Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20-40 mg m(-2) 2-h infusion, daily) and 5-fluorouracil (200 mg m(-2) 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1-33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1-40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m(-2). Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m(-2), respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62-92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (>or=grade 3, 87.9%) and thrombocytopenia (>or=grade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.

[Successful resection of endotracheal metastatic lung cancer using percutaneous cardiopulmonary support system: a case report].

We experienced a rare case of endotracheal metastasis derived from squamous cell lung cancer. The patient was 56 year-old male whose primary lung cancer of the left upper lobe was completely resected. Pathological diagnosis indicated stage IIB and he underwent two cycles of chemotherapy with CDDP + VDS. He had been asymptomatic thereafter, however, two years postoperative chest CT revealed a nodular lesion of the anterior carinal wall. Bronchofiberoptic examination showed same as CT finding and its brushing cytology confirmed squamous cell carcinoma. WE successfully resected his endotracheal metastatic lesion and reconstructed by direct sutures assisted by PCPS (Percutaneous Cardiopulmonary Support System). His postoperative course was uneventful. Majority of the reported cases of endotracheal metastases were treated conservatively as radiation, laser and/or chemotherapy. We conclude that PCPS is useful device for surgical management for selected cases.

Diagnostic accuracy of CT-guided automated needle biopsy of lung nodules.

OBJECTIVE: The purpose of this study was to determine the factors influencing diagnostic accuracy in CT-guided automated needle biopsies of lung nodules. SUBJECTS AND METHODS: One hundred thirty-eight consecutive CT-guided automated needle biopsy procedures were performed in 123 patients (124 pulmonary nodules). Factors for diagnostic accuracy were evaluated through analysis of the procedures, which were classified into a success group (true-positive and true-negative) and a failure group (false-positive and false-negative). RESULTS: Final diagnoses were 81 malignant lesions (91 biopsies) and 43 benign lesions (47 biopsies). More than two CT-guided biopsies were performed for 13 lesions. Seventy lesions were true-positive, 44 were true-negative, three were false-positive, and 21 were false-negative. The overall diagnostic accuracy was 82.6%. The sensitivity for malignancy and specificity for benign lesions were 76.9% and 93.6%, respectively. Positive and negative predictive values were 95.9% and 67.7%, respectively. Lesion size was a significant factor contributing to diagnostic accuracy (p = 0.014). Mean diameters of lesions (+/-SD) in the success and failure groups were 24.1+/-12.4 mm and 17.6+/-7.8 mm, respectively. For lesions 6-10 mm in diameter, diagnostic accuracy was 66.7%; for lesions 11-20 mm in diameter, 78.9%; for lesions 21-30 mm in diameter, 86.7%; for lesions 31-50 mm in diameter, 93.3%; and for lesions 51-70 mm in diameter, 100%. CONCLUSION: Lesion size was a determining factor in diagnostic accuracy. Diagnostic accuracy decreased in proportion to the decrease in the lesion diameter.

[Safety of video-assisted thoracic surgical (VATS) lobectomy without rib spreading for low respiratory function patients].

We performed VATS Lobectomies without rib spreading on 3 low respiratory function patients (FEV1.0 < 1.2 l) with primary lung cancer. Their post-operative courses were uneventful. During the 3 post-operative months, VC, FEV1.0, PF, and MVV did not decrease for the lost lung volume, while DLco decreased considerably.

An antisense EGFR oligodeoxynucleotide enveloped in Lipofectin induces growth inhibition in human malignant gliomas in vitro.

Epidermal growth factor receptor (EGFR) plays an important role in the progression of malignancy in gliomas. We studied the growth inhibition of the malignant glioma cell lines using an antisense EGFR oligodeoxynucleotide enveloped with Lipofectin. At a concentration of 5 microM of the antisense EGFR oligodeoxynucleotide enveloped with Lipofectin, the proliferation of three malignant glioma cell lines was significantly inhibited (p < 0.05) compared with that of the cells exposed to 5 microM sense EGFR oligodeoxynucleotide. The activity of the tyrosine kinase and the DNA synthesis was also significantly suppressed (p < 0.05). These findings show that the antisense EGFR oligodeoxynucleotide enveloped with Lipofectin has a possibility to become a useful gene therapy against malignant gliomas.

Testicular microlithiasis with mediastinal choriocarcinoma: a case report.

A 19-year-old Japanese male developed a cough, chest pain, and high fever. CT of the chest revealed a bulky mediastinal tumor (13 x 10 x 8 cm) and bilateral multiple pulmonary nodules. CT of the abdomen and pelvis was normal. Laboratory evaluation showed a beta human chorionic gonadotropin (beta HCG) level of 985 ng/mL. Testicular ultrasonography demonstrated multiple, bilateral punctate echoes characteristic of testicular microlithiasis (TM). No primary testicular tumor was detected. Needle biopsies of the testes did not reveal cancer and calcification. Transthoracic needle biopsy of the mediastinal tumor showed choriocarcinoma. No correlation is known between TM and choriocarcinoma without testicular cancer, but the incidence of TM in this patient may reflect his high human chorionic gonadotropin level.

