RESULTS: The HCM-PGA sheet using fibrin glue with a separate application method was shown to be significantly more effective by an air leakage pressure test than the other three methods. These results indicate that the HCM-PGA sheet is useful for preventing air leakage from the lung. CONCLUSIONS: The HCM-PGA sheet is more effective than conventional fibrin glue for controlling postoperative air leakage.

Porous-type tracheal prosthesis sealed with collagen sponge.

BACKGROUND: Reconstruction of a long section of the trachea is clinically problematic. Tracheal reconstructions using prostheses have met with limited success due to local infection, hemorrhage, luminal stenosis and prosthesis dislocation. METHODS: We have designed a porous type of tracheal prosthesis in which the mesh is sealed with collagen sponge. We used this prosthesis (50 mm in length) to reconstruct the cervical trachea in 10 mongrel dogs and evaluated its efficacy. RESULTS: One dog died due to an accident with anesthesia at 6 weeks and 1 of suffocation at 10 weeks. The other 8 dogs had an uneventful postoperative course until they were killed between 6 and 24 months after implantation. At sacrifice, all the prostheses had become completely incorporated into the host. Microscopic examination revealed advanced formation of a new epithelial lining in 1 dog at 6 months, and a confluent epithelial lining was observed in another dog at 12 months. Central stenosis was not significant in any of the animals. CONCLUSIONS: This tracheal prosthesis gives good results in canine tracheal reconstruction, and appears very promising for the clinical repair of tracheal defects.

Nerve regeneration across a 25-mm gap bridged by a polyglycolic acid-collagen tube: a histological and electrophysiological evaluation of regenerated nerves.

In the study reported here we have examined the nerve regeneration that occurs over a 25-mm gap using a novel biodegradable nerve guide tube. The tube was a composite of polyglycolic acid (PGA) mesh coated with collagen which was filled with neurotrophic factors. The left sciatic nerve of ten adult cats was dissected. The stumps were connected by the tube, and fixed gap. Histological examinations carried out 4-16 months after implantation of the tube revealed regeneration of well vascularized nerve tissue. Regeneration of both myelinated, unmyelinated axons and Schwann cells was confirmed by electron microscopy 5 months after surgery. Following injection of horseradish peroxidase (HRP) into a site peripheral to the regenerated segment of the sciatic nerves, motoneurons in the ventral horn of the spinal cord, afferent terminals in the medial portion of the dorsal column of the medulla oblongata, and sensory afferent nerve terminals in the dorsal horn of the spinal cord were labelled. Electrophysiological examinations revealed restoration of evoked electromyograms and sensory evoked potentials (SEPs) recorded from the cerebral cortex as well as the spinal cord. We also found that some of the regenerated motor axons exhibited branching in the regenerated segments. In two cases, a single motoneuronal axon from the regenerated side projected to both flexors and extensors, simultaneously. Our results indicate that the PGA-collagen composite tube is a promising tool for use as a nerve guide tube in peripheral nerve regeneration.

Relationship between stenting time and regeneration of neoesophageal submucosal tissue.

The authors developed a new type of artificial esophagus consisting of an inner silicone tube and an outer non antigenic collagen tube. The novel feature of this artificial esophagus is that the main part of the prosthesis is replaced by host tissue. In a previous study, the authors found that no stenosis of the artificial esophagus developed when the replacement part was stented for more than 4 weeks. It was considered that this stenosis was caused mainly by poor regeneration of submucosal tissue, rather than by the grade of reepithelialization. In this study, it was found that, in cases in which the stent dropped out within 3 weeks, fibrous tissue was noted beneath the neoesophageal epithelium. In such cases, neither muscle layers nor submucosal glands regenerated beneath the neoesophageal epithelium after replacement. However, in cases in which the stent dropped out more than 4 weeks after surgery, the neoesophagus was covered with a polylayer of squamous epithelium and had normal esophageal glands and a muscle layer. Therefore, it was concluded that muscle tissue and esophageal glands were able to regrow in the neoesophagus when the portion replaced by the artificial esophagus was stented for at least 4 weeks.

A new porous tracheal prosthesis sealed with collagen sponge.

