New molecule-targeting therapy with herceptin (trastuzumab), an anti-HER2 (c-erB-2) monoclonal antibody.
Explore the source record for details and available documents.
Antibodies, Monoclonal↗
Biomedical subjects
G Sakamoto
Publications and source records attributed to G Sakamoto.
Mammographic and clinicopathological features of mucinous carcinoma of the breast.
BACKGROUND: We attempted to improve the effectiveness of diagnostic techniques in mammographic imaging of mucinous carcinoma of the breast by defining the characteristics of mammographic images and investigating correlations between these images and various clinicopathological findings. METHODS: Clinicopathological investigations of 92 lesions in 90 cases of mucinous carcinoma of the breast were made. Mammography demonstrated 80 lesions with identical tumor shadow characteristics and these were divided into three patterns, circumscribed, indistinct and blended. Correlations between clinicopathological findings and mammographic images were investigated. RESULTS: Patients with mucinous carcinoma of the breast usually present with a palpable mass. The lymph node metastasis rate in this study was low and prognosis in the early postoperative period was satisfactory. On mammograms, the circumscribed pattern was the most frequent. The investigation of the correlation between histological sub-type and mammographic pattern showed a high percentage of pure type lesions exhibited in the circumscribed pattern while those of mixed histologic type often showed the indistinct pattern. Calcification frequency demonstrated on mammography was 75% for the indistinct and mixed patterns, and approximately 50% for the circumscribed pattern. A high rate of calcification seen outside the tumor shadow suggested a high frequency of invasion and the spread of cancer to neighboring tissues. The circumscribed pattern was least frequently associated with lymph node metastasis, followed by the indistinct and blended patterns in that order. CONCLUSION: Investigation of clinicopathological factors and mammographic findings in mucinous carcinoma of the breast suggests that mammography provides clinically valuable information for the treatment of this disease. These findings indicate the importance of careful mammographic observation at the time of diagnosis.
Adenocarcinoma, Mucinous↗
Identification of Rad51 alteration in patients with bilateral breast cancer.
The human Rad51 gene, HsRAD51, is a homolog of RecA of Escherichia coli and functions in recombination and DNA repair. BRCA1 and BRCA2 proteins form a complex with Rad51, and these genes are thought to participate in a common DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair. Additionally, we have shown that the pattern of northern blot analysis of the RadS gene is closely similar to those of the BRCA1 and BRCA2 genes. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancer. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. In both patients, blood DNAs showed a G-to-A transition in the second nucleotide of codon 150, which results in the substitution of glutamine for arginine. As this alteration was not present in any patients with breast or colon cancer examined, we assume that this missense alteration is likely to be a disease-causing mutation.
Blotting, Northern↗
A quantitative model using mean and standard deviation for evaluation of interobserver agreement in nuclear atypia scoring of breast carcinomas in a protocol study.
A quantitative model was devised for the purpose of evaluating interobserver agreement in the judgment of the nuclear atypia score of cancer cells in protocol studies. In this model, the mean nuclear atypia score (mu) among observers was considered to approximate the 'true' nuclear atypia score of the tumor, and with an identical mu the strength of interobserver agreement was evaluated by the difference between the ideal standard deviation (sigma) and the observed sigma in the slide conference session. This model was applied to the data of a total of 216 invasive ductal carcinomas acquired at eight slide conference sessions held for the standardization of nuclear atypia scoring and monitoring of interobserver agreement level for enrolled cases in a surgical adjuvant protocol on breast cancer. Compared with conventional percentage interobserver agreement and kappa statistics, the present model, named the lambda model, was more sensitive in detecting the improvement of interobserver agreement in nuclear atypia scoring with repetition of slide conference sessions. The lambda model was particularly effective for evaluating the session which included many intermediate cases with a score between 1 and 2 or between 2 and 3. Percentage interobserver agreement and kappa statistics could estimate the agreement irrespective of the number of observers, but the agreement tended to be underestimated when these intermediate cases were in the majority. The present method was considered to be complementary to conventional methods for evaluating interobserver agreement of cancer histology in protocol studies.
