Expression of desmoglein-I cell-adhesion molecule in primary tumors and metastatic lymph-nodes of esophageal cancer.

The expression of desmoglein I (DGI) in both primary turners and metastatic lymph node of esophageal carcinoma was studied immunohistochemically in 102 patients using an anti-DGI monoclonal antibody. Normal squamous epithelial cells strongly expressed DGI at their cell-cell boundaries. DGI expression in the tumors was divided into DGI (++), DGI (+), DGI (-) according to the staining intensity. DGI (+) or DG (-) tumors had lymph node metastases more frequently than DGI (++) tumors (p<0.01). DGI expression was the same or of less intensity, than in the primary tumor in 128 (85%) out of 151 metastatic lymph nodes. These results indicate that reduction or loss of DGI expression may promote lymph node metastases.

Enhanced efficacy of bleomycin adsorbed on silica particles against lymph node metastasis in patients with esophageal cancer: a pilot study.

BACKGROUND: Lymph node metastases occur very frequently and extensively in patients with esophageal cancer. The aim of this pilot study was to try the targeting chemotherapy for lymph node metastases by use of bleomycin adsorbed on silica particles (BLM-SI). METHODS: BLM-SI or bleomycin solution (BLM-SOL) was injected into the submucosa of the esophageal wall by means of endoscopy 3 days before operation in 16 patients with middle thoracic esophageal cancer. The distribution of bleomycin in the regional lymph nodes and surrounding connective tissues was studied. RESULTS: When BLM-SI was administered, bleomycin activity was found in both the regional lymph nodes and connective tissues, not only in the mediastinal region but also in the cervical and abdominal region. Bleomycin activity was significantly higher in all regions after BLM-SI administration than after BLM-SOL administration. Degenerative or necrotic changes were microscopically observed in 11 of 36 lymph nodes with metastatic foci. Bleomycin activity in the blood was significantly lower after BLM-SI was administered than after BLM-SOL. Serious systemic side effects except for fever were not observed in any patients. CONCLUSIONS: These results indicate that BLM-SI could be a useful treatment modality for targeting lymph node metastasis of esophageal cancer without serious side effects.

Enhancement of therapeutic efficacy of bleomycin by incorporation into biodegradable poly-d,l-lactic acid.

A new system for the delivery bleomycin (BLM) to target lesions was established by incorporating BLM into a small cylinder of a biodegradable polylactic acid (PLA) of low molecular weight. Cross-sectional analysis of the system (BLM-PLA) showed that BLM particles were uniformly enclosed in the PLA matrix. In vitro studies demonstrated that BLM was released continuously for more than 3 weeks from BLM-PLA immersed in saline. BLM-PLA was implanted subcutaneously into the backs of rats. A high concentration of BLM was maintained in the connective tissues near the implants for 2 weeks. In contrast, the level of BLM activity was low when a BLM solution (BLM-SOL) was administered subcutaneously by injection. The concentration of BLM in the abdominal lymph nodes was significantly higher following BLM-PLA implantation than following subcutaneous BLM-SOL injection. The inhibitory effects of BLM-PLA and BLM-SOL on tumor growth were compared with no treatment using a subcutaneously transplanted Yoshida sarcoma. The antitumor effect of BLM-PLA was significantly higher than that of BLM-SOL and no treatment. BLM-PLA also resulted in a more favorable distribution of BLM than BLM-SOL. Thus, BLM-PLA proved to be effective in controlling this experimentally transplanted tumor.

Comparison of transthoracic Doppler echocardiography and natriuretic peptides in predicting mean pulmonary capillary wedge pressure in patients with chronic atrial fibrillation.

