Synergistic effect of methotrexate and 1-beta-D-arabinofuranosylcytosine on the generation of DNA strand breaks in a human promyelocytic leukemia cell line.

We investigated the accumulation of DNA strand breaks in a human promyelocytic leukemia cell line, HL-60, treated with methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (Ara-C). The sequential treatment with MTX then Ara-C had a synergistic effect on the formation of DNA strand breaks, which was dependent on MTX and Ara-C concentrations. On the other hand, when Ara-C preceded MTX, no such synergism was observed. The addition of both thymidine and hypoxanthine to this system, but not thymidine or hypoxanthine alone, abolished the synergism. Pretreatment with MTX augmented the generation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. However, this augmentation did not necessarily correlate with the amount of strand breaks. Whatever the underlying mechanism of this synergism is, our present data provide one possible biochemical basis for sequential MTX and Ara-C therapy.

Experimental and theoretical demonstration of validity and limitations in fringe-resolved autocorrelation measurements for pulses of few optical cycles.

Using 3.6- and 5.3-fs pulses, we demonstrated theoretically and experimentally that fringe-resolved autocorrelation (FRAC) traces are distorted by bandwidth limitations of the second-harmonic generation (SHG) in 10-microm-thick, type I ss-BaB2O4 for pulses shorter than sub-5 fs. In addition, detailed numerical analysis of the SHG showed that the optimum crystal angle where the FRAC trace distortion becomes minimum is in disagreement not only with the phase-matching angle but also with the angle where the FRAC signal intensity becomes maximum. Furthermore, the apparent pulse duration measured at a nonoptimum angle was confirmed to become shorter than that of its transform-limited pulse, in excellent agreement with the calculated result.

Preoperative laser photodynamic therapy in combination with operation in lung cancer.

Fifteen patients with lung cancer were treated by combined preoperative photodynamic therapy and operation. Preoperative photodynamic therapy was performed for the purpose of either reducing the extent of resection or increasing operability. Clinically, five patients had Stage I disease, two had Stage II, seven had Stage III, and one had Stage IV. There were two cases of tracheal invasion from primary foci, three cases of intrabronchial polypoid tumor or invasion of the carina by primary lesions, eight cases of polypoid tumor or invasion of the main bronchus, and two cases of double primary foci. Argon dye lasers were used in this study. Preoperative laser photodynamic therapy was performed 48 to 72 hours after intravenous administration of hematoporphyrin derivative. Therapeutic conditions were 60 to 600 joules for the superficial invasive areas and additional 200 to 800 mW for 8 to 15 minutes for polypoid tumors. Operation was performed 1 to 9 weeks after photodynamic therapy. The initial purpose of photodynamic therapy was achieved in 11 of 15 patients treated. In four of five originally inoperable cases, conversion to an operable condition was achieved. Ten patients were originally candidates for pneumonectomy, and it became possible to reduce the extent of resection to lobectomy or bilobectomy in seven of them. This study suggests that photodynamic therapy may have an important role in combination with operation and other modalities in advanced lung cancers.

Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: a prospective randomized study.

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.

Gastric remnant carcinoma after partial gastrectomy for benign and malignant gastric lesions.

BACKGROUND: A retrospective study was designed to evaluate the clinicopathologic characteristics and prognosis of gastric stump carcinoma (GSC) after gastrectomy for gastric adenocarcinoma. STUDY DESIGN: A comparison of the clinicopathologic features was made between 12 cases of GSC and 27 cases of remnant carcinoma (RC) following gastrectomy for adenocarcinoma. The various factors influencing survival of both groups of patients were evaluated separately and by multivariate analysis. RESULTS: Gastric stump carcinoma emerges late after initial gastrectomy and has a significant tendency toward lymph node metastasis. No difference was observed between the survival curves for patients with GSC or RC after gastrectomy for malignancy. Serosal invasion was the factor most affecting survival. CONCLUSIONS: Early diagnosis is most important for management of the disease, and only patients with T2 staged GSC according to the Union Internationale Contre le Cancer classification system might benefit from extensive lymphadenectomies.

