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IgG4-related disease is a newly identified disease entity that has begun to attract attention, and international consensus diagnostic criteria for the condition have recently been proposed. The characteristic features of IgG4-related disease are lymphoplasmacytic infiltration involving a high proportion of IgG4-positive cells, fibrosis exhibiting a storiform pattern, and obliterative phlebitis. It can affect various organs, including the breast (in rare cases). IgG4-related disease has previously been referred to as inflammatory myofibroblastic tumor, plasma cell granuloma, or pseudolymphoma. We have experienced a case of IgG-related disease of the breast. Clinically and cytologically, the lesion was somewhat similar to a malignant tumor. An immunohistochemical examination of a core needle biopsy sample resulted in a correct diagnosis. In addition, a review of the patient’s clinical history revealed that the disease had affected areas other than the breast. Clinicians should be aware that breast lesions can be a focal manifestation of systemic disease, and overdiagnosis should be avoided by performing appropriate pathological analysis.

A 44-year-old woman was diagnosed cT4bcN3cM1(LYM), Stage IV triple-negative breast cancer.Enhanced computed tomography revealed ipsilateral axillary lymph node metastasis, 10 cm in diameter.The supraclavicular and cervical lymph nodes also had metastases.She received paclitaxel(90mg/m2, on days 1, 8, and 15 every 4 weeks)in combination with bevacizumab(10mg/kg, on days 1 and 15 every 28 days).Her height was 165 cm, and her body weight was 100 kg.After 1 course of chemotherapy, a metastatic axillary lymph node with necrotic changes was removed spontaneously.A few days later, she experienced severe bleeding from her axillary artery, and she went into hypovolemic shock.Despite undergoing surgical hemostasis, the bleeding recurred twice, so we performed coil embolization of her subclavian artery.Thirty -five days after the first occurrence of bleeding, the patient died of sepsis and ARDS due to left arm necrosis.Bevacizumab is effective for the treatment of large tumors, but when the tumor is close to an artery, clinicians should be wary of fatal bleeding after necrosis.

Objective The aim of the present study was to evaluate the usefulness of computed tomographic (CT) imaging in delineating tumor extent and guiding surgical management. Background The routine use of preoperative magnetic resonance imaging (MRI) is a controversial issue in breast cancer management. Negative studies with regard to the utility of MRI might be due to differences in positioning during imaging and subsequent surgery. Methods Candidates for breast-conserving surgery were eligible for the study. The surgeons marked the line of planned excision on the skin, which was also recorded on the CT image. Contrast-enhanced breast CT was performed in the supine surgical position. The CT results were used to help determine the extent of resection. The pathological findings were then compared with the CT-guided surgical plans. Results A total of 297 patients were involved. The surgeons widened the extent of resection in 42 (14.1%, 95% confidence interval 10.1%-18.1%) patients on the basis of the CT findings. Among the 6 patients whose procedures were changed to mastectomy, 4 had pathologically multicentric tumors and 2 had widely spread intraductal components. The remaining 36 patients underwent quadrantectomy instead of wide excision on the basis of the CT images. There were 3 patients in whom conversion from wide excision to quadrantectomy resulted in overexcision. Preoperative breast CT may have reduced the positive margin rate and also correctly changed the extent of surgery in 13.1% of patients. Conclusions This prospective study suggests that breast CT, carried out in the supine position, is useful in the preoperative determination of the optimal surgical procedure.

Since the concept of gene profile-based intrinsic subtypes was proposed, various studies on pathological characteristics have been performed. Particularly, triplenegative (TN) breast cancer, which is negative for all hormone receptors [estrogen receptor (ER) and/or progesterone receptor (PgR) and human epidermal growth factor 2 (HER2)], has been attracting attention because effects of endocrine and targeting therapies cannot be anticipated and thus selecting a treatment method is difficult. TN cancer accounts for about 10%-15% of all invasive breast cancer cases in Japanese, which is significantly lower than the incidence reported in the United States. Cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR) is positive in 80%, being classified as basal-like carcinoma, but it should be understood that TN breast cancer and basal-like carcinoma are not necessarily the same. Criteria for positivity judgment of ER, PgR, and HER2 were established to select treatment in cases positive for each marker, and greater importance is attached to strict accuracy control. Inversely, the level of negative findings to judge TN varies among the judgment criteria. In any case, the prognosis of TN breast cancer is poor. Pathologically, TN breast cancer shows certain morphological characteristics, such as high grade and a pushing margin, and abnormalities of BRCA1 and p53 are frequently noted. At present, as no effective therapeutic strategy has been established for TN breast cancer, further clarification of the molecular biological characteristics of such cancers is needed. In addition, the incidence of TN-type ductal carcinoma in situ (DCIS) is low, suggesting that TN does not remain preinvasive DCIS for a prolonged period and that it transforms to invasive cancer in an early stage. Because mammary gland basal cells have characters of progenitor or stem cells that differentiate into both luminal epithelium and myoepithelial cells, these cells may be utilized for the differential diagnosis of the benignity or malignancy of intraductal lesions in routine pathological practice. As proliferation markers, such as Ki-67, and multiple gene arrays for gene signature are also utilized to select adjuvant therapy, analysis may progress further in the future.

Sex steroids play important roles in the development of many human breast carcinomas, and aromatase inhibitors are used for the anti-estrogen therapy. Recent studies have demonstrated that aromatase suppressed 5α-dihydrotestosterone (DHT) synthesis in breast carcinoma cells, but intratumoral concentration of androgens and its significance have not been reported in the breast carcinoma patients treated with aromatase inhibitors. Therefore, we examined androgen concentrations in breast carcinoma tissues treated with exemestane, and further performed in vitro studies to characterize the significance of androgen actions. Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (n=9) than those without the therapy (n=7), and 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) status was significantly altered to be positive after the treatment. Following in vitro studies showed that 17βHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17βHSD2 expression was markedly suppressed by estradiol (E2) in T-47D cells. E2-mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17βHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment. 17βHSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients.