We have designed a new tracheal prosthesis to overcome problems with an earlier device, which included stenosis and exposure of its constituent mesh. A polypropylene mesh cylinder, reinforced with a polypropylene spiral, is sealed with collagen sponge made from porcine dermal collagen. Using this prosthesis, we performed cervical tracheal reconstructions on 11 dogs. Three dogs died within 3 months of reconstruction. Their causes of death were anesthetic accident, diarrhea, and suffocation, respectively. Bronchoscopically, the inner surface of the prosthesis was almost covered with host tissue by 2 months. However, in one dog, a relatively large area of the mesh was exposed in the tracheal lumen at 6 months; a smaller area was exposed in two other dogs. The appearance of the inner surface rapidly became lustrous, and central stenosis was not significant, even after 12 months. Histologically, an incomplete epithelial lining at 6 months was seen on the reconstructed surface and included ciliated columnar, cuboidal, and squamous epithelium. These observations have revealed that this prosthesis has high biocompatibility and the potential to overcome problems of stenosis of the prosthesis lumen. However, because ulceration persists with this prosthesis, additional improvement is needed to reduce the incidence of mesh exposure.

Replacement of long segments of the esophagus with a collagen-silicone composite tube.

Artificial esophagi designed thus far can be classified into three types in terms of the materials used: natural, artificial, and composite. In conventional models, even when artificial esophagi were made of ideal materials with high tissue affinity, they remained in the tissue as a foreign body, and therefore were not free of the complications caused by implanted material. The authors have designed a new type of artificial esophagus composed of a Silicone tube covered with nonantigenic collagen. The novel feature of this artificial esophagus is that the prosthesis does not remain in the implanted site, but is replaced by regenerated host tissue. Using this artificial esophagus, the authors have already succeeded in replacing a 5 cm gap in the esophagus. In this study, replacement of longer portions of the esophagus was assessed in seven dogs using a 10 cm long artificial esophagus. Stenosis did not occur in five of the seven dogs and, consequently, these dogs survived by oral feeding alone for more than 6 months without dry weight loss. The other two animals died of anesthetic accidents at the time of stent removal 6 weeks after surgery. In both cases, the internal surface of the neoesophagus was covered with a polylayer of squamous epithelium. Regenerated esophagi had normal esophageal glands and immature muscle tissue. It is therefore concluded that this new artificial esophagus is also applicable for replacement of long segments of esophagus.

A new tracheal prosthesis made from collagen grafted mesh.

The authors studied the efficacy of a new tracheal prosthesis made from mesh. The prosthesis, 50 mm long and 18-22 mm in diameter, is made from a Marlex mesh cylinder reinforced with a continuous polypropylene spiral that is grafted and coated with porcine collagen to increase its biocompatibility and provide an airtight seal during the initial implantation stage. Circumferential surgical resection and replacement of a seven to nine ring segment of the cervical trachea was performed in 20 adult mongrel dogs. At the time of surgery, a silicone tube was inserted into the tracheal prosthetic lumen to promote secretory transportation until the prosthesis was covered with host tissue. The silicone tube was removed during fiber bronchoscopy 1 month after surgery. With the exception of the prostheses in 3 dogs that died of unrelated causes, all were infiltrated by connective tissue and incorporated completely by the host. One of these 17 dogs died of suffocation caused by luminal stenosis 2.5 months after surgery, but the others survived until they were killed at more than 6 months. The luminal surfaces of the reconstructed tracheae were covered with respiratory epithelium to varying degrees, and in one dog killed at 22 months after surgery, confluent epithelization throughout the length of the prosthesis was confirmed histologically. In eight dogs, prosthetic luminal stenosis occurred because of overgrowth of granulation tissue, which generally was mild in all but three dogs. The authors conclude that this tracheal prosthesis is highly biocompatible and shows promise for clinical application.

Experimental reconstruction of the intrathoracic trachea using a new prosthesis made from collagen grafted mesh.

