Suppression of a squamous cell carcinoma (SCC)-related serpin, SCC antigen, inhibits tumor growth with increased intratumor infiltration of natural killer cells.

Squamous cell carcinoma (SCC) antigen (SCCA), a member of the ovalbumin serine proteinase inhibitor family, serves as a circulating marker of squamous cell carcinoma (SC). One of the SCCAs, SCCA1, has been suggested to play a role in the attenuation of apoptosis in vitro and in the augmentation of tumor growth in vivo. In the present study, the infection of a SCC cell line (SKG IIIa) with recombinant retrovirus that expressed the antisense SCCA mRNA suppressed expression of SCCA in vitro. Local administration of this retrovirus into tumors by inoculation in nude mice suppressed tumor growth. Treatment of tumor tissue in vivo is also associated with increased numbers of apoptotic tumor cells and large mononuclear cells in the tumor. To test the possible role of SCCA in the infiltration of large mononuclear cells, we analyzed the effect of SCCA1 on migration of natural killer (NK) cells induced by monocyte-chemoattractant protein-1 in vitro. SCCA1 suppressed migration of NK cells completely, and this inhibitory effect was lost by mutation of the reactive site loop of SCCA1. These results suggest that antisense SCCA may suppress the growth of SCC in vivo not only by the augmentation of intracellular apoptosis but also by the increased infiltration of NK cells into the tumor.

Novel forms of squamous cell carcinoma antigen transcripts produced by alternative splicing.

Squamous cell carcinoma antigen (SCCA) is a member of the ovalbumin serine protease inhibitor family, and the serum level of SCCA is a tumor marker of squamous cell carcinoma. Reverse transcription (RT)-PCR of the squamous cell carcinoma cell line showed the existence of a 156 base shorter transcript compared with that of SCCA1 cDNA. By inverse PCR, we cloned the full length cDNA of this SCCA (SCCA1b). Sequence analysis of the complete 1541 bp SCCA1b cDNA showed that it coded for 338 amino acids and had no typical signal sequence in the NH(2) terminus. The cDNA was expressed in Escherichia coli and the product was detected using Western blotting with antibodies against SCCA. Furthermore, RT-PCR of the full coding region of SCCA2 cDNA from cancer tissue showed the existence of a 63 base short transcript (SCCA2b). A comparison of SCCA1b and SCCA2b cDNA with the SCCA1 and SCCA2 genes showed that these messages were derived from each gene by an alternative splicing mechanism.

Isolated lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma.

OBJECTIVE: Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated. METHODS: TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. PHARMACOKINETICS STUDY: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats received an intravenous injection of 5 x 10(6) methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted. TOXICITY: Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg. PHARMACOKINETICS: Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002). EFFICACY: Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 +/- 10) than in the groups receiving intravenous melphalan (60 +/- 21) or buffered hetastarch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, respectively). CONCLUSION: Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.

Prostacyclin analog OP2507 prevents pulmonary arterial and airway constriction during lung preservation and reperfusion.

BACKGROUND: The effects of OP2507 on lung preservation with cold Euro-Collins solution and during the reperfusion period were evaluated. METHODS: For this study, canine lungs were flushed with a 10 micrograms/ml OP2507 solution (n = 7) or saline solution (control group, n = 7) (0.1 ml/kg body weight) and stored in the same solution. Pulmonary arterial pressure, pulmonary vascular resistance, airway pressure, respiratory capacity, and wet to dry weight ratio of the lungs were measured before and after 24 hours of cold preservation and after a 60-minute reperfusion period. RESULTS: Treatment with OP2507 significantly attenuated increases in pulmonary arterial pressure, pulmonary vascular resistance, and airway pressure after preservation and during the reperfusion period. Oxygen tension in outflow blood also was maintained with OP2507 treatment throughout the experimental period, whereas it was depressed during the reperfusion period in the control group. By electron microscopy, there was little evidence of vascular endothelial damage, such as cell swelling, detachment of endothelial cells from the lamina, and attenuation of the cytoplasm, in both groups. However, the tight junctions between cells were observed more clearly in the control group than in the OP2507 group, suggesting more cell membrane damage in the control group. CONCLUSIONS: Pretreatment with OP2507 prevented pulmonary artery and airway constriction after 12 hours of cold lung preservation and a decrease of oxygen tension in outflow blood during a 60-minute reperfusion period.