Aromatase inhibitors (AIs) have been employed as adjuvant therapy or as treatment for recurrent cases. However, when AI treatment fails, it is unclear which endocrine therapy is the most appropriate to introduce at this point and how effective it will be. In this study, we investigated the efficacy and safety of toremifene (TOR, Fareston(®)), a selective estrogen receptor modulator (SERM).Patients with recurrent or advanced breast cancer who had measurable or evaluable lesions, and were diagnosed as having progressive disease during AI treatment and subsequently given TOR at 120 mg/day (TOR120) as endocrine therapy were selected and analyzed retrospectively in relation to their medical history.Of a total of 83 cases examined, 80 were evaluable. The objective response rate (ORR) was 15.0% (12/80), the clinical benefit (CB) rate was 45.0% (36/80), and median time to failure (TTF) was 7.8 months. TOR120 was also effective in the progressive disease cases relapsed on AI treatment. When TOR120 was used, as a first-, second- or third-line treatment, the CB rate was 57% (32/56); this fell to 17% (4/24) when TOR120 was used as a fourth-line or later treatment. There was no response in the five estrogen receptor (ER)-negative cases, compared with an ORR of 15% (10/67) in ER-positive cases. In cases with a human epidermal growth factor receptor 2 (HER2) score of 0, 1+, and 2+, the ORR was 11% (7/61), while there was no response in the five cases with scores of 3+. TOR120 was effective in cases previously treated with tamoxifen (TAM), with an ORR and CB rate of 12 and 29%, respectively. The last AI used was anastrozole in 30 cases and examestane in 46; the response rates to TOR120 were similar in both groups. With regard to adverse effects, hot flushes and/or night sweating was observed in 10 and 12 cases, respectively, but all of them were categorized as grade 1, and the treatment was rated excellent in acceptability.TOR120 was rated excellent in acceptability, and high efficacy was observed when it was used up to third-line treatment for AI-failure cases, although this study may show some selection bias because of the retrospective study. In addition, it was also considered effective for TAM-failure cases.

BACKGROUND : ACD-A solution containing sodium citrate and citric acid is used as an anticoagulant agent during peripheral blood progenitor cell (PBPC) harvesting, and in rare cases can cause fatal citrate intoxication. The aim of this study was to establish effective methods for stabilizing ionized calcium (ICa) levels during PBPC harvesting. STUDY DESIGN AND METHODS : ICa was measured during 46 apheresis procedures conducted in 26 patients. Four patients in four procedures were infused with calcium gluconate solution before PBPC harvesting; three patients in six procedures were infused with calcium gluconate when symptoms of citrate intoxication appeared; and four patients in five procedures received a continuous infusion. Five patients in five procedures took an isotonic sports drink containing calcium when hypocalcemic symptoms appeared. The ICa level, blood pressure, and pulse rate were measured. RESULTS : ICa declined rapidly from the preapheresis level of 1.081(±0.092) m M to 0.937(±0.081) m M (13.3%, p < 0.0001) 10 minutes after the start of apheresis and continued to decline until the completion of the procedure. When patients received a continuous infusion of calcium during apheresis, ICa was relatively stabilized. ICa significantly rose (6.1 ± 3.6%, p < 0.02) within 2 to 5 minutes after oral intake of an isotonic sports drink containing calcium and was maintained within normal range for 31 to 55 minutes. CONCLUSION : An isotonic sports drink containing calcium has a quick stabilizing and a longer maintenance effect on ICa. Thus, we recommend the intake of an isotonic sports drink containing calcium as the easiest and best method for preventing hypocalcemia during apheresis.

Background Sentinel node biopsy is emerging as a technique to replace routine axillary lymph node dissection. The lymphatic mapping technique is still at a developmental stage and no standard technique exists. This study used technetium-99m colloidal rhenium sulphide with a mean particle size of 100 (range 50–200) nm for sentinel node mapping. Methods Eighty-seven patients with breast cancer, but no clinical evidence of axillary metastasis, were studied. One day before operation technetium-99m colloidal rhenium sulphide was injected at four points into breast tissue surrounding the tumour. Lymphoscintigraphy was performed 2 h after injection, and surgery was usually performed after 20 h. A hand-held γ probe guided sentinel node biopsy. Results Lymphoscintigraphy revealed axillary hot spots in all patients. During operation, the sentinel node was identified in all 87 patients (100 per cent). The number of sentinel nodes per patient ranged from 1 to 5 (mean 2). Metastatic sentinel nodes were identified in 37 of 87 patients. There were no false negatives. Conclusion This study suggests that technetium-99m rhenium sulphide is a suitable agent for sentinel node mapping in patients with breast cancer.

As the volume of blood processed in harvesting peripheral blood stem cells (PBSCH) for autologous stem cell transplantation increases, clinical symptoms associated with hypocalcemia can occur. In this study, we evaluated several calcium supplementation methods for the prevention of hypocalcemia during PBSCH apheresis.Ionized calcium (ICa) level in peripheral blood was measured in 35 procedures in 19 patients. ICa in patients with hypocalcemic symptoms was lower than that in those without symptoms, but the difference was significant only at 120 minutes of apheresis. Continuous injection of calcium during the procedure kept ICa almost within the normal range in three patients. In six patients who took an isotonic drink per os at the time symptoms appeared, ICa value increased within 3 minutes after intake.As hypocalcemia-associated symptoms mostly appeared at 120 minutes after the start of the procedure, prophylactic treatment is not difficult. Further, continuous injection of pharmaceutical calcium into a venous port with measurement of ICa is an excellent method for infants and patients unable to take isotonic drinks orally. Oral administration of an isotonic drink is the most effective way to control ICa level, even though these drinks have a low Ca content.

