5'-deoxy-5-fluorouridine, medroxyprogestrone acetate and mitoxantrone hydrochloride for advanced or recurrent breast cancer.

BACKGROUND: In treating advanced or recurrent breast cancer, anthracycline-containing chemotherapy is used for palliation and to maintain quality of life. However, there are several drawbacks including therapeutic failure and cardiotoxicity. We evaluated the efficacy and toxicity of combination chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR), medroxyprogestrone acetate (MPA) and mitoxantrone hydrochloride (MIT). METHODS: Sixteen patients with advanced or recurrent breast cancer were enrolled. Chemotherapy was given in a 28-day cycle, starting with MIT 10 mg/m2 intravenously on day 1, then oral 5'-DFUR 800 mg and MPA 800 mg daily. Two or more cycles were given. RESULTS: Fifteen patients were assessable for response and toxicity. Thirteen patients had been treated previously with an anthracycline containing regimen and 2 with CMF. There were 2 partial response patients (13.3%) and 1 complete response patient (6.7%). There were 11 patients showing no change (NC) (73.3%), one of whom was a minor responder and 7 with a long period of NC. There was only one with progressive disease patient. The overall response rate was 20.0%. Adverse events occurred in 5 patients (33.3%). Myelosuppression was the most common with 5 patients becoming leukopenic (33.3%). Nausea/vomiting was the second most common side effect, affecting 2 patients (13.3%). CONCLUSION: Given its high efficacy and preservation of QOL, the combination of MIT, 5'-DFUR and MPA can be a 2nd or 3rd line therapy for advanced or recurrent breast cancer, especially for anthracycline-resistant cases.

Relationship between nodal stage and the number of dissected perigastric nodes in gastric cancer.

To evaluate the rationality of the current nodal staging system in gastric cancer, we retrospectively analyzed 152 patients with perigastric node involvement localized to a single station, in whom the route of metastasis to distant nodes was limited. No significant differences in pathology or survival were observed between patients with stage n1 and those with stage n2-3 nodal involvement, but the mean (standard deviation) number of perigastric nodes dissected was 22.6 (12.6) in those with stage nl involvement and 18.5 (9.5) in those with stage n2-3 involvement (P = 0.04). When perigastric node involvement was localized to station 3, the mean number of dissected station 3 nodes was 7.7 (4.2) in nl patients and 5.3 (2.8) in n2-3 patients (P = 0.04). This tendency was also observed in patients with perigastric node involvement limited to either station 1 (P = 0.08) or station 6 (P = 0.11). Thus, patients with fewer perigastric nodes may have more lymphatics that bypass perigastric nodes and empty directly into distant nodes, increasing the likelihood of skip metastases. The number of positive nodes, affected to a lesser degree by lymphatic distribution than the location of positive nodes, should be incorporated into the staging criteria.

Prognostic significance of extranodal microscopic foci discontinuous with primary lesion in rectal cancer.

PURPOSE: The most common recurrence after curative resection of rectal carcinoma originates from tiny, undetectable residual foci within the pelvic cavity. The significance and methods used to predict the presence of extramural and extranodal microscopic cancer foci discontinuous with the main lesion of rectal cancers were investigated. METHODS: Four hundred twenty-seven patients who underwent resection of rectal carcinoma were studied. All resected specimens were examined for histologic evidence of extramural cancer separate from the main lesion. RESULTS: Extramural cancers not in continuity with the main rectal lesion were classified as follows: 1) extranodal microscopic cancers; 2) large tumor nodules; 3) lymph node metastases. Each classification was found to influence long-term prognosis. Among them, microscopic cancer was thought to be especially relevant because, by virtue of its microscopic nature, it may be left in the pelvic cavity, causing local recurrence. The existence of large tumor nodules and metastatic lymph nodes correlated closely with the presence of microscopic cancer. Because large tumor nodules and lymph node metastases are possibly detectable during the operation by palpation and may be analyzed by microscopic frozen sections, they might be useful predictors of the presence of microscopic cancers. CONCLUSIONS: In cases with extensive local rectal cancer spread, the nerve-sparing rectal resection that omits lateral dissection may be insufficient for local control because of incomplete removal of occult microscopic cancer, resulting in local recurrence. Presence of microscopic cancer correlates closely with large tumor nodules and metastatic lymph nodes. Intraoperative frozen section investigations may, thus, help in deciding on extent of location resection.