Isolated lung perfusion with FUDR in the rat: pharmacokinetics and survival.

BACKGROUND: Although surgical resection remains the mainstay of treatment for metastatic pulmonary colorectal cancer, 5-year survival approaches only 30% to 40%. We have developed a model of isolated left lung perfusion (ILP) with FUDR (2'-deoxy-5-fluorouridine) for the treatment of pulmonary colorectal metastases. FUDR ILP toxicity and pharmacokinetics were evaluated and compared with continuous intravenous infusion in the rat. METHODS: Toxicity was first evaluated in F344 rats (n = 17) after left ILP (20-minute perfusion at 0.5 mL/min) with 21 mg/mL (n = 11), 28 mg/mL (n = 2), 35 mg/mL (n = 2), and 70 mg/mL (n = 2) of FUDR. Animals were followed up and weights recorded for 14 days postoperatively before a right pneumonectomy was performed to evaluate the effect of FUDR perfusion on left lung function. In the second study, 32 rats (n = 8/group) underwent: systemic FUDR (intravenous), or ILP with 7, 14, and 21 mg/mL respectively (ILP 7, ILP 14, and ILP 21 groups). Left lungs and serum were analyzed for FUDR and 5-fluorouracil by high-performance liquid chromatography. RESULTS: Rats perfused with doses of FUDR greater than 21 mg/mL died perioperatively. All animals perfused at 21 mg/mL survived until day 14, and 8/11 survived a right pneumonectomy. Rats that survived ILP resumed normal weight gain and grooming habits within 1 week. Pharmacokinetic evaluation demonstrated that ILP at 21 mg/mL maximally elevated total lung FUDR and 5-fluorouracil levels (508.5 +/- 96.4 micrograms/g lung) in comparison with the ILP 14, ILP 7, and intravenous groups (299.1 +/- 44.8, 116.0 +/- 21.1, and 7.5 +/- 4.1 micrograms/g lung, respectively) (p < 0.05). Serum FUDR levels were 10.5 +/- 6.8, 1.3 +/- 0.5, 2.31 +/- 1.1, and 1.2 +/- 0.4 microgram/g lung (p = not significant) for intravenous, ILP 7, ILP 14, and ILP 21 groups, respectively. CONCLUSIONS: Isolated left lung perfusion with FUDR is well tolerated to a maximum dose of 21 mg/mL and results in significantly higher FUDR and 5-fluorouracil lung levels with low serum levels compared with intravenous treatment. These higher pulmonary levels may offer advantages in the treatment of pulmonary colorectal metastases.

Sequential bilateral isolated lung perfusion in the rat: an experimental model.

BACKGROUND: A model of isolated single-lung perfusion in the rat has been established in our laboratory to study the chemotherapeutic treatment of pulmonary metastases. A sequential bilateral isolated lung perfusion model was designed to investigate the feasibility of staged perfusions in the rat. METHODS: Twenty-four Fischer rats were randomized into three experimental groups of 8 rats each. All rats underwent left isolated lung perfusion. One, 2, or 3 weeks later, the rats in groups I, II, and III, respectively, underwent contralateral (right) perfusion. Five control animals (group IV) underwent sequential bilateral sham thoracotomies 1 week apart. Arterial blood gas analysis was performed 1 week after the second operation in the rats in groups I and IV. RESULTS: All animals survived the first operation, with 100% (8/8), 75% (6/8), and 100% (8/8) of the animals in perfusion groups I, II, and III, respectively, surviving the second operation. All control animals (group IV) survived the second sham thoracotomy. Arterial blood gas analysis did not show a significant difference in the oxygen or carbon dioxide partial pressure or the pH between group I and IV (p = 0.32, 0.96, and 0.76, respectively). CONCLUSIONS: Our experiments demonstrate that sequential bilateral isolated lung perfusion is safe in and well tolerated by the rat. This model can be used to investigate the safety and efficacy of staged perfusions with chemotherapeutic agents in the treatment of bilateral pulmonary metastases in the rat.

Isolated lung perfusion with doxorubicin prolongs survival in a rodent model of pulmonary metastases.

