Pretreatment apoptotic scores do not predict response to radiation therapy in oropharyngeal squamous cell carcinoma.

The prognostic value of tumor apoptosis was studied in patients with oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Forty-eight patients with oropharyngeal squamous cell carcinoma who received radical radiotherapy between 1990 and 1995 were enrolled in the study. The radiation treatment for all patients involved the administration of 65 Gy in 26 fractions over a 6.5-week period. The apoptotic index (AI; the apoptotic cell count per 1000 tumor cells ) was distributed from 0 to 10 with a median at 2 and a mode of 1. There was a significant linear correlation between the AI and mitotic index (MI) (r=0.393, 95% confidence interval: 0.129-0.605). The cause-specific 5-year survival for patients with AI greater than the median was 46% and for the counterpart was 41%. There was no difference in cause-specific survival between AI/MI greater than the median (50%) and AI/MI smaller than the median (36%). The number of patients was too small to draw definite conclusions, but the AI and the AI/MI before treatment were not shown to have a prognostic value for oropharyngeal squamous cell carcinoma in our study. The primary sites and treatment methods may influence the prognostic value of AI even for the same histological types.

[A case of tuberculous aneurysm of the aorta].

We reported a rare case of tuberculous aneurysm of the aorta managed successfully with urgent surgical therapy. A 35-year-old woman was admitted to our hospital complaining of fatigue and hemoptysis. Laboratory tests showed severe anemia, slight liver dysfunction, elevated level of C-reactive protein, and negative syphilis serologies. The chest roentgenogram revealed widening of right upper mediastinum, two nodular shadows in right middle lobe, and left-sided infiltration shadow with pleural effusion. The pleural effusion was bloody and its level of adenosine deaminase was normal. Culture of pleural effusion specimen remained negative. A computed tomography scans of the chest revealed an aortic aneurysm on the aortic hiatus. Rapid increase in pleural effusion was followed by hemothorax a few hours later. After operation, she received antituberculosis therapy. Histopathologically, the resected lung showed inflammatory process including granulation of giant cells and epithelioid cells. The specimens of the aortic aneurysm revealed rupture of whole layer of aortic wall and inflammatory cell infiltrations. These findings suggested that the case to be a tuberculous aneurysm of the aorta. Therefore, we diagnosed the case as the rupture of tuberculous aneurysm of the aorta.

Reduction of radiation-induced xerostomia in nasopharyngeal carcinoma using CT simulation with laser patient marking and three-field irradiation technique.

PURPOSE: Tumor control and reduction of postirradiation xerostomia in patients with nasopharyngeal carcinoma (NPC) using the three-field irradiation technique based on the CT-based simulation with laser patient marking was investigated. METHODS AND MATERIALS: Seventy-eight patients with NPC were consecutively treated between 1983 and 1993. In 33 patients treated before 1987, target volume was determined using a conventional x-ray simulator with a reference of CT images, and the primary site was treated by the conventional parallel-opposed two-field technique (Group I). In 45 patients treated from 1987, target volume was determined using a CT simulator slice by slice, the treatment field was projected onto the patient's skin by a laser beam projector mounted on a C-arm, and the primary site was irradiated by a three-fields (anterior and bilateral) technique (Group II). In Group II, the shape of each field was determined using a beam's eye view to reduce the dose to the bilateral parotid glands. The three-field technique reduced the dose to the superficial lobe of parotid gland to about two-thirds of the dose given by the two-field technique. Radiation-induced xerostomia was evaluated by clinical symptoms and radioisotope sialography. RESULTS: The 5-year survival rate and disease-free survival rate were 46.6 and 31.2% in Group I, and 46.8 and 46.5% in Group II. A large variation in the volume of parotid glands were demonstrated, ranging from 9 cm3 to 61 cm3 among patients treated with CT simulation. Forty percent of the patients in Group II showed no or mild xerostomia, whereas all of the patients in Group I showed moderate to severe xerostomia (p < 0.01). The radioisotope sialography study showed that the mean secretion ratio by acid stimulation was improved from 3.8% in the Group I to 15.2% in the Group II (p < 0.01). CONCLUSIONS: CT simulation was useful to determine the size and shape of each field to reduce the dose to the parotid gland, of which size varies largely among individual patients. The three-field technique based on CT simulation with laser patient markings is suggested to result in superior complication-free survival in terms of salivary dysfunction than did the conventional two-field technique with x-ray simulatior for NPC.