Intrathoracic tracheal replacement was performed in dogs using a tracheal prosthesis we had constructed from mesh. The prosthesis consists of Marlex mesh (polypropylene) reinforced with a continuous polypropylene spiral, and is grafted and coated with pig collagen (Types I and III). Complete surgical resection of the mediastinal trachea was performed in seven adult mongrel dogs. In 1 dog, a 4 tracheal ring segment (2 cm) was resected and replaced with a 3 cm prosthesis, and in 6 dogs, a 7 to 8 tracheal ring segment (4 cm) was resected and replaced with a 5 cm prosthesis. In the latter six dogs, a silicone tube was temporarily inserted into the replacement, and removed by bronchoscopy one month after surgery. In one dog that received a 4 cm replacement, we added omentopexy around the reconstructed trachea. The prostheses in all dogs were promptly infiltrated by surrounding tissue and incorporated by the host trachea. No dehiscence or air leakage was observed after surgery. Mild luminal stenosis was evident in one dog, and partial exposure of the mesh (ulceration) was observed in five dogs within an observation period of 3 to 26 months. However, in the dog that received omentopexy after tracheal reconstruction, no stenosis or ulceration was observed, and the luminal surface seemed lustrous even after 6 weeks. Formation of respiratory epithelium, which lined the prosthetic lumen, was seen to various degrees: in the 2 dogs killed 12 months and 26 months after surgery, confluent epithelization was confirmed histologically from the upper to the lower anastomosis of the prosthesis. The tracheal prosthesis is useful for the repair of intrathoracic tracheal defects and shows promise for clinical application with further investigation.

Artificial trachea and long term follow-up in carinal reconstruction in dogs.

We have already reported successful carinal reconstruction of the trachea with an observation period of 1 - 2 years. In this study, we evaluate the long-term safety and efficacy of the reconstruction after 5-years of follow-up. The Y-shaped Marlex mesh tube was reinforced with a polypropylene spiral and coated with atelocollagen made from porcine skin. The prosthesis was 60 mm long with an outer diameter of 18 mm. Replacement of the tracheobronchial bifurcation was preformed through a right thoracotomy in a beagle dog. Bronchoscopical examination and sampling of the tracheal epithelium was performed periodically to check the function of cilia. The implanted prothesis was promptly infiltrated by the surrounding connective tissue and completely incorporated by the host trachea and bronchus. Bronchoscopically, sufficient epithelization was confirmed from the upper to the lower site of anastomosis. After 5 years neither stenosis nor dehiscence was observed. In spite of there being mesh-exposure at the luminal surface, the dog had no clinical symptoms until sacrifice for pathological examination. The bent frequency of the cilia was maintained within the normal range, indicating functional recovery of the regenerating airway. Our tracheal prosthesis is promising for clinical repair of the tracheobronchial bifurcation.

[Analysis of T1N0M0 nonsmall cell lung cancer undergoing surgical resection without mediastinal lymph node dissection].

Eleven patients of T1N0M0 non-small cell lung cancer underwent relatively non-curative surgical resection without mediastinal lymph node dissection (the undissected group). The 5 year survival rate of this group was 70.7% and no significant difference in survival was found between the undissected group and the patients of T1N0M0 non-small cell lung cancer undergoing absolutely curative surgical resection (the dissected group). No patient died of pneumonia in the undissected group, while 4 aged patients in the dissected group died of pneumonia. This may suggest that mediastinal lymph node dissection is also injurious in distant period after surgery, especially in the aged patient. So "simple lobectomy" without mediastinal lymph node dissection may be considered as an elective procedure in the poor risk patient such as the aged, who has an early staged non-small cell lung cancer.

[Effect of ondansetron hydrochloride injection and tablet against nausea and vomiting in lung cancer patients receiving carboplatin].

