Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking.

The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.

Reproductive toxicity, mutagenicity and antigenicity of pamiteplase (genetical recombination).

Pamiteplase (genetical recombination), YM866, is a novel recombinant modified human tissue-type plasminogen activator developed by Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan. An intended route of administration in the clinical use of this drug is intravenous administration. We conducted an intravenous fertility and general reproduction studies of this drug in male and female rats and teratology study of this drug in rabbits at the dose levels of 0 (vehicle control), 0.1, 0.3 or 1 mg/kg/day. In the rat, no treatment-related abnormalities were observed up to the maximum dose in parental animals and their offspring. In the teratology study in rabbits, prolonged coagulation time at the injection site was observed at 0.3 mg/kg or more. One death and one abortion occurred at 1 mg/kg on days 22 and 23 of pregnancy, respectively. No toxic effects on the litters were observed up to the maximum dose. Results of evaluation of the mutagenicity of YM866 and its ability to induce chromosome aberrations using the L5178Y TK+/- mouse lymphoma assay, human lymphocyte chromosome aberration assay and the micronucleus assay in mice were negative. Evaluation of the immunogenicity of YM866 by repeated intravenous injection in chimpanzees elicited no confirmed antibody titers.

[Comparison of CAF plus MPA with CAF plus TAM for advanced or recurrent breast cancer--Kyushu CAFT Study Group of Advanced or Recurrent Breast Cancer].

A multi-center randomized comparison study of CAF + TAM therapy (Arm A) and CAF + MPA therapy (Arm B) in advanced or recurrent breast cancer was conducted at 37 institutions in Kyushu. Out of 119 registered cases, 114 were eligible and 76 were evaluable. The response rate was 42% (15/36) in Arm A and 58% (23/40) in Arm B. In the comparison of side effects, nausea/vomiting and anorexia were significantly less and moon face and body weight gain were significantly more in Arm B. Leucocytopenia was significantly inhibited in Arm B compared with Arm A, which indicated the myeloprotective effect of MPA. These results indicated that CAF + MPA therapy (Arm B) may be more advantageous than CAF + TAM therapy (Arm A) in advanced or recurrent breast cancer.

Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice.

Although acute renal failure is encountered with administration of nephrotoxic drugs, ischemia, or unilateral nephrectomy, there has been no effective drug which can be used in case of acute renal failure. Hepatocyte growth factor (HGF) is a potent hepatotropic factor for liver regeneration and is known to have mitogenic, motogenic, and morphogenic activities for various epithelial cells, including renal tubular cells. Intravenous injection of recombinant human HGF into mice remarkably suppressed increases in blood urea nitrogen and serum creatinine caused by administration of cisplatin, a widely used antitumor drug, or HgCl2, thereby indicating that HGF strongly prevented the onset of acute renal dysfunction. Moreover, exogenous HGF stimulated DNA synthesis of renal tubular cells after renal injuries caused by HgCl2 administration and unilateral nephrectomy and induced reconstruction of the normal renal tissue structure in vivo. Taken together with our previous finding that expression of HGF was rapidly induced after renal injuries, these results allow us to conclude that HGF may be the long-sought renotropic factor for renal regeneration and may prove to be effective treatment for patients with renal dysfunction, especially that caused by cisplatin.

Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus.

OBJECTIVE: This study evaluated the impact of aggressive surgery on survival in patients with carcinoma of the thoracic esophagus. SUMMARY BACKGROUND DATA: Prognostic value of lymph-node status for patients with esophageal carcinoma was emphasized, although it is currently under debate whether extensive lymph node dissection improves survival. METHODS: Two hundred ninety-five patients with thoracic esophageal carcinoma were admitted to Kagoshima University Hospital from December 1982 to December 1990. Esophagectomy was performed on 244 (82.7%) of these patients; 106 of whom underwent three-field lymphadenectomy (bilateral cervical, mediastinal, and abdominal regions) were analyzed regarding lymph-node status, tumor recurrence, and the effect of prognostic factors on survival using Cox's proportional hazards model. RESULTS: Hospital mortality and morbidity were 10.4% (11/106) and 65.1%, respectively. Seventy-eight patients (73.6%) had nodal involvement, including 49 patients with abdominal lymph-node metastases and 46 patients with recurrent nerve-node metastases. Five-year survival rates were 54.5% for 16 patients with a solitary nodal metastasis, 30.3% for stage III, 17.4% for stage IV, and 7.2% for 28 patients with six or more metastatic nodes. The most frequent sites of recurrence were the upper mediastinal region and the lung--its incidence increased significantly as the number of positive nodes increased. The most unfavorable prognostic factors included regional or recurrent nerve-node metastasis and patient age of more than 71 years. CONCLUSIONS: Three-field lymphadenectomy, including especially the removal of bilateral recurrent nerve nodes in the cervical region, is essential for improving the survival of patients with carcinoma of the upper two thirds of the thoracic esophagus.

[An adult of intrathoracic lipoma arising from the chest wall].