The potential role of fecal carbonic anhydrase II in screening for colorectal cancer.

Several studies have demonstrated a relationship between mucosal carbonic anhydrase (CA) isoenzymes, particularly CA II, and cancer of the large intestine. Recent work has suggested the potential usefulness of fecal CA assay for colorectal cancer screening. This clinical study examined the accuracy of fecal CA II as a marker of adenocarcinoma of the colon and rectum. An enzyme-linked immunosorbent assay was used to measure CA II in urine, serum, and stool samples from 31 colorectal cancer patients and 26 control subjects. An immunochemical fecal occult blood test was also performed in all study participants. Urine and serum CA II were similar in the two study groups. However, both the prevalence and the mean level of fecal CA II in the cancer patients were significantly higher than those in the control group. The detection rate for CA II in the stool was 65 per cent for the cancer patients versus 4 per cent for the control population. The fecal CA II test was similar in sensitivity and specificity to the immunochemical fecal occult blood test (65 vs 48%; 96 vs 100%). Measurement of fecal CA II might be useful in screening for colorectal cancer.

Expression of wild-type p53 tumor suppressor gene and its possible involvement in the apoptosis of thyroid tumors.

A good prognosis is often achieved in patients who have undergone treatment for human papillary carcinoma of the thyroid. On the assumption that this may be partly attributable to an apoptotic tendency of this special type of tumor, we measured DNA fragmentation, cell death by enzyme-linked immunosorbent assay (ELISA), and the expression of apoptosis-related genes. DNA fragmentation occurred more extensively in malignant tumor cells than in benign thyroid tumors or normal thyroid tissue, as examined by agarose gel electrophoresis and confirmed by the quantitative method using an ELISA kit. Although only expression of the tumor suppressor gene, p53, was increased in the tumor tissue, no expression of other genes, such as Fas, TNF, c-myc, c-fos or bcl-2, was observed in the normal, benign, or malignant tumor tissues, indicating that the roles of these gene functions, if any, were minimal in these tissues. Since p53 is closely related to cellular apoptosis and no point mutation was observed in the transcripts expressed by malignant cells, apoptosis and/or the production of an angiogenesis inhibitor induced by wild-type p53 molecules may be related to the favorable prognosis of patients treated for papillary carcinoma of the thyroid.

Immunohistochemical staining for the p53 protein and proliferating cell nuclear antigen in familial clustering of gastric cancer.

UNLABELLED: Purpose of this study was to assess the role of p53 gene and tumor proliferating activity in familial clustering of gastric cancer. MATERIALS AND METHODS: Among 344 patients who underwent resections for gastric cancer, 10 patients had two or more gastric cancer-affected, first-degree relatives. We classified them as the group of gastric cancer with family history (FGC). Eighty-seven patients with gastric cancer who had no relatives with any malignant neoplasm were classified as the sporadic group. The paraffin-embedded specimens were stained immuno-histochemically using monoclonal antibodies against the p53 product and proliferating cell nuclear antigen (PCNA). RESULTS: There was no significant difference in any clinicopathologic factor and the PCNA labeling index between the two groups. Staining for the p53 product was positive in 80% of the FGC group and in 38% of the sporadic group (P < 0.05). CONCLUSION: Our study suggests that overexpression of p53 protein is one of the familial factors that correlates with carcinogenesis in the stomach.

A clinical study on the significance of platelet-activating factor in the pathophysiology of septic disseminated intravascular coagulation in surgery.