The purpose of this study was to assess whether transthoracic Doppler echocardiography and serum natriuretic peptide levels could predict mean pulmonary capillary wedge pressure (PCWP) in patients with chronic atrial fibrillation. We examined mitral flow velocity and pulmonary venous flow (PVF) velocity patterns in 32 patients with chronic atrial fibrillation. Plasma A-type and B-type natriuretic peptide (ANP, BNP, respectively) levels in the peripheral vein were measured. Significant correlations were observed between mean PCWP and the following: peak velocity (r = 0.51) and deceleration time (r = -0.65) of the mitral flow; peak velocity (r = 0.64) and deceleration time (r = -0.80) of the PVF; BNP (r = 0.60); and ANP (r = 0.36). Stepwise multiple linear regression analysis selected PVF deceleration time and mitral flow deceleration time as independent predictors of PCWP. A cutoff value of PVF deceleration time of < or =150 ms and a mitral flow deceleration time of < or =100 ms predicted a mean PCWP of > or =18 mm Hg, with a sensitivity of 100% and 80% and a specificity of 96% and 85%, respectively. In conclusion, PVF deceleration time and mitral flow deceleration time obtained from transthoracic Doppler echocardiography are more accurate predictors of mean PCWP than values obtained with natriuretic peptides in patients with chronic atrial fibrillation.

Loco-regional treatment for esophageal cancer with bleomycin adsorbed to activated carbon particles.

Bleomycin (BLM) was adsorbed to activated carbon particles (BLM-CH), and the effective distribution of BLM in the regional lymph nodes and surrounding connective tissues was studied in 10 patients with mid-thoracic esophageal cancer. One ml of BLM-CH was injected submucosally into the tumor and normal esophageal wall endoscopically one or three days prior to operation. BLM activity was found both in the lymph nodes and connective tissues, not only in the mediastinal region but in the cervical and abdominal regions. Degenerative or inflammatory changes were microscopically observed in 6 out of 23 lymph nodes with metastatic foci. BLM-CH could be a useful tool in targeting chemotherapy for esophageal cancer.

Controlled release of cisplatin incorporated into biodegradable poly-d, l-lactic acid.

Using a melt-pressing technique, we produced a small solid cylinder containing cisplatin (CDDP) embedded in poly-d, l-lactic acid (CDDP-PLA). The in vitro release of CDDP from the polymer was examined in an immersion system. CDDP was released continuously for more than four weeks with no initial burst. Drug distribution for CDDP-PLA was compared with CDDP solution (CDDP-SOL) by subcutaneous administration into the back of rats. In the CDDP-PLA group, a high concentration of CDDP was maintained in the subcutaneous tissues near the implants for 20 days. However, in the CDDP-SOL group, the concentration of CDDP was low by 10 days after drug administration. CDDP-PLA may become a useful tool in locoregional chemotherapy as a solid type of drug delivery system with longlasting release.

Morphology of the designed biodegradable cisplatin microsphere.

We observed the morphological changes in microspheres containing cisplatin (CDDP) embedded in poly-d,l,-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS). The in vitro release of CDDP from CDDP-PPMS continued for more than four weeks. Scanning electron microscopy revealed that though the particles of CDDP-PPMS were spherical and superficially smooth, small pores with a superficial irregularity appeared six months later. CDDP-PPMS particles were found in the stomata of the omentum after intraperitoneal administration. When CDDP-PPMS was administered after Yoshida sarcoma cells were intraperitoneally transplanted, CDDP-PPMS was observed histologically in the necrotic tissues of the omentum. These experimental results confirmed the release of CDDP from CDDP-PPMS and the histological efficacy of CDDP-PPMS in the omentum against peritoneal metastasis.

[Drug distribution and antitumor effect of bleomycin incorporated in poly DL-lactic acid in rats].

