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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. [ABSTRACT FROM AUTHOR]

A 44-year-old man was attending routine follow-up 5 years after colon cancer resection, when ultrasonography detected a pancreatic tumor with a low echoic area. He had no symptoms. Computed tomography (CT) showed a protruding-type tumor, 4 cm in diameter, in the pancreatic head with central necrosis. Angiography revealed that the tumor was hypervascular. The serum somatostatin level was elevated, at 27 pg/ml (normal range, 1.0-12 pg/ml). As somatostatinoma of the pancreas was suspected, we performed pylorus-preserving pancreaticoduodenectomy. Histological and immunohistochemical staining confirmed somatostatinoma of the pancreas without nodal metastasis. Thus, if an endocrine tumor of the pancreas is suspected in a patient with a hypervascular tumor, the possibility of somatostatinoma should be included in the differential diagnosis.

Background: The estimation of coronary reperfusion in acute myocardial infarction (AMI) is important. The left ventricular (LV) Tei index is a noninvasive and sensitive parameter expressing overall LV function. We hypothesized that patients without good coronary reperfusion have worse LV function with a higher or worse Tei index compared to those with good reperfusion., Methods and Results: In 85 patients with first anteroseptal AMI, without other cardiac lesions such as prior myocardial infarction, LV hypertrophy or valvular disease, the Tei index was measured using Doppler echocardiography immediately after patients' arrival to the hospital, and the Thrombolysis in Myocardial Infarction (TIMI) grade was evaluated through subsequent coronary angiography. The Tei index was significantly greater in patients who did not have TIMI score of 3 compared to those with a TIMI of 3 (0.60+/-0.13 vs 0.46+/-0.06, p<0.0001). A Tei index >0.50 as the criteria for the absence of TIMI 3 had the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 75, 86, 94, 54 and 78%, respectively., Conclusion: An increased Tei index suggests the absence of adequate coronary reperfusion in patients with first anterior AMI without other lesion.

The newly developed echocardiographic technique called "tissue locus imaging" (TLI) can visualize temporal series of images in a single picture by maintaining the display of previous images with a shading function; therefore, it can display the whole systolic shift of the mitral leaflets toward the apex in a single picture and can potentially offer useful information on left ventricular (LV) function. In 36 consecutive patients with varying degrees of LV dysfunction (15 with coronary artery disease, 9 with cardiomyopathy, 3 with hypertension, 2 with aortic stenosis, 1 with aortic regurgitation, and 6 controls), the systolic shift of the mitral leaflets (X) by TLI showed a significant correlation with the LV ejection fraction (Y) by 2-dimensional echocardiography (Y = 7.2 x+13, r(2) = 0.83, p <0.01). TLI enables the evaluation and visualization of LV systolic function by displaying the whole systolic shift of the mitral leaflets toward the apex.

Background: Tei index, defined as the sum of isovolumic contraction and relaxation times divided by ejection time, has been proposed to express global left ventricular function. For patients with acute myocardial infarction (AMI), left ventricular function can potentially be a major determinant of hemodynamics with limited time for compensation, such as increased brain natriuretic peptide to attenuate congestion, and usually without any intervention to modify cardiac loading on arrival at the hospital during the acute phase. We, therefore, hypothesized that left ventricular function, expressed by the Tei index, allows noninvasive estimation of impaired hemodynamics for patients with AMI., Methods: We studied 86 consecutive patients with first AMI (34 inferoposterior and 52 anteroseptal). Tei index was obtained as: (a - b)/b, where a is the interval between the cessation and onset of mitral flow and b is the ejection time by aortic flow by pulsed Doppler echocardiography. By using pulmonary capillary wedge pressure (PCWP) > or = 18 mm Hg or <18 mm Hg and cardiac index (CI) < or = 2.2 L/min/m(2) or > 2.2 L/min/m(2) by consecutive catheterization, patients were classified into 4 subsets: subset I with normal hemodynamics; subset II with elevated PCWP; subset III with reduced CI; and subset IV with both elevated PCWP and reduced CI., Results: For patients with inferoposterior AMI, there was no significant correlation between the Tei index and PCWP or CI. For patients with anteroseptal AMI, however, the Tei index showed significant correlation both with PCWP (r = 0.59, P <.0001) and CI (r = -0.42, P <.01). Diagnosis of impaired hemodynamics (subset II-IV) by a Tei index > or = 0.60 showed a sensitivity, specificity, and accuracy of 86%, 82%, and 83%, respectively., Conclusions: Although the Tei index has limitations to evaluate hemodynamics in patients with inferoposterior AMI, the index allows approximate but quick and practical noninvasive estimation of impaired hemodynamics in patients with anteroseptal AMI.