[Clinical study of synchronous multiple primary cancer involving the lung].

Ten cases of synchronous multiple primary cancer involving the lung were experienced in our hospital during the period from January 1962 to May 1987. The incidence rate was 1.3% of all hospitalized cases of primary lung cancer. The counterpart organs were thyroid gland (4 cases), stomach (2 cases), colorectum (2 cases) and lung (2 cases). Three of four thyroid cancer cases were resected at the same time of pulmonary resection, whereas the stomach and colorectal cancer cases underwent two stage operation. Lung perfusion scintigraphy was very useful in determining the operative method for synchronous multiple primary lung cancer. The 5-year survival rate of all cases of synchronous multiple primary cancer involving the lung was 26.3%, with no hospital death. Surgical treatment is recommended for such cases when both cancers are expected to be resected completely.

Effects of opioid peptides on the tumoricidal activity of spleen cells from nude mice with or without tumors.

The present study was designed to explore the effects of opioid peptides on the immune systems of intact nude mice and nude mice bearing human ovarian cancer cells (KF). When spleen cells from intact nude mice were incubated with medium alone, a significant ability of spleen cells to lyse the KF cells was not observed. However, incubation of the spleen cells with 1 microM beta-endorphin or 1 microM alpha-endorphin induced a significant lytic activity on the KF cells. The control-level lytic activity was increased significantly to about 4.5-fold by 1 microM beta-endorphin and about 3.7-fold by 10 microM met-enkephalin. These results suggest that opioid peptides play a crucial role in cellular immunity. Thus, we examined plasma levels of beta-endorphin in patients with ovarian or uterine carcinoma. The plasma beta-endorphin levels in patients with ovarian or uterine carcinoma were significantly higher (more than twofold) than those of age-matched healthy women.

Changes of lymphocyte subsets in peripheral blood before and after operation of patients with advanced ovarian carcinoma.

Comparison was made between lymphocyte subsets in peripheral blood from patients with benign ovarian tumor and those with advanced ovarian carcinoma. In addition, changes of lymphocyte subsets of patients with ovarian carcinoma before and after operation were also examined. The percentage and absolute number of CD3-/HLA-DR+ (B cells) in peripheral blood from patients with advanced ovarian carcinoma were significantly lower than values from patients with benign ovarian tumor, whereas both percentage and absolute number of CD3-/HLA-DR- (null cells) cells in patients with advanced ovarian carcinoma were significantly higher. Although there was no significant difference in natural killer (NK) cell subsets (CD57+ CD16- and CD57+ CD16+ cells) between patients with benign ovarian tumor and ovarian carcinoma, the percentage and absolute number of CD57-/CD16+ (highly differentiated NK cells) cells in patients with ovarian carcinoma were significantly higher than those in patients with benign ovarian tumor. Both the absolute number and percentage of CD3+/HLA-DR+ (activated T cells) cells in ovarian cancer patients with minimal residual tumors after operation were significantly increased, compared to the levels before operation, while the values in the patients with large residual tumors were significantly decreased. In addition, the percentage and absolute number of CD3-/HLA-DR- (null cells) cells in the patients with minimal residual tumors were significantly decreased after operation, while values in the patients with large residual tumors remained unchanged before and after operation. The patients with minimal residual tumors after operation were characterized by a significant increase in the percentage of CD57- CD16+ (highly differentiated NK cells) cells. On the other hand, in the patients with large residual tumors no change of the NK cell subsets was observed before and after operation.

[Effects of lymphokine-activated killer cells and interleukin-2 on the ascites formation and the survival time of nude mice bearing human ovarian cancer cells].

Effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lymphokine-activated killer (LAK) cells on the ascites formation and the survival time was examined by using a nude mice model with malignant ascites by intraperitoneal inoculation of human ovarian cancer cells (HRA) derived from ascites of a patient with serous cystadenocarcinoma of the ovary. On 28 days after tumor inoculation, all nude mice in both untreated and spleen cells only treated groups formed ascites. Two of 10 nude mice treated with IL-2 only after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells only formed ascites by 14 days after tumor inoculation. When LAK cells and IL-2 were combined 5 of 10 mice survived without forming ascites during the experimental period. The survival time of the IL-2 only treated group was significantly prolonged, compared to that of medium only, spleen cells only and LAK cells only treated groups. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.

Adjuvant effects of calmodulin antagonists on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur) and a mixture of ftorafur and uracil (UFT) in nude mice bearing human ovarian carcinomas.

Effects of N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on antitumor activity of 1-(2-tetrahydrofuryl)-5-fluorouracil (ftorafur, FT) and a mixture of FT and uracil (UFT) were determined in nude mice bearing human ovarian carcinoma (KF cells). All nude mice developed palpable tumor 17 days after KF cell inoculation unless treated. A combination of UFT and calmodulin antagonists (W-5 and W-7) resulted in a delay in tumor formation in nude mice. One of 10 nude mice treated with a combination of UFT and W-5 and 3 of 10 nude mice treated with UFT and W-7 did not develop tumors during the experimental period. Tumor volumes in groups treated with the combinations of UFT and calmodulin antagonists were significantly smaller than those in the untreated group after 31 days of tumor inoculation. In addition, tumor volumes in a group treated with UFT plus W-7 were significantly smaller than not only those in the untreated group but also those in groups treated with UFT alone, FT alone, W-5 alone, or W-7 alone. The longest median survival time was also observed in the group treated with UFT plus W-7. 5-Fluorouracil (5-FU) content of the tumors of groups treated with FT plus W-5 or W-7 was similar to that of the group treated with FT alone. On the other hand, 5-FU content of a group treated with UFT plus W-7 was about twofold higher than that of a group treated with UFT alone. These results suggest that a synergistic effect of W-7 and UFT on inhibition of tumor growth and prolongation of survival time may result from accumulation of 5-FU in the tumor.

[Three cases of endobronchial hamartoma].

We reported three cases of endobronchial hamartoma. There were some difficulties in diagnosis of the disease by bronchoscopic examination, because the tumors were covered with normal bronchial epithelium. But X ray film and CT film contributed to the diagnosis when calcification of intra-bronchial tumor was observed. Three different modes of operation were performed as extirpation of tumor by wedge resection of upper lobe bronchus, sleeve resection of left S6 segmental bronchus, and right middle lobectomy.

[A case of chemotherapy by the transarterial catheter with reservoir against malignant lymphoma of the colon].

We had a case of malignant lymphoma of the colon with two lesions, one in the transverse colon and the other in the ascending colon. The tumor of the transverse colon was resected, but that of the ascending colon was unresectable. Chemotherapy was performed through the catheter with reservoir via the iliac artery into the right colic artery. Three months later, the tumor disappeared completely, and the ascending colon was resected. On histopathological examination, there was no lymphoma cell in the ascending colon. Chemotherapy by a transarterial catheter with reservoir is a new method of treatment against malignant lymphoma.

Effects of lymphokine-activated killer cells and interleukin-2 on the ascites formation and the survival time of nude mice bearing human ovarian cancer cells.

The effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lymphokine-activated killer (LAK) cells on the ascites formation and the survival time was examined using nude mice as a model, with malignant ascites produced by intraperitoneal inoculation of human ovarian cancer cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. Twenty-eight days after tumor inoculation, all nude mice in the untreated group and in the group treated with spleen cells alone formed ascites. Two of ten nude mice treated with IL-2 alone after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells alone had formed ascites 14 days after tumor inoculation. When LAK cells and IL-2 were combined, five of ten mice survived without forming ascites during the experimental period. The survival time of the group treated with IL-2 alone was significantly prolonged compared to the groups that received medium alone, spleen cells alone and LAK cells alone. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.

Prediction of clinical course and recurrence of human ovarian cancer by several serum tumor markers.