We investigated the efficacy of combination of ondansetron hydrochloride injection and tablet against nausea and vomiting in 22 lung cancer patients (total number of chemotherapy courses: 23) receiving chemotherapy of single-dose carboplatin (CBDCA) at a dose of 302.2 +/- 31.9 mg/m2. For suppressing emesis, the patients were given 4 mg of ondansetron injection on the day of CBDCA injection (Day 1), and 4 mg/day of ondansetron tablet for Days 2 to 5. The following results were obtained 5 days after the administration of carboplatin. 1) Control of nausea graded 'Good' or better counted for 95% or higher of all cases for each day of the chemotherapy. A complete nausea suppression rate was seen in 91.3%, 81.0%, 71.4%, 63.6% and 71.4% from Day 1 to Day 5, respectively. 2) Control of vomiting graded 'Major' control or better was achieved in 95% or more of all cases, for each day. The complete vomiting suppression rate observed from Day 1 to Day 5 was 91.3%, 78.3%, 65.2%, 69.6% and 91.3%, respectively. 3) Inhibitory effect on nausea and vomiting for each day of Days 1 to 5 graded as 'Effective' or better was shown in 90% or higher of all cases; based on overall judgement for Days 1 to 5, all cases were graded as 'Effective' or better. 4) The proportion of cases which was evaluated as 'Can eat most of the meal' was 88.0%, 73.9%, 50.7%, 50.7% and 65.2% from Days 1 to 5, respectively, against 95.7% prior to the start of chemotherapy. 5) No adverse drug reaction or abnormal clinical laboratory values were seen along with ondansetron. 6) In conclusion, combined treatment with ondansetron injection and tablet was considered clinically useful in control of nausea and vomiting during administration of carboplatin, and may also be useful for out-patient chemotherapy.

Preparation strategy for uniformly sized, polymer-based HPLC packing materials having practically acceptable column efficiency. 1. Copolymerization technique.

Uniformly sized, polymer-based packing materials affording excellent chromatographic performance in semimicro HPLC were prepared from mixtures of alkyl methacrylate and glycerol dimethacrylate by a copolymerization technique using a multistep swelling and polymerization method. A column efficiency of up to 13000 plates was obtained for a 2-mm-i.d. x 150-mm column with beads prepared from a 1:1 (v:v) mixture of an alkyl methacrylate and glycerol dimethacrylate. The packing materials exhibit a considerable improvement in column efficiency, as demonstrated on the separation of polyaromatic hydrocarbons (PAHs) having a relatively long retention time, which thus far has been a serious problem of polymer-based packing materials. Detailed studies suggested a rather limited optimum pore size, and its distribution was depicted to get the excellent column efficiency on polymer-based packing materials.

[A case of supravalvular aortic stenosis with spontaneous remission of peripheral pulmonary stenosis].

A 14-year-old junior high school boy was admitted to our institute. Previously he had been diagnosed as having peripheral pulmonary stenosis (Gay's classification, type IV) at the age of 2 years and 10 months. On this occasion, however, a diagnosis of supravalvular aortic stenosis was made, with a pressure gradient of about 120 mmHg, and all examinations showed spontaneous remission of peripheral pulmonary stenosis. He underwent a successful standard aortoplasty. This is the first reported case of spontaneous remission of peripheral pulmonary stenosis.

[Results of surgery in non-small cell lung cancer].

Two hundred and nine patients with non-small cell lung cancer underwent surgical treatment from January, 1978 to December, 1987 at the Kochi Municipal Hospital. There were 126 men and 83 women, varying in age from 36 to 85 years. The post-surgical stage distribution was as follows: 121 patients with Stage I, 22 with Stage II, 43 with Stage IIIA, 14 with Stage IIIB and 9 with Stage IV. The 5 year survival rate was 54% for all patients and only 3 patients of them (1.4%) died within the first month following operation. The 5 year survival rate was 71% for Stage I, 22% for Stage II, 38% for Stage IIIA, 36% for Stage IIIB and 25% for Stage IV. The 5 year survival rate was 66% for absolutely curative operation, 46% for relatively curative operation, 55% for relatively noncurative operation and 19% for absolutely noncurative operation. This series have 41 patients (19.6%) over 70 years old, and the 3 year and the 5 year survival rates for this high age group were 58% and 40%, respectively. Statistically, there was no significant difference in survival rate between this high age group and the younger group. Our successful experiences of the bronchoplastic procedures, extended resections and limited operations were also reported.

[Squamous cell carcinoma of the thymus].

