Hepatotoxicity of sub-nanosized platinum particles in mice.

Nano-sized materials are widely used in consumer products, medical devices and engineered pharmaceuticals. Advances in nanotechnology have resulted in materials smaller than the nanoscale, but the biologic safety of the sub-nanosized materials has not been fully assessed. In this study, we evaluated the toxic effects of sub-nanosized platinum particles (snPt) in the mouse liver. After intravenous administration of snPt (15 mg/kg body weight) into mice, histological analysis revealed acute hepatic injury, and biochemical analysis showed increased levels of serum markers of liver injury and inflammatory cytokines. In contrast, administration of nano-sized platinum particles did not produce these abnormalities. Furthermore, snPt induced cytotoxicity when directly applied to primary hepatocytes. These data suggest that snPt have the potential to induce hepatotoxicity. These findings provide useful information on the further development of sub-nanosized materials.

Relationship between immunological rejection and matrix GLA protein in cryopreserved vascular allografts.

INTRODUCTION: Cryopreserved tissue allografts used for cardiovascular diseases become calcified as a late complication after transplantation, probably caused by immunological rejection. Recent attention has been focused on the inhibitory effect of matrix Gla protein (MGP) on ectopic vascular calcification, but the behavior of MGP in cryopreserved allografts is uncertain. In this study we examined the relationship between immunological rejection and MGP in cryopreserved rat aortic grafts after transplantation. METHODS: Cryopreserved rat aortae were isografted or allografted intraperitoneally. Fresh isografts were also tested. The grafts were retrieved 9 days after transplantation and the intragraft MGP mRNA was measured by a real-time quantitative PCR method. The effect of daily administration of FK506 on MGP mRNA levels in cryopreserved isografts and allografts after transplantation was also evaluated. RESULTS: There was no significant difference in intragraft MGP mRNA levels between fresh and cryopreserved isografts 9 days after transplantation. MGP expression levels in cryopreserved allografts were significantly lower as compared to those in cryopreserved isografts (P < .01). Daily administration of FK506 enhanced intragraft MGP mRNA (ninefold) in cryopreserved allografts (P < .01), but not in cryopreserved isografts. CONCLUSIONS: Immunological rejection is likely to inhibit MGP expression in cryopreserved vascular allografts, resulting in late-onset calcification.

Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer.

The benefits of immunochemotherapy with a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, OK-432 (Picibanil), were reassessed in patients with resected non-small-cell lung cancer through a meta-analysis based on data from 1,520 patients enrolled in 11 randomized clinical trials. All 11 trials were started before 1991, and the subjects had been followed up for at least 5 years after surgery and randomization. In these trials, standard chemotherapy was compared with the same therapy plus OK-432. The endpoint of interest was overall survival, and analysis was based on intent-to-treat population without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 5-year survival rate for all eligible patients in the 11 trials was 51.2% in the immunochemotherapy group versus 43.7% in the chemotherapy group. The odds ratio (OR) for overall survival was 0.70 (95% CI = 0.56-0.87, p = 0.0010). Analysis of four trials in which central randomization was performed also reconfirmed a significantly longer survival time for the immunochemotherapy group (OR = 0.66, 95% CI = 0.44-1.00, p = 0.049). Based on these results of meta-analysis, it is postulated that postoperative adjuvant immunochemotherapy using OK-432 might improve the survival of patients after resection of non-small-cell lung cancer.

Oligomeric regulation of gastric H+,K+-ATPase.

The H+,K+-ATPase of intact gastric vesicles has two Km values for ATP hydrolysis, 7 and 80 microM. Irradiation of vesicles with ultraviolet light in the presence of 1 mM ATP resulted in K+-ATPase activity that shows only the low affinity ATP binding. The irradiation stimulated or inhibited proton uptake rate compared with control vesicles at high or low ATP concentrations, respectively. The relation between proton uptake rate and K+-ATPase activity at different ATP concentrations was linear with irradiated vesicles and nonlinear with control vesicles. These results indicate that hydrolysis at the high affinity ATP binding site regulates the energy-transport coupling in negative and positive manners at high and low ATP concentrations, respectively. The complete inhibition of K+-ATPase by a specific proton pump inhibitor E3810 (rabeprazole) (2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulf i nyl)-1H-benzimidazole sodium salt) occurred when E3810 bound to half of the alpha-subunit of H+,K+-ATPase in unirradiated vesicles at both 200 and 10 microM ATP, whereas the complete inhibition of proton uptake occurred when E3810 bound to half or a quarter of the alpha-subunit at 200 or 10 microM ATP, respectively. These results suggest that dimeric interaction between the alpha-subunits is necessary for the enzyme activity at all ATP concentrations and that dimeric or tetrameric interaction is necessary for proton transport at high or low ATP concentrations, respectively.