Metastatic gastric lymph node rate is a significant prognostic factor for resectable stage IV stomach cancer.

BACKGROUND: Stage IV gastric carcinoma is rarely curatively resected and almost invariably carries a poor prognosis. Several clinicopathologic factors are involved, but lymphatic spread of the cancer may significantly affect survival. STUDY DESIGN: A retrospective study was designed to evaluate whether the nodal metastatic rate (number of lymph node metastases/number of resected lymph nodes) is a parameter of lymphatic spread and could provide a significant prognostic factor. Several prognostic factors were assessed by multivariate analysis in 153 stage IV gastric carcinoma patients with histopathologic data on nodal metastasis. RESULTS: A significant difference in survival was observed in the stage IV cancer patients with total nodal or gastric nodal metastatic rates < 50% versus those with rates > 50%. Multivariate analysis revealed that a total nodal or gastric nodal metastatic rate > 50% was a highly significant prognostic factor. The gastric nodal metastatic rate can be used in patients who do not undergo an extended lymphadenectomy. CONCLUSIONS: Lymphatic spread of gastric carcinoma expressed in terms of the total nodal or gastric nodal metastatic rate is a significant prognostic factor. The latter can be calculated without pathologic data derived from extended lymphadenectomy, and so it is universally applicable.

Visualization of routes of lymphatic drainage of the gallbladder with a carbon particle suspension.

BACKGROUND: Although carcinoma of the gallbladder frequently spreads lymphatically, few reports exist about the evaluation of routes of lymphatic drainage of the gallbladder by vital staining. The purpose of this study was to visualize drainage routes and the extent of lymphatic flow from the gallbladder by using vital staining with a carbon particle suspension (CH40). STUDY DESIGN: In 20 patients, 0.3 to 0.5 mL of carbon particle suspension was injected into first station nodes for the gallbladder, the cystic node or pericholedochal node, intraoperatively. After a Kocher maneuver was performed, lymph nodes and lymphatic vessels blackened by the stain were visualized macroscopically. RESULTS: Lymphatic pathways from the gallbladder were classified into three routes: right, left, and hilar. The right route, which ran along the common bile duct to the superior retropancreaticoduodenal node or the retroportal node and reached the para-aortic nodes, was stained in 95 percent of patients. The left route, which traveled toward lymph nodes medial to the hepatoduodenal ligament through the posterior aspect of the head of the pancreas, was stained in less than 50 percent of patients. Among lymph nodes along the left route, the posterior common hepatic node was most frequently stained (45 percent). The hilar route, which ascended toward the hepatic hilus, was stained in 20 percent of patients. CONCLUSIONS: These data demonstrate that the right route is a main pathway of lymphatic drainage from the gallbladder, while the left and hilar routes are branch lines. The para-aortic nodes, regarded as final regional nodes for the gallbladder, should be removed during radical surgery for advanced carcinoma of the gallbladder. Drainage along the hilar route may cause metastasis to the liver.

Surgical treatment of Borrmann type IV gastric carcinoma: relevance of lymphadenectomy in improving survival.

BACKGROUND: Borrmann type IV gastric carcinoma carries a poor prognosis, even if curatively resected. The benefit of a lymphadenectomy is unknown. STUDY DESIGN: A retrospective study was designed to evaluate whether improvements have been made in the treatment of type IV gastric carcinoma over the past decade. The 345 patients with type IV carcinoma who underwent laparotomy within a recent 16-year period were split into two groups: one group of patients who underwent laparotomy between 1977 and 1985, and the other between 1986 and 1992. Survival data were compared between these two groups and prognostic factors for type IV gastric carcinoma were assessed by multivariate analysis. RESULTS: A significant difference in survival was observed between the groups, both of which underwent curative resection, despite a lack of difference in background factors. The improvement was more prominent among patients with nodal metastases and insignificant among patients without nodal metastases. Multivariate analysis identified nodal metastasis as a major independent prognostic factor. CONCLUSIONS: An improvement in outcome was presumably achieved through extended lymphadenectomy. However, the survival rate remains unsatisfactory, and further advances in the treatment of this disease are needed.