The effect of age on the prognosis of breast cancer remains controversial. To investigate the role of age, we reviewed 316 patients with stage I or II breast cancer. There were 14 patients below 34, 146 between 35 and 49, 115 between 50 and 65, and 41 over 66 years of age. No correlations were observed between age and clinicopathological variables. Breast cancer patients aged 34 or less had a significantly worse survival compared to those in the older age groups. Multivariate analysis also showed younger age to be a significant factor, followed by lymph node status. Therefore, younger age at onset is considered to be an independent prognostic factor.

With the growing use of mammography for routine breast cancer screening, tumors are now detected earlier and more frequently than ever before. Consequently, it is becoming increasingly important to define the exact location of early lesions to allow effective treatment through precision surgery. The most common form of noninvasive breast cancer— ductal carcinoma in situ (DCIS)—is not generally noticed as a palpable tumor but as calcification during breast screening with mammography. DCIS generally does not metastasize, and thus, localized surgery and radiotherapy can be used to treat this lesion, thereby sparing most of the unaffected breast tissue. More invasive lesions, however, such as invasive ductal carcinoma (IDC), also require complete resection, including a margin of unaffected tissue, to ensure complete removal. The situation is complicated by the coexistence of an intraductal component with IDC. If this intraductal lesion is missed during imaging when IDC is present, it may not be removed by subsequent surgery and can thus give rise to a positive surgical margin, increasing the likelihood of recurrence. In this special feature, authors present a review of each imaging modality together with results of their own recent studies aimed at overcoming the limitations associated with the diagnosis of intraductal component coexisting with IDC and DCIS. Among the imaging tests considered is mammography, a routine screening methodology for breast cancer, which can detect DCIS primarily by identifying microcalcification. This calcification is also useful for confirming the complete resection of lesions by specimen radiography, especially in breast-conserving surgery. However, only half of DCIS lesions are associated with calcification, and even if the lesion does contain calcification, the gland can become deformed by compression during the procedure, making it difficult to identify the exact site of calcification in surgery. Ultrasound examination is another commonly used imaging modality. Although it is considered to have poor reproducibility, it has high sensitivity and resolution for minute lesions, and the location of the lesion is easily projected onto the overlying skin. However, some DCIS lesions, without dilation of the duct, are missed by this diagnostic modality. In this edition, Nakajima et al. present results using B-mode, Doppler, and elastography for predicting intraductal components. Magnetic resonance imaging (MRI) is now considered the most sensitive method for detecting DCIS lesions. Its ability to image without radiation exposure is a great advantage over computed tomography (CT). MRI is thus more frequently used to identify early lesions in case of suspicious findings during physical examinations or other diagnostic imaging examinations. Tozaki et al. review the use of MRI for the detection of DCIS lesions, including the new Breast Imaging-Reporting and Data System (BI-RADS) terminology for MRI. Of particular note is the patient’s prone position during the scan, which limits application of MRI in surgery. Thus, if the lesion has a feature that could be detected by sonography, its combination with MRI could be a significant advantage in identifying the precise location and area of the lesion. Computed tomography is another effective imaging test for breast cancer. It is mainly used as a modality for staging of breast cancer, and it is not considered as the best I. Kimijima (&) Northern Fukushima Medical Center, Breast Center, Fukushima, Japan e-mail: kimijima0505@live.jp

Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen.The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events.A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated.Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

As ductal carcinoma in situ (DCIS) lesions can spread widely in the ductal-lobular segment, often without palpable tumor, complete resection of the lesion in breast-conserving surgery requires establishment of the precise location and extent of the lesion during preoperative imaging studies. We investigated the potential of multi-detector row computed tomography (MDCT) in detecting and delineating DCIS lesions. Overall, 74 patients with 75 DCIS lesions underwent breast MDCT. The size of the DCIS lesion in each patient was measured in the volume rendering images and compared to the size obtained by pathological mapping. The differences between the actual tumor size and that obtained from MDCT (L-Path and L-CT) were calculated, and the relationships between these differences and tumor characteristics were investigated. DCIS was detected fully or partially in 64 (84.9 %) of 75 lesions, whereas the detection rate of magnetic resonance imaging (MRI) was 90 %. The detection rate was not influenced by comedo/non-comedo status, but the detection rate of higher nuclear grade DCIS lesions tended to be higher than that of low grade lesions (p = 0.089), while the estimated size was also more accurate in the former (p = 0.046). Hormone receptor and Her2 status did not affect MDCT findings. MDCT is highly effective for detecting DCIS, especially the more aggressive types of DCIS. Moreover, the patient’s position during MDCT imaging is more similar to that during surgery than that during MRI, making MDCT a highly useful presurgical imaging technique for the assessment of DCIS.

p73, a homologue of p53, has been located at chromosome 1p36-33, a region of frequently observed loss of heterozygosity in breast cancers. The objective of the present study was to investigate the function of p73 in Japanese with breast cancers.Sixty Japanese patients with breast cancer were assessed by polymerase chain reaction single strand confirmation polymorphism analysis and direct sequencing to detect the p73 allele. p73 mRNA levels were also determined in 40 out of 60 patients by reverse-transcriptional polymerase chain reaction.We analyzed the entire open reading frame of the p73 gene by polymerase chain reaction single strand confirmation polymorphism and sequencing, and failed to identify any mutations of p73 in the encoding regions detected. Loss of heterozygosity of p73 was infrequent and only found in 9% of breast carcinomas. We revealed a few polymorphisms with a frequency of 13% - 29%, which had been reported previously. Down-regulation of p73 mRNA expression was observed in tumor tissues in comparison to the normal breast tissues. A significant inverse correlation was found between p73 transcripts and high histological grade, suggesting that down-regulated p73 expression could be related to poor prognosis in those patients.Our results suggest that p73 may serve as a tumor suppressor gene and its expression plays a role in tumorigenesis in Japanese patients with breast cancer.

