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.

Reversibility of bronchial cell atypia.

Various degrees of cellular atypia were induced in the bronchial epithelium of dogs by means of repeated submucous 20-methylcholanthrene injections. Thereafter, the 20-methylcholanthrene treatment was stopped, and the outcome of the bronchial cell atypias in individual dogs was studied using cytomorphological and cytochemical methods. The results suggest that the various degrees of 20-methylcholanthrene-induced cellular atypias, including those cytologically interpreted as malignant, may reflect reversible cellular alterations which disappear after removal of the carcinogen. Similar observations were made in a group of cigarette smokers who, after malignant-appearing cells were observed in the sputum material, stopped smoking or significantly reduced their cigarette consumption.

Hematoporphyrin derivative and laser photoradiation in the treatment of lung cancer.

Photoradiation therapy (PRT) was performed in 13 lung cancer cases and in one case of severely atypical squamous metaplasia following administration of hematoporphyrin derivative (HpD). The HpD is activated by visible red light (630 nm, 90 to 400 mW) from an argon dye laser. The cytocidal effects were due to the activation of the HpD, since 400 mW of power has in itself no effect on normal epithelium, even with long-term exposure. HpD is retained longer by malignant tissue than by normal tissue. Therefore, the lesions were irradiated with the red laser beam, delivered by a quartz fiber inserted through the instrumentation channel of the fiberoptic bronchoscope, 48 hours or more after intravenous injection of 2.5 to 4.0 mg/kg of HpD. A total of 14 cases received PRT. In one, two small, smooth-surfaced, squamous cell carcinoma tumors in the right B2b of a 74-year-old man who had refused surgery disappeared three days after HpD-photoradiation, and the patient remained disease-free 16 months after the treatment. In 12 cases of centrally located lung cancer local effects were obtained in all. However, there was no significant improvement in survival, attributable to the fact that all were advanced-stage cases. One patient with severely atypical squamous metaplasia requested treatment, and complete disappearance of metaplastic atypic was obtained.

Solitary bronchial mucosal neuroma.

A 68-year-old man who had had cough and sputum for ten months was referred to our hospital because sputum cytologic findings were suggestive of lung cancer. Fiberoptic bronchoscopy and biopsy revealed mucosal neuroma of the bronchi. There were no signs suggesting pheochromocytoma or medullary thyroid carcinoma. To our knowledge, this is the first case of solitary mucosal neuroma of the bronchi to be reported.

Five-year disease-free survival of a lung cancer patient treated only by photodynamic therapy.

A 59-year-old woman had suffered cough and sputum production for several months. Chest x-ray film findings were negative, but sputum cytology yielded a diagnosis of squamous cell carcinoma. This stage Ia lung cancer in the right upper lobe bronchus was deemed inoperable due to poor cardiopulmonary function. She was treated by photodynamic therapy in February 1981, involving intravenous injection of hematoporphyrin derivative and fiberoptic endoscopically delivered argon dye laser light. She responded well to the treatment and the lesion disappeared within a week. At present, she is apparently disease-free more than five years after treatment. This is the first known report of five-year disease-free survival following treatment of a malignant lesion by PDT only.

Fiberoptic bronchoscopic laser photoradiation for tumor localization in lung cancer.

Hematoporphyrin derivative (HpD) administration and laser photoradiation were combined to clarify the system's clinical applicability in localizing lung cancer tumors. It was used in 16 cases of lung cancer and in one case of severely atypical squamous metaplasia. Tumors were irradiated 48 hours after intravenous injection of 2.0 to 4.0 mg/kg HpD and fluorescence observed. Fluorescence was seen in 13 lung cancer cases in the case of squamous metaplasia, but results were negative in three of the cases of lung cancer. Among the positive cases was one of occult cancer and two invading the trachea, difficult to recognize by conventional fiberoptic bronchoscopy, as was the severely atypical squamous metaplasia. In the three lung cancer cases not fluorescing, the tumors were obscured by blood, necrotic tissue, or normal mucosa. The method holds promise in the diagnosis of malignant tumors. Nevertheless, it needs further refinement and more studies to elucidate definitive differentiation between malignant and severely atypical, nonmalignant tissue.