The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM classification.

BACKGROUND: The number of metastatic regional lymph nodes determines the new pN categories in the 5th edition of the TNM classification. STUDY DESIGN: Our retrospective study was conducted to compare the new method of defining lymph node status with the conventional classification, consisting of the anatomic extent of lymph node metastases, a well-established prognostic factor. The study was based on clinical data for 493 patients with gastric carcinomas who underwent potentially curative operations and had histologically confirmed nodal metastases. These patients were stratified into 1) n categories according to the Japanese Classification of Gastric Carcinoma, 2) the new pN categories, and 3) the pN categories determined by the number of metastatic perigastric nodes resected by standard D1 gastrectomy. Survival data were analyzed for each group. RESULTS: The number of metastatic nodes after D2 lymphadenectomy reflected prognosis well and was shown by multivariate analysis to be a strong independent prognostic factor. When the classification was performed limited to the metastatic perigastric nodes, stage migration was evident, but the variable remained competent as a prognostic indicator. CONCLUSIONS: The number of metastatic nodes is a promising determinant in the new international stage classification.

Chemosensitivity of gastric-cancer using adhesive tumor-cell culture system.

A total of 91 specimens of surgically resected tumors from 80 patients with gastric cancer were assayed for chemosensitivity using an adhesive tumor cell culture system (Life Trac ATCCS assay). Seventy-eight specimens of 91 had sufficient number of cells to grow in culture and 64 (82%) were evaluable excluding 8 low growth and 6 fungus contaminations. Cells (3x10(3)/ml/well) were cultured for 14 days and exposed to drugs on days 3-8. The growing cells were confirmed as cancer cells by immunohistochemical staining using monoclonal antibody to cytokeratin, epithelial membrane antigen and vimentin. IC90 value against (ADM, CDDP, CPM, 5-FU, MMC, MTX, VP-16, CBDCA and MMC+5-FU+MTX) was determined and population distribution of IC90 for each drug was obtained to serve as basic data for judging sensitivity. The 10th percentile of IC90 (mug/ml) was 0.01, 0.43, 1.23, 0.23, 0.01, 0.005, 0.14, 1.56 and 0.009+0.05+0.003 and median of IC90 was 0.02, 0.99, 2.31, 0.30, 0.06, 0.01, 0.39, 3.19 and 0.02+0.10+0.005, respectively. Population distribution of IC90 against each drug showed a specific pattern. Profiles of IC90 against various anticancer drugs differed in individual patients. Chemosensitivity of lymph node metatases seemed to be more resistant than that of their primary tumors. The ATTCS test was found to be useful as a sensitivity test for anti-cancer agents because of its reliability and excellent quantification.

Surgical treatment of early gastric cancer.

Our investigation comprises 778 cases of resection for early gastric cancer (27.4% of all stomach resections). The rate of lymph node metastasis was 1.2% in m (mucosal cancer) group, 3.3% in sm (submucosal cancer) 1 group and 22.6% in sm 2 group. In sm 2 group, lymph node extirpation of R2 is essential. The five year survival rates were 94.1% in the m group, 94.1% in the sm 1 group and 94.1 in the sm 2 group, respectively. The rate of recurrence of m group was 0.6%, against 3.3% for sm 2 group. Sm 2 with well-differentiated, n(+) and Borrmann types are high risk groups. Adjuvant chemotherapy is necessary to obtain improved surgical results for the high risk groups. Cases of early gastric cancer exist which are beyond help by surgical means.

The surgical treatment of cancer of the stomach.

