Toru Kumanohoso

Design and testing of a new cisplatin form using a base material by combining poly-D,L-lactic acid and polyethylene glycol acid 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 ≤28 mg/kg were alive, whereas in the CDDP‐SOL group, all rats given ≥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. Int. J. Cancer 76:709–712, 1998.© 1998 Wiley‐Liss, Inc.

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 μg/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.

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

Abstract 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.

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.

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.

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.

Asymptomatic somatostatinoma of the pancreatic head: Report of a case

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.

Local Chemotherapy of Esophageal Cancer with Bleomycin Adsorbed to Activated Carbon Particles

Increasing interest has recently been shown in targeting cancer chemotherapy using newly designed drug delivery systems [1]. Hagiwara et al. [2] developed activated carbon particles as a drug carrier having several advantages such as selective affinity for the lymphatic system and release of a designated fixed concentration of anticancer drug over a long period.

A Case of Early Baseloid Carcinoma Concomitant with Early Squamous Cell Carcinoma of the Esophagus.

3年半の逆追跡が可能であった類基底細胞癌と扁平上皮癌からなる早期多発癌の1例を経験したので報告する.症例は54歳の男性で検診の内視鏡検査で食道癌と診断されたが放置していた.3年半後, 再び検診を受け食道癌を指摘された.前回と入院時の内視鏡検査を比較すると, 上切歯列より26cmに推定深達度mの0-IIc型腫瘍が, 30cmに推定深達度smの0-Ip1型腫瘍が認められ, 軽度腫瘍が増大しているのみであった.右開胸・開腹によって食道亜全摘とリンパ節郭清を施行した.病理組織学的には口側の腫瘍は深達度m3の高分化型扁平上皮癌, 肛門側の腫瘍は深達度sm3の類基底細胞癌で, リンパ管侵襲は陽性であったがリンパ節転移は陰性であった.またその中間に組織学的検索で新たに深達度m2の高分化型扁平上皮癌が発見された.長期間経過観察可能であった類基底細胞癌と扁平上皮癌の早期多発癌の報告はまれであり, 発生や悪性度を考える上で示唆に富む症例と考えられた.