[Amyloidoma of bone: a case report and a review of the literature].
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Biomedical subjects
Publications and source records attributed to T Sano.
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Forty-five patients with advanced non-small cell lung cancer were randomly allocated to receive vindesine (3 mg/m2 every week) plus either high-dose cisplatin (120 mg/m2 every 4 weeks) or low-dose cisplatin (80 mg/m2 every 3 weeks). All patients were previously untreated. The response rate for the high-dose regimen of cisplatin was 39% (9/23) and that for the low-dose regimen of cisplatin was 33% (7/21); the difference was not statistically significant. Only one patient treated with high-dose cisplatin achieved complete response, lasting 6.5 months. The median duration of response was 5.6 months (range, 2.7-7.7) in the high-dose cisplatin group and 6.8 months (range, 1.9-8.9) in the low-dose cisplatin group. The median survival times for the 23 patients treated with the high-dose regimen of cisplatin and for the 21 patients treated with the low-dose regimen of cisplatin were 9.0 and 10.8 months, respectively. Significantly more azotemia occurred in the high-dose cisplatin group than in the low-dose cisplatin group (P less than 0.05). Combination chemotherapy with cisplatin and vindesine showed significant antitumor activity in patients with non-small cell lung cancer. However, the high-dose regimen of cisplatin did not result in a significantly better response rate or survival advantage, and was associated with greater toxicity.
A 53-year-old man complained of anorexia and abdominal distention of one month's duration. The chest X-ray demonstrated a mass in the left lung with hilar and mediastinal adenopathy and a lytic lesion in the right fourth rib. A transbronchoscopic biopsy of the mass revealed oat cell carcinoma (WHO classification). The endoscopic evaluation also revealed a gastric lesion (IIc type). Biopsy of this lesion indicated signet ring cell gastric cancer. An abdominal CT scan demonstrated multiple liver metastases. Based on these findings, the patient was diagnosed as having synchronous lung and gastric primaries, with liver and bone metastasis from lung cancer. Carboplatin (CBDCA) was administered by intravenous drip infusion of 450 mg/m2. After a second treatment with CBDCA about 3 weeks later, the patient achieved a partial response at the primary site of lung cancer as well as at the liver and bone metastases. In addition, repeat endoscopy of the stomach demonstrated a complete regression. A biopsy specimen taken by gastroscopy was negative for cancer cells. Subsequent chemotherapy for small cell lung cancer was administered with cyclophosphamide, adriamycin, and vincristine, and to date there is no evidence of recurrence. Further studies on CBDCA treatment of small cell lung cancer and gastric cancer are needed to establish the efficacy of this drug against these two histologically different cancers.
The in vitro response to seven chemotherapeutic drugs of three established human small cell lung cancer (SCLC) cell lines (NCI H69, H128, N231) was tested by a double soft agar clonogenic assay. Colony formation by the three cell lines was universally reduced more than 50% by continuous exposure to peak plasma concentrations of all the drugs. However by exposure to one-tenth of the peak plasma concentrations, the colony growth of H69 was reduced to 25.6% and 37.7% by etoposide and teniposide, respectively, and that of N231 was reduced to 46.7%, 39.0%, 27.5% by carboplatin, etoposide and teniposide, respectively. On the other hand colony formation by the three cell lines was not suppressed more than 50% by one-hour exposure to any of the drugs tested at one-tenth of the peak plasma concentrations. By one-hour exposure to drugs at the peak plasma concentrations, colony formation by H69, H128 and N231 was reduced more than 50% by cisplatin, etoposide, teniposide and nimustin, by adriamycin, teniposide and ACNU, and by adriamycin, etoposide, teniposide and nimustin, respectively. It was concluded that these three cell lines have similar sensitivity to seven drugs commonly used against small cell lung cancer.
Of the 66 patients with small cell lung cancer (SCLC) who were treated by combination chemotherapy with or without radiation therapy from July 1978 to December 1983 at the National Cancer Center Hospital, Tokyo, 12 (18%) survived over two years and nine (14%) have remained disease-free over three years. The two-year survival rates were compared according to the patient characteristics of sex, performance status (PS), extent of disease, histologic subtype, regimen of the initial chemotherapy and response to treatment. Sex, extent of disease and response to the initial chemotherapy were the most important prognostic factors. The prognosis for patients with liver or bone metastasis was poor. All disease-free survivors, except for two patients who were treated by surgical resection after chemotherapy, achieved complete response (CR) with chemotherapy with or without radiation therapy. Eleven of the 12 two-year survivors achieved CR. Because of the small number of patients in our study, it will be necessary to evaluate further the influence of prognostic factors in patients with SCLC in future studies.