Breast Neoplasms↗
Fat intake and breast cancer risk in an area where fat intake is low: a case-control study in Indonesia.
BACKGROUND: Associations of fat and other macronutrients with breast cancer risk are not clear in areas where fat intake is low. METHODS: We conducted a hospital-based case-control study from 1992 to 1995 in Jakarta, Indonesia. RESULTS: The study, based on 226 cases and 452 age and socioeconomic status matched controls, provided the following findings. (a) In the pre-marriage period, the greater the fat or protein consumption, the larger the risk, whereas decreasing risk with increasing carbohydrate intake was detected. The odds ratio (OR) for the highest quartile of intake relative to the lowest was 8.47 (95% CI: 4.03-17.8) for fat, 2.19 (95% CI: 1.30-3.69) for protein, and 0.16 (95% CI: 0.08-0.31) for carbohydrate. A positive association with fat and a negative one with carbohydrate were also observed for the post-marriage period, but of weaker magnitude compared to the pre-marriage period. (b) The effects of macronutrient intakes were stronger among premenopausal than among postmenopausal women. (c) Most of the associations of protein and carbohydrate were insignificant after adjustment for fat intake. CONCLUSIONS: These findings suggest that fat intake might be an important determinant of breast cancer among populations with a low fat diet in Indonesia.
Adult↗
Mapping of target regions of allelic loss in primary breast cancers to 1-cM intervals on genomic contigs at 6q21 and 6q25.3.
Allelic losses on the long arm of human chromosome 6 are frequently observed in cancers of the ovary, prostate, and breast. To identify the locations of putative tumor suppressor genes on 6q, we examined 192 primary breast cancers for patterns of allelic loss at 16 polymorphic microsatellite loci distributed along this chromosome arm. Allelic losses at one or more loci were observed in 105 (55%) of the tumors examined. Detailed deletion mapping with appropriate yeast artificial chromosome (YAC) contigs identified two distinct commonly deleted regions; one was confined to a 1-cM interval at 6q21 flanked by D6S1040 and D6S262 and the other to a 1-cM interval at 6q25.3 flanked by D6S305 and D6S411. Allelic losses at 6q21 were more frequent in invasive solid tubular and scirrhous carcinomas than in tumors of less aggressive histologic types (P = 0.0006). Allelic loss at 6q25.3 was associated with loss of progesterone receptor (P = 0.0256). Our results suggest the presence of two tumor suppressor genes for breast cancer on 6q that are likely to be associated with tumor progression and / or loss of hormonal dependency.
Adenocarcinoma↗
Evaluation of the interobserver agreement in the number of mitotic figures of breast carcinoma as simulation of quality monitoring in the Japan National Surgical Adjuvant Study of Breast Cancer (NSAS-BC) protocol.
In the National Surgical Adjuvant Study for Breast Cancer (NSAS-BC), node-negative breast cancers were divided into higher- and lower-risk groups according to the histopathological nuclear grade given at individual collaborating hospitals, and the higher-risk group was entered into a randomized protocol of adjuvant therapy. Because the nuclear grade was the composite of nuclear atypia and mitotic counts, maintenance of interobserver agreement in mitotic counts was indispensable for the success of the protocol study. Fourteen pathologists participating in the protocol judged whether or not 20 photomicrographs suspected of showing mitotic cancer-cell figures truly showed mitoses. After standardizing the counting method, these pathologists counted the number of mitotic figures per 10 high-power fields of hematoxylin-eosin-stained main-tissue sections of 20 tumors. Areas where mitotic counts were considered to be the most frequent by each pathologist were compared for these tumors. For the judgment of whether the photomicrograph indicated mitosis, the level of interobserver agreement was moderate (kappa = 0.569). In the observations of 20 tumors, interobserver agreement level of mitotic counts was moderate (kappa = 0.506), that of nuclear atypia scoring was fair (kappa = 0.265), and that of nuclear grading was substantial (kappa = 0.633). The counted area was almost the same among the observers in 9 tumors, split into two areas in 6, and dispersed in 5. Concordance in judgment was achieved in 7 of the first 9 and in all of the third 5, but only in one of the second 6. The cause of discordance was mostly derived from tumor heterogeneity and the difference in the site where mitoses were counted. Interobserver agreement level was considered to be satisfactory, and it was expected that the case entry would be performed appropriately in the protocol study. The selection of the counting area was confirmed to be important for the acquisition of high-level agreement level in mitotic counts.