乳癌における核形態と臨床病理学的諸因子との関連を検討した.原発乳癌90例および乳腺良性疾患13例を対象とした.May-Grunwald-Giemsa染色の細胞診標本を用いて約200個の核について核面積および核最大長径を画像解析装置を用いて計測した.核面積は乳腺良性疾患に比べて乳癌が有意に大きかった (P=0.00001).乳癌と臨床病理学的因子との検討では, 腫瘍径が大きくなるにつれて核面積も有意に大きくなっていた (P

Ductal carcinoma in situ (DCIS) accounts for 20%-25% of breast cancers detected at screening mammography. The lesions are diverse and commonly are classified on the basis of their mammographic features and histologic characteristics such as nuclear grade and presence or absence of necrosis. The most common mammographic finding in DCIS is microcalcifications, but a low-grade lesion without necrosis is less likely to manifest with calcifications than either an intermediate- or a high-grade lesion. Other mammographic findings might include a mass or architectural distortion. Magnetic resonance (MR) imaging has higher sensitivity than mammography for the detection of DCIS and greater accuracy for depicting the extent of disease. The MR imaging appearance of DCIS depends primarily on the presence and extent of abnormal periductal or stromal vascularity. Nonmasslike enhancement, the most common MR imaging finding, is often seen in association with clumped internal enhancement. The enhancement kinetics in dynamic MR studies vary, and no kinetic pattern is pathognomonic of a particular nuclear grade of DCIS. However, the kinetic pattern at delayed imaging does appear to be correlated with the mammographic findings: Mass lesions show strong washout; fine pleomorphic, fine linear, and fine linear-branching calcifications demonstrate a plateau enhancement pattern; and amorphous calcifications exhibit persistent enhancement. Multidetector computed tomography might be a useful adjunct to MR imaging for preoperative mapping.

The relation of the endocrinological factors to estrogen receptor (ER) status is still unclear. In this paper the effect of hypophyseal gonadotropins on ER status was studied in 40 postmenopausal patients with breast cancer. The plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels before and after luteinizing hormone-releasing hormone (LH-RH) stimulation at an i. v. dose of 100μg were measured time-depedently. ER in the tumor was measured by dextran-coated charcoal methods. Twenty-three out of the 40 patients were ER positive, 17 being negative. The basal levels of LH and FSH were 98.7±45.5 mIU/ml and 105.5±51.2 mIU/ml in ER positive patients, and were 91.4±31.4 mIU/ml and 87.5±32.6 mIU/ml in ER negatives, respectively. There was no significant difference in basal LH and FSH between ER-positive and negative patients. No ER-relating time-dependent pattern in LH and FSH levels was found. Responses after LH-RH stimulation were not different between two groups. In conclusion, hypophyseal gonadotropin levels and its reserves as host factors were not related with ER status in the postmenopausal patients with breast cancer.

ラット肝細胞の初代培養に,MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assayを応用し,培養肝細胞の生細胞数とMTT formazanの吸光度との間に良好な相関を確認した.すなわち,MTT assayにより培養肝細胞のviabilityを評価することが可能であることがわかった.そこで,このアッセイ系を用いて,ケノデオキシコール酸(CDCA)を種々の濃度,接触時間で培養液に添加した場合の肝細胞のviabilityを測定した.その結果,培養肝細胞のviabilityは,CDCAの濃度,接触時間依存性に低下した.さらに,Ca拮抗剤のニカルジピンがCDCAによる肝細胞障害を抑制した.このことから,CDCAによる肝細胞障害の発生にCa2+が関与することが示唆された.

A case of synchronous triple cancer which involved the tongue, breast and esophagus was experienced. A 58-year-old woman underwent right partial resection of the tongue with a diagnosis of tongue cancer. This was in stage I showing the histological feature of well-differentiated squamous cell carcinoma. The second neoplasm, a right breast cancer, was diagnosed about two months after the first operation. A modified radical mastectomy was done (stage II), and the solid tubular carcinoma was histologically revealed. Around 4 months after the second operation for breast cancer, poor appetite and a gradual body weight loss occurred, and then 3 months later, an esophageal cancer was detected. Biopsy specimen revealed moderately differentiated squamous cell carcinoma in an advanced stage. It was inoperable. Systemic chemotherapy failed to cure and the patient died 6 months later. In this paper clinical course as well as flow cytometric DNA analysis of this synchronous triple cancer which was performed by using these paraffin-embedded tissues is described. Triple carcinomas seen in the literature are also discussed.