The antitumor effects of two-drug simultaneous or sequential use of cisplatin, vindesine or etoposide were examined in human pulmonary adenocarcinoma cell lines by human tumor clonogenic assay. Different tumor cell lines (PC-9, PC-13 and PC-14) that originated from the same histological cell type responded quite variably to simultaneous and/or sequential therapy. The antitumor effects of various sequential combinations of cisplatin, vindesine and etoposide depended strongly on the nature of the individual tumor cell line tested.
A new bioassay method for cis-diamminedichloroplatinum (CDDP) using a human tumor clonogenic assay (HTCA) was developed and used to examine the pharmacokinetics of the active form of CDDP in different schedules of administration. The inhibition of colony growth of tumor cells decreased with increase in the % of fetal calf serum in RPMI1640 containing CDDP. By means of this assay, four administration schedules (A, B, C and D) of CDDP were examined. In patients given 40 mg/m2 of CDDP by iv infusion on day 1 twice with a 1 hr interval (schedule A), total platinum was still detectable in plasma at 6 hr by atomic absorption assay. However, the active form of CDDP was no longer detectable at 30 min. In patients treated with 20 mg/m2 of CDDP iv for 20 min daily (schedule B) from day 1 to day 4, the level of total platinum showed a cumulative increase. However, the active form of CDDP was no longer detectable at 30 min, and no cumulative effect was observed. In patients given a high dose (120 mg/m2) of CDDP iv for 30 min on day 1 (schedule C), the peak concentration of active form of CDDP was determined to be 5.0 to 7.0 micrograms/ml, and a level of more than 1.0 micrograms/ml was maintained even after 2 hr in one case. In 2 patients of this group the concentrations of active form of CDDP determined by HTCA were the same as those of ultrafiltrable platinum detected by atomic absorption assay. In 2 of 3 patients given 100 mg of CDDP into the pleural cavity, the active form of CDDP was detected in sera. High-dose CDDP administration was concluded to be preferable to low-dose therapy because of the higher peak concentration and longer residence time of the active form of CDDP in the plasma. Furthermore, it is suggested that a systemic effect of CDDP can be expected even when CDDP is given by intrapleural administration.
There are two strategies for evaluating the antitumor effect of IL-2. In the first approach IL-2 has been used to support the proliferation of T-effector cells or LAK cells in vitro in the hope that large quantities of these effector cells can be used therapeutically. This approach has shown some efficacy in animal models if LAK cells are administered in combination with IL-2. However, it is extremely difficult to standardize the numbers of lymphocytes and the biological activity of effector cells for clinical use. Recently the cloning of IL-2 has made available large quantities of purified recombinant IL-2 (rIL-2) for preclinical and clinical trials. Accordingly there have been recent attempts at injecting rIL-2 directly to stimulate effector cells in vivo. In this study, in vivo and in vitro augmentation of the cytotoxicity of spleen lymphocytes against syngeneic B-16 melanoma cells (induction of LAK cells) and the suppression of artificial pulmonary and liver metastases of B-16 melanoma in C57BL/6 mice was tried by subcutaneous multiple injections of high-dose human rIL-2. In addition, the immunosuppressive effect of a water-soluble nitrosourea derivative (ACNU) was determined in terms of the cytotoxicity of spleen lymphocytes, and the restoring effect of lymphokine-activated killer (LAK) cells and/or human recombinant interleukin-2 (rIL-2) on the cytotoxicities of spleen lymphocytes were examined in ACNU-treated C57 BL/6 mice. It was also tested whether the administration of LAK cells and/or rIL-2 could reduce the increased numbers of pulmonary metastases in ACNU-treated mice. The cytotoxicity of spleen lymphocytes against YAC-1 cells as well as against syngeneic B-16 and F-10 melanoma cells was augmented not only by incubation of spleen lymphocytes with human recombinant interleukin-2 (rIL-2) in vitro but also by injecting high-dose rIL-2 into C57BL/6 mice for more than 3 consecutive days. In animals injected with multiple high doses of rIL-2 subcutaneously, the numbers of tumor nodules in the lung were significantly decreased 21 days after intravenous tumor inoculation. In addition, in these groups of animals no liver metastases were observed although liver metastases were detected in 6/11 of control mice. The maximum effective dose of ACNU suppressed the cytotoxicity of spleen lymphocytes and pretreatment with ACNU enhanced the induction of artificial pulmonary metastases.(ABSTRACT TRUNCATED AT 400 WORDS)