BACKGROUND: To investigate the characteristic differences between disseminated intravascular coagulation (DIC) found in surgical sepsis (septic DIC) and those found in patients with advanced gastrointestinal cancer (cancer DIC), we focused on two substances, endotoxin and platelet- activating factor (PAF). PATIENTS AND METHODS: Coagulation test values were determined in 36 patients with DIC, and endotoxin and PAF concentrations in 13 of these patients. Seven septic patients were given a PAF antagonist to evaluate its usefulness in treating thrombocytopenia. RESULTS: Blood PAF and endotoxin concentrations were higher in patients with septic DIC, but they were almost normal in those with cancer DIC. Blood PAF concentrations showed a strong positive relationship to endotoxin only in septic DIC. There was a negative correlation between PAF concentrations and platelet counts in septic patients; platelet counts gradually increased after the administration of a PAF antagonist. CONCLUSIONS: PAF is inversely associated with platelet counts in patients with septic DIC. A PAF antagonist showed marked inhibitory effects on the characteristic changes of septic DIC, especially thrombocytopenia.

Thymidylate synthase inhibition by an oral regimen consisting of tegafur-uracil (UFT) and low-dose leucovorin for patients with gastric cancer.

PURPOSE: 5-Fluorouracil (5-FU) remains a standard therapy for patients with advanced gastric cancer. There has been no study using an oral regimen with a combination of tegafur, a masked compound of 5-FU, and leucovorin in gastric cancer. The purpose of this study was to determine whether orally administered low-dose leucovorin enhances thymidylate synthase (TS) inhibition when added to tegafur-uracil (UFT) in patients with gastric cancer. METHODS: A group of 26 patients with resectable gastric cancer were assigned to one of two regimens: UFT alone or UFT plus leucovorin. UFT, equivalent to 400 mg/day tegafur, with or without 30 mg/day leucovorin, was administered orally in divided daily doses every 12 h for 3 consecutive days prior to surgery. Tumor specimens were taken immediately following gastrectomy, and the TS inhibition rate (TSIR) was determined using a ligand-binding assay. RESULTS: The TSIR was significantly higher in the UFT plus leucovorin group than in the UFT alone group (P < 0.01). The TSIR in the patients treated with UFT alone ranged between 14% and 50%, while six of the eight patients treated with UFT plus leucovorin had a TSIR of 55% or higher. The remaining two patients in the group treated with UFT plus leucovorin, with a TSIR of 31% and 44%, had undifferentiated tumors. CONCLUSION: Our results suggest that orally administered low-dose leucovorin can add to the efficacy of UFT in patients with gastric cancer, and provide preliminary data for a randomized clinical trial.

Clinical and prognostic characteristics of papillary clear carcinoma of stomach.

Papillary clear carcinoma (PCC), a variant of gastric papillary adenocarcinoma, demonstrates the histologic features of cancer cells with clear cytoplasm and no nuclear polarity, resembling the primitive gut epithelium of the fetus. To clarify the clinical and prognostic characteristics of PCC, we examined operative specimens from 73 patients with gastric papillary adenocarcinoma. Light microscopic examination of hematoxylin and eosin (H&E) stained sections of specimens from 15 patients revealed the features of PCC. The patients with PCC demonstrated a higher incidence of Type 3 gross appearance, tumor invasion into the muscularis propria or beyond, involvement of distal lymph nodes, liver metastasis, elevated serum AFP concentrations, and palliative resections. In two subsets of patients who underwent curative resections of tumors invading the muscularis propria or beyond, those with PCC were found to have a significantly lower survival rate than those with other types of papillary adenocarcinoma (P < 0.05). PCC histology was a significant prognostic determinant according to multivariate analysis with the Cox proportional hazards model. We conclude that this subclassification of papillary adenocarcinoma, based on the cellular findings, is a useful prognostic indicator, and that intensive adjuvant therapy may be indicated for patients with the features of PCC, even if they have undergone curative resections.