Despite many recent reports on the effects of trastuzumab for breast cancer, many problems remain regarding combination drug treatment and its significance. We report our experience with advanced breast cancer patients who received combination therapy with trastuzumab+paclitaxel.Three patients with human epidermal growth factor receptor 2(HER2)-positive advanced breast cancer were the subjects. Combination therapy with trastuzumab and paclitaxel was carried out as a primary therapy, and its therapeutic effects were evaluated based on image findings, tumor markers and observation of resected specimens.The primary tumors in the three patients were all clinically complete response (cCR). Those in two surgically treated patients were near pathologically complete response (pCR), ie, a small amount of cancer cells remained in the galactophore, whereas the histological therapeutic effect was Grade 2b. In two patients with liver metastases, the metastatic tumor disappeared on the image after the therapy. In two patients whose tumor marker was increased at the first examination, the level of increase was markedly lowered by the therapy. Neither infusion reaction nor heart functional impairment was found in any of the three patients.For patients with advanced breast cancer, a regimen containing trastuzumab would produce significant therapeutic effects if the cancer is HER2-positive. The regimen would also contribute to the prognosis of such patients since it might produce pCR. Since the risk of severe adverse effects is low and the treatment with trastuzumab can be conducted safely as an ambulatory treatment, high patient QOL seems possible. These findings suggest that combination therapy with trastuzumab+paclitaxel is effective as a primary therapy for HER2-positive advanced breast cancer.

Recently, aromatase inhibitors (AI) are widely used in postoperative adjuvant therapy for breast cancer. Nevertheless, studies of postoperative therapeutic strategies for recurrent breast cancer are insufficient.Data on 12 post-menopausal advanced/recurrent breast cancer patients in our department during June 2003- April 2007 were used for this study. No patient had responded to high-dose toremifene (TOR), a third-generation AI. Their therapeutic outcomes were analyzed retrospectively. The median observation period of the subjects was 16.1 months (4.0-40.9 months). Subjects were all hormone-sensitive. Overexpression of HER2 protein was found in only one case. During AI therapy immediately prior, exemestane (EXE) and anastrozole (ANA) had been given in nine and three cases, respectively.The complete response rate of AI therapy was 16.7% (2/12). The clinical benefit rate was 58.3% (7/12). The median of time to progression (TTP) was 33.8 weeks. Neither the presence nor absence of past history of treatment with tamoxifen (TAM) or other chemotherapies affected the anti-tumor effect. Analysis by the site of metastasis or recurrence revealed that the therapeutic effects were better for non-life-threatening cases in the lung, pleura, soft tissue, etc. The severities of adverse effects were all less than grade 2; the major ones were flushing and sweating.Results show that high-dose TOR given at an early stage can provide clinical benefits for post-menopausal advanced/recurrent breast cancer not responding to AI.

Upon performing contact thermography on the patients with breast cancer, the thermograms obtained were classified into 3 types (hot spot: H, irregular vascular pattern: IV, and asymmetrical thermal pattern: AT). The following results have been obtained as a result of making an assessment regarding how the findings are reflected on the classification of clinically morbid periods.1) Positive AT and IV findings were observed on the thermograms even in the breast cancers in comparatively early stages.2) H findings showed that the positive rate became higher as tumorous diameter became larger and further that high positive rates were exhibited in scirrhus carcinoma.3) In the relation with nuclear DNA amount, positive rates of H findings were high in aneuploid cases.4) The change in thermography showed a positive correlation with the change in dermal blood stream.From the above, it was found that the contact thermography has a nature a little different from the conventional test methods and that its usefulness was observed rather in the judgement on the malignancy of breast cancer cells but not as diagnostic test method. Further, a possibility of foreknowing the risk of breast cancer to occur was suggested.

Effects of rehabilitation after mastectomy were investigated for recovery rate of movable range of the affected shoulder joint and swelling rate of affected upper limb. Patients undergone Stewart's transverse incision and closed without skin graft were subjected. On a preoperative day, postoperative 7th day, the day of discharge, and one year after operation, movable range of various exercises of the shoulder joint and circumference length of the forearm and upper arm were measured to calculate the recovery rate of movable range and swelling rate of upper limb. Correlations between the recovery rate and operative procedures, conservation of the pectoral nerve, and the between-flaps tension, as well as changes in the swelling rate were studied. As a result, there were little effects on impaired movement function of the shoulder joint due to resection of pectoralis major and/or minor muscle. In one year after mastectomy around 90% of movable range could be recovered in all kinds of exercise. Resection of the pectoral nerve produced atrophy of pectoralis major muscle and impaired the exercise function. If the between-flaps tensions were within 200 g or less, the tension gave no effect on the recovery rate of movable range. The maximum increase in the circumference length of the forearm and upper arm appered on the first year after mastectomy, which were both 3.5 cm, and no remarkable swelling disturving daily activities of patients were observed.

To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter.A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years.The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF.Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.

Purpose: We compared the therapeutic usefulness of doxifluridine (5′-DFUR) alone and a combination of 5′-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. Patients and Methods: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5′-DFUR alone or 5′-DFUR plus CPM. All patients initially received 5′-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5′-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5′-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5′-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. Results: Of the 1,088 eligible women, 546 were assigned to receive 5′-DFUR alone and 542 were assigned to receive 5′-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5′-DFUR plus CPM than in those who received 5′-DFUR alone (log-rank test, P = .021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5′-DFUR group and 32.3% of patients (175 of 542) in the 5′-DFUR plus CPM group (χ2 test, P < .001). Conclusion: Combination therapy with 5′-DFUR plus CPM is more effective in preventing recurrence than 5′-DFUR alone.