Photoradiation therapy with hematoporphyrin derivative in early and stage 1 lung cancer.

Photoradiation therapy with hematoporphyrin derivative was used in 13 cases of early-stage and eight cases of stage 1 central-type lung cancer. The lesions were photoradiated superficially or interstitially by an argon dye laser with a power of 80 to 600 mW for 10 to 40 minutes at 48 hours or more after intravenous injection of 2.5 to 5.0 mg of hematoporphyrin derivative (Photofrin) per kilogram of body weight. Eight of the 13 early-stage cases were treated with photoradiation only, due to poor pulmonary function or refusal of surgery. Macroscopically complete tumor remission was obtained in all eight cases, and the patients are free of disease at 13 to 41 months after photoradiation therapy, except two patients who died at 16 and 31 months after therapy, due to chronic obstructive pulmonary disease and cerebral infarction, respectively. Five cases were resected following photoradiation therapy. Complete remission was demonstrated histologically in two and significant remission in three, and all are free of disease at 7 to 30 months after surgery. The histologic type was squamous cell carcinoma in all cases. In eight stage 1 cases (seven squamous cell carcinomas and one large cell carcinoma), surgery was performed in three after photoradiation therapy, and the remaining five cases were not resected, due to poor pulmonary function or refusal of surgery. Apparent complete remission was obtained in two of the nonresected cases (one died of cerebral infarction at 27 months, while recurrence occurred 15 months after photoradiation therapy in the other) and significant remission in six. In three nonresected cases with significant remission, two patients died of pneumonia unrelated to the photoradiation treatment at 11 and 4 months, respectively, after such treatment. The reason why only significant remission was obtained in early and stage-1 cases was due to the penetration of the argon dye laser beam being limited due to the location of the tumor or the degree of intrabronchial or extrabronchial growth in eight cases. In one other case the power of the argon dye laser beam was insufficient due to technical difficulties. Indications for photoradiation therapy were discussed in relation to the histologic findings in the specimens following such therapy. Procedures were performed under local anesthesia in all cases. Our results indicate that with present methods, photoradiation therapy is effective in cases of superficial invasion or intramural invasion, but curative effects can hardly be expected in cases growing beyond the normal muscular or cartilaginous layer.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative cytochemical differences between young and old patients with lung cancer.

In order to study differences in the tumor growth and frequency of metastases between younger and older patients with lung cancer, we investigated the nuclear DNA and nuclear protein according to age by means of cytophotometry after combined staining with Feulgen and Naphthol Yellow S. On the basis of Feulgen-Naphthol Yellow S staining method, 13 patients less than 40 years old and 16 patients older than 70 years were investigated. Our results showed no significant difference in nuclear DNA contents between young and old patients, but there were significantly higher nuclear protein contents (p less than 0.05) and nuclear protein to nuclear DNA (NP/DNA) ratios (p less than 0.001) in young patients than in old patients. This suggests that young patients may have higher tumor proliferation (high nuclear protein contents and NP/DNA ratios). The lower nuclear protein content and NP/DNA ratio of older cases is in keeping with the general phenomenon of slower tumor growth and less frequent metastases in such cases.

Nuclear DNA content in squamous cell carcinoma, small cell carcinoma, and bronchiolo-alveolar carcinoma of the lung.

Nuclear DNA content in individual, morphologically identified tumor cells from 33 squamous lung carcinomas, 20 small cell lung carcinomas, and 10 bronchiolo-alveolar carcinomas were analyzed by means of cytophotometry on Feulgen-stained histologic and cytologic specimens. Twenty-eight of the squamous cell carcinomas and 17 of the small cell carcinomas had high and scattered DNA values, indicative of high malignancy potentials. None of the bronchiolo-alveolar carcinomas showed such high DNA values. These results are in line with clinical experience that squamous cell and small cell carcinoma are associated with rapid progression and death in patients, whereas bronchiolo-alveolar carcinomas have a more indolent course.

