[A case of severe pulmonary hypertension progressing within a short period and complicated by chronic hepatitis and idiopathic interstitial pneumonia].
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Biomedical subjects
Publications and source records attributed to M Sakatani.
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C3H/HeN mice subcutaneously injected repeatedly with Nocardia rubra cell wall skeleton (N-CWS) acquired cellular immunity against N-CWS. In these N-CWS-immunized mice, the serum colony-stimulating factor (CSF) and granulocyte-macrophage colony-forming units in the bone marrow remarkably increased after an intraperitoneal (i.p.) injection of N-CWS compared with those in normal control mice given an single i.p. injection. To analyze the effects of secondary immune response to N-CWS on CSF production by splenocytes, whole mononuclear leukocytes (WMNL), nylon fiber-nonadherent splenocytes (NADC), and plastic-adherent splenocytes (ADC) were cultured in the presence of N-CWS, and then the supernatants of each cell fraction were assayed for CSF. A fraction of WMNL from immunized mice was found to produce more CSF than WMNL from control mice, and either fraction of NADC or ADC separated from WMNL produced markedly less potent CSF when cultured separately. However, when NADC from immunized mice were cultured with ADC from either immunized or normal mice, CSF production recovered to the level shown by WMNL. The role of ADC could be substituted for by cell-free culture medium of either ADC plus N-CWS or the J774 cell line, in which high interleukin-1 activity was detected. A surface marker study showed that depletion of either Lyt-1.1+ or Lyt-2.1+ cells caused a striking loss of CSF production. These data suggested that CSF in the sera of immunized mice challenged with an N-CWS i.p. injection is mainly produced by N-CWS-sensitized T lymphocytes with help of a macrophage-derived humoral factor(s).
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In order to evaluate the clinical benefit of Nocardia rubra cell wall skeleton (N-CWS), a randomized controlled study was performed with inoperable lung cancer patients entered in 5 institutions from October 1978 to June 1981. Patients without pleural effusions were treated initially with conventional therapies such as chemotherapy and/or radiotherapy, according to common protocol, and then patients in performance statuses 0 to 3 were randomized into control and N-CWS groups with stratification into 16 categories according to 4 histological types and 4 clinical stages In the N-CWS group, 400 micrograms N-CWS were initially injected once or twice into the bronchial tumor using a fiberoptic bronchoscope, and subsequently 200 micrograms of N-CWS were injected at monthly intervals into the skin from the shoulders to upper arms. Of 309 patients, 118 patients in the N-CWS group and 108 patients in the control group were eligible for statistical analysis. There was statistically no significant difference in survival rate between the control and the N-CWS groups. According to histological type, significant prolongation of the survival period was observed in patients with small-cell carcinoma. The 97 patients with pleural effusions were initially randomized into control and N-CWS groups. In the control group, local chemotherapy with Adriamycin was performed and, in the N-CWS group, local administrations and monthly intracutaneous injections of N-CWS were given. Tube thoracostomy was performed in both groups. The local response rate was statistically greater in the N-CWS group than in the control group, and survival period was also prolonged significantly in the N-CWS group. The main adverse reactions to N-CWS were skin lesions in the injected sites and fever, but these were temporary and not serious.
The lyophilized, squalene-treated Nocardia rubra cell wall skeleton (N-CWS) was confirmed to produce tumoricidal peritoneal macrophages resulting in inhibition of tumor growth when injected locally into the syngeneic ascites fibrosarcoma, AMC 60 in ACI/N rats. Furthermore, N-CWS was found to augment therapeutic effect when administered repeatedly after a single local injection of mitomycin-C (MMC). To analyze the effects, various in vitro cytolysis assays were performed using N-CWS-activated peritoneal macrophages. When tumor target cells were exposed in vitro to MMC, the resulting cytolysis in the presence of N-CWS-activated macrophages was similar to cytolysis of intact target cells. On the other hand, when N-CWS-activated macrophages were exposed to MMC, the tumoricidal activity was lost significantly, depending on exposure to MMC. When tumor target cells and N-CWS-activated macrophages were simultaneously exposed to MMC, tumor-cell cytolysis was strikingly depressed. In the final experiment, combined injection of MMC and N-CWS into the ascites tumor resulted in remarkable increases not only in peritoneal exudate cell number, but also in in vitro tumoricidal activity of peritoneal macrophages as compared to those induced by either agent alone. In addition, the production of tumoricidal macrophages by IP injection of MMC alone was also noticeable, as described previously. These results possibly indicate the involvement of macrophage activation in induction of therapeutic effect in chemoimmunotherapy.
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Differential induction of squamous cell carcinomas, adenomas, and adenocarcinomas was observed in the lungs of male C57BL/6 and C3H/He mice after repeated intratracheal instillation of benzo(a)pyrene (BP) and charcoal powder suspended in 0.9% NaCl solution. when a high dose of BP (1.0 mg BP and 0.5 mg charcoal powder) was instilled intratracheally once a week for 8 weeks or when a low dose of BP (0.5 mg BP and 0.5 mg charcoal powder) was instilled once a week for 16 weeks, squamous cell carcinomas were induced in high incidence (77 to 87%) in the early period of observation, whereas pulmonary adenomas and adenocarcinomas were induced in low incidence (0. to 48%) in the late period of observation in both strains of mice. On the other hand, when a low dose of BP was instilled intratracheally once a week for 8 weeks, pulmonary adenomas and adenocarcinomas were induced in high incidence (76 to 91%), but squamous cell carcinomas were induced in low incidence (9 to 26%). These results show that a larger quantity of BP instilled intratracheally was needed for induction of squamous cell carcinomas than for induction of adenomas and adenocarcinomas in the lung of mice. Thus, when the carcinogen is administered to a single organ of a single mouse strain by the same route, different amounts of carcinogen have different effects on the incidences of various histological types of tumors.