In the first part of this late phase II study, we determined the recommended clinical dose of CGS20267 to be 1.0 mg once daily for the treatment of postmenopausal women with advanced or recurrent breast cancer. To further evaluate the efficacy and safety of CGS20267 at the derived or recommended clinical dose, 30 more patients were enrolled in the second part of the study, and were added to the patients treated at 1.0 mg in the first part. As a result of putting the first and second parts together, the objective response rate at 1.0 mg was found to be 38.3%, which was almost equal to that of the early phase II study (40.7%). Drug-related adverse events occurred in 35.4% of the patients at 1.0 mg, and all of the events were of grade 2 or lower. These results demonstrated that CGS20267 1.0 mg once daily is effective and well tolerated in the treatment of postmenopausal women with advanced or recurrent breast cancer.

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer.

BACKGROUND The intraductal spread of breast carcinoma can occur along the mammary ductal/lobular systems (MDLS) with no invasion of tissues. Because ductal anastomoses in the MDLS are considered to be a possible risk factor for extensive intraductal spread of breast carcinoma, the architecture of the MDLS has important therapeutic implications for patients treated with breast-conserving surgery. METHODS An entire breast resected by subcutaneous mastectomy from a 69-year-old woman with ductal carcinoma in situ (DCIS) was examined in submacroscopic sections by stereomicroscopic and histologic techniques. Serial 2-mm sections underwent computer-assisted complete three-dimensional reconstruction of all MDLS. RESULTS The entire breast that was studied contained 16 MDLS that were arranged radially, with the nipple at the center. Of these 16 MDLS, 4 (25.0%) had ductal anastomoses whereas the remaining 12 MDLS had no ductal anastomoses and completely independent regional anatomy. Ductal anastomoses were observed at 11 sites in the 4 MDLS. The 2 of 11 ductal anastomoses that connected different MDLS (18.2%) were situated > 4 cm from the nipple. The remaining nine ductal anastomoses connected ducts within the same MDLS; their location varied from near the nipple to the peripheral region. In the specimen examined, DCIS extended only within a single MDLS and did not spread between different MDLS via ductal anastomoses. CONCLUSIONS To the authors' knowledge, the current study is the first time the complete architecture of all MDLS in an entire breast has been studied three-dimensionally. The risk of promoting the intraductal spread of disease during surgery may be greater when intraductal lesions extend more peripherally than centrally. The features of ductal anastomoses may provide a significant anatomic clue regarding negative surgical margins in breast-conserving surgery. Cancer 2001;91:2263–72. © 2001 American Cancer Society.

This report describes a rare case of a giant hamartoma that developed in the right breast of a 17-year-old girl. No abnormalities were found by endocrinological studies and a well-circumscribed tumor, approximately 20 cm in diameter, was easily enucleated without bleeding during surgery, following which the bilateral breasts became nearly symmetrical. Histologic features revealed predominant fibrous stroma and scattered normal or occasionally dysplastic mammary glands without neoplastic properties. No distorted lobular structures indicating fibroadenoma characteristics were observed. Subgross and stereomicroscopic analysis of serial 2-mm-thick sections revealed mature normal lobules and predominant fibrous interstitial components. Therefore, the tumor was diagnosed as a giant hamartoma of the breast, according to the histologically non-neoplastic features and the delimited macroscopic appearance. This is a rare mammary gland disease characterized by the fact that although each of the histological components seemed to be normal, their constitution was abnormal. It appears that not only histological features but also clinical details are indispensable for the diagnosis of this disease.

Background To assess whether lymph nodes are consistently negative below a certain tumor size, we investigated the incidence and predictors of lymph node metastasis in breast cancer patients with tumors under 2 cm in size.

BACKGROUND: Prognostic factors for predicting the recurrence of node-negativebreast cancers have been controversial. The present study was performed to elucidate practically useful prognostic factors using formalin-fixed paraffin sections. METHODS: This was a case-controlled multi-institutional study that composed 40 patients with recurrent node-negative breast cancer and 80 patients with node-negative breast cancer but without recurrence after radical surgery. Tumors weresmaller than 3 cm in diameter and were treated surgically between January 1, 1985 and December 31, 1990. The recurrent and non-recurrent cases were matched with regard to their age, adjuvant chemotherapy and the year in which surgery was performed. Fourteen immunohistochemical factors and 8 histological factors of theprimary tumor were studied on formalin-fixed, paraffin-embedded sections by immunohistochemical and histochemical analyses. RESULTS: According to univariate analysis, factors such as progesterone receptor (PgR), MIB-1, CD44v6, CD44v9 and platelet-derived endothelial cell growth factor (PDECGF) were significantly different between the recurrent and non-recurrent groups (ply; 0.1; Wilcoxon-Mann-Whitney analysis). Chi-squared test showed significant differences in MIB-1, cdc2 and stromal plasminogen activator receptor (suPAR). Histologically, mitotic count was also significantly different between the two groups (p0.005). Multivariate analysis revealed that positivity for cdc2 (p=0.01), high mitotic count (p=0.04) and negativity for CD44v9 (p=0.02)were independent prognostic factors among variables selected by univariate analysis, and that positivity for MIB-1 (p=0.03) and cdc2 (p =0.01), and negativity for CD44v9 (p =0.03) were independent prognostic factors among the immunohistochemical markers examined. CONCLUSION: Our results indicated that positivity for MIB-1 and cdc2, high mitotic count and negativity for CD44v9 could serve as independent factors for predicting the recurrence of node-negative breast cancer.