Two bleomycin (BLM)-containing agents (BLM-PLA, BLM-SOL) were prepared, and the drug distribution and antitumor effect were studied. BLM-PLA is an agent in which BLM is incorporated into biodegradable low-molecular-weight polylactic acid, and BLM-SOL is an aqueous solution of BLM. BLM-PLA or BLM-SOL was subcutaneously administered in the back of rats. When BLM-PLA was implanted, high BLM activity of the connective tissues near the implants was maintained for 2 weeks. On the other hand, BLM activity was very low when BLM-SOL was administered. The effects of BLM-PLA, BLM-SOL and nontreatment on tumor growth and survival time were compared using subcutaneous tumor of Yoshida sarcoma in 21 rats each. The survivors and mean survival time in BLM-PLA group, BLM-SOL group and nontreatment group was 14 and 44.6 days, 5 and 23.7 days, and 0 and 11.3 days, respectively. BLM-PLA was superior to BLM-SOL in both drug distribution and antitumor effect, and consequently BLM-PLA could be a useful tool in loco-regional chemotherapy.

[Experimental study on cisplatin microspheres incorporated in polylactic acid and polyethylene glycol acid].

Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by the solvent evaporation method in an oil-in-oil emulsion system. When CDDP-MS was preserved in phosphate-buffer saline, the dissolution rate of cisplatin from CDDP-MS was 14% after one day, 25% after 5 days, 33% after 7 days, 66% after 21 days and 85% after 30 days. CDDP-MS and CDDP aqueous solution (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of cisplatin in 42 rats each. On days 0.5, 1, 5, 7, 14 and 21, omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of the CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Consequently, it was suggested that CDDP-MS is useful as a carrier in a drug delivery system, since it improves the burst effect and releases CDDP for a long time without serious side effects.

[Experimental study of cisplatin microspheres incorporated in polylactic acid and polyethylene glycol acid on peritoneal carcinomatosis in rats].

Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by solvent evaporation method in oil-in-oil emulsion system. CDDP-MS and CDDP aqueous solutions (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of CDDP in 72 rats each. On 0.5, 1, 7, 14, 21 and 30 days, the omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of the CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Additionally, acute toxicity of anticancer drug in CDDP-MS group was reduced, compared with CDDP-SOL. The effects of CDDP-MS, CDDP-SOL, empty-MS and non-therapy group on survival time were compared using intraperitoneally administered Yoshida sarcoma. The survival time in CDDP-MS, CDDP-SOL, non-therapy and empty-MS group were 43 +/- 24, 11.7 +/- 4.7, 9.8 +/- 1.1, and 7.8 +/- 1.1 days each. Consequently, it was suggested that CDDP-MS is useful as a tool in loco-regional chemotherapy using drug delivery system.

[A basic study on usefulness of bleomycin incorporated in poly DL-lactic acid].

Poly DL-lactic acid (PLA) is one of the biodegradable polymers. Bleomycin (BLM) incorporated into small cylinders of PLA blends was prepared as a new dosage (BLM-PLA). When BLM-PLA was preserved in saline, the dissolution rate of BLM from BLM-PLA was 49.2% after 7 days, 85.2% after 14 days and 99.7% after 21 days, respectively. BLM-PLA was implanted subcutaneously into the back of 36 rats. On days 3, 7, 14, 21, 28 and 35, the connective tissues near the implants, lymph node, lung, liver and kidney were removed and BLM activity was measured. The BLM concentration was maintained at a high level in the connective tissues until 14 days, and in the lymph node between 21 and 28 days. On the other hand, the BLM level was low in the lung, liver and kidney. Consequently, it was suggested that PLA is useful as a carrier for drug delivery system and that administration of BLM-PLA is an effective anti-cancer modality, especially in local chemotherapy.

In vivo activity of bleomycin incorporated with biodegradable poly-d,l-lactic acid and implanted in the mediastinum of dogs.