A 68-year-old woman was admitted with cough and dyspnea. Her chest X-ray showed right pleural effusion and a mediastinal tumor. She underwent mediastinotomy following a preoperative diagnosis of invasive thymoma. A tumor originating from the thymus had invaded the right middle lobe and pericardium, and multiple pleural dissemination was also found. Therefore, considering the patient's age and pulmonary function, we performed only subtotal resection of the tumor. The pathological diagnosis was poorly differentiated squamous cell carcinoma. The patient received irradiation and chemotherapy including Cisplatin after surgery, but she died 1 year later because of rapid progression of distant metastases.

[A case of large cell carcinoma of the lung which is suspected of producing granulocyte colony-stimulating factor].

A 41-year-old male complaining of fever and left shoulder pain was admitted to our hospital for further examination of an abnormal shadow on chest X-ray film. His laboratory data on admission showed marked leukocytosis and elevation of serum alkaline phosphatase. The diagnosis of large cell carcinoma of the lung was made by percutaneous biopsy and he was staged clinically as T3N0M0. Chemotherapy including CDDP and VDS resulted in resolution of symptoms and normal laboratory data. After three courses of chemotherapy, he underwent left upper lobectomy with chest wall resection. Pathological diagnosis of the resected tumor was large cell carcinoma with giant cells, and he was staged postoperatively as T3N0M0. Since colony stimulating activity was demonstrated in both homogenate of tumor cells and tumor conditioned medium, and preoperative serum granulocyte colony-stimulating factor (G-CSF) was 105 pg/ml, we concluded that leukocytosis in this patient was caused by G-CSF produced by tumor cells. The patient was in good health two years after surgery with no signs of recurrence.

[Carinal resection for primary lung cancer--with special attention to a modified double-barrel method].

Carinal resection for primary lung cancer was clinically evaluated. Carinal resection was performed in 18 patients, 17 males and one female, with a mean age of 64 years. Nine patients underwent carinal reconstruction and the other 9 sleeve or wedge pneumonectomy. The carinal reconstruction was of the montage type in one patient, the one-stoma type in 2, and the modified double-barrel method in 6. The modified double-barrel method is a technique that we developed by adding bronchial end-to-side anastomosis to the tracheobronchial end-to-end anastomotic site. A pedicled intercostal muscle flap was used for covering the anastomotic site. The postoperative respiratory complications after carinal reconstruction were anastomosis failure in 4 patients (pin-hole in 3) and respiratory failure in 2. However, no anastomosis stricture occurred, and recovery was satisfactory. There were no respiratory complications after pneumonectomy. One patient had renal failure before surgery and died of multiple organ failure 23 days after a montage type carinal reconstruction. The other 17 patients did well and could be discharged from the hospital and the overall mortality rate was 5.6%. No anastomosis stricture occurred in the modified double-barrel method. By carinal reconstruction covering of the anastomotic site is mandatory to prevent fatal postoperative complications.

Biodegradation and tumorigenicity of implanted plates made from a copolymer of epsilon-caprolactone and L-lactide in rat.

Flat plates made from a copolymer of epsilon-caprolactone and L-lactide (P-CL-LA) [50:50 (w/w), molecular weight 1.62 x 10(5); 20 x 10 x 1 mm size] were subcutaneously implanted into 50 young, male Wistar rats (P-CL-LA group). After 24 months the plates had become a mass of small pieces, which were concentrated in an area of 3 x 2 x 1 mm. For comparison, 50 rats were implanted with medical-grade polyethylene plates (PE group) while another set of 50 rats was subjected to the same operation but without an implant (Sham Op group). Tumors arose in 25 rats from the P-CL-LA group: 24 were malignant mesenchymal tumors at the implant sites. In the PE group, tumors appeared in 16 rats (14 at the implant sites and two ectopically). The average tumor latency was 578+/-84 days in the P-CL-LA group and 452+/-102 days in the PE group. There was no difference in tumor incidence between the P-CL-LA and PE groups (p < 0.05). In the Sham Op group, two malignant tumors appeared over 2 years. Pathologically, these induced tumors arose from the inflammatory cells surrounding the degrading fragments of P-CL-LA within the tissue capsule. This indicates that relatively slowly degrading material can induce malignant tumors at a similarly high rate to nonabsorbable medical grade PE, at least in this animal model.