From 1965 to 1977, 2421 patients with gastric cancer underwent operation in our hospital. 66% were males (mean age 55.9 years) and 34% females (mean age 52.2 years); 31% had a mucosal (m) and submucosal cancer (sm); 16.8% had intramuscular cancer (pm); a curative operation was performed in 62.0% of cases. The five and ten year survival rates of the advanced cancer group are 52.5% and 42.3%, whereas in the early cancer cases they are 95.0% and 85.4% respectively. These five and ten-year survival rates are significantly lower in patients with lymph node metastasis (43.3% and 35.4%). Thirty five per cent of the patients who underwent resection from 1957 to 1963 required an enlarged total gastrectomy, compared with 15% in the present series.

Measurements of gaze movements while driving.

In this study, gaze movements of drivers driving through an intersection were investigated. Gaze movements of drivers in large vehicles were compared with those in small vehicles. There were both similarities and differences in the visual search behaviors of drivers of large and small vehicles. The two groups were similar in that, when approaching an intersection, drivers made repeated saccadic gaze movements; after entering the intersection, saccadic gaze movements were directed ahead in the direction of turning. Differences arose in the frequency and distribution of gaze movements. The number of gaze movements was significantly greater in drivers of large vehicles. The distribution of gaze movements in driving a large vehicle showed a peak at the point 50 to 60 degrees to the right and left of the median plane of the driver. The distribution of gaze movements of drivers of small vehicles showed no peak across the visual field.

[Prostaglandin E1 (PGE1) prevents the pressure responses to tracheal intubation in hypertensive patients].

Forty-five hypertensive patients for elective abdominal surgery were investigated regarding the effects of PGE1 on the cardiovascular responses to tracheal intubation. Administration of PGE1 at the dose of 0.10 or 0.20 micrograms.kg-1.min-1 for 10 minutes before tracheal intubation significantly reduced the blood pressure responses immediately after the intubation and 2 minutes later. The increases in heart rate were not altered with and without the administration of PGE1. So the increases in rate pressure products were markedly reduced with PGE1 compared with the control values. Plasma concentration of catecholamines was measured before and after tracheal intubation. Norepinephrine was elevated markedly immediately after the intubation and this change was not affected by the infusion of PGE1. These results demonstrate that PGE1 ameliorates the pressure responses by the release of norepinephrine and thus reduces the increases in rate pressure products immediately after tracheal intubation.

[Clinical use of prostaglandin E1 during intracranial surgery].

Prostaglandin E1 was administered to 19 patients to induce hypotension during intracranial surgery. Urine volume during the operation and after the first day was well maintained, and serum BUN and creatinine were within normal ranges after the surgery. Serum GOT and GPT increased significantly on the 7th and 14th day after the operation compared with the control, but this did not seem to be the results of PGE1 administration. LDH and ALP showed no significant change. Thirty minutes and two hours after the administration of PGE1, arterial blood oxygen tension decreased significantly. These results suggest that PGE1 does not adversely affect the liver and kidneys, and it can be used safely and is useful to control blood pressure during intracranial operation.

[Surgical treatment of gastric cancer based on biological behavior].

In this paper, we discuss the biological behavior considered important in surgical treatment for gastric cancer. Of the types of early gastric cancer, the Borrmann type, the histologically well differentiated type and that with metastasis to the lymph nodes belong to the high-risk group. In pm gastric cancer where cancer has infiltrated to the muscularis gropia, nearly 50% metastasis to the lymph node is observed. This is a therapeutic group for which removal of the lymph nodes is most effective. Of pm gastric cancer, the prognosis of the well differentiated type is poor. Adjuvant chemotherapy proves considerably effective for this type. When the relationship between the histologic type and prognosis is examined, the prognosis of the well differentiated type in pm is poor. As the cancer infiltrates to ss, and se, the prognosis of the poorly differentiated type, particularly the scirrhous type, becomes poor. Of the Borrmann IV type with the poorest prognosis among the various types of gastric cancer, there are two kinds, namely, that with a relatively good prognosis and the other with a very poor prognosis. The two can be classified macroscopically. These two groups appear to be different from each other in their biological behavior. Gastric cancer in the aged has a high percentage of metastasis to the lymph nodes, being characterized by a high incidence of Borrmann II type and multiple cancer. The prognosis is not necessarily poor.