Breast Neoplasms↗
Dietary macro/micro-nutrients as a breast cancer risk: findings from nutritional case-control study in Jakarta, Indonesia.
Explore the source record for details and available documents.
Adult↗
Allelic loss at 1p34-36 predicts poor prognosis in node-negative breast cancer.
Allelic losses of specific chromosomal regions in the DNA of tumor cells, which imply loss of tumor suppressor genes normally resident at those loci, may become useful postoperative prognostic indicators for breast cancers that have not yet metastasized to lymph nodes. To examine whether specific allelic losses might correlate with postoperative disease-free survival, we tested tumors from a cohort of 228 node-negative breast cancer patients for allelic losses at 18 microsatellite loci chosen to represent either a known tumor suppressor gene or a region where genetic alterations are frequent in breast tumors. We followed the patients clinically for 5 years or until death (if patient death occurred before completion of 5 years of follow-up). Patients whose tumors had lost an allele at 1p34-36 bore significantly higher risks of postoperative recurrence than those whose tumors retained both alleles of the markers in that region [the 5-year recurrence rate was 15% among patients with losses versus 2% among patients with retention (P = 0.001)]. Multivariate analysis demonstrated that allelic loss at 1p34-36 was an independent postoperative predictor of shorter disease-free survival (hazard ratio, 5.8; P = 0.0117). Thus, allelic losses at 1p34-36 in a tumor might have a potential to serve as a negative prognostic indicator to guide postoperative management of breast cancer patients, especially in the selection of high-risk women who will benefit from adjuvant chemotherapy and endocrine therapy.
Adult↗
[Day surgery for breast cancer].
Explore the source record for details and available documents.
Ambulatory Surgical Procedures↗
Correlation of Allelic Loss with Poor Postoperative Survival in Breast Cancer.
BACKGROUND: Allelic losses of tumor suppressor genes or the chromosomal regions harboring them in the DNA of tumor cells may become useful postoperative prognostic indicators. METHODS: To examine whether specific allelic losses correlate with postoperative survival in a five-year prospective follow-up, we tested tumors from a cohort of 504 breast cancer patients for allelic loss of 18 microsatellite markers representing either known tumor suppressor genes or regions where genetic alterations are frequent in breast tumors. RESULTS: Patients with allelic loss at 1p34, 3p25, 8p22, 13q12, 17p13.3, or 17q21.1 had a significantly higher risks of postoperative mortality compared withthose whose tumors retained both alleles at those loci (at 1p34, the 5-year mortality rate was 23% among patients with loss vs 10% with retention, p 0.0100; at 3p25, 22% vs 9%, p =0.0014; at 8p22, 24% vs 7%, p =0.0177; at 13q12, 19%vs 8%, p=0.0093; at 17p13.3, 19% vs 9%, p=0.0078; and at 17q21.1, 17% vs 10%, p =0.0475). CONCLUSION: Allelic losses at these loci can serve as negative prognostic indicators to guide post-operative management, especially in the selection of thosewho will benefit from intensive adjuvant therapies.
Journal Article↗
Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability.
The extent to which microsatellite instability (MI) contributes to the etiology of breast cancer has not been established in any large-scale studies. We examined 528 samples of tumor DNA from patients with primary breast cancer for MI, using 14 polymorphic CA-repeat markers. The frequency of MI in these tumors was unexpectedly low (10/528, 1.9%). The ten MI+ tumors were analyzed for mutations in five potential target genes that contain simple repeat sequences (TGFBIIR, IGF2R, hMSH6, BAX and PTEN/MMAC1). A somatic insertion of an extra adenine in the (A)6 region at codon 321-323 (exon 8) of the PTEN/MMAC1 gene, leading to a frame-shift, was identified in one tumor. This observation represented the first documented instance of PTEN/MMAC1 alteration in a MI+ primary breast cancer.