Background: Differentiation of pseudonormal/restrictive from normal mitral flow is still clinically problematic. Pseudonormal/restrictive flow is usually associated with left ventricular dysfunction, which can be detected by Doppler Tei index, combining systolic and diastolic function. Therefore, the purpose of this study was to test the feasibility of the Tei index to differentiate pseudonormal/restrictive from normal mitral flow., Methods: In 26 patients with anteroseptal acute myocardial infarction and early diastolic mitral flow velocity (E) to late diastolic mitral flow velocity (A) ratio (E/A) > or = 1, left ventricular volumes; E and A; deceleration time of E; and the Tei index, defined as the sum of the isovolumic contraction and relaxation time divided by ejection time, were evaluated by Doppler echocardiography, and pulmonary capillary wedge pressure was measured by catheterization. Pseudonormal/restrictive mitral flow was defined as E/A > or = 1 associated with pulmonary capillary wedge pressure > 12 mm Hg., Results: There were 19 and 7 patients with pseudonormal/restrictive and normal mitral flow, respectively. Among the indices of left ventricular function, the Tei index achieved the best correlation with pulmonary capillary wedge pressure (r(2) = 0.66, P <.0001). By setting the Tei index > or = 0.55 as the criteria for pseudonormal/restrictive mitral flow, this diagnosis had the sensitivity, specificity, and accuracy of 84%, 100%, and 88%, respectively., Conclusion: The Tei index allows noninvasive differentiation of pseudonormal/restrictive from normal mitral flow.

The Doppler total ejection isovolume (Tei) index is useful for estimating global cardiac function. However, the relation between the right ventricular (RV) Tei index and RV infarction has not been investigated. The relation between the RV Tei index and severity of RV infarction was evaluated in 25 patients with inferior wall acute myocardial infarction (13 with and 12 without RV infarction). RV infarction was diagnosed when right atrial pressure was > or = 10 mm Hg or when right atrial pressure/pulmonary capillary wedge pressure was >0.8 by catheterization. The RV Tei index was significantly increased in patients with RV infarction compared with those without (0.53 +/- 0.15 vs 0.38 +/- 0.14, p <0.05). The RV Tei index in patients with severe RV infarction (right atrial pressure > or = 15 mm Hg) was significantly smaller compared with those with mild/moderate RV infarction (right atrial pressure <15 mm Hg) and showed no significant difference in patients with myocardial infarction but without RV infarction (0.44 +/- 0.09 vs 0.61 +/- 0.16 vs 0.38 +/- 0.14, severe RV infarction vs mild/moderate RV infarction vs no RV infarction, p <0.01). The RV Tei index is generally increased in patients with RV infarction; however, severe RV infarction can be manifested with limited or no increase in the Tei index (pseudonormalization).