High-dose intravenous (IV) metoclopramide has shown efficacy with few side effects for the treatment of nausea and vomiting on the day of cisplatin administration. From November 1984 to January 1986, two randomized trials in an antiemetic study were conducted. In trial I, the antiemetic effect of a short course of high-dose dexamethasone was compared with that of high-dose metoclopramide in 29 patients with lung cancer receiving chemotherapy containing cisplatin (80 mg/m2 IV) in a randomized controlled trial. Dexamethasone was given IV at a dose of 16 mg 1/2 hr before and 8 mg, 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin. Metoclopramide was given IV at a dose of 2 mg/kg, 1/2 hr before and 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin. Major emetic control (0-2 episodes of vomiting) during the 24 hr after cisplatin administration was achieved in 55% (6/11) and 67% (12/18) of the patients receiving dexamethasone and metoclopramide, respectively, without serious toxicity. The duration of nausea or anorexia was similar for the two treatment groups. In trial II, the combination of metoclopramide and dexamethasone was compared with metoclopramide alone to assess the additive antiemetic effect of the two drugs in 23 patients with lung cancer receiving cisplatin at a dose of 120 mg/m2 IV in a randomized cross-over study. A major antiemetic response was observed in 27% (3/11) and 92% (11/12) of the patients receiving metoclopramide alone and metoclopramide plus dexamethasone, respectively (p less than 0.005). The duration of nausea and anorexia was similar for the two treatment groups. Patients tended to prefer the combination of metoclopramide and dexamethasone; however, the difference was not statistically significant (p = 0.14) in the small number of patients entered in this study. Despite excellent control of acute chemotherapy-induced emesis, 45% of 52 patients experienced delayed nausea and vomiting more than 24 hr after cisplatin administration even among those who had had an excellent short-term response to the antiemetic agents.
Recently the number of patients with lung cancer who receive chemotherapy has been increasing rapidly. Therefore it has become difficult to treat all patients with advanced lung cancer on the basis of accurate protocol in long-term hospitalization. Accordingly we tried to treat patients within one week in each of a number of chemotherapy protocols (short-term hospitalization) and to follow them in the outpatient department. We were able to accept 61 admissions of 38 patients for chemotherapy from June to December 1985. Thus it was possible to take care of more than three times as many patients as could be cared for by long-term hospitalization for chemotherapy. Three patients could not be discharged within one week and eight had to be readmitted because of leucopenia, thrombocytopenia, or dehydration. It was considered to be possible to decrease the number of such patients by more careful and appropriate hydration and to detect them by appropriate intervals of examination in the outpatient department. We concluded that short-term hospitalization is one of the methods which can make chemotherapy of lung cancer more effective.
The nucleophilic attack of lithiated pyrimidines to a suitably-protected 3-ketosugar, afforded the 3-branched sugar stereospecifically, followed by intramolecular glycosylation to give 6,3'-methano-cyclo-pyrimidine nucleosides. The 2'-deoxygenation was achieved by sequential protection, deprotection and radical reduction.
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Through our retrospective analysis of HTCA and clinical effects as well as fundamental studies, the following results were obtained: In this retrospective study, HTCA for lung cancer showed a predictive accuracy of 71%, a true positive rate of 50% and a true negative rate of 77%. To obtain good predictive accuracy, HTCA should be modified to provide conditions comparable to those in vivo with regard to drug concentration and drug exposure time. More precise analysis of the pharmacokinetics of anticancer agents might yield methodological improvement. A decrease in the chemosensitivity spectrum in vitro was observed after chemotherapy. This might be related to evidence that patients with prior chemotherapy exhibited a poor response rate to chemotherapy. There were no active anticancer agents against specimens with aplating efficiency of more than 0.04%. More extensive prospective trials will be necessary to determine the clinical value of HTCA. HTCA could be a superior assay for detecting the anti-tumor activity of new agents and a useful method for in vitro phase II study.