Cooperative clinical trial of photodynamic therapy with photofrin II and excimer dye laser for early gastric cancer.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a recently developed endoscopic method for treating malignant tumors. For obtaining more photodynamic action with less thermal effect, we employed as the excitation light source for PDT an excimer dye laser, which is a pulsed laser with extremely high peak power, instead of an argon dye laser, which is a continuous wave laser and has been used conventionally. STUDY DESIGN/MATERIALS AND METHODS: The effect of PDT using Photofrin II and the excimer dye laser was evaluated in 27 patients with early gastric cancer. RESULTS: Complete responses (CR) were obtained in 88% of 24 assessable patients and the response rate was 100%. CR was observed in all cases of lesions of superficial depressed type without ulceration and/or with tumor diameter less than 2 cm. Regarding toxicity, mild cutaneous reaction and photosensitivity were seen and lasted several weeks. There were no serious abnormalities in laboratory tests. CONCLUSION: We conclude that PDT is a promising modality for early gastric cancer.

Photodynamic therapy for multiple primary bronchogenic carcinoma.

In recent years, multiple primary lung cancers have been reported with greater frequency, partly as a result of technologic advances in the detection of lung cancer and therapeutic achievements in its management. Photodynamic therapy (PDT) is a relatively new therapy used with increasing frequency in the treatment of a wide variety of malignancies, including central lung cancers. In PDT, the differential retention of an injected photosensitizer by malignant tissue is exploited by treatment with a low-power laser beam delivered endoscopically. Since 1980, 145 patients with central lung cancers, including 35 cases of endoscopically evaluated early-stage lesions were treated with PDT at Tokyo Medical College. Thirteen of these 145 patients had multiple primary bronchogenic carcinomas, five cases of which were synchronous with the rest, metachronous. Three of 13 patients with multiple tumors had early-stage lesions and were treated with endoscopic PDT alone. In the other ten cases, PDT was used to treat accessible early-stage foci although operative excision was required for advanced lesions. Mean survival after PDT, alone or in combination with surgery, was 38 months (range, 14 to 87 months), and seven patients remain alive to date. It was concluded that PDT is useful in extending the therapeutic options for, and improving the prognosis of patients with, multiple primary bronchogenic carcinomas.

The present status of bronchoscopic Nd:YAG laser.

In Japan, the first bronchoscopic Nd:YAG laser applied clinically was performed in our institute 10 years ago, and based on this decade of experience, the indications, effectiveness, and limitations were studied. Between 1980 and 1989, a total of 202 cases were treated by Nd:YAG laser in our institute. Among them, 94 (46.5%) cases were primary lung cancers, 10 (5.0%) cases were primary tracheal malignancies, 56 (27.7%) cases were metastatic tracheal tumors, 6 (3.0%) cases were benign tracheal tumors, and 36 (17.8%) cases were nontumorous tracheal lesions. The indications for Nd:YAG laser therapy were defined as emergency widening of airway, curative treatment, reduction of tumor size, nontumorous benign lesions, and hemostasis. The desired therapeutic effects were obtained in 55/58 (94.8%) for emergency airway widening, 22/27 (81.5%) for curative treatment, 69/88 (78.4%) for reduction of tumor size, and 48/68 (70.6%) for nontumorous benign lesions. While performing Nd:YAG laser treatment, some limitations, such as poor residual pulmonary function, tumor size, tumor depth, cartilage structure, granulation, and stricture length, were encountered. Since bronchoscopic Nd:YAG laser treatment has become a well-established therapeutic modality for tracheobroncheal lesions, areas to be addressed in the future are the training of bronchoscopic laser therapists and research on the extension of applications. To increase the range of clinical applications, it is hoped that makers of laser systems will provide tunable wavelength machines at reduced cost.

Association of point mutation in c-Ki-ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes.

The correlation between clinicopathologic findings and point mutation in codon 12 of c-Ki-ras gene was examined in primary lung adenocarcinomas using polymerase chain reaction and oligonucleotide hybridization techniques. The mutation was detected in ten of 67 cases (15%). Microscopically, mutation-positive cases revealed a tendency to be well differentiated (P less than 0.01). Especially, the incidence of the mutation-positive cases was significantly higher in goblet cell type (three of four) than in other types (five of 56) (P less than 0.001). None of 21 cases of pure Clara cell type showed the mutation (P less than 0.05). The mutation was detected frequently in tumors with no lymph node metastasis (P less than 0.05), with larger tumor size (P = 0.01), and T2 cases (P less than 0.01). Cigarette smoking was not always a contributing factor for mutation. This study revealed that the point mutation of c-Ki-ras codon 12 in lung adenocarcinoma has been associated with the cytologic subtype.