BACKGROUND: We developed a rodent model of unilateral pulmonary metastases to evaluate long-term survival after isolated lung perfusion with doxorubicin. METHODS: In the model development study, on day 0, two groups of F344 rats (n = 15) underwent transient right pulmonary artery occlusion for either 5 or 10 minutes at the time of intravenous injection of methylcholantrene-induced sarcoma cells. On day 14, all animals were sacrificed and lung nodules counted. In the survival study, on day 0, 21 rats received intravenous injection of sarcoma cells with concomitant 10-minute right pulmonary artery occlusion. On day 7, eight rats underwent left isolated lung perfusion with doxorubicin (6.4 mg/kg); five rats underwent perfusion with buffered Hespan; six untreated rats were studied as controls. RESULTS: Ten of fifteen animals (67%) in the model study with 5-minute pulmonary artery occlusion had right-sided tumor nodules. Ten-minute occlusion resulted in a tumor-free right lung in all animals. In the survival study, all animals in the Hespan and control groups died of massive tumor replacement of the left lung, with median survival times of 20 and 18 days, respectively. The median survival time of 36 days for the animals undergoing isolated lung perfusion with doxorubicin was significantly longer (p < 0.00001). The left lung of two of the doxorubicin perfused rats was tumor-free at 6 weeks. CONCLUSIONS: Isolated lung perfusion with doxorubicin results in a durable response and prolongs survival in the treatment of experimental sarcoma pulmonary metastases.

Isolated lung perfusion with cisplatin in a rat lung solitary tumor nodule model.

BACKGROUND: The present study was conducted to evaluate the toxicity, pharmacokinetics and anti-tumor potency of isolated lung perfusion (ILP) with cisplatin in a visible lung tumor nodule model in rats. MATERIALS AND METHODS: A solitary tumor nodule was established by the injection of Methylcholanthrene-induced sarcoma cells into the left lung. Thirty rats were randomized to undergo ILP with either 0.1, 0.25, or 0.5 mg/mL cisplatin and buffered hespan (BHE), or with an intravenous injection of 1.0 or 2.5 mg cisplatin. RESULTS: The highest dose of cisplatin tolerated by the rats was 0.1 mg/mL for perfusion. A much higher platinum concentration in the tumor, of 6.67 +/- 1.64 vs. 2.51 +/- 0.60 micrograms/g tissue, but a significantly lower concentration in the serum and kidneys, was achieved by perfusion compared to that achieved by intravenous injection. A significantly lower tumor weight and 20% complete treatment response was achieved in rats given cisplatin than in those given BHE perfusion at 43.9 +/- 11.6 vs. 226.3 +/- 44.6 mg. CONCLUSION: ILP with cisplatin achieved superior results to intravenous injection according to the levels of toxicity and pharmacokinetic analysis, and it was effective against a visible tumor nodule model in rats.

The long-term evaluation of pulmonary toxicity following isolated lung perfusion with melphalan in the rat.

The present study was conducted to evaluate the long-term pulmonary toxicity of isolated lung perfusion (ILP) with melphalan in the rat model. F344 rats were treated by ILP with 1 mg of melphalan or buffered hespan (BHE). The rats in the melphalan group were sacrificed randomly 30, 60, 90, 120, 150, and 180 days after the perfusion. Pulmonary toxicity was evaluated by pathological analysis. In the melphalan group, light and electron microscopic findings revealed perivascular and peribronchial edema, and septal thickening with cellular infiltration of the interstitial space 30 days after the perfusion, but all of these changes had disappeared by 60 days. Azan stain showed a slight increase of the connective tissue at the alveolar wall in the melphalan group, but no progressive pulmonary interstitial fibrosis was observed after 180 days. Transmission electron microscopy showed minimal proliferation of the type II pneumocytes of normal appearance in the melphalan group. In conclusion, the long-term pulmonary toxicity of ILP with melphalan is acceptable; however clinical trials of this therapy need to be conducted.

Dissecting aortic aneurysm involving an anomalous right subclavian artery and isolated left vertebral artery: case report and review of the literature.

A 54-year-old hypertensive woman was admitted with severe interscapular back pain. A chest radiograph showed marked widening of the mediastinum. Aortography demonstrated a DeBakey type III, a thoracic aortic dissection and an anomalous right subclavian artery which was associated with an isolated left vertebral artery. The patient underwent aortic arch replacement with 5 branches and made an uneventful recovery. As far as we can determine, this is the first reported occurrence of these anomalies together with acquired disease of the aorta.