Objective: The mechanism of higher incidence of ischemic mitral regurgitation in patients with inferior compared with anterior myocardial infarction despite less global left ventricular remodeling and dysfunction is controversial. We hypothesized that inferior myocardial infarction causes left ventricular remodeling, which displaces posterior papillary muscle away from its normal position, leading to ischemic mitral regurgitation., Methods: In 103 patients with prior myocardial infarction (61 anterior and 42 inferior) and 20 normal control subjects, we evaluated the grade of ischemic mitral regurgitation on the basis of the percentage of Doppler jet area, left ventricular end-diastolic and end-systolic volumes, midsystolic mitral annular area, and midsystolic leaflet-tethering distance between papillary muscle tips and the contralateral anterior mitral annulus, which were determined by means of quantitative echocardiography., Results: Global left ventricular dilatation and dysfunction were significantly less pronounced in patients with inferior myocardial infarction (left ventricular end-systolic volume: 52 +/- 18 vs 60 +/- 24 mL, inferior vs anterior infarction, P<.05; left ventricular ejection fraction: 51% +/- 9% vs 42% +/- 7%, P <.0001). However, the percentage of mitral regurgitation jet area and the incidence of significant regurgitation (percentage of jet area of 10% or greater) was greater in inferior infarction (percentage of jet area: 10.1% +/- 7.5% vs 4.4% +/- 7.0%, P =.0002; incidence: 16/42 (38%) vs 6/61 (10%), P <.0001). The mitral annulus (area = 8.2 +/- 1.2 cm2 in control subjects) was similarly dilated in both inferior and anterior myocardial infarction (9.7 +/- 1.7 vs. 9.5 +/- 2.3 cm2, no significant difference), and the anterior papillary muscle-tethering distance (33.8 +/- 2.6 mm in control subjects) was also similarly and mildly increased in both groups (35.2 +/- 2.4 vs 35.2 +/- 2.8 mm, no significant difference). However, the posterior papillary muscle-tethering distance (33.3 +/- 2.3 mm in control subjects) was significantly greater in inferior compared with anterior myocardial infarction (38.3 +/- 4.1 vs 34.7 +/- 2.9 mm, P =.0001). Multiple stepwise regression analysis identified the increase in posterior papillary muscle-tethering distance divided by body surface area as an independent contributing factor to the percentage of mitral regurgitation jet area (r2 = 0.70, P <.0001)., Conclusions: It is suggested that the higher incidence and greater severity of ischemic mitral regurgitation in patients with inferior compared with anterior myocardial infarction can be related to more severe geometric changes in the mitral valve apparatus with greater displacement of posterior papillary muscle caused by localized inferior basal left ventricular remodeling, which results in therapeutic implications for potential benefit of procedures, such as infarct plication and leaflet or chordal elongation, to reduce leaflet tethering.

Differentiation of normal from pseudonorma/restrictive mitral flow is not necessarily easy. Pseudonormal/restrictive flow is usually associated with left ventricular (LV) dysfunction, which can be detected using the TEI index, combining systolic and diastolic function. The purpose of this study was to test the feasibility of using the TEI index to differentiate pseudonormal/restrictive from normal mitral flow. In 33 patients with mitral flow E/A > or = 1 and LV mid-diastolic pressure measured by catheterization, the LV volumes, mitral E and A velocity, deceleration time of the E velocity, and the TEI index, defined as the sum of the isovolumic contraction and relaxation time divided by ejection time, were evaluated using Doppler echocardiography. Pseudonormal/restrictive mitral flow was defined as mitral flow E/A > or = 1 associated with LV mid-diastolic pressure > 12 mmHg. There were 22 and 11 patients with normal and pseudonorma/restrictive mitral flow, respectively. Among the indices of LV function, the TEI index achieved the best correlation with LV mid-diastolic pressures (r2 = 0.63, p < 0.0001). By setting the TEI index > or = 0.65 as the criteria for pseudonormal/restrictive mitral flow, this diagnosis had sensitivity, specificity, and accuracy of 82%, 96%, and 91%, respectively. TEI index allows noninvasive differentiation of pseudonormal /restrictive from normal mitral flow.