Photodynamic diagnosis in respiratory tract malignancy using an excimer dye laser system.

Equipment has been developed for the early-stage diagnosis and treatment of cancer using an excimer dye laser. The excimer laser beam is obtained by exciting XeCl. A 405 nm beam tuned by DPS dye is used for tumour localization and a 630 nm beam obtained with a rhodamine B dye is used for treatment. The equipment was applied clinically on the basis of extensive experimental research. Effectiveness for cancer localization was examined in 11 cases: four were early stage (three lung cancer and one vocal cord cancer), four were stage I, two were stage III and one was stage IV. All cases were squamous cell carcinoma except for one case of adenocarcinoma. Fluorescence was recognized in all lesions and the equipment was effective for localization.

[Clinical studies on reconstruction procedure of total layer chest wall resection].

The results of clinical studies on 16 reconstruction procedure after total layer chest wall resection in 14 cases of malignant tumor of the chest wall were reported. The 14 cases consisted of two cases with recurrent primary chest wall tumor, two cases of primary breast cancer, seven cases of recurrent breast cancer, and others. The reconstruction procedure after total layer chest wall resection was conducted using only various myocutaneous flaps (eight cases using latissimus dorsi of the resected side, three cases using the abdominitis of the resected side, three cases using latissimus dorsi of the non-resected side, and two cases using a pectoralis major myocutaneous flap of the non-resected side). reconstruction only using a myocutaneous flap proved to be satisfactory for preventing early stage postoperative respiratory distress and maintaining the stability of the chest wall and respiratory function during prolonged observation. Namely, use of myocutaneous flap is the best approach of reconstruction the chest wall after total layer chest wall resection. We confirmed that reconstruction with latissimus dorsi myocutaneous free flap of the non-resected side with microvascular anastomosis of thoracodorsal vessels was useful for posterior chest wall tumors invading the latissimus dorsi muscle. Also, our results demonstrated the insertion of an omental flap under the myocutaneous flap was useful for cases with secondary chest wall infection or vascular damage caused by preoperative high dose irradiation.

Change in a complex translocation involving band 7q34 and 9p- in a case of T-cell lymphoblastic lymphoma.

The authors report a case of T-cell type non-Hodgkin's lymphoma (NHL) in which neoplastic cells possessed a three-way translocation involving chromosomal bands 3q21, 7q34, and 22q11, as well as partial monosomy of the short arm of chromosome 9. In the literature, most reported cases of 7q32-q36 abnormalities had T-cell type leukemia/lymphoma and were younger than 20 years. Two NHL cases, including the current case, were diagnosed as having lymphoblastic lymphoma with a leukemic transformation. The neoplastic cells of the reported cases commonly showed CD2 (E-rosette receptors) and CD38. All 17 patients but three manifested a mediastinal mass at diagnosis and seven had central nervous system lesions or pleural infiltration. Furthermore, five of the 19 reported cases also showed 9p- change.

[A case report of mediastinal malignant lymphoma with long survival following combination chemotherapy using adriamycin, vincristine and cyclophosphamide].

Mediastinal B-cell malignant lymphoma of a 22-year-old female was successfully treated by combination chemotherapy including Adriamycin, Vincristine and Cyclophosphamide. She suffered from dyspnea and axillary tumor in September 1984. Roentgenological examination revealed a large anterior mediastinal tumor. Biopsy of the axillary tumor yielded a diagnosis of metastatic undifferentiated carcinoma from thymus by hematoxylin and eosin. Radiotherapy and chemotherapy including CDDP and ACNU resulted in a symptom-free period of only 2 months. Superior vena cava syndrome and massive pleural effusion recurred. Salvage chemotherapy including Adriamycin, Vincristine and Cyclophosphamide resulted in rapid therapeutic effect. Six courses of chemotherapy were administered, and she is alive and well 4 years after the first salvage chemotherapy. A definitive diagnosis of B-cell lymphoma was made after review of biopsy specimens using immunohistochemical procedures. To select adequate treatment for mediastinal malignant lymphoma, reliable diagnostic procedures including immunohistochemistry are needed. Intensive chemotherapy with appropriate drugs may obtain good response even in advanced cases, such as this.

[A clinico-pathological study of resected lung cancer cases accompanied by pleural dissemination].

