Biomedical subjects
Publications and source records attributed to F Kasumi.
In the Cancer Institute Hospital, two kinds of breast conservation have been adopted. Q + Ax is applied for cancers at the upper--outer quadrant and LUART is applied for those at other quadrants. The method, clinical matters, pathological findings and results are discussed together with the LUART of the national BCT group study funded by the Japanese Ministry of Welfare.
Using 11 restriction fragment length polymorphism markers, we examined loss of heterozygosity on the long arm of chromosome 17, where one or more genes responsible for hereditary breast and ovarian cancers may be present, in sporadic forms of 94 ovarian and 246 breast cancers. Loss of heterozygosity was observed in 33 of 84 (39.3%) ovarian and in 88 of 214 (41.1%) breast cancers that were informative with at least one marker. Detailed deletion mapping of chromosome 17q in these cancers identified two distinct, commonly deleted regions. One was located between 17q12 and 17q21.3 and the other between 17q25.1 and 17q25.3. In breast cancers, the proximal commonly deleted region was between two loci defined by markers CI17-701 and CI17-730 at 17q21.3, which are 2.4 cM apart. This segment overlaps the region that includes the putative gene for hereditary breast and ovarian carcinomas. The results suggest that at least two tumor suppressor genes associated with sporadic ovarian and breast cancers are present on chromosome 17q and that one of them may be the same gene that is responsible for the hereditary form.
From chromosomal region 17q21.3, where a tumour suppressor gene(s) for breast and ovarian cancers is thought to be present, we have isolated a novel gene from a cosmid clone that revealed somatic rearrangements in two breast cancers. The gene (MDC) encodes a 524-amino acid metalloprotease-like, disintegrin-like and cysteine-rich protein with sequence similarity to members of the snake-venom metalloprotease/disintegrin family and guinea-pig sperm-surface protein PH-30. These proteins have been implicated in cell-cell or cell-extracellular matrix interactions. Rearrangements in both tumours involve multiple exons and disrupt the coding region of the new MDC.
To examine the role of loss of heterozygosity (LOH) during tumor development and/or progression, we looked for correlations between metastasis of breast cancer to a regional lymph node(s) and LOH of chromosomal arms 11p, 13q, 16q, 17p, and 17q, where frequent losses in primary tumors have been detected. No correlation between lymph node metastasis and LOH of chromosomes 13q, 16q, or 17q was observed. However, tumors showing LOH of chromosomes 11p (chi 2 = 10.82, P less than 0.01) and 17p (chi 2 = 6.78, P less than 0.01) revealed a significantly higher incidence of metastasis to a regional lymph node(s) than tumors without LOH on these chromosomal arms. Furthermore, only four of 30 (13%) patients with tumors that retained both 11p and 17p had metastasis to a regional lymph node(s), compared with 24 of 32 (75%) patients with tumors that had lost both 11p and 17p. Analysis of LOH with markers on chromosomes 11p and 17p in a large number of tumors indicated that the peritelomeric region of each of these chromosomal arms contains a tumor suppressor gene that may be associated with tumor progression, particularly metastasis to a regional lymph node(s).
A gene called "prohibitin" was isolated as a candidate antiproliferating gene in rat liver cells. We have isolated the human homologue of the rat prohibitin gene and mapped it to chromosome 17q12-21 where a gene responsible for hereditary breast cancer was localized. DNA sequence analysis of 2 exons in this gene in 23 sporadic breast cancers, which showed loss of heterozygosity on the long arm of chromosome 17 or developed in patients 35 years old or younger, identified 4 cases of somatic mutation; 2 of these were missense mutations; 1 showed a 2-base deletion resulting in truncation of the gene product due to a frame shift; the other had a C to T transition in an intron adjacent to an intron-exon boundary. These results suggest that this gene may be a tumor suppressor gene and is associated with tumor development and/or progression of at least some breast cancers.