BACKGROUND: Recently objective quantification of immunohistochemical estrogenreceptor (ER) and progesterone receptor (PgR) staining in breast cancer by image cytometry has been predominantly performed by measuring the area of positivelystained cells. However, in sample preparations of immunostained hormone receptors, both the stained area and the intensity of staining vary. In this study, we performed quantification of the stained area by measuring, tailing intensity using image cytometry. METHODS: Quantitative analysis of ER and PgR immunohistochemistry was performed using image cytometry. The obtained values were presented as % of positive staining (% PS). Comparison of % PS with values obtained by EIA and with clinicopathological features was performed. RESULTS: The % PS values and the natural logarithm of the EIA levels of the hormone receptors showed a significant positive correlation for both ER and PgR. The concordance of the results obtained by the two methods was 96.3% for ER and 73.7% for PgR. The ER-% PS values of postmenopausal patients were significantly higher than those of premenopausal patients, whereas the PgR-% PS values of the former group were significantly lower than those of the latter group. CONCLUSION: The quantification of ER and PgR in immunostained preparations using % PS as a parameter was reproducible and showed a high correlation with values obtained by EIA. It was shown that only menopausal status affects hormone receptor levels when analyzing the relationship between % PS measurements and clinicopathological features.

BACKGROUND: Abnormal glycosylation patterns have been recognized as a featureof carcinomaassociated mucins. The expression of the Tn antigen in breast cancer tissue was investigated to assess its prognostic relevance. METHODS: Formalin-fixed, paraffin-embedded materials from 219 patients with breast cancer were used. Immunohistochemical staining of the Tn antigen was retrospectively investigated and a lesion staining 10% or more was considered positive RESULTS: Tn antigen expression was present in 99 (45%) of 219 lesions. There were no correlations between Tn antigen expression and mean patient age, nodal status, estrogen receptor status, or menopausal status, but there was a slightly significant association between Tn and tumor size. Patients negative for the Tn antigen had a significantly better survival rate than those who were positive. Multivariate analysis also indicated that Tn expression correlated significantly with overall survival in addition to nodal status and tumor size. CONCLUSION: Tn expression was a significant prognostic factor in breast cancer, but the significance was lost on multivariate analysis. The biological implication of Tn expression in breast cancer needs further investigation.

Loss of heterozygosity (LOH) on chromosome 6q is often observed in breast cancer, suggesting the existence of a putative tumor suppressor. Recently, a human homolog of the Drosophila warts tumor suppressor gene, h-warts/LATS1, was identified and mapped at chromosome 6q24-25.1. Mutation analysis of the h-warts/LATS1 was performed using 25 breast cancer tissues by RT-PCR SSCP analysis. Although LOH of the h-warts/LATS1 was found in one patient, no mutations were found. Two polymorphisms were found, but neither of them caused amino acid substitutions. Further investigations are necessary to elucidate the role of the h-warts/LATS1 gene in the carcinogenesis of breast cancer.

Adenoid cystic carcinoma of the breast is an uncommon form of cancer, and only a few articles have described the cytological findings of this disease. We report herein the case of a 48-year-old woman who presented with a breast mass beneath the nipple, the aspirate from which consisted of globules of mucous balls surrounded by epithelial cells with scant cytoplasm and hyperchromatic nuclei. Microscopically, the tumor was formed by myoepithelial cells and glandular epithelial cells in a biphasic pattern. Immunohistochemical study revealed positivity for smooth muscle actin. A left total mastectomy with axillary lymph node dissection was performed. None of the 22 axillary lymph nodes contained metastases, and the patient remains well and free from recurrence 29 months after her operation. This case report provides some information about the cytological diagnosis and the accuracy of fine-needle aspiration, which must be considered despite the rarity of this disease.

Fatty acid synthase (FAS) is the key enzyme required for the conversion of dietary carbohydrates to fatty acids. Recent studies have demonstrated that high levels of FAS expression occur in a variety of cancers, including breast cancer. We evaluated 243 primary breast cancer patients in the period between 1989 and 1996. Immunohistochemical staining for FAS was performed on formaline-fixed, paraffin-embedded sections. FAS staining intensity was graded as low or high. The expression of FAS was high in 145 (60%) and low in 98 cases (40%). A weak correlation between FAS expression and nodal status was noted in premenopausal patients (p=0. 01). FAS was associated with estrogen receptor (p=0.0022) and progesterone receptor (p=0.0085) status. We found that a low expression of FAS was significantly related to a shorter disease-free survival (DFS) rate in estrogen receptor positive patients (p=0.024) and a similar trend was recognized in progesterone receptor positive patients (p=0.083). The low FAS group showed better DFS and OS in all but ER-/PgR- cases (p=0.011, 0.076). This study showed close correlations between immunohistochemical FAS expression and steroid hormone receptors in premenopausal patients. The use of FAS expression may increase the diagnostic utility of ER and PgR in premenopausal patients. FAS may be able to predict the responsiveness of tumors to endocrine therapy.

The proto-oncogene bcl-2 is demonstrated to block a final common pathway leading to apoptosis and is expressed in more than half of human breast cancers. Invasive breast cancer has reduced bcl-2 immunostaining compared with normal breast epithelia and preinvasive breast lesions. As an inhibitor of apoptosis, bcl-2 should correlate with highly aggressive tumor biology and resistance to hormonal/cytotoxic therapy. However, high bcl-2 expression has been shown to associate with a number of favorable prognostic factors including ER positivity, PgR positivity, low histological grade, well-differentiated tumor, absence of c-erbB-2 and p53. Unexpectedly, numerous studies have shown that tumors with high bcl-2 expression are more responsive to hormone therapy and have more favorable disease-free and overall survival. The clinical significance of bcl-2 in tumorigenesis and prognosis of breast carcinomas from the data recently published are reviewed. Its role in modulation of hormonal/cytotoxic therapy and future directions are also discussed.