Breast Neoplasms↗
Frequent multiplication of chromosome 1q in non-invasive and papillotubular carcinoma of the breast.
Carcinogenesis is considered to be a multistep process that may involve cumulative genetic alterations; one of these mechanisms, gain of chromosomal material, has the potential to activate tumor-promoting genes in breast carcinogenesis. Using 12 polymorphic microsatellite markers on the long arm of chromosome 1 (1q), we examined 130 sporadic breast carcinomas for abnormalities in the copy numbers of these loci in tumor cells using a differential PCR method. We also sought correlations between alterations on 1q and several clinicopathological parameters. At every locus examined, a 2-3-fold increase in copy number of an allele in tumor material was observed in one third of the tumors (46 of 130, 35%), indicating 'multiplication' of 1q. This multiplication involved the entire long arm in majority of those tumors (43 cases, 93%). The multiplication of 1q was observed more frequently in non-invasive ductal and papillotubular histological types than in solid-tubular and scirrhous types (13/25, 52% vs. 27/90, 30%) (P = 0.041). The predominant chromosomal alterations on 1q in breast carcinomas are found to be multiplications rather than losses. The multiplication represents polysomy of the entire region of 1q, and may confer a growth advantage during development and/or progression of non-invasive ductal and papillotubular histologic types of breast carcinomas.
Adenocarcinoma, Papillary↗
Frequent multiplication of chromosomal region 8q24.1 associated with aggressive histologic types of breast cancers.
Carcinogenesis is considered to be a multi-step process that may involve cumulative genetic alterations. One such alteration, gain of chromosomal material, has the potential for activating genes that promote carcinogenesis in breast tissues. Using 14 polymorphic microsatellite markers on the long arm of chromosome 8 (8q), we examined 142 sporadic breast cancers for abnormalities in the copy-numbers of these loci. At each locus examined, a 2- to 3-fold increase in intensities of bands representing single alleles was observed in 57 (40%) of the tumors, indicating that 'multiplication' of the DNA sequence had occurred on 8q. A 16-cM region on 8q24.1 was commonly multiplied among the tumors with partial multiplications. Multiplication on 8q24.1 was observed more frequently in invasive solid-tubular or scirrhous tumors (48/92, 52%) than in less aggressive histologic types (7/25, 28%, P = 0.031). Thus, multiplication of tumor-promoting gene(s) located on 8q24.1 may play a role in the development and/or progression of a substantial proportion of primary breast cancers, particularly those of the invasive histology.
Alleles↗
Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1.
BACKGROUND: Frequent allelic losses on the short arm of chromosome 8 in several types of human cancers, and deletion maps of this region in tumor DNAs, have suggested that 8p harbors one or more genes that are important for suppressing tumorigenesis in the tissues in question. METHODS: To define the locations of potential tumor suppressor genes involved in breast carcinoma, the authors examined 144 primary breast carcinomas for loss of heterozygosity at 18 highly polymorphic microsatellite loci on 8p. They also sought correlations between allelic loss on 8p and several clinicopathologic parameters. RESULTS: Allelic loss was observed in 74 of the 144 sporadic breast carcinomas examined. Whereas more than half of the informative tumors showed loss of an allele at every locus on the short arm, 32 showed partial or interstitial deletions. Deletion mapping in this panel of tumors identified two distinct commonly deleted regions, one in a 1-cM interval flanked by D8S511 and D8S1991 at 8p22-p23.1, and the other in a 16-cM interval flanked by D8S136 and D8S1477 at 8p22-p21. Allelic losses in both of these regions were observed more frequently in tumors of the solid-tubular or scirrhous type than in less aggressive histologic types. Furthermore, allelic loss in either region occurred more frequently in larger and infiltrative tumors (T1 < T2 < T3). CONCLUSIONS: The association of allelic losses on 8p with advanced tumor stage and aggressive histologic type implies that loss or inactivation of one of at least two putative tumor suppressor genes on 8p may contribute to the progression of breast carcinoma.
Breast Neoplasms↗
Frequent allelic loss at the TOC locus on 17q25.1 in primary breast cancers.