A total of 26 lung cancer cases accompanied by pleural dissemination were resected between June 1977 and June 1988. Of these 16 cases were male and 10 cases were female. Their age was 34-78, and the average age was 56.7 years. The histologic type was adenocarcinoma in 23 cases, 1 was large cell carcinoma, 1 was combined adenosquamous cell carcinoma, and 1 was combined adeno-small cell carcinoma. Of these 23 adenocarcinoma cases, 15 were well differentiated, 7 were moderately differentiated, and 1 was poorly differentiated. There was no correlation between tumor size and pleural dissemination. Pleural effusion was observed in 8, 5 had bloody effusion and the other 3 had yellow effusion. Exact preoperative diagnosis and evaluation of extent was very difficult in pleural dissemination cases except for the pleural effusion cases. Concerning the operation method in these cases pleuropneumonectomy was performed in 10, pleurolobectomy in 6, and lobectomy in 10. Prognosis of cases of resected pleural dissemination was very poor. The median survival time was 16 months, The 1-year survival rate was 56.3%, the 2-year survival rate was 23.2%, the 3-year survival rate was 15.4%, and the 4-year survival rate was 7.7%. There was no 5-year survivor in lung cancer cases of this group. Malignant pleural effusion cases had a poorer prognosis, with 6 of 8 cases dying within 1 year from operation. No remarkable therapeutic effects were achieved by adjuvant chemotherapy. In the single case of preoperative hyperthermia, histological therapeutic effect (Ef 2) was recognized. These results suggest that there is no indication of operation in malignant pleural effusion cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Direct current therapy for local control of malignant tumors].

Sixteen malignant tumors of soft tissue (15 cases) were treated with low voltage direct current (DC therapy) with or without systemic chemotherapy. Two platinum or stainless steel electrodes were placed in the tumor and around 10 volts of direct current was passed for 1 hour. In cases in which chemotherapy was performed, single or combined anticancer agents consisted of ADM and BLM were administered simultaneously with DC therapy by systemic route. Ten cases (11 tumors) out of 15 cases received no other local treatment. Histological examination was performed in 6 of 11 lesions, and in all lesions pathological therapeutic effects were recognized. Decrease in tumor size was observed in 9 lesions. In 2 cases the tumors disappeared completely after DC therapy only. In one case receiving DC therapy with chemotherapy, the tumor decreased dramatically and became resectable. Main complications were slight pain during treatment and slight fever after treatment, but special treatment for these complications was not necessary. Our results suggested that DC therapy with or without systemic chemotherapy was useful for local control of malignant tumors. And also if DC therapy had been performed simultaneously with chemotherapy the therapeutic effects seemed to be more emphasized than single use of these therapies.

A cell kinetic study of pulmonary adenocarcinoma by an immunoperoxidase procedure after bromodeoxyuridine labeling.

By in vitro labeling with bromodeoxyuridine (BrdU) and immunohistochemical staining with anti-BrdU monoclonal antibody, the tumor cell kinetics were investigated in 52 resected pulmonary adenocarcinomas. The values of the BrdU labeling index (LI) varied widely among cases of adenocarcinoma in comparison with four cases of small cell carcinoma and ten cases of squamous cell carcinoma examined as controls. The LI was below 3.0 in 60% of the adenocarcinomas. When the LI was analyzed according to the cytologic subtypes of adenocarcinoma, the values were low for goblet cell type and type II alveolar cell type, whereas the values for the bronchial surface epithelial cell type varied widely (average, 5.2) and those for the Clara cell type were intermediate (average, 1.8). A comparison of the LI with TNM classification, histologic differentiation, degree of nuclear atypia, and mitotic cell count showed a correlation between the LI and each of these prognostic factors. Thus, the possibility of the BrdU LI being a useful new prognostic factor of pulmonary adenocarcinomas was suggested.

Detection of a novel antigen (1G12) on the surface of peripheral blood mononuclear cells from cancer patients by a sensitive radioimmunoassay. A possible marker for the early diagnosis of cancer.

A murine monoclonal antibody designated 1G12 has been produced by immunizing mice with A549 human lung adenocarcinoma. Using radiolabeled monoclonal antibody 1G12, a sensitive radioimmunoassay to detect 1G12 antigen has been developed. The antigen was detected on the surface of peripheral blood mononuclear cells (PBMC). A study was performed to examine the frequency of distribution of this antigen on the surface of PBMC from healthy donors and patients with cancer. An antigen level of above 30 units per 1 x 10(6) PBMC was considered positive. None of 41 healthy donors (0%) and 16 of 96 patients (16.7%) with benign diseases of the lung, ovary, and uterus were positive. In contrast, 27 of 41 patients (65.8%) with lung cancer, 14 of 18 patients (77.8%) with ovarian cancer, and 16 of 27 patients (59.2%) with uterine cervical cancer had elevated levels of 1G12 antigen. When patients were grouped by stages of cancer, PBMC from patients in relatively early stages (stages I and II) also gave positive results, i.e., 9 of 17 patients (59.2%) with lung cancer, 6 of 10 patients (60%) with ovarian cancer, and 11 of 22 patients (50%) with uterine cervical cancer of these stages were positive. These results suggest that the detection of 1G12 antigen on PBMC of patients may be useful for early diagnosis of cancers.