[Thymic undifferentiated carcinoma with resection of superior vena cava: report of a case].

A case of a 75-year-old woman with thymic undifferentiated carcinoma was reported. Thymic carcinoma infiltrated the right pleura, epicardium, and superior vena cava. Total thymectomy with resection of the right pleura, epicardium, and superior vena cava was performed. The superior vena cava was reconstructed with a ringed Goretex. The patient received the chemotherapy such as CDDP, VDS and MMC, and also received radiation therapy (total 5,000 rad). The postoperative clinical course was uneventful. The definition and therapy of thymic carcinoma is unclear. We think that complete resection of carcinoma is necessary even if cancer infiltrates the superior vena cava.

[Experience of absorbable staple in lobectomy].

We examined the differences between absorbable staple and un-absorbable staple in inflammatory reaction during the early post-operative period in lung cancer patients. From october 1993 to august 1994, absorbable staples (GIA 75-.060; United States Surgical Co., Ltd.) or un-absorbable staples (Multifire GIS 60 Titanium (3.8mm); United States Surgical Co., Ltd.) were applied in 10 lung cancer patients each. Duration of air leakage, massive pleural effuion (more than 100 ml/day), and high fever (over 38 degrees C), as well as the changes of leukocyte counts in peripheral venous blood and C reactive protein were compared between the two groups. The absorbable staple group show a mildly increased inflammatory reactions than those of un-absorbable staple group, but those were not significant differences. Absorbable staple was shown to be completely absorbed until 6 months in animal model. Absorbable staple is thought to be superior to un-absorbable staple, instead of mildly increased inflammatory reaction during the early post-operative period.

[Subjective criteria of chest CT findings for predicting pathological features and postoperative outcomes of small peripheral lung cancer (< or = 2 cm)].

One hundred fifty five patients with completely resected peripheral non-small cell lung cancer, clinically diagnosed 2 cm or less in diameter, are retrospectively reviewed on their preoperative chest CT films, clinico-pathological features, and postoperative outcomes. Pathologic type was classified according to Noguchi's classification. 7% and 8% of all the patients had pathologic N 1 and N 2 diseases, respectively. 19% of all the patients undergone limited resection (segmentectomy or partial resection). Maximum area of the tumor/soft tissue density area of the tumor (M/S ratio) was manually measured by chest CT film. According to the logistic regression analysis, M/S ratio was the only predicting factor of regional lymph node metastasis among factors including pleural indentation, spiculation, and maximum area of the tumor. Univariate analysis showed that maximum area of the tumor, pleural indentation, and M/S ratio were the significant factor for postoperative disease free survival. According to multivariate analysis of postoperative disease free survival with adjustment for operative modality, the result was same as that of univariate analysis. In conclusion, our determined criteria of the chest CT accurately predicted pathological status and postoperative outcome of patients with small peripheral lung cancer. These factors would be useful for stratification factor of prospective clinical study.

[Clinical analysis of 130 cases of Siberian silicosis].

One hundred thirty patients with Siberian silicosis occurring under exposure to large amounts of dust at labor in a siberian mine were analyzed for 67 clinical and 122 laboratory data. Eighty-eight of 130 patients are now alive, but 42 have already died. When they started work, 122 of the patients were under thirty years of age. The duration of work was 7 to 12 months for 17 patients, 13 to 18 for 43, and 19 to 24 for 40. Seventy-six of 99 patients were initially diagnosed with lung tuberculosis and 23 with silicosis. Almost all patients have complained of respiratory symptoms such as shortness of breath, cough, sputum, and cyanosis. All of the pulmonary function tests including %VC, FEV1.0/FVC, V25/height, RV, TLC, and DLco showed abnormal values. The chest roentogenograms showed 3 of type 1, 22 of type 2, 55 of type 3, and 124 of type 4. Of 124 type-4, large opacities, 84 were type A, 28 B, and 12 C. Of 416 small opacities, 144 were type P, 191 Q, and 81 R. The complications and secondary changes that appeared with progression of the disease were lung emphysema, hilar and mediastinal lymphnode enlargement, egg shell calcification in lymphnode, and bulla or bleb.