A 34-year-old male with intrathoracic lipoma arising from the chest wall is described. Although asymptomatic, the patient was pointed out an abnormal shadow on the chest X-ray film taken at the mass survey. No findings of CT suggested lipoma. The tumor, measuring 2.5 x 2.0 x 1.5 cm in diameter, was surgically removed, and the diagnosis of lipoma was confirmed postoperatively by histopathologic examination.

[Significance of preservation of tracheal proper sheath at the time of cervical and upper mediastinal lymph node dissection for thoracic esophageal cancer].

Extended lymph node dissection in the neck and upper mediastinum often brings about postoperative pulmonary complications. Since September 1987, we have performed this type of lymph node dissection in 18 patients paying special attention to the preservation of tracheal proper sheath along with left bronchial artery and autonomic nerve branches. We compared their postoperative respiratory and circulatory outcomes with those of 17 patients in whom lymph node dissection was carried out without consideration for these aspects. Tracheal mucosal damage, respiratory functional parameters such as PaO2, AaDO2 and Qs/Qp and actual incidence of pneumonia significantly improved in recent cases undergoing meticulous dissection in the neck and upper mediastinum. However, neither circulatory dynamics nor incidences of recurrent nerve palsy and arrhythmia showed a significant improvement. The postoperative period required for reappearance of cough reflex was shorter in this group of patients, but the difference was not significant. The results indicated that pulmonary disorders occurring frequently after extended lymph node dissection for thoracic esophageal cancer was able to be well controlled by meticulous dissection procedure as mentioned above.

Occult lymph node metastasis in gastric cancer with submucosal invasion.

To evaluate more precisely the incidence of lymph node metastasis in patients with submucosally invaded (sm) gastric cancer, three additional sections were made from the remaining half of 1,794 lymph nodes taken from 57 patients, for a detailed reexamination. Lymph node metastasis was demonstrated in 19 nodes from 11 patients by the initial routine examination; however, the detailed reexamination showed cancer involvement in a further nine lymph nodes from eight patients. Of these eight patients, metastasis had not been detected in any lymph nodes by routine examination in six. Macroscopically, the lesion was of the depressed or mixed type in six of the eight patients. From the intranodal location and growth pattern of the cancer foci, lymph nodes with occult metastasis were divided into the marginal sinus type, the medullary sinus type, and the mixed type, with the marginal type being found most frequently. The overall incidence of lymph node metastasis in patients with sm gastric cancer was as high as 29.8% (17/57) in this series. Moreover, a follow-up study revealed that two patients with occult metastasis died of cancer recurrence postoperatively. Accordingly, systematic regional lymph node dissection should be carried out at the time of surgery for sm gastric cancer.

[A case of postoperative chylothorax successfully treated by chemical pleurodesis with OK-432].

Recently, cases of postoperative chylothorax have increased concomitantly with the increase in number of aggressive thoracic surgery. Chylothorax was complicated on the 6 th postoperative day in a 69-year-old male who underwent right lower lobectomy with mediastinal lymph node dissection for adenocarcinoma of the lung. After the leaking point from thoracic duct was confirmed by lymphangiography and chest CT, OK-432 1.5 KE was instilled into the intrapleural space through a intrathoracic tube. By this procedure, the chylous fistulas were completely cured. Application of OK-432, even in such a small dose as 1.5 KE, appeared very useful for the treatment of postoperative chylothorax.

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.

Uptake of bleomycin adsorbed on to activated carbon particles by regional lymph nodes of the esophagus in dogs.

Two bleomycin (BLM)-containing agents (BLM-CH, BLM-SOL) were prepared, and the possible usefulness of BLM-CH in the targeting of chemotherapy for esophageal cancer was studied. BLM-CH is an agent in which BLM is adsorbed on to activated carbon particles, and BLM-SOL is an aqueous solution of BLM. BLM-CH or BLM-SOL was injected into the submucosa of the middle thoracic esophagus of 14 mongrel dogs under endoscopic control. Three days after the administration, regional lymph nodes, connective tissues, liver, lung and spleen were removed, and BLM in the specimens was measured. When BLM-CH was administered, BLM was demonstrated not only in the lymph nodes near the injection site but also in the cervical and abdominal ones. In contrast, BLM was not detected in any lymph nodes when BLM-SOL was administered. Light and electron microscopic observation showed that activated carbon particles diffused and were distributed in the lymph nodes. The latter findings also revealed their existence in the interstices of lymphatic tissues and macrophages. When BLM-CH was injected, BLM in the blood was significantly lower when compared with the results of BLM-SOL administration. The results obtained indicate that BLM-CH may probably become a useful tool in targeting chemotherapy for esophageal cancer.

[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.

[A case of chondrosarcoma of the thoracic vertebra].

A case of chondrosarcoma of the thoracic vertebra in a 47-year-old female is described. Chest X-ray, CT and MRI disclosed an abnormal mass lesion in the posterior mediastinum. The lesion was surgically removed through right thoracotomy. The operative findings revealed that the lesion, hard and measuring 6.5 x 4.5 x 4.5 cm in diameter, was originated from the 7th and 8th thoracic vertebra. The lesion was histopathologically diagnosed chondrosarcoma. The chondrosarcoma arising from the thoracic vertebra is very rare, and only 10 cases have hitherto been reported in the Japanese literature.