Surgical strategy for patients with gastric carcinoma with submucosal invasion. A multivariate analysis.

BACKGROUND: Early gastric cancer can be treated by endoscopic excision or simple wedge surgical resection. Standard gastrectomy often is advised if submucosal invasion is found, even though only 15-25% of these patients have lymph node metastases. In this study, the risk of lymph node involvement was examined by multivariate analysis to develop a simple discriminant function for surgical decision making in this setting. METHODS: The authors determined factors significantly correlated with lymph node involvement in a retrospective review of 196 patients with gastric adenocarcinoma invading into, but not beyond, the submucosa. Depth and horizontal spread of cancer in the submucosa were evaluated in addition to ordinary pathologic factors. Discriminant analysis for lymph node involvement was performed using explanatory variables chosen from the results of the univariate analyses. RESULTS: Lymph node involvement correlated significantly with larger tumor size; greater dimension of submucosal invasion; deeper submucosal invasion; gross appearance of Type I, IIc + III or IIa + IIc; and severity of vessel invasion. Of the variables, the amount of lymphatic invasion, macroscopic appearance, and maximum dimension of submucosal infiltration were selected as effective predictors of lymph node involvement according to discriminant analysis. A correct discrimination of 74.8% was obtained with a linear discriminant function using these variables. Lymph node involvement was observed in 50% of the cases with a discriminant score less than -1 and in 25% of those with a score between -1 and 0, whereas no lymph node involvement was observed in those with a score greater than 2. CONCLUSIONS: Discriminant function as used in this study provided a useful criterion for additional surgery for patients with gastric carcinoma invading the submucosa who were treated initially by localized excision. Prophylactic lymph node dissection may not be necessary for a discriminant score greater than 2, whereas extended lymphadenectomy would be recommended for a score less than -1.

Long-term results of curative resection of "minimally invasive" colorectal cancer.

PURPOSE: The aim of this study was to determine the long-term outcome after curative resection of colorectal cancers that extend only into the submucosa ("minimally invasive") and to evaluate potential histologic predictors of lymph node metastases. METHODS: Seventy-nine patients who underwent curative resection of minimally invasive colorectal cancer and were followed for at least five years were studied retrospectively. RESULTS: The series was comprised of 53 men and 26 women, with a mean age of 61 years. The lesion was in the colon in 47 patients and the rectosigmoid or rectum in 32 patients. Open surgery followed attempted endoscopic tumor removal in 25 patients. Lymph node metastasis, found in 11/79 patients (13.9 percent), was associated with worse outcome: 36.4 percent of node(+) patients developed recurrence, vs. only 5.9 percent of node(-) patients (P < 0.005). The cumulative survival rate was also worse in node(+) vs. node(-) patients: 72.7 percent vs. 91.1 percent at five years (P < 0.05) and 45.5 percent vs. 65.3 percent at ten years (P < 0.05). Five histopathologic characteristics were identified as risk factors for lymph node metastasis: 1) small clusters of undifferentiated cancer cells ahead of the invasive front of the lesion ("tumor budding"); 2) a poorly demarcated invasive front; 3) moderately or poorly differentiated cancer cells in the invasive front; 4) extension of the tumor to the middle or deep submucosal layer; 5) cancer cells in lymphatics. Whereas patients with three or fewer risk factors had no nodal spread, the rate of lymph node involvement with four or more risk factors was 33.3 percent and 66.7 percent, respectively. CONCLUSIONS: Metastasis is not infrequent in "minimally invasive" colorectal cancer. Appropriate bowel resection with lymph node dissection is indicated if such a lesion exhibits more than three histologic risk factors for metastasis.

The Urinary Excretion of Pyridinium Cross-links as Markers of Bone Meta stasisin Breast Cancer.