The possible usefulness of bleomycin incorporated with biodegradable poly-d, l-lactic acid (BLM-PLA) for targeting chemotherapy for esophageal cancer was studied in vivo. Local levels of BLM after administration were compared with those after injection of BLM-SOL, an aqueous solution of BLM. BLM-PLA or BLM-SOL was administered into the upper mediastinum under a right thoracotomy in 36 mongrel dogs. On days 10, 20, and 30 after administration, connective tissues, lymph nodes, lung, liver, kidney, and spleen were removed, and BLM activity was measured. High activity of BLM was detected for 30 days after BLM-PLA administration in both the connective tissues and the lymph nodes, compared with BLM-SOL administration. BLM activity was low in the other organs after BLM-PLA administration. BLM in the blood was significantly lower after administration of BLM-PLA than BLM-SOL. The results indicate that BLM-PLA may become a useful tool in targeting chemotherapy for esophageal cancer.

Controlled release of poly-D,L-lactic acid containing bleomycin.

By use of four types of in vivo degradable polylactic acid (PLA), i.e. PLA with an average molecular weight of 1500 (1500DL), 2200 (2200DL), 2800 (2800DL) and 3500 (3500DL), preparations of bleomycin (BLM)-containing solid forms (polymers) were tested. The in vitro release of BLM from the polymers was also examined in an immersion system. By the melt-pressing technique, five types of BLM (2.5 mg) containing solid forms, i.e. 1500DL polymer, 2200DL polymer, 2800DL polymer, 3500DL polymer and 1500DL + 3500DL (a mixture of 1500DL and 3500DL) polymer were prepared. In all five types of polymers, cumulative BLM release was controlled to less than 5% by the third day and no initial burst of the release was observed. BLM release from the polymer continued for 3 weeks at the shortest and 6 weeks at the longest. Various polymers containing BLM could be useful for the site of drug administration or anti-cancer release pattern.

Expression of desmoglein I in squamous cell carcinoma of the esophagus.

Desmoglein I (DGI) is major component of the desmosomal membrane core that plays an important role in epithelial cell adhesion. The aim of this study was to explore the correlation between the expression of DGI and the clinicopathological findings of esophageal cancer. DGI expression was immunohistochemically examined using an anti-DGI monoclonal antibody in 139 patients with squamous cell carcinoma of the esophagus. Normal squamous epithelial cells strongly expressed DGI at their cell-cell boundaries. According to the intensity and pattern of DGI expression, the cancerous tissues were divided into three groups: DGI (++), DGI (+), and DGI (-). Of the 139 tumors, 35 (25%) were DGI (++), 65 (47%) were DGI (+), and 39 (28%) were DGI (-). A good inverse correlation between DGI expression and tumor invasion, lymph node metastasis, lymphatic invasion, and vessel invasion was observed. These results indicate that DGI expression may be a significant factor for invasion, metastasis, and prognosis of human esophageal cancer.

[Correlation between respiratory or circulatory state and postoperative extravascular lung water volume in patients undergoing surgery for esophageal carcinoma of the thorax].

Postoperative extravascular lung water index (EVLWI, ml/kg) was analyzed in 30 patients who underwent esophagectomy through right thoracotomy for esophageal carcinoma from the day of operation to 5th postoperative day, in order to clear the correlation between respiro-circulatory state and EVLWI. The results are as follows. 1. EVLWI on 1st postoperative day correlated significantly not only with blood loss during operation (p < 0.01, r = 0.65) but also with systemic vascular resistance index on 1st postoperative day (p < 0.05, r = -0.43). 2. EVLWI correlated with the respiratory index (RI) on the 2nd and 4th postoperative day (p < 0.01), suggesting that EVLWI is an important indicator in judging the respiratory state following esophagectomy. 3. EVLWI on 4th postoperative day correlated with accumulative fluid balance up to 4th postoperative day (p < 0.05, r = 0.41), however neither correlated with other hydrostatic parameters nor the COP-PCP gradient. Furthermore, EVLWI on 4th postoperative day correlated more significantly with oxygen consumption index (p < 0.05, r = 0.58) than that with accumulative fluid balance up to 4th postoperative day. According to those results, the increased systemic vascular permeability immediately after the surgery attributes to the increase of EVLWI on the 1st postoperative day. Whereas, the increased EVLWI on 4th postoperative day depends on not only the hydrostatical factors but also the increased pulmonary vascular permeability caused by the surgical maneuver to the lung during esophageal surgery.