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.

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.

Percutaneous fine-needle cytology for lung cancer diagnosis.

The authors have performed 1,758 needle cytology procedures since 1966 in cases suspected of lung cancer. The results of percutaneous aspiration fine-needle cytology in 232 patients with lung cancer lesions between January 1973 and August 1984 are discussed. Of the 232 cases, lung cancer was diagnosed in 211 cases by this needle cytology technique. This procedure was performed only in peripheral tumors. Positive diagnosis was obtained in 32 out of 36 cases (88.89%) of tumors less than 2 cm in diameter and 179 out 196 cases (91.33%) 2 cm or more in diameter. Twenty-one cases showed false-negative results for malignant diagnosis. There were two false-positive cases, which were resected on a diagnosis of lung cancer that was later revised to inflammatory lesions. The specimens were apparently obtained from areas of severely atypical squamous metaplastic cells. Among 1,758 procedures, 209 complications were observed. In conclusion, for the diagnosis of peripheral lung cancer, percutaneous needle cytology yields a high degree of diagnostic accuracy and is safe, rapid, and economical.

[Clinical studies of BRL 28500 (clavulanic acid/ticarcillin) in the treatment of intraperitoneal infections and biliary tract infections].

Clinical studies have been conducted on BRL 28500 (a formulation containing 15 parts ticarcillin (TIPC) plus 1 part clavulanic acid (CVA]. BRL 28500 was administered at doses of 1.6 g or 3.2 g b.i.d., generally for 10 days by drip infusion to patients with intraperitoneal infections or biliary tract infections. Drug concentrations in the ascites were determined. A total of 76 cases was treated with BRL 28500. These cases included 49 intraperitoneal infections (suppurative peritonitis 29, postoperative peritonitis 20) and 18 biliary tract infections (cholecystitis 5, cholangitis 13). Nine cases were excluded from evaluation according to the committee's assessment. The clinical improvement as assessed by surgeons in charge increased with the duration of continued treatment and efficacies were assessed as 57.1% on day 5, 63.1% on day 7 and 77.8% on day 10 in intraperitoneal infections. Corresponding results in biliary tract infections were 38.9%, 40.0% and 42.9%, respectively. From these results, it is clear that the degree of improvement is related to the duration of treatment. The clinical usefulness as assessed by surgeons in charge of the study was 63.8% in intraperitoneal infections (suppurative peritonitis 75.0%, postoperative peritonitis 47.4%) and 58.8% in biliary tract infections (cholecystitis 100%, cholangitis 41.7%). The overall rate of usefulness was 62.5%. The clinical efficacy rates as assessed by the committee were 81.6% in intraperitoneal infections (suppurative peritonitis 93.1%, postoperative peritonitis 65.0%) and 66.7% in biliary tract infections (cholecystitis 100%, cholangitis 53.8%). In cases where causative organisms were isolated, the efficacies were 92.9% in suppurative peritonitis, 58.8% in postoperative peritonitis, 50.0% in cholangitis and overall, 69.2%. In cases from which TIPC-resistant organisms were isolated, the overall efficacy rate was 65.4% (suppurative peritonitis 88.9%, postoperative peritonitis 58.3% and cholangitis 40.0%). Regarding bacteriological effect as assessed by the committee, the eradication rate was 76.9% in intraperitoneal infections and 40.0% in biliary tract infections (71.0% overall). In cases from whom ticarcillin-resistant organisms were isolated the corresponding rates were 68.4% and 33.3% respectively, (63.6% overall). In 4 patients with peritonitis drug levels in the ascites were determined following administration of BRL 28500 by drip infusion. Good levels of both TIPC and CVA were detected 1 to 3.5 hours after administration.(ABSTRACT TRUNCATED AT 400 WORDS)

[One-stage resected case of dumbbell type tumor of the posterior mediastinum].