Application of interferometry to the measurement of the pitch of threads on a lead screw.

A rapid, interferometric method for measuring the pitch of a nonrotating lead screw that involves no mechanical contact with the thread is described. The moving plane mirror of a Michelson interferometer is set on the axis of the lead screw. The lead screw is mounted on the carriage of a machine which moves it parallel to its axis. The Michelson fringes are counted continuously as the screw threads are moved across a light beam. The Michelson interferometer uses the green line of a (198)Hg isotope electrodeless lamp. The passage of a pitch point, to punctuate the fringe count, is sensed by photoelectric microscopes, and associated electronic circuitry, as described herein. The performance of the apparatus is presented.

Biological role of SCC antigen.

SCC antigen is a tumor-associated protein of squamous cell carcinoma of various organs. So far, two genes (SCC Ag-1 and SCC Ag-2) have been identified, and their products are highly homologous and classified as serine protease inhibitors (serpin). Recombinant SCC antigen-1 inhibits chymotrypsin and cathepsin L in vitro, indicating that it is inhibitory type serpin. Transduction of tumor cells with SCC antigen-1 reveals that SCC antigen-1 inhibits apoptosis of tumor cells induced by anticancer drug, TNFalpha or NK cells. Therefore SCC antigen-1 may work in cancer cells for tumor growth, and in normal squamous epithelium for differentiation by means of the inhibition of apoptosis. Recombinant SCC antigen-2 inhibits cathepsin G and mast cell chymase, suggesting that it protects epithelial cells from the inflammation induced by these proteases.

[Recurrent thymic carcinoid tumor--report of a case].

A previously operated 62-year-old male with recurrent thymic carcinoid tumor was reported. This patient underwent resection of the thymic carcinoid tumor through left thoracotomy 7 years ago. Although the postoperative clinical course was uneventful, an anterior mediastinal tumor on the patient's chest was discovered after an X-ray examination due to a traffic accident in July, 1989. With the diagnosis of recurrent thymic carcinoid tumor, he underwent an excision of the anterior mediastinal tumor and residual thymus. He also underwent partial resection of the pericardium, mediastinal pleura, and left upper lobe of the lung. 42 cases with thymic carcinoid tumor that have been reported in the Japanese literature were reviewed. A perusal in the relevant literature suggested that total thymectomy was advisable because partial thymectomy was associated with a high risk of local recurrence and metastases.

[Congenital esophago-bronchial fistula in adult--report of a case].

A 52-year-old man had been having cough on drinking water since 30 years. He coughed out blood 20 years ago. Chest roentgenogram showed the infiltrating shadow in the right lower lung field and the left hilum. Chest computed tomogram in the left atrium level showed fistulous communication between the bronchus and the esophagus and cavity lesion. Esophagogram showed fistulous communication between the bronchus (rt. B7) and the middle third of the esophagus. Bronchogram showed the stenotic lesion of the right B7a and B*. And abnormal bronchus was revealed and fistula was suspected. The orifice of the fistula was seen by esophageal endoscopy. Through the right posterolateral thoracotomy, fistelectomy and covering with pleural flap over the esophageal suturing site were performed. Histologic finding of the resected specimen revealed fistula's wall composing of smooth muscle lined with squamous cell layer. This case is categorized as Braimbridge type II. The postoperative course was uneventful and the patient is now in free of complaints at the 6th month's P.O.D.

[Modified Naclerio-Langer method under thoracoscopic procedure for pneumothorax due to rupture of a large bulla].

We managed a patient with pneumothorax caused by a large bulla by so called modified Naclerio-Langer method under thoracoscopic procedure. A 76-year-old female was hospitalized with recurrent left pneumothorax. Uncer the right lateral position, 3 Surgi ports were inserted through 5, 7, 9th intercostal space. There was a large bulla, 10 cm in diameter, with rupture at the ventral side. The bulla wall was partially resected and many bronchiolar openings were seen at the caudal side. Gregarious bronchiolar openings were resected with Endo GIA. Two residual openings were closed with 3-0 Dexon suture. The base of bulla was pleuralised by suturing the edges of the removed cyst with running suture of 3-0 Dexon. Because no air leaks was detected, a chest drain was inserted. Operation time was 215 minutes and she was discharged on 20th postoperative day. This procedure is usefull and not invasive.