In a retrospective multicenter study to investigate the correlation between estrogen (ER) and/or progesterone receptors (PgR) in primary breast cancer with patient prognosis, 3118 patients with operable breast cancer (International Union Against Cancer Stages I, II, and III) were investigated from ten hospitals in Japan who underwent surgery from October 1972 to December 1982; 3089 were evaluable. The ER-positive and PgR-positive cancers were found in 56% and 34% of patients, respectively. The positivities decreased as the tumor size increased but were independent on lymph node metastasis. There were no significant differences in relapse-free survival (RFS) in relation to receptor status (median follow-up, 89 months [ER], 84 months [PgR]). However, in patients with four or more positive nodes, those with PgR-positive cancer had a longer RFS. The patients with ER-positive cancer survived significantly longer than ER-negative ones, with the greatest difference seen in those with four or more positive nodes. There was a significantly longer postrelapse survival (PRS) for patients with ER-positive cancer because of the different distribution of the major metastasis and better responses to first-line and subsequent treatments. Cox's multivariate analysis showed that overall survival but not PRS was affected by ER (and more weakly by PgR) because of the longer PRS in patients with ER-positive cancer.
To study the effects of family history and reproductive, anthropometric, and dietary factors on the risk of breast cancer among low risk populations, we conducted a hospital-based case-control study involving 908 patients with breast cancer and their matched controls, in Japan. A positive family history of breast cancer significantly increased the risk of breast cancer (odds ratio = 1.52, 95% confidence interval: 1.14-2.03). The risk further increased with increasing number of family members affected. Obesity, single marital status, fewer births, a late childbirth, and less consumption of green-yellow vegetables and dairy products were also associated with an increased risk of breast cancer. These associations were independent in multivariate analyses. There was no increase in risk associated with consumption of high fat foods. When analyzed by menopausal status, the association with family history of breast cancer, especially in the first degree of relatives, was more evident for premenopausal breast cancer. The associations with obesity and lower consumption of dairy products were more pronounced for postmenopausal breast cancer, while those with lower parity and single marital status were stronger for premenopausal breast cancer.
We have examined the amplification unit at chromosome band 11q13 in 12 primary tumors and one cancer cell line (A431) with 15 DNA markers. The amplified region and size varied from one tumor to another; the smallest amplicon was estimated to be 700 kb long and the largest was 4.5 Mb long at maximum, on the basis of a physical map. Furthermore, the DNA amplified in tumors was not always continuous, because in three cases one locus within the amplicon was not amplified. The amplified region common to all 13 cancers consisted of 500 kb of DNA which incorporated eight defined loci (BCL-1, cCI11-524, cCI11-283, cCI11-234, HBI-1, cCI11-454, HSTF1, and INT2). As two of them, cCI11-524 and cCI11-454, were found to contain DNA sequences conserved in other species, one or both of these loci might encode the gene(s) that may be associated with progression of these tumors.
Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation were clarified by means of a case-control study of matched non-pregnant and non-lactating patients with breast cancer. From 18 institutions in Japan, a total of 192 subjects with breast cancer diagnosed during pregnancy (72 cases) and lactation (120 cases) were collected between 1970 and 1988, accounting for 0.76% of all breast cancer patients. The duration of symptoms was longer and tumor size was larger in the study subjects. Although the disease-free interval was longer than that in the control patients, the survival time was shorter. There was no characteristic difference in histologic type. Vascular invasion and lymph node metastasis were found more frequently in the subjects. The positive rates of estrogen receptor and progesterone receptor were lower in the subjects. The 5- and 10-year survival rates of the study patients were 65% and 55%, respectively, and these survivals were significantly lower than those of the control (P < 0.001). The survival rates were poorer in the subjects, in accordance with stage and lymph node metastasis. The results suggest that most of the patients with breast cancer diagnosed during pregnancy and lactation are in a more advanced stage because of a delay in detection and diagnosis, and hence have unfavorable prognosis. Therefore, it is important to diagnose and treat early for improvement of prognosis in patients with breast cancer during pregnancy and lactation.