Background: Recently proposed Doppler Tei index, defined as the sum of isovolumic contraction time or mitral valve closure to aortic valve opening time and isovolumic relaxation time or aortic valve closure to mitral valve opening time divided by ejection time, is a simple measure which enables noninvasive estimation of combined systolic and diastolic function and prediction of patients' prognosis. However, effects of valve dysfunction on Tei index have not been investigated. This study was designed to compare Tei index before and after surgical valve replacement or repair to evaluate effects of valve dysfunction on Tei index., Methods: Participants consisted of 76 consecutive patients with aortic or mitral valve surgery (26 patients with aortic stenosis [AS], 16 with aortic regurgitation, 17 with mitral stenosis, and 17 with mitral regurgitation). Doppler Tei index was evaluated before and after the surgery by obtaining (a-b)/b, where a is the interval between the cessation and onset of Doppler mitral filling flow and b is the aortic flow ejection time., Results: Tei index significantly increased after surgery in patients with AS (0.38 +/- 0.07 to 0.49 +/- 0.06, P <.001), aortic regurgitation (0.60 +/- 0.20 to 0.70 +/- 0.18, P <.01), mitral stenosis (0.34 +/- 0.03 to 0.39 +/- 0.04, P <.01), and decreased with no significance in mitral regurgitation (0.50 +/- 0.03 to 0.46 +/- 0.03). Percent change in Tei index after valve surgery was maximal in patients with AS (27 +/- 6 vs 17 +/- 2 vs 16 +/- 6 vs -9% +/- 6%, AS vs aortic regurgitation vs mitral stenosis vs mitral regurgitation, P <.001)., Conclusion: Tei index significantly changes after valve surgery especially in patients with AS. Considerations for the effects of valve dysfunction on Tei index are required for its application to evaluate ventricular function in patients with valve disease.

Objectives: We sought to test whether isolated mitral annular (MA) dilation can cause important functional mitral regurgitation (MR)., Background: Mitral annular dilation has been considered a primary cause of functional MR. Patients with functional MR, however, usually have both MA dilation and left ventricular (LV) dilation and dysfunction. Lone atrial fibrillation (AF) can potentially cause isolated MA dilation, offering a unique opportunity to relate MA dilation to leaflet function., Methods: Mid-systolic MA area, MR fraction, LV volumes and papillary muscle (PM) leaflet tethering length were compared by echocardiography among 18 control subjects, 25 patients with lone AF and 24 patients with idiopathic or ischemic cardiomyopathy (ICM)., Results: Patients with lone AF had a normal LV size and function but MA dilation (isolated MA dialtion) significant and comparable to that of patients with ICM (MA AREA: 8.0 +/- 1.2 vs. 11.6 +/- 2.3 vs. 12.5 +/- 2.9 cm(2) [control vs. lone AF vs. ICM]; p < 0.001 for both lone AF and ICM). However, patients with lone AF had only modest MR, compared with that of patients with ICM (MR fraction: -3 +/- 8% vs. 3 +/- 9% vs. 36 +/- 25%; p < 0.001 for patients with ICM). Multivariate analysis identified PM tethering length, not MA dilation, as an independent primary contributor to MR., Conclusions: Isolated annular dilation does not usually cause moderate or severe MR. Important functional MR also depends on LV dilation and dysfunction, leading to an altered force balance on the leaflets, which impairs coaptation.

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.

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.

Microspheres containing cisplatin (CDDP) embedded in poly-d,l-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS) were developed to improve treatment of malignant effusions. In vitro studies demonstrated that CDDP was released continuously for more than 4 weeks from CDDP-PPMS without initial burst. CDDP-PPMS was compared with CDDP aqueous solution (CDDP-SOL) by i.p. administration in rats for 1) tissue distribution, 2) toxicity and 3) therapeutic effects against Yoshida sarcoma. We found that the CDDP concentration in the omentum was maintained at a higher level than in the CDDP-SOL group, while the particles of CDDP-PPMS were observed in the stomata of the omentum by electron microscopy. Concentrations of CDDP in the lung, liver, kidney and blood were lower in the CDDP-PPMS group than in the CDDP-SOL group. All rats given CDDP-PPMS containing < or = 28 mg/kg were alive, whereas in the CDDP-SOL group, all rats given > or = 16 mg/kg died from side effects. The LD50 of CDDP-PPMS and CDDP-SOL were 32.8 and 14.8 mg/kg, respectively. The survival of rats with peritoneal metastasis was better in the CDDP-PPMS group than in the CDDP-SOL group.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.