We reported a dumbbell type tumor of the posterior mediastinum. The patient was an asymptomatic 40-year-old male. An abnormal shadow in the right lower lung field was pointed out in a mass survey. We recognized a dumbbell type tumor in the posterior mediastinum by chest CT and MRI. The tumor invaded the intervertebral canal through the spinal foramen. It was most clearly seen by MRI myelography. Operation was performed with the patient in a prone position and with an L-shaped skin incision of the back and 11th intracostal thoracotomy and Th11 laminectomy. The dumbbell type tumor was completely removed by this operation. The pathological diagnosis was Schwannoma. The post operative course was good. The one-stage operation is useful for dumbbell type tumors of the posterior mediastinum.

[Laser and cancer therapy].

Two kinds of laser were employed in the treatment of cancers of various organs: a high energy vaporization therapy by a Nd-YAG laser and a photoradiation therapy (PRT) by an argon dye laser (red light with 630 nm wave length) after i.v. administration of hematoporphyrin derivative (HpD). In the former, the lesion was vaporized with a power of 40-80 W with continuous wave or pulse wave transmitted endoscopically. Improved condition was obtained in 59.3% among 27 malignant lesions of the trachea and bronchi. The indications of this method were discussed in relation to the tumor location and type of growth. In PRT the lesion was photoradiated with a power of 100-2,000 mW for 10-30 minutes, 48 hours or more after i.v. injection of 2.5-5.0 mg/kg HpD. PRT was performed in 170 cancer cases consisting of 69 cases of lung cancer, 9 cases of esophageal cancer, 22 cases of gastric cancer, 18 cases of bladder cancer and other 52 cases of various organs. In 29 cases of early stage cancers complete tumor remission was obtained in 65.5%, especially in early stage central type lung cancer. Local effect was obtained in all advanced cases. The method is also available to reduce the extent of resection or to widen the indications of surgery preoperatively. However, there are many problems in PRT such as the activation mechanism of HpD, diagnosis of early stage cancer candidates for PRT, indications and limitations.

[Surgery of lung cancer and the clinical application of basic studies].

We performed several basic studies concerning lung cancer and their results were applied clinically. One was the establishment of cultured lung cancer cell strains and they were employed for sensitivity tests of anticancer agents and to study histogenesis of oat cell carcinoma and monoclonal antibody. Another study was the experimental induction of lung cancer in dogs. We succeeded in inducing canine central type lung cancer. Using epithelial cells from the various stages recognized in the carcinogenetic process. We measured DNA distribution and nuclear protein amounts, and we indicated the relationship between the carcinogenetic process and DNA pattern. Among 2,633 lung cancer cases 1,072 were resected. The 5-year survival of the latest 384 resected cases was 80.3% in stage I. The reasons for this relatively high survival rate is probably because of increased numbers of early stage central type lung cancer due to increasing sputum cytology surveys. Adjuvant therapy was performed using nocardia rubra cell wall skeleton and/or chemotherapy with CDDP. However, significantly better results were not obtained. The surgical results were discussed in 425 cases aged 70 years and over. The therapeutic results and indications of photodynamic therapy in early stage central type lung cancer were presented.

[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.

[Laser photodynamic therapy with hematoporphyrin derivative in lung cancer].

Photodynamic therapy (PDT) using hematoporphyrin derivative (HpD) was performed in 100 cases with lung cancer. The efficacy and limitation of this therapy were evaluated in this paper. Of these 19 cases were early stage lung cancer (Ia) and there were 16 stage I, 11 stage II, 38 stage III and 16 stage IV. The indications of PDT to obtain complete cure should be limited to cases of early stage lung cancer satisfying the following conditions. The focus should be visible endoscopically. Submucosal tumor invasion should be limited to within the bronchial cartilage. The dose of HpD should be more than 2.5 mg/kg body weight but less than 5mg. The light dose should be more than 180 Joules/cm2 in cases of superficial tumor. In advanced lung cancer cases, PDT was effective to treat the local lesion for the improvement of performance status. Combination PDT with surgery made it possible to increase the indications of surgery or reduce the extent of resection area in some cases.