We have previously reported carcinoembryonic antigen (CEA) measurement in nipple discharge to be a useful adjunct in the diagnosis of non-palpable breast cancer. We have now developed a "microdot-immunobinding assay" using a specially constructed device to screen efficiently large numbers of patients with nipple discharge for non-palpable breast cancer. The method is as follows: a sample of nipple discharge is placed on a solid phase monoclonal anti-CEA antibody and, if CEA is present in the discharge, it will be detected by a second monoclonal anti-CEA antibody conjugated with alkaline phosphatase. The use of bromochloroindolyl phosphate as a chromogen results in a stable color reaction that can be semiquantitatively analyzed with the naked eye. CEA levels determined by this microdot assay correlated well with those determined using the earlier Elmotec assay. To determine the accuracy of the method, a collaborative study involving 11 institutes in Japan was organized. The CEA levels in nipple discharges from 77 patients undergoing surgery, 44 of whom were diagnosed as having breast cancer, were assayed. The results were that 17 of the 23 patients with palpable breast cancer, and 16 of the 21 patients with non-palpable breast cancer exhibited CEA values > 400 ng/ml, a cut-off value determined in a previous study. The overall accuracy (78%) of this test for diagnosing non-palpable breast cancer was higher than that obtained from ductography or cytology. The system may thus be of use in the screening of early breast cancer.
Pathological investigations for intramammary spread of breast cancer of 205 partially resected specimens were performed by making continuous section every 5 mm width of the whole specimen. The materials were 167 quadrantectomized and 38 lumpectomized specimens. The results showed that the margin of 15.6% of quadrantectomized and 28.9% of lumpectomized specimens were positive for cancer, main causes of which were intraductal spread of cancer occupying 65% of positive margin in quadrantectomy and 91% in lumpectomy, multiple cancer, interstitial spread of cancer and so on. Multiple cancers were found in eleven (6.6%) quadrantectomized and in one (2.6%) lumpectomized specimens. Second cancers were 11 noninvasive ductal and 3 invasive cancers, including two triple cancers. Fifteen cases of quadrantectomy and 4 of lumpectomy were changed to be mastectomized because of positive margin or nodal involvements. Radiotherapy was performed for 33 cases. The median 31 months follow-up results of 186 partially mastectomized breast in 184 patients were as follows; one local recurrence in lumpectomy, two new cancers in residual breast, two distant metastases and one death for other cause of death. Quadrantectomy plus axillary dissection without radiotherapy assured of pathological complete resection was safe enough at the present.
In order to detect common regions of deletion, 219 breast tumors were examined for loss of heterozygosity at several loci on chromosomes 3p, 16q, and 17 by restriction fragment length polymorphism analysis. Allelic deletions of loci on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, were analyzed and compared with histopathological and clinical features. Common regions of deletion were detected within chromosomal bands 3p13-14.3, 16q22-23, 17p13 (two separated loci), and 17q21. Concordant losses of alleles on chromosomes 3p, 13q, 16q, 17p, and 17q were observed. A significant association was detected between loss of heterozygosity on chromosomes 17p and 17q and amplification of the erbB2 oncogene (17p, P = 0.000721, by Fisher's exact test; 17q, P less than 0.001, chi 2 = 12.135). Furthermore, tumors showing highly malignant phenotypes had accumulated more genetic changes at the loci studied than those having less malignant phenotypes on the basis of histopathological classification, lymph node metastasis, and tumor size. These results suggested that accumulation of genetic alterations, including loss of function of tumor suppressor genes on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, may contribute to tumor development and/or progression in primary breast cancer.
Microdochectomy is usually performed on patients with nipple discharge caused by intraductal proliferative lesions, such as intraductal papilloma and carcinoma. But this operation often sacrifices large amounts of normal mammary gland even when the lesion is a benign intraductal papilloma a few millimeters in diameter. We have developed duct endoscopy for the mammary duct system, and have reliably performed biopsies for intraductal proliferative lesions intraductally. From June 1989 to April 1990, we examined 22 cases by duct endoscopy, and performed endoscopic biopsy in 16 cases. The method of endoscopic biopsy is as follows. First, a bougie is inserted, without anesthesia other than Xylocaine jelly, into the orifice of the duct to enlarge it. Second, the outer cylinder and the inner needle are inserted; then the inner needle is removed, and the endoscope is inserted. After examination, the outer cylinder is moved up to the lesion to be biopsied and the endoscope is taken out. Then a sample is taken into the outer cylinder by aspiration. We diagnosed 10 cases of benign lesion and 5 cases of malignant lesion by cytological and/or histological examination. In conclusion, endoscopic biopsy, aided by duct endoscopy, is a useful and harmless diagnostic procedure in the evaluation of nipple discharge.