[Problems of surgical management of Borrmann's type IV stomach cancer--with special reference to subdivision of Borrmann's type IV].

Type IV of Borrmann's classification was subdivided into IVa and IVb according to the gross aspect of the mucosal surface of surgical specimens. Type IVa indicates the presence of slight elevation or depression, type IVb includes the rest of type IV. Of 2682 gastrectomized patients, 151 (5.6%) were classified as type IVa and 253 (9.4%) as type IVb. The 5-year survival rate of patients with type IVa who underwent curative gastrectomy was 36.0%; of patients with type IVb it was 17.5%. The difference in these survival rates was statistically significant. Between types IVa and IVb, there were no significant differences with respect to serosal invasion, lymph node metastasis, tumor size, and age and sex distribution. Therefore, other clinical and/or biological factors should be considered as reasons for the difference in the survival rates between these two groups. From this point of view, subdivision Borrmann's type IV is useful in evaluating the postoperative prognosis.

[Surgical results of scirrhous carcinoma of the stomach].

Type IV of Borrmann's classification is divided into subtypes IVa and IVb on the basis of gross characteristics of the mucosal surface of surgical specimens. Subtype IVa indicates the presence of slight elevation or depression; subtype IVb includes the rest of type IV. The five-year survival rate for patients who had undergone curative gastrectomy was 36.4% for subtype IVa and 15.0% for subtype IVb. The difference in these rates was statistically significant. No significant differences between subtypes IVa and IVb were found, however, with respect to serosal invasion, lymph node metastasis, tumor size, or age or sex distribution. Other clinical and biological factors must therefore be considered to explain these differences in survival rate. The five-year survival rate was 14.3% in patients with scirrhous carcinoma of subtype IVb, and 84.8% in those with scirrhous carcinoma simulating early carcinoma.

[A case of breast cancer with multiple bone metastases effectively treated with UFT and tamoxifen].

A 51-year-old female with advanced breast cancer involving multiple bone metastases was daily administered 400 mg of UFT and 20 mg of tamoxifen. X-ray examination revealed remarkable osteosclerosis. Laboratory data revealed a high serum alkali phosphatase level of 820 mU/ml(at 3 months), which gradually decreased to 274 mU/ml with pain relief at 11 months after the beginning of this chemotherapy.

[Factors in the prognosis of early gastric cancer].

Prognosis factors for 1,012 subjects who underwent gastrectomy for early gastric cancer were studied over a 21-year period from 1965 to 1985. We divided submucosal cancer (sm) into two subgroups, classifying the one as sm II-1 with small cancerous nests in the submucosa and the other as sm II-2. Our cases of early gastric cancer fell into the following groups: m(mucosal cancer), 451 cases; sm II-1, 106; sm II-2, 396 and multiple cancer, 59. The rate of lymph node metastasis was 1.1% in the m group, 5.7% in the sm II-1 group, 24.5% in the sm II-2 group and 6.8% in the multiple group. Gastrectomy with removal of the second-group lymph node proved adequate for sm II-2 group. The five year survival rate was 94.5% in the m group, 94.9% in sm II-1 group, 93.6% in the sm II-2 group and 91.7% in the multiple cancer group. The rate of recurrence in m group was 0.9%, against 3.3% for sm II-2 group. The sm II-2 with histologically well-differentiated type, n(+) and macroscopically Borrmann type are high-risk groups. Adjuvant chemotherapy is necessary to obtain improved surgical results for the high risk group. There was a total of 21 non-curative resection cases among which distant metastases were observed. Cases of early gastric cancer exist which are beyond help by surgical means.