The collagen cross-links, pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) excreted in urine have recently been suggested as new markers of bone metastasis. In a pilot study we measured Pyr and D-Pyr in 61 patients with breast cancer, 16 with known bone metastasis and 45 with no recognized metastasis in bone. Twenty healthy female subjects were also measured as controls. The mean values (+/-SD) of Pyr and D-Pyr in the group with bone metastasis were significantly higher (Pyr: p<0.01, D-Pyr: p <0.05) than those in the group without bone metastasis and in the control group. The mean (+/-SD) values of postmenopausal women were significantly higher than those of premenopausal in the group without bone metastasis (p<0.05) and in the control group (p<0.01). Therefore, the effect of menopause should be taken into account in the diagnosis of bone metastasis by assays of Pyr and D-Pyr. Setting the cut-off values (mean + 2SD of the values of control) for pre and postmenopausal patients, the accuracy for Pyr was 71.4% in premenopausal and 75.8% in postmenopausal patients; and for D-Pyr it was 71.4% and 78.8% respectively. We consider that measurement of urinary collagen cross-links assays can contribute to the early detection of metastatic spread to bone in breast cancer.

A Case of Stromal Sarcoma of the Breast Coexisting with Noninvasive Ductal Carcinoma.

This paper describes a very rare case of stromal sarcoma of the breast coexisting with simultaneous noninvasive ductal carcinoma in the same breast. A 75-year-old female was seen at our hospital for a lump in the right breast. On physical examination, a 10 x 8 cm well-difined and movable hard mass with a smooth surface was palpated in the upper outer quadrant of the breast. Aspiration cytology suggested a non-epithelial tumor with marked dysplasia (class 3b). Drill biopsy revealed probable stromal sarcoma. Simple mastectomy and axillary lymphonode sampling was performed. Histologically, the tumor was stromal sarcoma in the upper outer quadrant of the breast. In addition, noninvasive ductal carcinoma was simultaneously detected in the upper inner quadrant of the breast as an independent lesion. No positive axillary nodes were found. To date, as far as we could investigate, there was no preceding case report of both stromal sarcoma and carcinoma in the single patient at the same time.

Roles of histological findings and serum AFP levels in the prognosis of AFP-producing gastric cancers.

We investigated the roles of histological findings and serum AFP levels in the prognosis of gastric cancers which produce AFP. We considered the typical features of such gastric cancers to be the medullary growth of undifferentiated cancer cells with clear, or slightly eosinophilic, abundant cytoplasm and pleomorphic large round nuclei, forming either papillary clear carcinomas or hepatoid carcinomas. Seventeen patients with AFP-producing gastric cancers were observed in the period, 1979-1991. They were divided into two groups: those with (n 5) and those without (n 12) the typical histological features mentioned above. Their clinicopathological findings and prognoses were compared. Both groups showed a male dominance, gross Borrmann's type 2 or 3 appearances, diagnoses made at an advanced stage and metastatic involvements of the liver. The patients with the typical histological features showed a significantly higher AFP serum level and a significantly shorter survival. The patients who lacked the typical findings, and with serum AFP levels > or = 100 ng/ml, had poorer prognoses, while those lacking the typical histological features, and serum AFP levels < 100 ng/ml had better prognoses. The combination of histological findings and serum AFP level appeared to be useful in predicting the prognosis of AFP-producing gastric cancers. Intensive adjuvant therapy, e.g., chemotherapy administered via hepatic arterial infusion, may be indicated for patients at a high risk of recurrence following curative surgery.

Massive intestinal bleeding caused by an ileal arteriovenous malformation: report of a case.

We report herein the case of a 43-year-old man in whom gastrointestinal bleeding was found to be caused by a large arteriovenous malformation (AVM) in the ileum. Emergency angiography proved invaluable in disclosing the AVM as the bleeding source, after which the patient was successfully treated by surgery. Although the number of reports of AVM has recently been increasing, ileal AVMs are still relatively rare. Moreover, according to the Japanese literature, no other patient has had such marked and large feeding arteries and draining veins as those in the patient described in this report.