This report summarizes the clinicopathologic findings in 11 cases of low papillary carcinoma of the breast accompanied by the morphologic feature of mucus leakage into the mammary stroma. These cases were characterized by two morphologic findings. First, abundant mucus produced by the tumor cells filled the intraductal spaces where neoplastic epithelium formed very low papillary projections, ie, a feature of mucinous-producing low papillary carcinoma in situ. Second, there was expansive leakage of mucus into the mammary stroma occasionally accompanied by a few epithelial cells. All the cases showed a high level of mucus production and contained no elements of invasive ductal carcinoma or ordinary invasive mucinous carcinoma. These cases have no evidence of direct invasion of the mammary stroma by malignant cells. The average age of the 11 patients was 41 years. Foci of microcalcification were seen in some tumors (seven cases; 64%). There were no cases with lymph node metastases. All the patients underwent mastectomy with no adjuvant therapy, and they are currently alive and well.
We report 11 cases with cancer of the thoracic esophagus developing after postoperative irradiation therapy for the breast cancer. Irradiation was done immediately after mastectomy in these cases and the irradiation field included the unilateral or bilateral parasternal region. They received a total dose ranging from 35 Gy to 60 Gy and the dose received to the thoracic esophagus was estimated from 10 Gy to 48 Gy. All cancer sites were involved in the irradiation filed. The latent intervals of 10 cases from radiation to the manifest of cancer ranged between 10 to 19 years. Among 4777 women undergone mastectomy for breast cancer between 1946 and 1980 in our hospital, 8 women (0.17%) developed cancer of the thoracic esophagus, whereas 5 (0.335%) out of 1534 women treated with mastectomy and radiotherapy with Linac between 1964 and 1980 developed cancer of the thoracic esophagus. Higher incidence of esophageal cancer in patients treated with surgery and radiation suggests that these cancers might be induced by radiation. Eight patients had esophagectomy and 4 patients of them received postoperative irradiation. They have survived from 9 months to 13 years. Two patients were controlled well by the irradiation alone. It is interesting that radiation therapy is sensitive to the possible radiation induced cancer of the thoracic esophagus. Follow up study should be directed to the possible development of second malignancy in patients who survive for a long time after radiation therapy.
Allele loss on a specific chromosome has implied the existence of a tumor suppressor gene such as the p53 gene and the RB gene. In order to determine which chromosome(s) carries a tumor suppressor gene(s) that contributes to tumor progression in primary breast cancer, we analyzed the loss of heterozygosity for each autosomal chromosome arm by using 39 restriction fragment length polymorphism markers including 25 variable numbers of tandem repeat probes. In 79 primary breast cancers, we found the frequent loss on the long arm of chromosome 13 (21%), the long arm of chromosome 16 (45%), and the short arm of chromosome 17 (56%). Interestingly, breast cancers in which loss of both chromosomes 13q and 17p was detected showed more malignant histopathological features, and a group of the tumors in which chromosome 16q loss was detected presented with frequent lymph node metastasis. Furthermore, the result of the deletion mapping on chromosome 17p implied the existence of a tumor suppressor gene distal to the p53 gene as well as the p53 gene itself for primary breast cancer. These results suggest that at least 4 tumor suppressor genes exist on chromosomes 13q, 16q, and 17p for primary breast cancer.
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From breast cancer cases that were mastectomized between 1970 and 1987 at the Cancer Institute Hospital, 43 breast cancers during phases of pregnancy and lactation (pregnancy 11 cases, lactation 32 cases) have been analyzed. Taking the patient's age and the calendar-year at the time of diagnosis into account, we collected 43 cases as controls and compared the result. It was found that breast cancers during pregnancy and lactation metastasized to the lymph nodes at the same frequency as in the control cases, in lymph node-positive cases and in tumors of the same size the metastases involved more lymph nodes than in the control cases. Further, the survival rate of breast cancers during pregnancy and lactation was poorer in the lymph node-positive cases than in the controls. Therefore, we have concluded that pregnancy and lactation promote the progress of a metastatic cancer.