Measurement of serum tumor markers [lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBD), LDH-4, erythrocyte sedimentation rate (ESR), carcinoembryonic antigen (CEA), beta 2-microglobulin (beta 2M) and CA 125] was done before and after operation, and during the course of chemotherapy in 43 patients with advanced primary ovarian cancer. Pre-operative positive results for these serum tumor markers were 94.4% for CA 125, 62.2% for beta 2M, 54.8% for HBD, 51.3% for ESR and 46.5% for LDH, respectively. In a group of patients from whom most of the tumor mass had been removed, LDH, LDH-4 and HBD significantly declined after the operation, whereas in a group of patients with a large residual tumor after operation no significant change in any of the serum tumor markers examined was observed after operation. Except for CEA, all serum tumor markers in patients with complete response to chemotherapy significantly decreased after 3 courses of chemotherapy. From the analysis of predictive values for the recurrence of ovarian cancer, the most reliable tumor markers as a single marker appeared to be CA 125 and CEA, followed by ESR, LDH and LDH-4. However, in about 10% of cases, abnormal levels of CA 125 or CEA before treatment returned to the normal range after treatment and an increase in the other tumor markers was observed with a relapse of disease in the absence of an increase in CA 125 or CEA. These results suggest that in addition to such tumor markers as CA 125 or CEA, a combination assay of several tumor markers is necessary for monitoring of treatment of ovarian cancer.

Adjuvant effects of prostaglandin D2 to cisplatin on human ovarian cancer cell growth in nude mice.

Adjuvant effects of prostaglandin D2 to cisplatin on tumor growth were studied by using nude mice bearing HR cells derived from human ovarian carcinoma. Combinations of 0.2 or 0.4 microgram/ml cisplatin and 0.05 or 0.1 microgram/ml prostaglandin D2, which did not affect the HR cell proliferation alone, resulted in a significant inhibition of cell proliferation. In addition, tumor take of HR cells by nude mice in groups treated with a combination of cisplatin and prostaglandin D2 was inhibited. Although there was no significant difference between tumor volumes in mice treated with prostaglandin D2 alone or cisplatin alone and untreated mice, when cisplatin was administered with 1 mg/kg prostaglandin D2 the tumor volume was significantly smaller on days 21 and 35, compared to that of untreated mice. When cisplatin and 2 or 4 mg/kg prostaglandin D2 were combined, the tumor growth was significantly inhibited after day 21, compared not only to that of untreated mice but also of mice treated with cisplatin alone or prostaglandin D2 alone. Such a combination therapy by cisplatin and prostaglandin D2 seemed to result in prevention by prostaglandin D2 of immunological suppression which may be induced by cisplatin. Thus, such a combination therapy brought about a significant prolongation to the survival time.

Effects of cimetidine on interleukin-2 production by peripheral blood lymphocytes in advanced ovarian carcinoma.

The present study was designed to elucidate the effect of cimetidine on CD4 and CD8 positive cells, interleukin-2 (IL-2) production and IL-2 receptor expression in peripheral blood lymphocytes (PBL) from patients with advanced ovarian carcinoma during the course of combination chemotherapy. The absolute number of CD8 (but not CD4) positive cells in PBL from patients with advanced ovarian carcinoma before surgery was significantly higher than that with benign ovarian tumor, while the IL-2 productivity was significantly lower. However, the IL-2 receptor expression was comparable to that with benign ovarian tumor. When a combination chemotherapy consisting of cisplatin, adriamycin and cyclophosphamide was given to these ovarian cancer patients, the IL-2 production was markedly depressed. If cimetidine was given with the combination chemotherapy, the inhibition of IL-2 production by chemotherapy was significantly diminished with a significant increase of CD4 positive cells. On the other hand, the IL-2 receptor expression was not affected by this treatment. When treatment with cimetidine was initiated after completion of chemotherapy, the depressed IL-2 production was restored to the level of control patients with benign ovarian tumor. The restoration seemed to result from an increase in proportion of CD4 positive cells. However, the expression of IL-2 receptor remained unchanged even if cimetidine was given.

The mechanism of acquired resistance to cisplatin by a human ovarian cancer cell line.