Carcinogenic activity of benzo[a]pyrene alone was tested for the induction of lung cancer in rabbits. Rabbits received intrabronchial instillation of 5 or 40 mg of benzo[a]pyrene suspended in sterile saline every 10 to 14 days. Cancer incidences were approximately 42% of the rabbits that survived for more than 300 days. These cancers included squamous cell carcinoma, adenocarcinoma, undifferentiated cell carcinoma, fibrosarcoma, and mixed type. In the same experiment amyloidosis was seen in 16 rabbits.
Repeated intravenous administrations of oil-attached Nocardia rubra cell-wall skeleton (N. rubra-CWS) prevented the induction of lung cancer by intrabronchial instillations of 3-methylcholanthrene in rabbits. Amyloidosis was seen after giving 3-methylcholanthrene, and the incidence was higher in the N. rubra-CWS administered rabbits than in the controls.
Four hundred fifty-five patients with lung cancer were treated with oil-attached cell-wall skeleton of bacillus Calmette-Guérin (BCG-CWS) as adjuvant immunotherapy following initial conventional therapy. The overall survival period of the patients was prolonged significantly as compared with that of 380 patients in a historical control group receiving initial conventional therapy alone (p less than 0.0001). The prolongation of the survival period of the patients was also statistically significant when classified according to clinical stages and histological cell types. The therapeutic effect was remarkable in patients combined with malignant pleurisy. Intrapleural injection of BCG-CWS resulted in not only prevention of accumulation of pleural effusion and abrogation of tumor cells but also in prolongation of survival period (P = 0.016). No serious side effects due to BCG-CWS were experienced. From the previous experimental studies and clinical experiences with human tumors, it can be concluded that adjuvant immunotherapy with BCG-CWS is a useful therapeutic modality for lung cancer, especially in cases combined with malignant pleurisy.
Bronchopulmonary washings from a patient with pulmonary alveolar proteinosis who underwent therapeutic pulmonary lavage were examined. There were large amounts of protein and lipids of which main classes were phospholipid, cholesterol and free fatty acid. The major component of phospholipids recovered from the washings was lecithin rich in palmitic acid. We also found a high IgG level in the washings. Both the findings of free cholesterol in high concentration in the washings and the electrophoretic pattern of protein in the washings suggested that the alveoli-filling material of our patient was not wholely derived from passive transudation of plasma constituents.
The effect of radiotherapy on peripheral blood lymphocytes (PBL) of lung cancer and the effect of BCG cell-wall skeleton (BCG-CWS) on recovery of impaired PBL were examined. A remarkable depression of the absolute number of E- or EAC-rosette cells and of the response of PBL to mitogens were observed immediately after radiotherapy, and these continued for several months. With BCG-CWS immunotherapy, the response of PBL to phytohemagglutinin recovered rapidly, compared with non-vaccinated patients. The response of PBL to pokeweed mitogen seemed to give similar results. These results suggested that BCG-CWS injection to the patient receiving radiotherapy was effective for recovery of T-cell response.
Squamous cell carcinomas were readily induced in the lung of C57BL/6 mice by repeated intratracheal instillations of benzo[a]pyrene with charcoal powder suspended in saline solution. Intratracheal instillations were performed once a week for 8 weeks, and the observation period of the experiment was 40 weeks. Some of the tumors were highly keratinized and others were moderately keratinized squamous cell carcinomas. At a later period of observation, poorly differentiated squamous cell carcinomas were found. Invasion into blood vessels was occasionally seen but metastasis to regional lymph nodes or distant metastasis was not found. One tumor from the mouse killed on the 280th day was successfully transplanted subcutaneously into C56BL/6 mice. This mouse, killed on the 84th day after the first tranplantation, had a pulmonary metastasis.
The effect of oil-attached BCG cell-wall skeleton on the induction of pleural fibrosarcomas by 3-methylcholanthrene in mice was examined. The pleural fibrosarcomas were induced by a substernal injection of 3-methylcholanthrene into the thoracic cavity of ddO mice. One week after the injection of 3-methylcholanthrene, 100 mug of oil-attached BCG cell-wall skeleton was injected subcutaneously every week for 10 weeks. In the observation period of 130 days, the incidence of pleural fibrosarcoma was 67% in the control mice and 39% in the mice treated with BCG cell-wall skeleton. The latent period of tumor induction was prolonged in the mice treated with BCG cell-wall skeleton.
The usefulness of the cell-wall skeleton of Mycobacterium bovis BCG (BCG-CWS) to the management of malignant pleural effusion is demonstrated in this report. In two patients with malignant pleurisy the oil-attached BCG-CWS reduced the pleural effusion in volume when injected intrapleurally. The following intradermal injections of BCG-CWS into the bilateral upper arms repeated monthly prevented the reaccumulation of the effusion and improved other clinical conditions of the patients. The possible mechanism responsible for this effect is discussed in relation to previous experimental and clinical studies.