Sporadic breast cancers often show allelic losses on the long arm of chromosome 17. Since the BRCA1 gene lies at 17q21.1 and the TOC locus, associated with esophageal cancer, lies at 17q25.1, either gene could be the target of those losses. We examined both loci in 178 primary breast cancers, using microsatellite markers covering the relevant regions of 17q, and observed allelic losses in 97 tumors (55%). Losses were most frequent at markers around the TOC locus (48% at D7S1839 and 43% at D17S1603), where we identified a distinct commonly deleted region within a I -cM interval. Another larger, separate commonly deleted region including the BRCA1 gene was also identified, which exhibited 45% of allelic loss (at D17S934). Allelic loss on 17q was more frequent in tumors of the solid-tubular histologic type (P = 0.0129) and in estrogen-negative and progesterone-negative tumors (P = 0.0281 and 0.0196, respectively). The results indicated that BRCA1 and TOC are independent targets of allelic loss on 17q in primary breast cancers, and that inactivation of the TOC locus in particular may play an important role in the genesis of sporadic breast tumors.
BRCA1 Protein↗
The location of positive nodes partly influences the prognostic value of the number of positive nodes in breast cancer patients.
BACKGROUND: The aim was to determine whether the number of positive lymph nodes or the location of lymph node metastasis (location number) would permit a more accurate prediction of prognoses. METHODS: We compared the survival rates of 3922 patients with primary breast cancer in relation to the location number and the number of positive lymph nodes. Survival rates were calculated by the Kaplan-Meier method and analyzed using the log rank test. RESULTS: Within the n1 alpha group, the presence of one or two positive nodes was associated with significantly better survival than the presence of three positive nodes. These groups should therefore be distinguished. Within the n1 beta group, there was no significant difference in survival between patients with four and those with seven or more positive nodes. Comparisons of n1 beta and n2 patients after subgrouping by the number of positive nodes (4-9 and 10 or more) revealed a significantly poorer prognosis in the n2 group. CONCLUSIONS: When the prognosis of breast cancer is considered from the viewpoint of lymph node metastasis, the location number as described in the General Rules is an excellent classification. However, we should be aware of possible differences in the prognosis depending on the number of positive nodes, as this is masked by the location number.
Adult↗
The efficacy and limitations of repeated slide conferences for improving interobserver agreement when judging nuclear atypia of breast cancer. The Japan National Surgical Adjuvant Study of Breast Cancer (NSAS-BC) Pathology Section.
BACKGROUND: The pathology section of the Japan National Surgical Adjuvant Study of Breast Cancer protocol study was set up to establish histological criteria for assessing high-risk node-negative breast cancers and standardize the subjective criteria used by collaborating pathologists for nuclear grading of cancers. METHODS: In order to standardize the nuclear atypia criteria, five slide conferences were held. A total of 57 observers assigned nuclear atypia scores to 119 breast carcinomas that were presented using a slide projector or a TV monitor and discussed their histological findings. The percentage interobserver agreements per tumor and per conference and kappa value per conference were estimated and compared among the conferences. The percentage intraobserver reproducibility per tumor between the last two conferences was compared with the percentage interobserver agreement for 20 tumors. The kappa value was also calculated for each of 27 observers to evaluate scoring reproducibility. RESULTS: The percentage interobserver agreement per conference was constant (75-78%) throughout the five meetings and the rate of tumors with > 80% agreement per tumor became higher in later conferences. The kappa value was 0.42, 0.25, 0.42, 0.51 and 0.50 for the first, second, third, fourth and fifth conferences, respectively. The tumors with a lower percentage interobserver agreement also had a lower percentage intraobserver reproducibility and such scoring variations were attributed to the intermediate nature of the degree of tumor atypia. In 26 of 27 observers, intraobserver agreement for 20 tumors was estimated from the kappa value to range from moderate to almost perfect. CONCLUSION: We concluded that the repeated slide conferences conducted by the pathology section were an effective means of standardizing the subjective histopathological criteria used to assess tumors. However, the achievement of a good scoring agreement would be difficult for tumors with an intermediate degree of atypia.
Breast Neoplasms↗