[Left S1+2+3 segmentectomy by using the auscultatory triangle thoracotomy].

We performed a left S1+2+3 segmentectomy by preserving latissimus dorsi muscle on 3 patients with primary lung cancer and measured pre-operative and post-operative respiratory function. During the 3 post-operative months, VC, FEV1.0, Peak flow and MVV recovered almost to the same level of pre-operative values, while DLCO did not recover sufficiently. Seroma should be ignored for the first 4 post-operative weeks unless infection appears, because seroma will be absorbed naturally.

Isolation and characterization of a thiamin transport gene, THI10, from Saccharomyces cerevisiae.

We isolated a thiamin transporter gene, THI10, from a genomic library of Saccharomyces cerevisiae by the complementation of a yeast mutant defective in thiamin transport activity. The THI10 gene contained an open reading frame of 1,794 base pairs encoding a 598-amino acid polypeptide with a calculated molecular weight of 66, 903. The nucleotide sequence of THI10 is completely identical to that of an anonymous DNA (open reading frame L8083.2) mapped to chromosome XII; two other genes (open reading frames YOR071c and YOR192c) in chromosome XV are extremely similar to THI10. Moreover, the THI10 gene product showed significant sequence homology with yeast allantoin and uracil transporters. Hydropathy profile suggested that THI10 product is highly hydrophobic and contains many transmembrane regions. Gene disruption of the THI10 locus completely abolished the thiamin transport activity and thiamin binding activity in yeast plasma membrane fraction. Both the transport and thiamin binding activities were restored in the disrupted cells when the THI10 open reading frame was expressed by yeast GAL1 promoter, suggesting that the THI10 gene encodes for the thiamin transport carrier protein. Northern blot analysis demonstrated that THI10 gene expression is regulated at the mRNA level by intracellular thiamin pyrophosphate and that it requires a positive regulatory factor encoded by THI3 gene.

[Usefulness of 7 day therapy with cefluprenam in the management of respiratory tract infections].

Efficacy and safety of a newer injectable cephalosporin, cefluprenam (CFLP) on cases with bacterial pneumonia and chronic respiratory tract infections were evaluated at a dose of 1g (potency), d.i.d for 7 days. 1. Of 130 cases in total, 116 cases were enrolled for the clinical efficacy evaluation. The efficacy rate (excellent and good responses) was 94.8% (110/116). The efficacy rate was 93.8% (60/64) for cases with bacterial pneumonia, and 96.2% (50/52) for cases with chronic respiratory tract infections. The recurrence was noted in 1.2% (1/82). The bacteriological response rate was 100.0% (32/32) for gram positive cocci, 93.8% (15/16) for gram negative rods and 97.9% (47/48) in total. 2. Adverse drug reactions were noted in 3.9% (5/129), consisting of 2 cases with skin rash, 1 case with drug fever, 1 case with skin rash and skin itching and 1 case with drug fever and headache. The abnormal laboratory changes were noted in 23.6% (30/127), mainly containing the elevation in GPT and GOT, and eosinophylia. The safety rate (no problem evaluation) was 74.8% (95/127). 3. The usefulness rate (very useful and useful evaluations) was 93.1% (108/116). As suggested by the evaluation on the secondary endpoint in the phase III comparative studies with both bacterial pneumonia and chronic respiratory tract infections, it was confirmed that the 7 day therapy of CFLP was promising for treatment of moderate bacterial pneumonia and chronic respiratory tract infections, because the high clinical efficacy was obtained and also the incidence of allergic reactions with CFLP was almost the same as that of ceftazidime (CAZ) evaluated highly safe. Based on these results, it was concluded that CFLP was useful in the management of moderate respiratory tract infections and also the recommended therapeutic period with CFLP was within 7 days.

Inhibition of 12-O-tetradecanoylphorbol-13-acetate induced Epstein-Barr virus early antigen activation by natural colorants.

Natural colorants such as anthocyanins, betalains, carotenoids, curcuminoids and chlorophylls have been widely used in the food processing industry and in beverages. Most of these colorants constitute part of human dietary components and are considered to be harmless and non-toxic. As a part of the study of natural products to identify non-toxic cancer chemopreventive agents, we have investigated several natural colorant extracts from vegetables and fruits of daily human consumption for their cancer chemopreventive action using the short-term in vitro assay which involves inhibition of Epstein-Barr virus early antigen activation (EBV-EA) induced by phorbol esters. Our study has identified several plant extracts that show profound activity in the EBA assay.

[Preliminary screening for antiviral AIDS drugs. VIII. Report for fiscal year 1995].

Preliminary screening of antiviral AIDS drugs has been carried out using three different in vitro assay systems. Among 96 samples of different origin tested, two were shown to inhibit the growth of HIV in vitro. One of the positive samples (plant origin) has hopeful signs, as the ranges of effective doses are wider than those of most of positive samples which had been found by us.

Contraction and intracellular calcium-ion elevation of cultured human aortic smooth muscle cells by endothelin-1, vasoactive intestinal contractor (VIC) and the derivatives.