A new human cell line designated OMC-1 was established from a metastatic lesion of Virchow lymph node of a large cell non-keratinizing squamous cell carcinoma of the uterine cervix. OMC-1 was successively subcultured 30 times in about 15 months. The monolayer cultured cells appeared to be epithelial with a pavement-like arrangement and tendency to pile up without contact inhibition. Electronmicroscopy showed desmosomes and well-developed tonofilaments. The population doubling time was 43-70 hours, the saturation density was 1.3-1.7 X 10(5) cells/cm2, the plating efficiency was 23-25% and the mitotic index was 3.3-4.8%. Chromosome studies showed aneuploidy and a modal number of 45. After subcutaneous transplantation into nude mice, the cells grew into solid large cell non-keratinizing squamous cell carcinomas. By the flow cytometric analysis, the phase fractions of the cells was G1 + G0 = 40.1%, S = 24.9% and G2 + M = 35.0%. The OMC-1 cells produced TA-4 in culture media. TA-4 was also demonstrated immunohistochemically in the original tumor tissue, cultured cells and tumors in nude mice.
The anti-cancer effect of Etoposide was tested in in vitro in cultures of cells taken from a squamous cell carcinoma of the uterine cervix (SKG-IIIb). Growth inhibition was tested by the regrowth assay method, inhibition of DNA synthesis by the uptake of 3H-thymidine, and morphological changes by the method of Limburg et al. The concentrations of Etoposide used were similar to the blood levels recommended for clinical use. The regrowth assay showed that the effective concentration of Etoposide for 50% cell kill was 7.5 micrograms/ml in 2-hour and 1.0 microgram/ml in 24-hour cultures. The 3H-thymidine uptake test showed that a concentration of 13 micrograms/ml for 2 hours or of 3.5 micrograms/ml for 24 hours resulted in 50% inhibition of DNA synthesis. Morphological changes were much greater in the 2-hour cultures at the higher concentration of Etoposide than in the 24-hour cultures at the lower concentration. Investigation of the drug sensitivity by cell kinetics disclosed prolongation of the cell cycle occurring after 96 hours at 1.0 microgram/ml and inhibition of cell cycle progression occurring after 24 hours at 10.0 micrograms/ml and after 4 or 8 hours at 50.0 mu/ml. Thus, the anti-cancer effect of Etoposide on SKG-IIIb depends on both the concentration and exposure time and is related to its ability to inhibit cell growth and DNA synthesis and to cause morphological changes in the cancer cells.
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The mechanism of the binding of 2-(4'-hydroxyphenylazo)benzoic acid (HABA) to bovine serum albumin was studied by relaxation methods as well as the binding isotherm using gel chromatography. A single relaxation was observed over a wide range of HABA concentration except at the extremes of high concentration where another slow process was observed. The concentration dependence of the reciprocal relaxation time of the fast process decreased monotonically with increase in concentration of HABA at constant polymer concentration. The data were analyzed on the basis of Brown's domain structure model and were found to be consistent with a sequential binding mechanism. The azohydrazon tautomerism of HABA was identified with the intramolecular step of the complex. The activation parameters of the step, determined from the temperature dependence of the relaxation time of the fast process, showed that this step is rate limited by an enthalpy barrier in both forward and backward directions. Comparison of the activation parameters with those of other serum albumin-ligand systems suggests that there is an enthalpy-entropy compensation in the activation process of the intramolecular step with the compensation temperature at about 270 K; the enthalpy-entropy compensation is thought to be related to the hydrophobic nature of the ligand.
Previously we constructed an infectious hop stunt viroid (HSV) cDNA clone, PHS-P2P, which carries two copies of full-length HSV cDNA tandemly and generates HSV RNA when it is inoculated into cucumber plants. The in vitro transcript of the cDNA clone was also infectious. To investigate the essential regions for infectivity of HSV, we introduced a short deletion or insertion into the HSV sequence of pHS-P2P using restriction sites (XhoI site for pHI-X1, PvuI site for pHI-P1, and BamHI site for pHI-B1) and assayed the infectivities of these mutagenized clones. None of these mutagenized clones and their transcripts were infectious under the conditions used. Simultaneous inoculation of two or three of non-infectious mutagenized clones or the transcripts from them did not restore the infectivity.