The present study was designed to elucidate the mechanism of resistance to cisplatin. A cisplatin-resistant cell line (KFr) was established from KF cells derived from human serous cystadenocarcinoma of the ovary. The DNA histogram revealed an increase of S-phase cells and a decrease of G1-phase cells in cultured KFr cells, compared to that in cultured KF cells. Although the cisplatin content in the KF cells incubated with cisplatin at 10 micrograms/ml increased in a time-dependent manner, that in the KFr cells remained unchanged during the experimental period. When 0.5 mg of cisplatin was administered ip to nude mice with KF or KFr tumor, the cisplatin content in the KFr tumor was significantly lower than that in the KF tumor. The KFr cells showed a cross-resistance to L-phenylalanine mustard, while no cross-resistance to vincristine or 5-fluorouracil was observed. These findings suggest that the mechanism of cisplatin resistance in the KFr cells involves a decrease of cisplatin accumulation in the tumor cells.

[Effect of calmodulin antagonists (W-5 and W-7) on antitumor activity of Tegafur and UFT (Tegafur plus uracil)].

The effect of calmodulin antagonists (W-5 and W-7) on antitumor activity of 1-(2-Tetrahydrofuryl)-5-fluorouracil (Tegafur; FT) and FT plus uracil (UFT) was examined by using nude mice bearing human ovarian carcinoma (KF cells). All nude mice developed a palpable tumor 17 days after KF cell inoculation unless treatment was done. A combination of UFT and calmodulin antagonists (W-5 or W-7) resulted in a delay in tumor formation in nude mice. One of 10 nude mice treated with a combination of UFT and W-5 and 3 of 10 nude mice treated with UFT and W-7 did not develop tumors during the experimental period. Tumor volume in the treatment groups combined with calmodulin antagonists was significantly less than in those in the untreated group after 31 days of tumor inoculation. In addition, tumor volume in a UFT plus W-7 treated group was significantly less than those not only in the untreated group but also in the UFT alone, FT alone, W-5 alone and W-7 alone treated groups, suggesting a synergistic inhibitory effect on tumor growth. The longest median survival time was also observed in a UFT plus W-7 treated group. 5-Fluorouracil (5-FU) content in the tumor of groups treated with FT plus W-5 or W-7 was similar to that in a group treated with FT alone. On the other hand, that of a group treated with UFT plus W-7 was about 2-fold higher than that of a UFT -only treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Establishment of a cisplatin-resistant human ovarian cancer cell line and the mechanism of resistance].

A cisplatin-resistant cell line was established by using KF-1 cells derived from human serous cystadenocarcinoma of the ovary. This resistant cell line, designated "KFr", was capable of proliferating in the presence of 1.0 microgram/ml cisplatin. It had doubling times of 24.8 and 27.2 hr in the presence of 0.5 and 1.0 microgram/ml cisplatin, respectively. The morphologic characteristics of the KFr cells were an enlarged nucleus and prominent nucleoli, unlike the nucleus and nucleoli of the parent KF-1 cells. The degree of resistance to cisplatin of the KFr cells was about 20 times as great as that of the KF-1 cells, with regard to the concentrations of cisplatin required for 50% inhibition of cell proliferation. Although the cisplatin content in the KF-1 cells incubated with 10 micrograms/ml cisplatin was increased in a time-dependent manner, that in the KFr cells reached the plateau level after 1.5 hr incubation with cisplatin. After about 4 hr incubation, the cellular content in the KFr cells was about a half of that in the KF-1 cells. When 0.5 mg cisplatin was administered i.p. to nude mice with KF-1 or KFr tumor, the cisplatin content in the KFr tumor was significantly lower than that in the KF-1 tumor. The KFr cells showed a cross-resistance to melphalan, while no cross-resistance to vincristine or 5-fluorouracil was observed. When 5 microM W-5 or W-7 was added in the presence of concentrations of cisplatin that hardly inhibited cell proliferation, the KFr cell proliferation was markedly inhibited. These findings suggest that the cisplatin resistance in the KFr cells may be due to an impaired cisplatin-transport mechanisms and can be overcome by calmodulin antagonists.