Lymph node metastasis and the recurrence of esophageal carcinoma with emphasis on lymphadenectomy in the neck and superior mediastinum.

A series of 335 patients with squamous cell carcinoma of the thoracic esophagus undergoing resection and reconstruction via a right thoracotomy and laparotomy with cervical anastomosis between 1973 and 1990, were reviewed. Prior to 1982, the removal of lymph nodes was limited to the nodes in the mediastinum below the tracheal bifurcation and upper abdomen (142 patients). Nodal metastases were found in 89 of these patients at operation. The upper abdominal nodes were the most frequent sites of metastasis (47.2%). None of the 38 patients with positive nodes sampled from the neck and superior mediastinum survived for more than 45 months. In the 50 patients with recurrences, 30 were in the neck and/or superior mediastinum. During or after 1983, the superior mediastinal nodes, particularly the bilateral recurrent nerve nodal chains, were routinely removed (193 patients). Nodal metastasis was proven in 131 of the 193 patients, in whom 87 (45.1%) had metastasis in the neck and superior mediastinum. Eleven of these 87 patients survived for 45 months or more. In the 61 patients with recurrences, 20 were in the neck and/or superior mediastinum. These data suggest that recurrent nerve nodal chains should be removed to improve survival in patients with esophageal carcinoma.

Prophylactic action of allopurinol against chemotherapy-induced stomatitis--inhibition of superoxide dismutase and proteases.

The activities of superoxide dismutase (SOD) and several proteases were measured in kidney of mice treated with allopurinol in order to elucidate the mechanism of prophylactic action of allopurinol against chemotherapy-induced stomatitis. The following results were obtained. Following 3 day administration of allopurinol 20 mg/day per os (Group C), the concentrations of allopurinol and oxipurinol in the renal tissue were 203.9 +/- 52.1 and 1141.7 +/- 194.8 micrograms/g, respectively. The SOD activity was significantly lower in Group C than in the untreated control group (p < 0.01). The enzyme activities of papain and trypsin were suppressed in Group C. However, the other proteases tested were not affected by the administration of allopurinol, indicating only weak anti-protease action of allopurinol. These results suggest that allopurinol may be effective to prevent chemotherapy-associated stomatitis via both direct and indirect actions to oral mucosa, that include inhibitory actions on xanthine oxidase as well as protease.

Monophasic transmitral flow pattern with less increase in heart rate indicates left ventricular dysfunction.

When heart rate (HR) increases, mitral flow can become monophasic. Prolonged isovolumic contraction and relaxation time (ICT and IRT), directly related to left ventricular (LV) function, can potentially influence the HR with monophasic mitral flow. The present study investigated the relation between HR that causes monophasic flow and LV function. During diagnostic catheterization, HR was increased using right atrial pacing by 2 beats/min every 2 min in a stepwise manner until the development of monophasic mitral flow in 17 patients with normal sinus rhythm. ICT, IRT, end-diastolic and end-systolic LV volumes, LV ejection fraction, LV peak + and -dP/dt, peak (+dP/dt)/P, and the relaxation time constant (tau) were measured by Doppler echocardiography or catheterization when monophasic mitral flow developed. The monophasic HR varied from 74 to 106 beats/min. By univariate analysis, ICT (p<0.01, r2=0.73), LV peak +dP/dt (p<0.05, r2=0.37), peak (+dP/dt)/P (p<0.01, r2=0.71), peak -dP/dt (p<0.05, r2=0.25), and tau (p<0.05, r2=0.33) had a significant correlation with monophasic HR. By multivariate analysis, prolonged ICT and reduced LV peak -dP/dt independently contributed to monophasic mitral flow with less increase in HR. Monophasic mitral flow with less increase in HR indicates impaired LV systolic and diastolic function during isovolumic contraction and relaxation.