Correlation of expression of ABH blood group carbohydrate antigens with metastatic potential in human lung carcinomas.

METHODS. The expression of ABH blood group carbohydrate antigens was examined histochemically in tumors and adjacent nontumorous tissues of 89 cases of human lung carcinoma in which nontumorous tissues expressed blood group carbohydrate antigens compatible with the erythrocyte blood group types. RESULTS AND CONCLUSIONS. Loss of ABH blood group antigens in lung carcinomas correlated with their metastatic potential, especially with the recurrence of hematogenous metastasis. Consequently, patients with tumors that retained compatible ABH blood group antigens showed a better prognosis than patients with tumors of altered antigenic profiles. The loss of blood group B antigen more significantly affected both the hematogenous metastasis and prognosis than that of A and H antigens.

Modified pancreaticogastrostomy following pancreaticoduodenectomy.

A modified pancreaticogastrostomy without gastrotomy was performed in 46 patients undergoing pancreaticoduodenectomy for malignant or benign disease. Postoperative complications related to the modified pancreaticogastrostomy occurred in one patient (2%). Operative mortality was 4% and was unrelated to the pancreaticogastrostomy itself. During the first postoperative year, four patients died of causes unrelated to the original disease process, and nine patients died of recurrent carcinoma. The remaining 31 patients were alive and well at a mean follow-up of 20 months. Results of postoperative gastroscopy were normal in all patients studied. A modified pancreaticogastrostomy without gastrotomy is a safe and effective procedure for pancreatic reconstruction in pancreaticoduodenectomy.

A new family of heparin-binding growth/differentiation factors: increased midkine expression in Wilms' tumor and other human carcinomas.

Midkine (MK) and heparin-binding growth-associated molecule/pleiotrophin form a new family of heparin-binding growth/differentiation factors. We studied MK gene expression in human tumors. In normal human reference tissues, MK was highly expressed in the mucosal tissue of the small intestine, moderately in the thyroid, weakly in the tissues of the lung, colon, stomach, kidney, and spleen, and not at all in the liver. All of 6 surgically removed specimens of Wilms' tumor highly expressed MK. Also, a moderate to intense level of MK expression was noted in the majority of surgically removed hepatocellular carcinomas. The MK mRNA level was analyzed in a number of cultured and nude mice-transplanted lines of human tumors. In stomach, colon, pancreatic, lung, and esophageal carcinomas, a moderate to high level of MK expression was found in the majority of them. These results suggest an important role of MK in the development and/or biological behavior of tumors and raised a possibility to use MK as a diagnostic marker. Heparin-binding growth associated molecule/pleiotrophin mRNA was low or scarcely detectable in samples analyzed thus far except for significant levels of the expression that were observed in PA-1 teratocarcinoma cells and in some surgical specimens of Wilms' tumor.

Inflammatory pseudotumor of the spleen: report of a case.

A case of an inflammatory pseudotumor arising in the spleen of a 60-year-old Japanese male is described herein. This benign lesion is extremely rare, with only 12 cases, including our own, having been reported in the world literature. We preoperatively diagnosed the splenic tumor as a metastasis, due to the coexistance of advanced stage carcinoma in the sigmoid colon. However, after splenectomy, histopathological examination of the mass revealed an inflammatory process. Inflammatory pseudotumors often pose diagnostic difficulties because the clinical and radiologic findings are suggestive of malignancy. The clinical and pathological features of cases previously reported are reviewed following the presentation of this case.

Influence of preoperative performance status on survival time of patients with advanced gastric cancer following noncurative resection.

The relationship between preoperative performance status (PS) and the survival time of 152 patients with gastric cancer was determined following macroscopic noncurative resection and postoperative chemotherapy. There were no preoperative differences in laboratory data between the patients who led a normal life or those with a fully ambulatory performance status (PS 0 or 1) and those who were often bedridden (PS 2 or 3). Neither was there any difference between the groups with regard to clinicopathological factors. The doses of drugs prescribed were lower for patients with PS 2-3. There was no difference in the occurrence of drug toxicity between the groups. The patients with PS 0-1 had a significantly longer survival time than did those with PS 2-3 (P < 0.05). PS, a factor more easily measured than the stage of disease at the time of admission, correlates with survival time. We interpret our findings to mean that for patients with gastric cancer who are symptom-free or who are ambulatory with symptoms, clinical trials of drugs may prolong survival time.

Hepatocellular carcinoma coexistent with adenomatous hyperplasia: report of a case.

We would like to draw attention to hepatic tumor-like lesions which frequently complicate the differential diagnosis of hepatocellular carcinoma (HCC), while considering their pathology and diagnosis by radiographic imaging. In particular, adenomatous hyperplasia is recognized as a precancerous lesion of HCC, and the relationship between adenomatous hyperplasia and the multicentric development of HCC is recognized. We observed a patient who demonstrated hyperplastic changes in both the liver cells and a well-differentiated HCC lesion adjacent to the adenomatous hyperplasia, suggesting a multicentric development of the HCC. The histopathological features of adenomatous hyperplasia are also described.