The lymph node micrometastasis was retrospectively immunohistochemically investigated in 185 patients with node-negative breast cancer and compared with the routine conventional findings. The monoclonal antibodies to epithelial membrane antigen (EMA) and mucinous-like carcinoma antigen (MCA) were used. Of 19 EMA-positive cases, 16 were false positive. Therefore only 3 cases were found to show staining with both EMA and MCA. The patients are all living and well and free of recurrence. No micrometastasis was immunhistochemically demonstrated in 11 node-negative breast cancer patients with subsequent metastases. The results of the present study indicate that the detection rate containing occult cells afforded by conventional routine evaluation is sufficient, at least in Japanese.

Mutations in the p53 gene were analysed in 50 cases with breast cancer by PCR-SSCP and direct DNA sequencing. Mutations were found in 10 of 50 cases (20%) including a case with Tis, and loss of the normal allele was found in five of these cases. Eight of the 10 mutations occurred within highly conserved domains, but no mutational hot spots were found. GC to AT transitions were the most frequent mutations (six of 10 cases), while mutations at CpG dinucleotides were found in three cases (30%). AT to TA transversions were the second most frequent mutation (20%). The level of expression of p53 protein was assessed by Western blot analysis in 62 cases. Overexpression of p53 protein was detected in 21 of 62 cases (34%) including a case with Tis. There was a strong correlation between missense mutations in the p53 gene and overexpression of p53 protein. Overexpression of p53 protein was closely associated with increasing tumour size and ER-negative status among the various factors investigated, suggesting that p53 overexpression may reflect the lack of differentiation in breast cancer.

Immunohistochemical c-erbB-2 protein overexpression was detected in 34 of 124 (27.4%) paraffin-embedded breast cancer specimens. Although no difference was seen between the c-erbB-2 positive and negative groups in 5-year disease-free survival, 5-year overall survival was significantly less favorable in the c-erbB-2 positive group. Furthermore, patients graded as having positive c-erbB-2 staining and aneuploid DNA showed significantly poorer survival than those in other categories. The significant prognostic factors, determined by a multivariate analysis, were nodal status and c-erbB-2 overexpression. Our findings therefore suggest that c-erbB-2 expression is a prognostic factor in breast cancer and that it could be useful in the determination of postoperative adjuvant therapy.

The relationship of estrogen receptor(ER) status to DNA ploidy was investigated in 121 patients with breast cancer who underwent surgery. Lymph node status was evaluated histologically and ER levels were determined by the dextran-coated charcoal method, with a level of 3 fmol/mg·protein being considered positive. Flow cytometric DNA content was analyzed using paraffin-embedded tissue blocks. Sixty-three per cent of the specimens were ER+, while 37 per cent were negative. Sixty-one patients (50.4 per cent) were diploid and 60 aneuploid. A statistically significant correlation between the ER positivity rate and diploid DNA was found. Higher ER levels were seen in the postmenopausal patients with diploid tumors than in those with aneuploid tumors and there was a significant tendency for ER levels to be higher in the diploid tumors. Nodal status was not correlated with ER positivity or ploidy pattern. The present results indicate that ER levels are correlated with DNA ploidy, and reflect the degree of functional differentiation.

e12025 Background: Capecitabine (X) is converted into 5-FU by thymidine phospholylase (TP). Cyclophosphamide (C) has been shown to make TP higher in the preclinical study. Therefore, the combination of capecitabine and cyclophosphamide (XC) is thought to have a synergistic activity. We explored the efficacy of XC for metastatic breast cancer patients. Methods: 50 metastatic breast cancer patients were treated with XC in our medical center between April 2004 and December 2008. Median patient age was 58 years old (range: 34–79 years old). 36 patients were postmenopausal. X was 1675mg/m2 days 1–21 and C was 67mg/m2 days 1–14 on a 28-day cycle in all-oral combination. This therapy was continued until progression of disease or unacceptable toxicities occurring. Results: Median time to treatment failure was 28 weeks (range: 2–158 weeks). 9 patients were not evaluable for tumor response. Among 41 evaluable patients, complete response (CR) was observed in 2.4% (1 patient) and partial response (PR) was 29.2% (12 patients). Stable disease (SD) was 41.4% (17 patients) and progression of the disease (PD) was 26.8% (11 patients). The objective response rate (CR+PR) was 31.7% and the overall clinical benefit (CR+PR+SDÅÜ24 weeks) was 53.6%. Significant toxicities were uncommon: grade 3 toxicities were encountered for neutropenia in 1 patient, anorexia in 1 patient and hand-foot syndrome in 2 patients. Conclusions: XC is an effective regimen in metastatic breast cancer, and this therapy is of an easy administration and very well tolerated. No significant financial relationships to disclose.

Abnormal DNA content has been considered as an additional criterion for determining the biological behavior of a tumor. Flowcytometric DNA analysis was done on 121 patients with thyroid carcinoma encountered during the period between 1975 and 1987. Tumor tissues were sampled from paraffin-embedded blocks and the histology of thyroid carcinoma found to consist of 91 papillary, 23 follicular, 2 medullary, 1 squamous cell and 4 anaplastic carcinomas. The incidence of aneuploidy in thyroid carcinoma was 7.4 per cent (9 patients) while that of diploidy was 92.6 per cent (112 patients). The aneuploid specimens consisted of 6 papillary, 1 follicular, 1 medullary and 1 anaplastic carcinomas and, of 4 anaplastic carcinoma patients with subsequent death within 6 months, only 1 was aneuploid. As an indicator of proliferative potential, S-phase fraction (SPF) was also determined by flow cytometry, but this could not be used as an independent prognostic factor. The aneuploid patients showed a significantly decreased survival rate (p less than 0.01). Thus, although DNA measurement proved useful for predicting the survival of aneuploid patients, there is some discrepancy between DNA content and the biological behavior of the tumor.