Effects of endothelin (ET) family peptides and their derivatives on cellular contraction and calcium-ion level were examined by using cultured human vascular smooth muscle cells (VSM). Contraction of cultured human VSM, isolated from human fetal aortic segments, was induced within 1 min after the treatment with ET-1 (100 nM) as seen in the changes of cytosolic calcium-ion localization. In parallel with the cell contraction, cytosolic calcium-ion level in the human VSM increased very rapidly and then dropped with some oscillation as determined by Anchorage Cell Analyzing System. It was noted that transient calcium-ion mobilization rather than sustained calcium-ion influx was significant in the contraction of cultured human VSM. Vasoactive intestinal contractor (VIC), three amino acids different from ET-1, had less activity in increase of intracellular calcium-ion level and in percent of response cells than ET-1, ET-2, and VIC-S4L6 (one amino acid different from ET-1). EC50 of ET-1, VIC-S4L6, ET-2, and VIC were 0.5 nM, 0.6 nM, 2.0 nM, and 20 nM, respectively. VIC-like peptide (VIC-LP), 16 amino acids fragment of VIC precursor protein, had no effect with a single administration of up to 10 microM. However, the increase in calcium-ion level by VIC was suppressed with a prior treatment of cells with high concentration (10 microM) of VIC-LP. The establishment of cultured human VSM for the simultaneous examination of the contraction and calcium-ion level will provide a new system to study signal transduction of vasocontractor peptides.

Isolation of a Thiamine-binding Protein from Rice Germ and Distribution of Similar Proteins.

A thiamine-binding protein was purified from rice germ (Oryza sativa L.) by extraction, salting-out with ammonium sulfate, and column chromatography. From the results of molecular mass, Kd and Bmax values for thiamine-binding, binding specificity for thiamine phosphates and analog, the protein was suggested to be identical to the thiamine-binding protein in rice bran. The thiamine-binding protein w as more efficiently purified from rice germ than from rice bran. The protein was rich in glutamic acid (and/or glutamine) and glycine. The protein did not show immunological similarity to thiamine-binding proteins in buckwheat and sesame seeds. However proteins similar to the thiamine-binding protein from rice germ existed in gramineous seeds. They were suggested to have thiamine-binding activity and to be of the same molecular mass as the thiamine-binding protein.

Inhibitory effects of lantadenes and related triterpenoids on Epstein-Barr virus activation.

To search for possible antitumor promoters, inhibitory effects of lantadenes and related triterpenoids from Lantana camara L. (Verbenaceae) on Epstein-Barr virus activation, were tested. The substitutions on the carboxylic acid through an ester bond might play an important role in the activity.

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage by green tea extract in rat.

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMII injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.

Anti-tumour-promoting glyceroglycolipids from the green alga, Chlorella vulgaris.

Two new monogalactosyl diacylglycerols were isolated from the freshwater green alga, Chlorella vulgaris, as anti-tumour promoters, together with three monogalactosyl diacylglycerols and two digalactosyl diacylglycerols. The new monogalactosyl diacylglycerol containing (7Z,10Z)-hexadecadienoic acid showed a more potent inhibitory effect toward tumour promotion than the other glycerolipids isolated.

Inhibitory effects of quassinoids on Epstein-Barr virus activation.

Short-term in vitro assays for tumor promoters and anti-tumor promoters (Epstein-Barr virus activation test) were carried out for 45 quassinoids. As a result, some quassinoids showed potent activity, more than 50% inhibition at a molar ratio of 1:1 (TPA/quassinoids). These results led to the following structure-activity relationships: (1) a methyleneoxy bridge and side chain enhance the activity and (2) a sugar moiety reduces the activity.

Adenosine kinase-deficient mutant of Saccharomyces cerevisiae.

A cordycepin-resistant mutant strain of Saccharomyces cerevisiae (CD-R2) was found to be deficient in adenosine kinase. This mutant accumulated S-adenosylhomocysteine during growth in the presence of exogenous adenosine and it grew in a pseudohyphal manner in the presence of this nucleotide.

Inhibitory effect of natural carotenoids on Epstein-Barr virus activation activity of a tumor promoter in Raji cells. A screening study for anti-tumor promoters.

As a screening study for anti-tumor promoters, 51 carotenoids with diverse structures were examined for their inhibitory effects on the Epstein-Barr virus activation activity of 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The results showed that most of the carotenoids exhibited inhibitory activity, and in general, no cytotoxicity on Raji cells was observed in the assay. Among the carotenoids, beta-cryptoxanthin, lutein, and lactucaxanthin showed the strongest inhibitory activity, superior to the well known anti-tumor promoter, beta-carotene. Heteroxanthin, peridinin, and halocynthiaxanthin showed cytotoxicity at the high concentration (1000 molar ratio per TPA), but indicated a strong inhibitory effect at the lower concentrations, which were only weakly toxic (500 and 100 molar ratios). Based on these results, the essential moiety for the activity of carotenoids was considered to be the 3-hydroxy-epsilon-end group.